WO2025085489A1

WO2025085489A1 - Gspt1-degrading compounds, anti-cd33 antibodies and antibody-drug conjugates and uses thereof

Info

Publication number: WO2025085489A1
Application number: PCT/US2024/051525
Authority: WO
Inventors: Mimi L. Quan; Qian Zhang; Sayumi YAMAZOE; Yam Bahadur POUDEL; Dan Zhu; Andrew Evan WURMSER; Robert James HOEY; Catherine Macdonald JENNINGS; Lawrence Richard DEARTH; Ken Kunwei LIU; Naresh Chennamsetty; Ruchita Rajendra THAKORE
Original assignee: Bristol Myers Squibb Co
Current assignee: Bristol Myers Squibb Co
Priority date: 2023-10-17
Filing date: 2024-10-16
Publication date: 2025-04-24
Anticipated expiration: 2026-04-17

Abstract

The present application relates to particular anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of making and using the antibodies, as well as immunoconjugates comprising the anti-CD33 antibodies. The present application also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present application also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates.

Description

GSPT1-DEGRADING COMPOUNDS, ANTI-CD33 ANTIBODIES AND ANTIBODY-DRUG CONJUGATES AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of US Provisional Application No.63/591,013, filed October 17, 2023, which is incorporated by reference herein in its entirety for any purpose. SEQUENCE LISTING [0002] The present application contains a Sequence Listing, which has been submitted electronically in XML format. Said XML copy was created on October 3, 2024, is named “01277-0040-00PCT_ST26.xml”, and is 93,755 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD [0003] The present application relates to anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of making and using the antibodies. The present application also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present application also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates. BACKGROUND [0004] There exists a need for safe and effective agents and methods for treating, preventing and managing cancer, including for cancers that are refractory to standard treatments, while reducing or avoiding the toxicities and/or side effects associated with some existing therapies. [0005] The present disclosure provides such agents, including GSPT1 degraders and anti- CD33 antibody-drug conjugates comprising GSPT1 degraders. SUMMARY [0006] The present disclosure relates to anti-CD33 antibodies, nucleic acids encoding the antibodies, vectors and host cells comprising the nucleic acids, and methods of both making and using the antibodies. The present disclosure also relates to antibody-drug conjugates comprising an anti-CD33 antibody and a GSPT1 degrader. The present disclosure also relates to linker-drug moieties comprising GSPT1 degraders useful in antibody-drug conjugates. For example, embodiments of the disclosure include the following: [0007] A compound of any of the structural formulas depicted herein (e.g., Structural Formula I', II', III', IV', V', a structure from Table A), or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein. [0008] An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28; b) (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; c) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; d) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; or e) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68. [0009] An isolated nucleic acid encoding an antibody or antigen-binding portion thereof described herein, or a vector comprising same, or a host cell comprising the isolated nucleic acid or vector. [0010] A method for making an anti-CD33 antibody or antigen-binding portion thereof, comprising culturing a host cell comprising an isolated nucleic acid encoding the anti-CD33 antibody or antigen-binding portion thereof, or a vector comprising the isolated nucleic acid under conditions suitable for expression of the antibody or antigen-binding portion thereof. [0011] An antibody-drug conjugate comprising an antibody or antigen-binding portion thereof described herein and a cytotoxic agent. [0012] An antibody-drug conjugate of any of the structural formulas depicted herein (e.g., Structural Formula I", II", III", IV", V"), or a pharmaceutically acceptable salt thereof. [0013] A pharmaceutical composition comprising (i) a compound, isolated antibody or antigen-binding portion thereof, or antibody drug conjugate and (ii) a pharmaceutically acceptable carrier. [0014] A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an isolated antibody or antigen-binding portion thereof described herein, an antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing. [0015] Use of an isolated antibody or antigen-binding portion thereof described herein, or antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing for the preparation of a medicament for treating cancer in a subject in need thereof. [0016] An isolated antibody or antigen-binding portion thereof described herein, or an antibody-drug conjugate described herein, or a pharmaceutical composition of either of the foregoing for use in treating cancer in a subject in need thereof. [0017] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the claims. All references cited herein are incorporated in their entirety by reference. BRIEF DESCRIPTION OF THE DRAWINGS [0018] FIGs.1A-1E show the results of tests of CD33-M and its progeny antibodies for selective affinity for CD33+ cells compared to vadastuximab (VADA) or isotype control. Levels of antibody binding were analyzed by determining the mean fluorescence intensity (MFI) by flow cytometry. FIG.1A is a graph showing results in HEK293 cells engineered to express the full-length coding sequence of cynomolgus CD33. FIG.1B is a graph showing results in HEK293 cells engineered to express a truncated form of human CD33 lacking the V-domain. FIG.1C is a graph showing results in Molm13 cells, a CD33+ AML cancer cell line. FIG.1D is a graph showing results in MV4-11 cells, a CD33+ AML cancer cell line. FIG.1E is a graph showing results in CD33-negative Pfeiffer cells. [0019] FIGS.2A-2F show the results of tests of binding affinity to endogenous CD33 in human and cynomolgus monocytes for CD33-M, vadastuximab, and isotype control. Monocytes were isolated from 3 human peripheral blood mononuclear cell (PBMC) samples and 3 cynomolgus samples by flow cytometry gating with anti-CD14 and anti-CD159a antibodies, excluding doublets and dead cells. The geometric MFI (gMFI) of AF647 at each concentration was graphed on a log scale as non-linear regression curve. Results in monocytes isolated from human PBMCs from donor 1, donor 2, and donor 3 are shown in graphs in FIGS.2A-2C. Results in monocytes isolated from cynomolgus PMBCs from donor 1, donor 2, and donor 3 are shown in graphs in FIGS.2D-2F. [0020] FIGS.3A-3E show the results of tests of binding affinity to endogenous cynomolgus CD33 in neutrophils for CD33-M and the progeny antibodies of CD33-M. PBMCs isolated from three cynomolgus blood donors were stained with AF647-conjugated CD33 antibodies and CD33 binding analyzed by flow cytometry. The neutrophil population was gated using a side scatter/CD45+ plot after excluding doublets and dead cells. Geometric MFI (gMFI) at each concentration was graphed on a log scale as non-linear regression curves. CD33 expression and antigen density in cynomolgus neutrophils were confirmed by flow cytometry. [0021] FIGS.4A-4C show the results of tests of ability to mediate internalization for antibodyies CD33-M and VADA. CD33+ MOLM-13 cells (left pane), CD33+ MV4-11 cells (middle pane), or CD33-negative Pfeiffer cells (right pane) were incubated with various concentrations (32 pM-10 nM) of antibody CD33-M or VADA labeled with acid-sensitive fluorescent Fab fragments that become fluorescent in the endosome. Cells were stained with the Fab-labeled antibody on ice and, after washing off unbound antibody, incubated at 37°C for four hours. Cells were then analyzed by flow cytometry, recording the geometric MFI (gMFI) at each concentration of antibody. [0022] FIGS.5A-5B show the results of an immunogenicity assessment of CD33 C2 antibodies. Using the EpiMatrix platform T-cell epitope content of each antibody were expressed as EpiMatrix scores and Tregitope-adjusted EpiMatrix Scores of VH and VL domains (FIG.5A) or as Tregitope-adjusted EpiMatrix Score, Tregitope content, and predicted Ab response (FIG.5B). [0023] FIG.6 shows a Western blot analysis of tumor tissue processed for GSPT1 degradation and apoptosis (cleaved caspase 3). The tumor tissue was collected from MV4-11- Luc AML xenograft mice that had been administered a single 10 mg/kg dose of antibody CD33-B conjugated to payload linker LP2. Terminal collection of tumor tissue was performed at 0, 6, 24, 48, 72, 168, and 216 hours post-dosing; results are shown for each time point. [0024] FIG.7 shows a graph of GSPT1 and cleaved caspase 3 levels in tumor tissue collected from MV4-11-Luc AML xenograft mice that had been administered a single 10 mg/kg dose of antibody CD33-B conjugated to payload linker LP2. Terminal collection of tumor tissue was performed at 0, 6, 24, 48, 72, 168, and 216 hours post-dosing; results are shown for each time point. [0025] FIGS.8A-8B show results from in vitro human serum stability of various CD33- GSPT1-ADCs having different linkers in an in vitro cytotoxicity assay in Molm13 cells (FIG.8A) and MV-411 AML cells (FIG.8B). Cultures were assayed for viability after 3 days by CellTiter –Glo and IC50 values were plotted over time. [0026] FIGS.9A-9G show results of in vitro potency assays of novel C2 antibodies (CD33- B, CD33-C, CD33-F, CD33-M) when formatted as an ADC using various linker-payload configurations in Molm-13, MV4-11, OCI-AML2, HL-60, U-937, and Pfeiffer cells. ADCs were administered at concentrations ranging from 0.03pM to 55nM. Unconjugated payload compound 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea, was included for comparison. In FIG.9A, ADC cytotoxicity is expressed as IC50 values (nM). In FIGS.9B-9G, ADC cytotoxicity is expressed as dose- response curves. [0027] FIGS.10A-10B show tumor growth inhibition and survival results in an AML xenograft model. MV-411-Luc tumor cells were engrafted by tail vein injection and allowed to acclimatize for approximately 10 days. After day 10, ADCs were administered at 10 or 3mg/kg, 3-times once per week (QWX3). Alternatively, vehicle or a non-conjugated, equimolar mixture (i.e., 1:8) of antibody and payload were administered as negative controls. The bioluminescent signature of the tumor cells was tracked at the indicated time points for approximately 30 days as indicated in FIG.10A. FIG.10B shows the Kaplan Meier survival profiles of the animals tracked for 120 days post-engraftment. Each experimental group was comprised of 8 animals (n=8, FIG.10A and FIG.10B). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS I. Definitions [0028] Unless otherwise defined, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. [0029] The following abbreviations may be used herein:

[0030] In this application, the use of “or” means “and/or” unless stated otherwise. In the context of a multiple dependent claim, the use of “or” refers back to more than one preceding independent or dependent claim in the alternative only. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit unless specifically stated otherwise. [0031] Exemplary techniques used in connection with recombinant DNA, oligonucleotide synthesis, tissue culture and transformation (e.g., electroporation, lipofection), enzymatic reactions, and purification techniques are described, e.g., in Sambrook et al. Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), among other places. [0032] As used herein, the term “about” refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated. The term “about” generally refers to a range of numerical values (e.g., +/-5-10% of the recited range) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). When terms such as at least and about precede a list of numerical values or ranges, the terms modify all of the values or ranges provided in the list. In some instances, the term about may include numerical values that are rounded to the nearest significant figure. [0033] The term “polypeptide” refers to a polymer of amino acid residues, and is not limited to a minimum length. A “protein” may comprise one or more polypeptides. Such polymers of amino acid residues may contain natural or non-natural amino acid residues, and include, but are not limited to, peptides, oligopeptides, dimers, trimers, and multimers of amino acid residues. Both full-length proteins and fragments thereof are encompassed by the definition. The terms also include post-expression modifications of the polypeptide, for example, glycosylation, sialylation, acetylation, phosphorylation, and the like. Furthermore, for purposes of the present invention, a “polypeptide” or “protein” refers to a polypeptide or protein, respectively, which includes modifications, such as deletions, additions, and substitutions (generally conservative in nature), to the native sequence, as long as the protein maintains the desired activity. These modifications may be deliberate, as through site- directed mutagenesis, or may be accidental, such as through mutations of hosts that produce the proteins or errors due to PCR amplification. A protein may comprise two or more polypeptides. [0034] “CD33” or “sialic acid binding immunoglobulin-like lectin 3 (Siglec-3),” or “SIGLEC-3,” or “SIGLEC3,” as used herein, refers to human CD33 (huCD33; UniProt ID: P20138-1), unless expressly noted otherwise (i.e., murine CD33, cynomolgus CD33, or the like). Exemplary human CD33 amino acid sequences are shown in SEQ ID NO: 97 and SEQ ID NO: 99. [0035] The term “antibody” herein refers to a molecule comprising at least complementarity- determining region (CDR) 1, CDR2, and CDR3 of a heavy chain and at least CDR1, CDR2, and CDR3 of a light chain, wherein the molecule is capable of binding to antigen. The term is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies, diabodies, etc.), full length antibodies, single-chain antibodies, antibody conjugates, and antibody fragments, so long as they exhibit the desired CD33-specific binding activity. [0036] An “isolated” antibody is one that has been separated from a component of its natural environment. In some aspects, an antibody is purified to greater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC) methods. For a review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007). [0037] An “antigen” refers to the target of an antibody, i.e., the molecule to which the antibody specifically binds. The term “epitope” denotes the site on an antigen, either proteinaceous or non-proteinaceous, to which an antibody binds. Epitopes on a protein can be formed both from contiguous amino acid stretches (linear epitope) or comprise non- contiguous amino acids (conformational epitope), e.g., coming in spatial proximity due to the folding of the antigen, i.e., by the tertiary folding of a proteinaceous antigen. Linear epitopes are typically still bound by an antibody after exposure of the proteinaceous antigen to denaturing agents, whereas conformational epitopes are typically destroyed upon treatment with denaturing agents. [0038] An “anti-CD33 antibody” or a “CD33-antibody” or an “antibody that specifically binds to CD33” or an “antibody that binds to CD33” and similar phrases refer to an antibody that specifically binds to CD33 as defined herein. [0039] The term “heavy chain” refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full-length heavy chain” refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence. [0040] The term “light chain” refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence. [0041] The term “complementarity determining regions” (“CDRs”) as used herein refers to each of the regions of an antibody variable region which are hypervariable in sequence and which determine antigen binding specificity. Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 or heavy chain CDR1, CDR-H2, CDR-H3), and three in the VL (CDR- L1, CDR-L2, CDR-L3). Unless otherwise indicated, the CDRs are determined according to the sequence table herein. [0042] “Framework” or “FR” refers to the residues of the variable region residues that are not part of the complementary determining regions (CDRs). The FR of a variable region generally consists of four FRs: FR1, FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1-CDR-H1(CDR- L1)-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4. [0043] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable domains of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework regions (FRs) and three complementary determining regions (CDRs). See, e.g., Kindt et al. Kuby Immunology, 6^th ed., W.H. Freeman and Co., page 91 (2007). A variable domain may comprise heavy chain (HC) CDR1-FR2-CDR2-FR3-CDR3 with or without all or a portion of FR1 and/or FR4; and light chain (LC) CDR1-FR2-CDR2-FR3-CDR3 with or without all or a portion of FR1 and/or FR4. That is, a variable domain may lack a portion of FR1 and/or FR4 so long as it retains antigen-binding activity. A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol.150 :880-887 (1993) ; Clarkson et al., Nature 352 :624-628 (1991). [0044] The light chain and heavy chain “constant regions” of an antibody refer to additional sequence portions outside of the FRs and CDRs and variable regions. Certain antibody fragments may lack all or some of the constant regions. From N- to C-terminus, each heavy chain has a variable domain (VH), also called a variable heavy domain or a heavy chain variable region, followed by three constant heavy domains (CH1, CH₂, and CH₃). Similarly, from N- to C-terminus, each light chain has a variable domain (VL), also called a variable light domain or a light chain variable region, followed by a constant light (CL) domain. [0045] The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain at Gly446 and Lys447 (EU numbering). Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine and lysine, respectively. Therefore, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc region may or may not be present. Thus, a “full-length heavy chain constant region” or a “full length antibody” for example, which is a human IgG1 antibody, includes an IgG1 with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5^th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991. [0046] “Effector functions” refer to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down regulation of cell surface receptors (e.g., B cell receptor); and B cell activation. [0047] The “class” of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called ^, ^, ^, ^, and ^, respectively. The light chain of an antibody may be assigned to one of two types, called kappa (κ) and lambda (λ), based on the amino acid sequence of its constant domain. [0048] An “antibody fragment” or “antigen-binding fragment” or “antigen-binding portion” refers to a fragment or portion of an antibody other than an intact antibody that binds the antigen (i.e., CD33) to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)₂; diabodies; linear antibodies; single-chain antibody molecules (e.g., scFv, and scFab); single domain antibodies (dAbs); and multispecific antibodies formed from antibody fragments. For a review of certain antibody fragments, see Holliger and Hudson, Nature Biotechnology 23:1126-1136 (2005). [0049] The terms “full length antibody”, “intact antibody”, and “whole antibody” are used herein interchangeably to refer to an antibody having a structure substantially similar to a native antibody structure or, in the case of an IgG antibody, having heavy chains that contain an Fc region as defined herein above. [0050] The term “chimeric” antibody refers to an antibody in which a portion of the heavy and/or light chain is derived from a particular source or species, while the remainder of the heavy and/or light chain is derived from a different source or species. [0051] A “humanized” antibody refers to a chimeric antibody comprising amino acid residues from non-human CDRs and amino acid residues from human FRs. In certain aspects, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non- human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization. [0052] A “human antibody” as used herein refers to antibodies produced from human immunoglobulin sequences, such as antibodies produced in non-human animals that comprise human immunoglobulin genes (such as XenoMouse® and VelocImmune® mice), and antibodies selected using in vitro methods, such as phage display, wherein the antibody repertoire is based on a human immunoglobulin sequences. [0053] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. [0054] A “multispecific” antibody is one that binds specifically to more than one target antigen, while a “bispecific” antibody is one that binds specifically to two antigens. An “antibody conjugate” is an antibody conjugated to one or more heterologous molecule(s), including but not limited to a therapeutic agent or a label. [0055] Antibodies may be modified as part of the production process in certain host cells or through metabolism in vivo. An antibody or antibody region amino acid sequence herein is intended to encompass not only the specific amino acid sequence, but also that sequence as post-translationally modified, for instance, including side chain modifications and cleavages. Such a post-translational modification can occur, for instance, as a result of production of the antibody in a host cell and/or as a result of post-translational modification in vivo in an animal (e.g., a human). [0056] In some embodiments, an antibody disclosed herein comprises a post-translational modification (e.g., one or more post-translational modifications). Post-translational modifications can include, e.g., ubiquitination, phosphorylation, acetylation, hydroxylation, methylation, glycyosylation, AMPylation, prenylation, deamidation, elimylation, citrullination, and carbamoylation. In some embodiments, the antibody is not post- translationally modified. [0057] As noted above, antibodies can undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain, often a Gly-Lys. This cleavage can occur, for instance, as a result of the process of production of the antibody in a host cell. An antibody produced by expression of a specific nucleic acid molecule encoding a full-length heavy chain can include the full-length heavy chain, or it can include a cleaved variant of the full-length heavy chain, such as a heavy chain lacking a C-terminal Lys or a C-terminal Gly-Lys. [0058] Other types of post-translational modifications can occur during production of antibodies, or otherwise in vivo, such as the modification of an amino acid side chain. For instance, an N-terminal Glu or Gln residue on an antibody chain can be post-translationally modified to an N-terminal pyroglutamate (also known as pyrrolidine carboxylate; abbreviated pE). [0059] “Percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antibody sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. [0060] The term “signal sequence” or “leader sequence” refers to a sequence of amino acid residues located at the N terminus of a polypeptide that facilitates secretion of a polypeptide from a mammalian cell. A leader sequence may be cleaved upon export of the polypeptide from the mammalian cell, forming a mature protein. Leader sequences may be natural or synthetic, and they may be heterologous or homologous to the protein to which they are attached. Nonlimiting exemplary leader sequences also include leader sequences from heterologous proteins. In some embodiments, an antibody lacks a leader sequence. In some embodiments, an antibody comprises at least one leader sequence, which may be selected from native antibody leader sequences and heterologous leader sequences. [0061] The term “nucleic acid molecule” or “polynucleotide” includes any compound and/or substance that comprises a polymer of nucleotides. Each nucleotide is composed of a base, specifically a purine- or pyrimidine base (i.e. cytosine I, guanine (G), adenine (A), thymine (T) or uracil (U)), a sugar (i.e. deoxyribose or ribose), and a phosphate group. Often, the nucleic acid molecule is described by the sequence of bases, whereby said bases represent the primary structure (linear structure) of a nucleic acid molecule. The sequence of bases is typically represented from 5’ to 3’. Herein, the term nucleic acid molecule encompasses deoxyribonucleic acid (DNA) including e.g., complementary DNA (cDNA) and genomic DNA, ribonucleic acid (RNA), in particular messenger RNA (mRNA), synthetic forms of DNA or RNA, and mixed polymers comprising two or more of these molecules. The nucleic acid molecule may be linear or circular. In addition, the term nucleic acid molecule includes both sense and antisense strands, as well as single stranded and double stranded forms. Moreover, the herein described nucleic acid molecule can contain naturally occurring or non- naturally occurring nucleotides. Examples of non-naturally occurring nucleotides include modified nucleotide bases with derivatized sugars or phosphate backbone linkages or chemically modified residues. Nucleic acid molecules also encompass DNA and RNA molecules which are suitable as a vector for direct expression of an antibody of the invention in vitro and/or in vivo, e.g., in a host or patient. Such DNA (e.g., cDNA) or RNA (e.g., mRNA, circular RNA) vectors, can be unmodified or modified. [0062] An “isolated” nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. An isolated nucleic acid includes a nucleic acid molecule contained in cells that ordinarily contain the nucleic acid molecule, but the nucleic acid molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. [0063] “Isolated nucleic acid encoding an anti-CD33 antibody” refers to one or more nucleic acid molecules encoding anti-CD33 antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and such nucleic acid molecule(s) present at one or more locations in a host cell. [0064] The term “vector”, as used herein, refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes the vector as a self- replicating nucleic acid structure as well as the vector incorporated into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as “expression vectors”. [0065] The terms “host cell”, “host cell line”, and “host cell culture” are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. [0066] In this disclosure, “binds” or “binding” or “specific binding” and similar terms, when referring to a protein and its ligand or an antibody and its antigen target for example, or some other binding pair, means that the binding affinity between the members of the binding pair is sufficiently strong that the interaction cannot be due to random molecular associations (i.e. “nonspecific binding”). Such binding typically requires a dissociation constant (K_D) of 1μM or less, and may often involve a KD of 100 nM or less. [0067] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). Affinity can generally be represented by the dissociation constant (K_D). Affinity of an antibody for an antigen can be measured by common methods known in the art, such as surface plasmon resonance (SPR), for instance. [0068] The terms “reduce” or “inhibit” more generally refer to a decrease or cessation of any event (such as protein ligand binding) or to a decrease or cessation of any phenotypic characteristic or to the decrease or cessation in the incidence, degree, or likelihood of that characteristic. To “reduce” or “inhibit” is to decrease, reduce or arrest an activity, function, and/or amount as compared to a reference. It is not necessary that the inhibition or reduction be complete. For example, in certain embodiments, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 20% or greater. In another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 50% or greater. In yet another embodiment, by “reduce” or “inhibit” is meant the ability to cause an overall decrease of 75%, 85%, 90%, 95%, or greater. [0069] “Treatment” or “treating” as used herein, covers any administration or application of a therapeutic for disease in a human, and includes inhibiting the disease or progression of the disease or one or more disease symptoms, inhibiting or slowing the disease or its progression or one or more of its symptoms, arresting its development, partially or fully relieving the disease or one or more of its symptoms, or preventing a recurrence of one or more symptoms of the disease. [0070] The terms “subject” and “patient” are used interchangeably herein to refer to a human unless expressly indicated otherwise (i.e., a murine subject or the like). [0071] The term “cancer” is used herein to refer to a group of cells that exhibit abnormally high levels of proliferation and growth. A cancer may be benign (also referred to as a benign tumor), pre-malignant, or malignant. Cancer cells may be solid cancer cells or leukemic cancer cells. [0072] Examples of cancers applicable to methods of treatment herein include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular nonlimiting examples of such cancers include squamous cell cancer, small-cell lung cancer, pituitary cancer, esophageal cancer, astrocytoma, soft tissue sarcoma, non-small cell lung cancer (including squamous cell non-small cell lung cancer), adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, renal cell carcinoma, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer, melanoma, and various types of head and neck cancer (including squamous cell carcinoma of the head and neck). [0073] As used herein, the term “tumor,” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. “Neoplastic,” as used herein, refers to any form of dysregulated or unregulated cell growth, whether malignant or benign, resulting in abnormal tissue growth. Thus, “neoplastic cells” include malignant and benign cells having dysregulated or unregulated cell growth. [0074] As used herein, “hematologic malignancy” refers to cancer of the body's blood- forming and immune system—the bone marrow and lymphatic tissue. Such cancers include leukemias, lymphomas (Non-Hodgkin's Lymphoma), Hodgkin's disease (also called Hodgkin's Lymphoma) and myeloma. [0075] The term “leukemia” refers to malignant neoplasms of the blood-forming tissues. The leukemia includes, but is not limited to, chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and acute myeloblastic leukemia. The leukemia can be relapsed, refractory or resistant to conventional therapy. [0076] As used herein, “promyelocytic leukemia” or “acute promyelocytic leukemia” refers to a malignancy of the bone marrow in which there is a deficiency of mature blood cells in the myeloid line of cells and an excess of immature cells called promyelocytes. It is usually marked by an exchange of regions of chromosomes 15 and 17. [0077] As used herein, “acute lymphocytic leukemia (ALL)”, also known as “acute lymphoblastic leukemia” refers to a malignant disease caused by the abnormal growth and development of early nongranular white blood cells, or lymphocytes. [0078] As used herein, “T-cell leukemia” refers to a disease in which certain cells of the lymphoid system called T lymphocytes or T cells are malignant. T cells are white blood cells that normally can attack virus-infected cells, foreign cells, and cancer cells and produce substances that regulate the immune response. [0079] The term “relapsed” refers to a situation where patients who have had a remission of leukemia after therapy have a return of leukemia cells in the marrow and a decrease in normal blood cells. [0080] The term “refractory or resistant” refers to a circumstance where patients, even after intensive treatment, have residual leukemia cells in their marrow. [0081] “Anti-cancer agents” refers to anti-metabolites (e.g., 5-fluoro-uracil, methotrexate, fludarabine), antimicrotubule agents (e.g., vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g., cyclophosphamide, melphalan, carmustine, nitrosoureas such as bischloroethylnitrosurea and hydroxyurea), platinum agents (e.g. cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubicin, adriamycin, daunomycin), topoisomerase inhibitors (e.g., etoposide, camptothecins), anti-angiogenesis agents (e.g. Sutent® and Bevacizumab) or any other cytotoxic agents, (estramustine phosphate, prednimustine), hormones or hormone agonists, antagonists, partial agonists or partial antagonists, kinase inhibitors, and radiation treatment. [0082] The term “effective amount” or “therapeutically effective amount” refers to an amount of a drug effective for treatment of a disease or disorder in a subject, such as to partially or fully relieve one or more symptoms. In some embodiments, an effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. [0083] A “biological sample” as used herein refers to a sample taken from a subject or from an animal. Examples of biological samples include tissue samples and liquid biological samples, such as whole blood, serum, plasma, blood supernatant, or synovial fluid. A biological sample may be taken directly from a subject or may be first chemically or physically modified in some fashion prior to use, for example, in order to assist in analysis of the sample. [0084] A “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, formulation auxiliary, or carrier conventional in the art for use with a therapeutic agent that together comprise a “pharmaceutical composition” for administration to a subject. A pharmaceutically acceptable carrier is non- toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation. The pharmaceutically acceptable carrier is appropriate for the formulation employed. For example, if the therapeutic agent is to be administered orally, the carrier may be a gel capsule. If the therapeutic agent is to be administered subcutaneously, the carrier ideally is not irritable to the skin and does not cause injection site reaction. [0085] “Aliphatic” refers to a straight or branched and/or cyclic hydrocarbon chain group consisting solely of carbon and hydrogen atoms, having from one to 25, one to 20, one to 15, one to ten, one to eight, one to six, one to five, or one to four carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., alkyl, alkenyl, cycloalkyl, and the like. In some embodiments, aliphatic contains no unsaturation. In some embodiments, aliphatic is a straight or branched chain. In some embodiments, aliphatic comprises a cycle. In some embodiments, aliphatic comprises a straight or branched chain and a cycle. [0086] “Alkyl” refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten, one to eight, one to six, one to four, or one to three carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. [0087] “Alkenyl” refers to a straight or branched chain unsaturated group consisting solely of carbon and hydrogen atoms, having from two to eight, two to six or two to four carbon atoms, wherein the unsaturation is present only as double bonds and wherein the double bond can exist between any two carbon atoms in the chain, e.g., ethenyl, prop-1-enyl, but-2-enyl, and the like. The straight or branched chain unsaturated group is attached to the rest of the molecule by a single bond. [0088] “Alkoxy” refers to the group having the formula —OR wherein R is alkyl. An “optionally substituted alkoxy” refers to the group having the formula —OR wherein R is an optionally substituted alkyl as defined herein. [0089] “Alkoxyalkyl” refers to an alkoxy group as defined herein which is attached to the rest of the molecule by an alkyl group as defined herein. [0090] “Amino” refers to a radical having the formula —NR′R″ wherein R′ and R″ are each independently hydrogen, alkyl or haloalkyl. An “optionally substituted amino” refers to a radical having the formula —NR′R″ wherein one or both of R′ and R″ are optionally substituted alkyl as defined herein. [0091] “Aryl” refers to a 5- to 18-membered, 6- to 18-membered, 6- to 10-membered, or 6- membered carbocylic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic ring systems, wherein at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracenyl, acenaphthylenyl, azulenyl, fluorenyl, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non- aromatic ring, examples of which are acenaphene, indene, and fluorene. [0092] “Cycloalkyl” refers to a stable monovalent monocyclic or bicyclic hydrocarbon group consisting solely of carbon and hydrogen atoms, having from three to 12, three to ten, or three to seven carbon atoms, which is saturated, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decalinyl, norbornane, norbornene, adamantyl, bicyclo[2.2.2]octane and the like. [0093] “Cycloalkoxy” refers to a cycloalkyl group as defined herein which is attached to the rest of the molecule by an oxygen atom. [0094] “Ene” or “enyl,” when used as a suffix herein, means that the group being modified with the suffix is attached to the rest of the molecule through two or more points of attachment (typically, two), e.g., alkylene, alkenylene, and the like. The group may be attached to the rest of the molecule through any two suitable atoms in the group. [0095] “Halo, “halogen” or “halide” refers to F, Cl, Br or I. In some embodiments, halo is fluoro or chloro. In a particular embodiment, halo is fluoro. [0096] “Haloalkyl” refers to an alkyl group, in certain embodiments, C_1-6alkyl group, in which one or more of the hydrogen atoms are replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl 1-chloro-2-fluoroethyl, 2,2-difluoroethyl, 2- fluoropropyl, 2-fluoropropan-2-yl, 2,2,2-trifluoroethyl, 1,1-difluoroethyl, 1,3-difluoro-2- methylpropyl, 2,2-difluorocyclopropyl, (trifluoromethyl)cyclopropyl, 4,4-difluorocyclohexyl and 2,2,2-trifluoro-1,1-dimethylethyl. [0097] “Haloalkoxy” refers to the group having the formula —OR wherein R is haloalkyl, as defined herein. [0098] “Heterocycle” or “Heterocyclyl” refers to a stable 3- to 15-membered, 3- to-12 membered, 4- to 12-membered, 4- to 7-membered, 5- to 12-membered, or 5- to 6-membered non-aromatic ring radical which consists of carbon atoms and from one to five heteroatoms selected from a group consisting of nitrogen, oxygen and sulfur. In one embodiment, the heterocyclic ring system radical may be a monocyclic, bicyclic or tricyclic ring or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen or sulfur atoms in the heterocyclic ring system radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated. The heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Exemplary heterocyclic radicals include, morpholinyl, piperidinyl, piperazinyl, pyranyl, pyrrolidinyl, oxetanyl, azetidinyl, quinuclidinyl, octahydroquinolizinyl, decahydroquinolizinyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.2]octanyl, isoindolinyl, indolinyl and others. [0099] “Heterocyclyloxy” refers to a heterocyclyl group as defined herein which is attached to the rest of the molecule by an oxygen atom. [0100] “Heteroaryl” refers to a heterocyclyl group as defined above which is aromatic. The heteroaryl groups include, but are not limited to monocyclyl, bicyclyl and tricyclyl groups, and may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heteroaryl groups include, but are not limited to: furanyl, imidazolyl, oxazolyl, isoxazolyl, pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, benzimidazolyl, imidazo[4,5-b]pyridinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl and others. [0101] “Oxo” refers to =O. [0102] “Sugar acid” refers to a monosaccharide with a carboxyl (-COO/-COOH) group at one or both ends of its chain, e.g., glyceric acid, xylonic acid, gluconic acid, ascorbic acid, neuraminic acid, ketodeoxyoctulosonic acid, glucuronic acid, galacturonic acid, iduronic acid, tartaric acid, mucic acid, and saccharic acid. [0103] “EC50” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% potency or effect of a maximal response, such as cell growth or proliferation measured via any of the in vitro or cell-based assay described herein. [0104] “IC₅₀” refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as cell growth or proliferation, measured via any of the in vitro or cell-based assay described herein. [0105] Pharmaceutically acceptable salts include, but are not limited to, amine salts, such as but not limited to N,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates. [0106] As used herein and unless otherwise indicated, the term “hydrate” means a compound provided herein or a salt thereof, that further includes a stoichiometric or non-stoichiometeric amount of water bound by non-covalent intermolecular forces. [0107] As used herein and unless otherwise indicated, the term “solvate” means a solvate formed from the association of one or more solvent molecules to a compound provided herein. The term “solvate” includes hydrates (e.g., mono-hydrate, dihydrate, trihydrate, tetrahydrate and the like). [0108] Unless stated otherwise specifically described in the specification, it is understood that the substitution can occur on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group. [0109] Where the number of any given substituent is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. [0110] When the groups described herein, with the exception of alkyl group, are said to be “substituted,” they may be substituted with any appropriate substituent or substituents. Illustrative examples of substituents are those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; oxygen (═O); B(OH)2, O(alkyl)aminocarbonyl; cycloalkyl, which may be monocyclic or fused or non-fused polycyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), or a heterocyclyl, which may be monocyclic or fused or non-fused polycyclic (e.g., pyrrolidyl, piperidyl, piperazinyl, morpholinyl, or thiazinyl); monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridinyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl) aryloxy; aralkyloxy; heterocyclyloxy; and heterocyclyl alkoxy. When the alkyl groups described herein are said to be “substituted,” they may be substituted with any substituent or substituents as those found in the exemplary compounds and embodiments disclosed herein, as well as halogen (chloro, iodo, bromo, or fluoro); alkyl; hydroxyl; alkoxy; alkoxyalkyl; amino; alkylamino; carboxy; nitro; cyano; thiol; thioether; imine; imide; amidine; guanidine; enamine; aminocarbonyl; acylamino; phosphonate; phosphine; thiocarbonyl; sulfinyl; sulfone; sulfonamide; ketone; aldehyde; ester; urea; urethane; oxime; hydroxyl amine; alkoxyamine; aryloxyamine, aralkoxyamine; N-oxide; hydrazine; hydrazide; hydrazone; azide; isocyanate; isothiocyanate; cyanate; thiocyanate; B(OH)₂, or O(alkyl)aminocarbonyl. [0111] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and/or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound is described as having one of two tautomeric forms, it is intended that both tautomers be encompassed herein. [0112] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. [0113] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form. [0114] Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase. [0115] Also provided herein are isotopically enriched analogs of the compounds provided herein. Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and toxicity profiles, has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et. al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et. al., Mutation Res.308: 33 (1994); Gordon et. al., Drug Metab. Dispos., 15: 589 (1987); Zello et. al., Metabolism, 43: 487 (1994); Gately et. al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact.117: 191 (1999). [0116] Without being limited by any particular theory, isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) decrease the number of doses needed to achieve a desired effect, (4) decrease the amount of a dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any are formed, and/or (6) decrease the production of deleterious metabolites in specific tissues and/or create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not. [0117] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C—H bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), substitution of a deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down. This phenomenon is known as the Deuterium Kinetic Isotope Effect (“DKIE”). (See, e.g, Foster et al., Adv. Drug Res., vol.14, pp.1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp.79-88 (1999)). [0118] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C—H bond is broken, and the same reaction where deuterium is substituted for hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium is substituted for hydrogen. Without being limited by a particular theory, high DKIE values may be due in part to a phenomenon known as tunneling, which is a consequence of the uncertainty principle. Tunneling is ascribed to the small mass of a hydrogen atom, and occurs because transition states involving a proton can sometimes form in the absence of the required activation energy. Because deuterium has more mass than hydrogen, it statistically has a much lower probability of undergoing this phenomenon. [0119] Tritium (“T”) is a radioactive isotope of hydrogen, used in research, fusion reactors, neutron generators and radiopharmaceuticals. Tritium is a hydrogen atom that has two neutrons in the nucleus and has an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly found as T2O. Tritium decays slowly (half-life=12.3 years) and emits a low energy beta particle that cannot penetrate the outer layer of human skin. Internal exposure is the main hazard associated with this isotope, yet it must be ingested in large amounts to pose a significant health risk. As compared with deuterium, a lesser amount of tritium must be consumed before it reaches a hazardous level. Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and typically gives numerically larger isotope effects. [0120] Similarly, substitution of isotopes for other elements, including, but not limited to, ¹³C or ¹⁴C for carbon, ³³S, ³⁴S, or ³⁶S for sulfur, ¹⁵N for nitrogen, and ¹⁷O or ¹⁸O for oxygen, may provide kinetic isotope effects. [0121] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon-hydrogen (C—H) bond to either a carbon-oxygen (C—O) or carbon-carbon (C—C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamic, and acute and long- term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. As a result, these drugs often require the administration of multiple or high daily doses. [0122] Isotopic enrichment at certain positions of a compound provided herein may produce a detectable KIE that affects the pharmacokinetic, pharmacologic, and/or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. In one embodiment, the deuterium enrichment is performed on the site of C—H bond cleavage during metabolism. [0123] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls. II. Exemplary Anti-CD33 Antibodies [0124] Novel antibodies directed against CD33, such as human CD33, are provided. Anti- CD33 antibodies include, but are not limited to, humanized antibodies, chimeric antibodies, mouse antibodies, human antibodies, and antibodies comprising the heavy chain and/or light chain CDRs discussed herein. In some embodiments, an isolated antibody that binds to CD33 is provided. In some embodiments, a monoclonal antibody that binds to CD33 is provided. In some embodiments, the antibody binds to human CD33. In some embodiments, the antibody binds to human CD33 comprising the amino acid sequence of SEQ ID NO: 97, and/or binds to human CD33 comprising the amino acid sequence of SEQ ID NO: 99. [0125] In some embodiments, an anti-CD33 antibody comprises a heavy chain variable region and a light chain variable region. In some embodiments, an anti-CD33 antibody comprises at least one heavy chain comprising a heavy chain variable region and at least a portion of a heavy chain constant region, and at least one light chain comprising a light chain variable region and at least a portion of a light chain constant region. In some embodiments, an anti-CD33 antibody comprises two heavy chains, wherein each heavy chain comprises a heavy chain variable region and at least a portion of a heavy chain constant region, and two light chains, wherein each light chain comprises a light chain variable region and at least a portion of a light chain constant region. As used herein, a single-chain Fv (scFv), or any other antibody that comprises, for example, a single polypeptide chain comprising all six CDRs (three heavy chain CDRs and three light chain CDRs) is considered to have a heavy chain and a light chain. In some embodiments, the heavy chain is the region of the anti-CD33 antibody that comprises the three heavy chain CDRs. In some embodiments, the light chain is the region of the anti-CD33 antibody that comprises the three light chain CDRs. [0126] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 27 or 28. [0127] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28. [0128] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising an amino acid sequence of SEQ ID NO: 4; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41. [0129] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41. [0130] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46. [0131] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46. [0132] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 10; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (d) LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (e) LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59. [0133] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59. [0134] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from (a) HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (b) HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (c) HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (d) LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (e) LCDR2 comprising the amino acid sequence of SEQ ID NO: 61-66; and (f) LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68. [0135] In some embodiments, the anti-CD33 antibody comprises six CDRs including (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61- 66; (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68. [0136] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0137] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0138] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0139] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0140] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0141] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0142] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0143] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0144] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0145] In some embodiments, the anti-CD33 antibody comprises six CDRs an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0146] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0147] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27. [0148] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0149] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0150] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0151] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0152] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0153] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0154] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0155] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0156] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0157] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0158] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0159] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0160] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0161] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0162] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0163] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0164] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0165] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40. [0166] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0167] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0168] In some embodiments, an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0169] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0170] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0171] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0172] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45. [0173] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45. [0174] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46. [0175] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46. [0176] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45. [0177] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45. [0178] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0179] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0180] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0181] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0182] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0183] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0184] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0185] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0186] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0187] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0188] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0189] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58. [0190] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0191] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0192] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0193] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0194] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0195] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0196] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0197] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO:61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0198] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0199] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0200] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0201] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0202] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0203] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0204] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0205] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0206] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0207] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0208] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0209] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67. [0210] In some embodiments, an anti-CD33 antibody comprises at least one, two, three, four, five, or six CDRs selected from an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0211] In some embodiments, the anti-CD33 antibody comprises six CDRs including an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0212] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; and (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3. [0213] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6. [0214] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9. [0215] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12. [0216] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; and (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15. [0217] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27 or 28. [0218] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41. [0219] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (ii) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (iii) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46. [0220] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59. [0221] In some embodiments, the anti-CD33 antibody comprises at least one, at least two, or all three VL CDR sequences selected from (i) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (ii) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; (iii) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68. [0222] In some embodiments, any of the six CDRs provided herein can be combined as subparts with any of the other CDRs provided herein, for a total of six CDRs in a construct. Thus, in some embodiments, two CDRs from a first antibody (for example, HCDR1 and HCDR2) can be combined with four CDRs from a second antibody (HCDR3, LCDR1, LCDR2, and LCDR3). In some embodiments, two or fewer residues in one or more of the CDRs can be replaced to obtain a variant thereof. In some embodiments, two or fewer residues can be replaced in 1, 2, 3, 4, 5, or 6 of the CDRs. [0223] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27 or 28; wherein the VH domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73, and the VL domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. [0224] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; wherein the VH domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73, and the VL domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. [0225] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; wherein the VH domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73, and the VL domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. [0226] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; wherein the VH domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73, and the VL domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. [0227] In some embodiments, the anti-CD33 antibody comprises (I) a VH domain comprising at least one, at least two, or all three VH CDR sequences selected from (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; and (II) a VL domain comprising at least one, at least two, or all three VL CDR sequences selected from (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68; wherein the VH domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73, and the VL domain comprises a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. [0228] In some embodiments, an anti-CD33 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 69, 70, 71, 72, or 73. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VH sequence in SEQ ID NO: 69, 70, 71, 72, or 73, including post-translational modifications of that sequence. [0229] In some embodiments, an anti-CD33 antibody is provided, wherein the antibody comprises a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VL sequence in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82, including post-translational modifications of that sequence. [0230] In some embodiments, an anti-CD33 antibody comprises a heavy chain variable domain (VH) sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 69, 70, 71, 72, or 73 and a light chain variable domain (VL) having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a VL sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 69, 70, 71, 72, or 73. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs (that is, in the FRs). Optionally, the anti-CD33 antibody comprises the VH sequence in SEQ ID NO: 69, 70, 71, 72, or 73 and the VL sequence of SEQ ID NO: 74, 75, 76, 77, 78, 79, 80, 81, or 82, including post-translational modifications of one or both sequences. [0231] In some embodiments, an anti-CD33 antibody comprises a VH as in any of the embodiments provided herein, and a VL as in any of the embodiments provided herein. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 69 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 75, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 71 and SEQ ID NO: 76, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 75, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 77, respectively, including post- translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 74, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 70 and SEQ ID NO: 78, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 78, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 79, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 72 and SEQ ID NO: 80, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 69 and SEQ ID NO: 81, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the VH and VL sequences in SEQ ID NO: 73 and SEQ ID NO: 82, respectively, including post- translational modifications of those sequences. [0232] In some embodiments, an anti-CD33 antibody comprises a heavy chain (HC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, a HC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the HC sequence in SEQ ID NO: 83, 84, 85, 86, or 87, including post-translational modifications of that sequence. [0233] In some embodiments, an anti-CD33 antibody is provided, wherein the antibody comprises a light chain (LC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, a LC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the LC sequence in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96, including post-translational modifications of that sequence. [0234] In some embodiments, an anti-CD33 antibody comprises a heavy chain (HC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, 84, 85, 86, or 87 and a light chain (LC) sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, a HC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, and a LC sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity contains substitutions (for example, conservative substitutions), insertions, or deletions relative to the reference sequence, but an anti-CD33 antibody comprising that sequence retains the ability to bind to CD33. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 83, 84, 85, 86, or 87. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96. In some embodiments, substitutions, insertions, or deletions occur in regions outside the CDRs. Optionally, the anti-CD33 antibody comprises the HC sequence in SEQ ID NO: 83, 84, 85, 86, or 87 and the LC sequence of SEQ ID NO: 88, 89, 90, 91, 92, 93, 94, 95, or 96, including post-translational modifications of one or both sequences. [0235] In some embodiments, an anti-CD33 antibody comprises a HC as in any of the embodiments provided herein, and a LC as in any of the embodiments provided herein. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 83 and SEQ ID NO: 88, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 89, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 85 and SEQ ID NO: 90, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 89, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 91, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 88, respectively, including post- translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 88, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 84 and SEQ ID NO: 92, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 92, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 93, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 86 and SEQ ID NO: 94, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 83 and SEQ ID NO: 95, respectively, including post-translational modifications of those sequences. In some embodiments, the antibody comprises the HC and LC sequences in SEQ ID NO: 87 and SEQ ID NO: 96, respectively, including post-translational modifications of those sequences. [0236] In various embodiments, an anti-CD33 antibody provided herein may comprise pyroglutamic acid (pyroGlu or pE) in place of glutamic acid (Glu or E) at the N-terminus. In some embodiments, pyroGlu is formed by cyclization of an N-terminal Glu during expression and/or purification of the antibody. Thus, a Glu (E) at the N-terminus of an antibody chain sequence provided herein may be replaced with a pyroGlu, and antibodies comprising pyroGlu in place of Glu at the N-terminus the sequences provided herein are contemplated. Thus, in some embodiments, an anti-CD33 antibody is provided, wherein the antibody comprises a heavy chain variable domain comprising the sequence of any one of SEQ ID NO: 69, 70, 71, 72, or 73, wherein the N-terminal Glu (E) is replaced with a pyroGlu (pE). Similarly, an anti-CD33 antibody is provided, wherein the antibody comprises a heavy chain comprising the sequence of any one of SEQ ID NO: 83, 84, 85, 86, or 87, wherein the N- terminal Glu (E) is replaced with a pyroGlu (pE). [0237] In various embodiments, the antibody is a monoclonal antibody. [0238] In various embodiments, an anti-CD33 antibody specifically may comprise any of the following properties, singly or in combination.In some embodiments, the antibody binds to human CD33 with an affinity (K_D) of less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, from 0.01 nM to 5 nM, from 0.01 nM to 1 nM, from 0.05 nM to 1 nM, from 0.1 nM to 1 nM, from 0.1 nM to 0.5 nM, from 0.05 nM to 0.5 nM, from 0.05 nM to 0.1 nM, or from 0.5 nM to 1 nM. In some embodiments, the antibody binds to cynomolgus monkey CD33 with a KD less than 5 nM, less than 1 nM, less than 0.5 nM, less than 0.1 nM, from 0.01 nM to 5 nM, from 0.01 nM to 1 nM, from 0.05 nM to 1 nM, from 0.1 nM to 1 nM, from 0.1 nM to 0.5 nM, from 0.05 nM to 0.5 nM, from 0.05 nM to 0.1 nM, or from 0.5 nM to 1 nM. In some embodiments, the antibody binds to human CD33 with a K_D of less than 1.5 nM. In some embodiments, the antibody binds to cynomolgus monkey CD33 with an affinity (KD) of less than 10 nM. In some embodiments, affinity is determined using biolayer interferometry. [0239] In some embodiments, the antibody binds human CD33. In some embodiments, the human CD33 comprises the amino acid sequence of SEQ ID NO: 97. In some embodiments, the human CD33 comprises the amino acid sequence of SEQ ID NO: 99. In some embodiments, the antibody binds the monomeric form of human CD33. In some embodiments, the antibody binds the dimeric form of human CD33. In some embodiments, the antibody binds cynomolgus monkey CD33. In some embodiments, the cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody binds the monomeric form of cynomolgus monkey CD33. In some embodiments, the antibody binds the dimeric form of cynomolgus monkey CD33. [0240] In some embodiments, the antibody does not significantly bind to human Siglec 6. In some embodiments, the antibody does not significantly bind to human Siglec 8. [0241] In some embodiments, the antibody is capable of mediating internalization of the antibody in CD33+ cells. In some embodiments, the antibody internalizes after binding to CD33+ cells. In some embodiments, the antibody has a Tregitope-adjusted EpiMatrix Score equal to or less than 0, equal to or less than -25, or equal to or less than -45. III. Exemplary Antibody Variants, Fragments, and Constant Regions [0242] In many embodiments, an antibody specifically binding to CD33 may further incorporate any of the features, singly or in combination, as described in the sections that follow. A. Antibody Fragments [0243] In certain embodiments, an antibody provided herein is an antibody fragment. In some embodiments, the anti-CD33 antibody is an antibody fragment selected from an Fv, single- chain Fv (scFv), Fab, Fab’, or (Fab’)₂. Antibody fragments include, but are not limited to, Fab, Fab’, Fab’-SH, F(ab’)2, Fv, and scFv fragments, and other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med.9:129-134 (2003). For a review of scFv fragments, see, e.g., Pluckthün, in The Pharmacology of Monoclonal Antibodies, vol.113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp.269-315 (1994); see also WO 93/16185; and U.S. Patent Nos.5,571,894 and 5,’87,458. For discussion of Fab and F(a’')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No.5,869,046. [0244] Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161; Hudson et al., Nat. Med. 9:129-134 (2003); and Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat. Med.9:129-134 (2003). [0245] Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No.6,248,516). [0246] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein. B. Bispecific or Multispecific Antibodies [0247] In certain embodiments, an antibody provided herein is a multispecific antibody, for example, a bispecific antibody. Multispecific antibodies are monoclonal antibodies that have binding specificities for at least two different sites. In certain embodiments, one of the binding specificities is CD33 and the other is for any other antigen. In certain embodiments, bispecific antibodies may bind to two different epitopes of CD33. Bispecific antibodies may also be used to localize drugs such as cytotoxic agents or to localize detection labels to cells that express CD33. some embodiments, the multispecific antibody (e.g., bispecific antibody) comprises a first variable domain comprising the CDRs or variable regions as described herein. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. [0248] In some embodiments, an antibody provided herein is a bispecific antibody comprising a first antigen-binding domain that binds CD33 and a second antigen-binding domain that binds a second antigen. In various embodiments, the first antigen-binding domain is an antigen-binding domain that binds CD33 described herein. In some embodiments, the bispecific antibody is an immune cell engager. In some embodiments, the second antigen binding domain binds an antigen on the surface of T cells. In some embodiments, the second antigen binding domain binds an antigen on the surface of NK cells. In some embodiments, the second antigen binding domain of the bispecific antibody binds an antigen selected from CD3, CD16, CD16A, NKG2C, or NKG2D. [0249] Techniques for making multispecific antibodies include, but are not limited to, recombinant co-expression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J.10: 3655 (1991)), and “knob-in-hole” engineering (see, e.g., U.S. Patent No.5,731,168). Multi-specific antibodies may also be made by engineering electrostatic steering effects for making antibody Fc-heterodimeric molecules (WO 2009/089004A1); cross-linking two or more antibodies or fragments (see, e.g., US Patent No.4,676,980, and Brennan et al., Science, 229: 81 (1985)); using leucine zippers to produce bi-specific antibodies (see, e.g., Kostelny et al., J. Immunol., 18(5):1547-1553 (1992)); using “diabod” technology for making bispecific antibody fragments (see, e.g., Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)); and using single-chain Fv (sFv) dimers (see, e.g. Gruber et al., J. Immunol., 152:5368 (1994)); and preparing trispecific antibodies as described, e.g., in Tutt et al. J. Immunol.147: 60 (1991). [0250] Engineered antibodies with three or more functional antigen binding sites, including “Octopus antibodies,” are also included herein (see, e.g. US 2006/0025576). C. Human Antibodies [0251] In certain embodiments, an antibody provided herein is a human antibody. Human antibodies can be made by any suitable method. Nonlimiting exemplary methods include making human antibodies in transgenic mice that comprise human immunoglobulin loci. See, e.g., Jakobovits et al., Proc. Natl. Acad. Sci. USA 90: 2551-55 (1993); Jakobovits et al., Nature 362: 255-8 (1993); Lonberg et al., Nature 368: 856-9 (1994); and U.S. Patent Nos. 5,545,807; 6,713,610; 6,673,986; 6,162,963; 5,545,807; 6,300,129; 6,255,458; 5,877,397; 5,874,299; and 5,545,806. [0252] Nonlimiting exemplary methods also include selecting human antibodies from phage display libraries. See, e.g., Hoogenboom et al., J. Mol. Biol.227: 381-8 (1992); Marks et al., J. Mol. Biol.222: 581-97 (1991); and PCT Publication No. WO 99/10494. D. Chimeric and Humanized Antibodies [0253] In certain embodiments, an antibody provided herein is a chimeric antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No.4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof. [0254] In certain embodiments, a chimeric antibody is a humanized antibody. In some embodiments, an antibody provided herein is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. Generally, a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody, and FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody optionally will also comprise at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve antibody specificity or affinity. [0255] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci.13:1619-1633 (2008), and are further described, e.g., in Riechmann et al., Nature 332:323-329 (1988); Queen et al., Proc. Nat’l Acad. Sci. USA 86:10029-10033 (1989); US Patent Nos.5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting); Padlan, Mol. Immunol.28:489-498 (1991) (describing “resurfacing”); Dall’Acqua et al., Methods 36:43-60 (2005) (describing “FR shuffling”); and Osbourn et al., Methods 36:61-68 (2005) and Klimka et al., Br. J. Cancer, 83:252-260 (2000) (describing the “guided selection” approach to FR shuffling). [0256] Human framework regions that may be used for humanization include but are not limited to framework regions selected using the “best-fit” method (see, e.g., Sims et al. J. Immunol.151:2296 (1993)); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carte r et al. Pro c. Natl. Acad. Sci. USA, 89:4285 (1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, Front. Biosci.13:1619-1633 (2008)); and framework regions derived from screening FR libraries (see, e.g., Baca et al., J. Biol. Chem.272:10678-10684 (1997) and Rosok et al., J. Biol. Chem.271:22611-22618 (1996)). [0257] In some embodiments, the humanized antibodies may comprise a human IgG1, IgG2, IgG3, or IgG4 heavy chain constant region. E. Glycosylation and Pegylation Variants [0258] In certain embodiments, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos.5,714,350 and 6,350,861 by Co et al. [0259] Glycosylation of the constant region on N297 can be prevented by mutating the N297 residue to another residue, e.g., N297A, and/or by mutating an adjacent amino acid, e.g., 298 to thereby reduce glycosylation on N297. [0260] Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies described herein to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Led 3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al. (2002) J. Biol. Chem.277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases {e.g., beta(l,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech.17: 176-180). [0261] Another modification of the antibodies described herein is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. In some embodiments, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol” is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (CI-CIO) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies described herein. See for example, EP 0154316 by Nishimura et al. and EP 0401384 by Ishikawa et al. F. Constant Regions [0262] In some embodiments, the antibody is a full-length antibody. In some embodiments, an antibody described herein comprises one or more human constant regions. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from κ and λ. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region. In some embodiments, an antibody described herein comprises a human IgG constant region, such as an IgG1, IgG2, IgG3, or IgG4. In some embodiments, the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, an antibody described herein comprises a human IgG4 heavy chain constant region. In some such embodiments, an antibody described herein comprises an S241P mutation in the human IgG4 constant region. In some embodiments, an antibody described herein comprises a human IgG4 constant region and a human κ light chain. [0263] In some embodiments, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain at Gly446 and Lys447 (EU numbering). Antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain and/or a cleaved variant of the full-length heavy chain. In some embodiments, the C-terminal lysine, or the C-terminal glycine and lysine, of the Fc region may or may not be present. Thus, a “full-length heavy chain constant region” or a “full length antibody” for example, which is a human IgG1 antibody, includes an IgG1 with both a C-terminal glycine and lysine, without the C-terminal lysine, or without both the C-terminal glycine and lysine. [0264] The choice of heavy chain constant region can determine whether or not an antibody will have effector function in vivo. Such effector function, in some embodiments, includes antibody-dependent cell-mediated cytotoxicity (ADCC) and/or complement-dependent cytotoxicity (CDC), and can result in killing of the cell to which the antibody is bound. In some methods of treatment, including methods of treating some cancers, cell killing may be desirable, for example, when the antibody binds to a cell that supports the maintenance or growth of the tumor. Exemplary cells that may support the maintenance or growth of a tumor include, but are not limited to, tumor cells themselves, cells that aid in the recruitment of vasculature to the tumor, and cells that provide ligands, growth factors, or counter-receptors that support or promote tumor growth or tumor survival. In some embodiments, when effector function is desirable, an antibody comprising a human IgG1 heavy chain or a human IgG3 heavy chain is selected. [0265] In certain embodiments, an antibody provided herein is altered to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed. [0266] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH₂ domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure. In some embodiments, modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibodies with certain improved properties. For example, in some embodiments an antibody may be afucosylated, for example, by mutating residues such as Asn297 that are normally glycosylated with fucose-containing glycosylations, or through other means. In some embodiments, antibodies herein may comprise an afucosylated human IgG1 constant region. [0267] Antibodies are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibodies may have reduced fucosylation and/or improved ADCC function. Examples of such antibodies are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); US Patent No.6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibodies may have improved CDC function. Such antibodies are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). [0268] Antibodies are also provided with amino-terminal leader extensions. For example, one or more amino acid residues of the amino-terminal leader sequence are present at the amino- terminus of any one or more heavy or light chains of an antibody. An exemplary amino- terminal leader extension comprises or consists of three amino acid residues, VHS, present on one or both light chains of an antibody. [0269] The in vivo or serum half-life of human FcRn high affinity binding polypeptides can be assayed, e.g., in transgenic mice, in humans, or in non-human primates to which the polypeptides with a variant Fc region are administered. See also, e.g., Petkova et al. International Immunology 18(12):1759-1769 (2006). [0270] In some embodiments of the invention, an afucosylated antibody mediates ADCC in the presence of human effector cells more effectively than a parent antibody that comprises fucose, Generally, ADCC activity may be determined using the in vitro ADCC assay as herein disclosed, but other assays or methods for determining ADCC activity, e.g. in an animal model etc., are contemplated. [0271] In certain embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320, 322, 330, and/or 331 (EU numbering) can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or the C1 component of complement. This approach is described in further detail in U.S. Patent Nos.5,624,821 and 5,648,260, both by Winter et al. [0272] In some examples, one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C1q binding and/or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Patent Nos.6,194,551 by Idusogie et al. [0273] In some examples, one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351 by Bodmer et al. In some examples, the Fc region can be modified to decrease antibody dependent cellular cytotoxicity (ADCC) and/or to decrease the affinity for an Fcγ receptor by modifying one or more amino acids at the following positions: 234, 235, 236, 238, 239, 240, 241 , 243, 244, 245, 247, 248, 249, 252, 254, 255, 256, 258, 262, 263, 264, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 299, 301, 303, 305, 307, 309, 312, 313, 315, 320, 322, 324, 325, 326, 327, 329, 330, 331, 332, 333, 334, 335, 337, 338, 340, 360, 373, 376, 378, 382, 388, 389, 398, 414, 416, 419, 430, 433, 434, 435, 436, 437, 438 or 439 (EU numbering). Exemplary substitutions include 236A, 239D, 239E, 268D, 267E, 268E, 268F, 324T, 332D, and 332E. Exemplary variants include 239D/332E, 236A/332E, 236A/239D/332E, 268F/324T, 267E/268F, 267E/324T, and 267E/268F7324T (EU numbering). Other Fc modifications that can be made to Fcs are those for reducing or ablating binding to FcγR and/or complement proteins, thereby reducing or ablating Fc- mediated effector functions such as ADCC, ADCP, and CDC. Exemplary modifications include but are not limited substitutions, insertions, and deletions at positions 234, 235, 236, 237, 267, 269, 325, 328, 330, and/or 331 (e.g., 330 and 331), wherein numbering is according to the EU index. Exemplary substitutions include but are not limited to 234A, 235E, 236R, 237A, 267R, 269R, 325L, 328R, 330S, and 331S (e.g., 330S, and 331S), wherein numbering is according to the EU index. An Fc variant can comprise 236R/328R. Other modifications for reducing FcγR and complement interactions include substitutions 297A, 234A, 235A, 237A, 318A, 228P, 236E, 268Q, 309L, 330S, 331 S, 220S, 226S, 229S, 238S, 233P, and 234V, as well as removal of the glycosylation at position 297 by mutational or enzymatic means or by production in organisms such as bacteria that do not glycosylate proteins. These and other modifications are reviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691. For example, the human IgG1.3 Fc constant region contains L234A, L235E, and G237A substitutions. The IgG1fa.P238K (or IgG1.P238K) contains a P238K substitution. The IgG1.1f comprises L234A, L235E, G237A, A330S, and P331S substitutions. (All numbering under the EU index.) [0274] Fc variants that enhance affinity for an inhibitory receptor FcγRIIb can also be used. Such variants can provide an Fc fusion protein with immunomodulatory activities related to FcγRIIb cells, including for example, B cells and monocytes. In one embodiment, the Fc variants provide selectively enhanced affinity to FcγRIIb relative to one or more activating receptors. Modifications for altering binding to FcγRIIb include one or more modifications at a position selected from the group consisting of 234, 235, 236, 237, 239, 266, 267, 268, 325, 326, 327, 328, 330, 331, and 332, according to the EU index. Exemplary substitutions for enhancing FcγRllb affinity include but are not limited to 234A, 234D, 234E, 234F, 234W, 235D, 235E, 235F, 235R, 235Y, 236D, 236N, 237A, 237D, 237N, 239D, 239E, 266M, 267D, 267E, 268D, 268E, 327D, 327E, 328F, 328W, 328Y, 330S, 331S, and 332E. Exemplary substitutions include 235Y, 236D, 239D, 266M, 267E, 268D, 268E, 328F, 328W, and 328Y. Other Fc variants for enhancing binding to FcγRIIb include 235Y/267E, 236D/267E, 239D/268D, 239D/267E, 267E/268D, 267E/268E, and 267E/328F. (All numbering under the EU index.) [0275] Other modifications for enhancing FcγR and complement interactions include but are not limited to substitutions 298 A, 333A, 334A, 326A, 2471, 339D, 339Q, 280H, 290S, 298D, 298V, 243L, 292P, 300L, 396L, 3051, and 396L. These and other modifications are reviewed in Strohl, 2009, Current Opinion in Biotechnology 20:685-691. Fc modifications that increase binding to an Fcγ receptor include amino acid modifications at any one or more of amino acid positions 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 279, 280, 283, 285, 298, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305, 307, 312, 315, 324, 327, 329, 330, 335, 337, 338, 340, 360, 373, 376, 379, 382, 388, 389, 398, 414, 416, 419, 430, 434, 435, 437, 438 or 439 of the Fc region, wherein the numbering of the residues in the Fc region is that of the EU index as in Patent Publication No. WO 00/42072. [0276] Optionally, the Fc region can comprise a non-naturally occurring amino acid residue at additional and/or alternative positions known to one skilled in the art (see, e.g., U.S. Pat. Nos.5,624,821; 6,277,375; 6,737,056; 6,194,551; 7,317,091; 8,101,720; PCX Patent Publications WO 00/42072; WO 01/58957; WO 02/06919; WO 04/016750; WO 04/029207; WO 04/035752; WO 04/074455; WO 04/099249; WO 04/063351; WO 05/070963; WO 05/040217, WO 05/092925 and WO 06/020114). [0277] The affinities and binding properties of an Fc region for its ligand can be determined by a variety of in vitro assay methods (biochemical or immunological based assays) known in the art including but not limited to, equilibrium methods (e.g., enzyme-linked immunoabsorbent assay (ELISA), or radioimmunoassay (RIA)), or kinetics (e.g., BIACORE analysis), and other methods such as indirect binding assays, competitive inhibition assays, fluorescence resonance energy transfer (FRET), gel electrophoresis and chromatography (e.g., gel filtration). These and other methods can utilize a label on one or more of the components being examined and/or employ a variety of detection methods including but not limited to chromogenic, fluorescent, luminescent, or isotopic labels. A detailed description of binding affinities and kinetics can be found in Paul, W. E., ed., Fundamental immunology, 4th Ed., Lippincott-Raven, Philadelphia (1999), which focuses on antibody-immunogen interactions. [0278] In certain embodiments, the antibody is modified to increase its biological half-life. Various approaches are possible. For example, this can be done by increasing the binding affinity of the Fc region for FcRn, For example, one or more of more of following residues can be mutated: 252, 254, 256, 433, 435, 436, as described in U.S. Pat. No.6,277,375. Specific exemplary substitutions include one or more of the following: T252L, T254S, and/or T256F. Alternatively, to increase the biological half life, the antibody can be altered within the CH1 or CL region to contain a salvage receptor binding epitope taken from two loops of a CH₂ domain of an Fc region of an IgG, as described in U.S. Patent Nos.5,869,046 and 6,121,022 by Presta et al. Other exemplary variants that increase binding to FcRn and/or improve pharmacokinetic properties include substitutions at positions 259, 308, 428, and 434, including for example 2591, 308F, 428L, 428M, 434S, 43411.434F, 434Y, and 434X1. Other variants that increase Fc binding to FcRn include: 250E, 250Q, 428 L, 428F, 250Q/428L (Hinton et al.2004, J. Biol. Chem.279(8): 6213-6216, Hinton et al.2006 Journal of Immunology 176:346-356), 256A, 272A, 286A, 305A, 307A, 307Q, 311A, 312A, 376A, 378Q, 380A, 382A, 434A (Shields et al., Journal of Biological Chemistry, 2001, 276(9):6591-6604), 252F, 252T, 252Y, 252W, 254T, 256S, 256R, 256Q, 256E, 256D, 256T, 309P, 311 S, 433R, 433S, 4331, 433P, 433Q, 434H, 434F, 434Y, 252Y/254T/256E, 433K/434F/436H, 308T/309P/311S (Dall’Acqua et al. Journal of Immunology, 2002, 169:5171-5180, Dal’Acqua et al., 2006, Journal of Biological Chemistry 281:23514-23524). Other modifications for modulating FcRn binding are described in Yeung et al., 2010, J Immunol, 182:7663-7671. [0279] In certain embodiments, hybrid IgG isotypes with particular biological characteristics can be used. For example, an IgG1/IgG3 hybrid variant can be constructed by substituting IgG1 positions in the CH₂ and/or CH₃ region with the amino acids from IgG3 at positions where the two isotypes differ. Thus a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., 274Q, 276K, 300F, 339T, 356E, 358M, 384S, 392N, 397M, 4221, 435R, and 436F. In some embodiments described herein, an IgG1/IgG2 hybrid variant can be constructed by substituting IgG2 positions in the CH₂ and/or CH₃ region with amino acids from IgG1 at positions where the two isotypes differ. Thus a hybrid variant IgG antibody can be constructed that comprises one or more substitutions, e.g., one or more of the following amino acid substitutions: 233E, 234L, 235L, +236G (referring to an insertion of a glycine at position 236), and 327A. [0280] Moreover, the binding sites on human IgG1 for FcγRI, FcγRII, FcγRIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R.L. et al. (2001) J. Biol. Chem.276:6591-6604). Specific mutations at positions 256, 290, 298, 333, 334 and 339 were shown to improve binding to FcγRIII. Additionally, the following combination mutants were shown to improve FcγRIII binding: T256A/S298A, S298A/E333A, S298A/K224A and S298A/E333A/K334A, which has been shown to exhibit enhanced FcγRIIIa binding and ADCC activity (Shields et al., 2001). Other IgG1 variants with strongly enhanced binding to FcγRIIIa have been identified, including variants with S239D/I332E and S239D/I332E/A330L mutations which showed the greatest increase in affinity for FcγRIIIa, a decrease in FcγRIIb binding, and strong cytotoxic activity in cynomolgus monkeys (Lazar et al., 2006). Introduction of the triple mutations into antibodies such as alemtuzumab (CD52-specific), trastuzumab (HER2/neu-specific), rituximab (CD20- specific), and cetuximab (EGFR- specific) translated into greatly enhanced ADCC activity in vitro, and the S239D/I332E variant showed an enhanced capacity to deplete B cells in monkeys (Lazar et al., 2006). In addition, IgG1 mutants containing L235V, F243L, R292P, Y300L and P396L mutations which exhibited enhanced binding to FcγRIIIa and concomitantly enhanced ADCC activity in transgenic mice expressing human FcγRIIIa in models of B cell malignancies and breast cancer have been identified (Stavenhagen et al., 2007; Nordstrom et al., 2011). Other Fc mutants that can be used include: S298A/E333A/L334A, S239D/I332E, S239D/I332E/A330L, L235V/F243L/R292P/Y300L/ P396L, and M428L/N434S. [0281] In certain embodiments, an Fc is chosen that has reduced binding to FcγRs. An exemplary Fc, e.g., IgG1 Fc, with reduced FcγR binding comprises the following three amino acid substitutions: L234A, L235E and G237A. [0282] In certain embodiments, an Fc is chosen that has reduced complement fixation. An exemplary Fc, e.g., IgG1 Fc, with reduced complement fixation has the following two amino acid substitutions: A330S and P331S. [0283] In certain embodiments, an Fc is chosen that has essentially no effector function, i.e., it has reduced binding to FcγRs and reduced complement fixation. An exemplary Fc, e.g., IgG1 Fc, that is effectorless comprises the following five mutations: L234A, L235E, G237A, A330S and P331S. [0284] When using an IgG4 constant domain, it can include the substitution S228P, which mimics the hinge sequence in IgG1 and thereby stabilizes IgG4 molecules. Fc modifications described in WO 2017/087678 or WO2016081746 may also be used. [0285] In certain embodiments, the glycosylation of an antibody is modified. For example, an aglycoslated antibody can be made (i.e., the antibody lacks glycosylation). Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen. Such carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence. For example, one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site. Such aglycosylation can increase the affinity of the antibody for antigen. Such an approach is described in further detail in U.S. Patent Nos.5,714,350 and 6,350,861 by Co et al. [0286] Glycosylation of the constant region on N297 can be prevented by mutating the N297 residue to another residue, e.g., N297A, and/or by mutating an adjacent amino acid, e.g., 298 to thereby reduce glycosylation on N297. [0287] Additionally or alternatively, an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures. Such altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies. Such carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies described herein to thereby produce an antibody with altered glycosylation. For example, EP 1,176,195 by Hanai et al. describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation. PCT Publication WO 03/035835 by Presta describes a variant CHO cell line, Led 3 cells, with reduced ability to attach fucose to Asn(297)-linked carbohydrates, also resulting in hypofucosylation of antibodies expressed in that host cell (see also Shields, R.L. et al. (2002) J. Biol. Chem.277:26733-26740). PCT Publication WO 99/54342 by Umana et al. describes cell lines engineered to express glycoprotein-modifying glycosyl transferases {e.g., beta(l,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech.17: 176-180). [0288] Another modification of the antibodies described herein is pegylation. An antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. To pegylate an antibody, the antibody, or fragment thereof, typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment. In some embodiments, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term “polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (CI-CIO) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide. In certain embodiments, the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies described herein. See for example, EP 0154316 by Nishimura et al. and EP 0401384 by Ishikawa et al. IV. Nucleic Acid Molecules Encoding Anti-CD33 Antibodies [0289] Nucleic acid molecules comprising polynucleotides that encode one or more chains of anti-CD33 antibodies described herein are provided. In some embodiments, a nucleic acid molecule comprises a polynucleotide that encodes a heavy chain or a light chain of an anti- CD33 antibody. In some embodiments, provided is an isolated nucleic acid encoding any one of the anti-CD33 antibodies provided herein. In some embodiments, a nucleic acid molecule comprises both a polynucleotide that encodes a heavy chain and a polynucleotide that encodes a light chain, of an anti-CD33 antibody. In some embodiments, a first nucleic acid molecule comprises a first polynucleotide that encodes a heavy chain and a second nucleic acid molecule comprises a second polynucleotide that encodes a light chain. [0290] In some such embodiments, the heavy chain and the light chain are expressed from one nucleic acid molecule, or from two separate nucleic acid molecules, as two separate polypeptides. In some embodiments, such as when an antibody is an scFv, a single polynucleotide encodes a single polypeptide comprising both a heavy chain and a light chain linked together. [0291] In some embodiments, a polynucleotide encoding a heavy chain or light chain of an anti-CD33 antibody comprises a nucleotide sequence that encodes a leader sequence, which, when translated, is located at the N terminus of the heavy chain or light chain. The leader sequence may be the native heavy or light chain leader sequence, or may be another heterologous leader sequence. [0292] Nucleic acid molecules may be constructed using recombinant DNA techniques conventional in the art. In some embodiments, a nucleic acid molecule is an expression vector that is suitable for expression in a selected host cell. V. Anti-CD33 Antibody Expression and Production A. Vectors [0293] Vectors comprising polynucleotides that encode anti-CD33 heavy chains and/or anti- CD33 light chains are provided. In some embodiments, provided herein is a vector comprising a nucleic acid encoding any one of the anti-CD33 antibodies described herein. Vectors comprising polynucleotides that encode anti-CD33 heavy chains and/or anti-CD33 light chains are also provided. Such vectors include, but are not limited to, DNA vectors, RNA vectors (e.g, mRNA and circular RNA, self-amplifying RNA vectors, etc.), phage vectors, viral vectors (e.g., pox virus vectors, vaccinia virus vectors, adenovirus vectors, modified vaccinia virus Ankara (MVA) vectors, etc.), retroviral vectors, etc. In some embodiments, a vector comprises a first polynucleotide sequence encoding a heavy chain and a second polynucleotide sequence encoding a light chain. In some embodiments, the heavy chain and light chain are expressed from the vector as two separate polypeptides. In some embodiments, the heavy chain and light chain are expressed as part of a single polypeptide, such as, for example, when the antibody is an scFv. [0294] In some embodiments, a first vector comprises a polynucleotide that encodes a heavy chain and a second vector comprises a polynucleotide that encodes a light chain. In some embodiments, the first vector and second vector are transfected into host cells in similar amounts (such as similar molar amounts or similar mass amounts). In some embodiments, a mole- or mass-ratio of between 5:1 and 1:5 of the first vector and the second vector is transfected into host cells. In some embodiments, a mass ratio of between 1:1 and 1:5 for the vector encoding the heavy chain and the vector encoding the light chain is used. In some embodiments, a mass ratio of 1:2 for the vector encoding the heavy chain and the vector encoding the light chain is used. [0295] In some embodiments, a vector is selected that is optimized for expression of polypeptides in CHO or CHO-derived cells, or in NSO cells. Exemplary such vectors are described, e.g., in Running Deer et al., Biotechnol. Prog.20:880-889 (2004). [0296] In some embodiments, a vector is chosen for in vivo expression anti-CD33 heavy chains and/or anti-CD33 light chains in animals, including humans. In some such embodiments, expression of the polypeptide is under the control of a promoter that functions in a tissue-specific manner. For example, liver-specific promoters are described, e.g., in PCT Publication No. WO 2006/076288. B. Host Cells [0297] In various embodiments, anti-CD33 heavy chains and/or anti-CD33 light chains may be expressed in prokaryotic cells, such as bacterial cells; or in eukaryotic cells, such as fungal cells (such as yeast), plant cells, insect cells, and mammalian cells. Such expression may be carried out, for example, according to procedures known in the art. In some embodiments, provided herein are host cells comprising an isolated nucleic acid encoding any one of the anti-CD33 antibodies described herein. In some embodiments, provided herein are host cells comprising a vector comprising a nucleic acid encoding any one of the anti-CD33 antibodies described herein. In some embodiments, provided herein is a host cell that produces any one of the anti-CD33 antibodies described herein. Exemplary eukaryotic cells that may be used to express polypeptides include, but are not limited to, COS cells, including COS 7 cells; 293 cells, including 293-6E cells; CHO cells, including CHO-S and DG44 cells; PER.C₆® cells (Crucell); and NSO cells. In some embodiments, anti-CD33 heavy chains and/or anti-CD33 light chains may be expressed in yeast. See, e.g., U.S. Publication No. US 2006/0270045 A1. In some embodiments, a particular eukaryotic host cell is selected based on its ability to make desired post-translational modifications to the anti-CD33 heavy chains and/or anti-CD33 light chains. For example, in some embodiments, CHO cells produce polypeptides that have a higher level of sialylation than the same polypeptide produced in 293 cells. [0298] Introduction of one or more nucleic acids into a desired host cell may be accomplished by any method, including but not limited to, calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, etc. Nonlimiting exemplary methods are described, e.g., in Sambrook et al., Molecular Cloning, A Laboratory Manual, 3^rd ed. Cold Spring Harbor Laboratory Press (2001). Nucleic acids may be transiently or stably transfected in the desired host cells, according to any suitable method. [0299] In some embodiments, one or more polypeptides may be produced in vivo in an animal that has been engineered or transfected with one or more nucleic acid molecules encoding the polypeptides, according to any suitable method. [0300] In some embodiments, provided herein is a method for making an anti-CD33 antibody described herein, comprising culturing a host cell described herein under conditions suitable for expression of the antibody. In some embodiments, the method further comprises recovering the antibody produced by the host cell. C. Purification of Anti-CD33 Antibodies [0301] Anti-CD33 antibodies may be purified by any suitable method. Such methods include, but are not limited to, the use of affinity matrices or hydrophobic interaction chromatography or size exclusion chromatography. D. Cell-free Production of Anti-CD33 Antibodies [0302] In some embodiments, an anti-CD33 antibody is produced in a cell-free system. Nonlimiting exemplary cell-free systems are described, e.g., in Sitaraman et al., Methods Mol. Biol.498: 229-44 (2009); Spirin, Trends Biotechnol.22: 538-45 (2004); Endo et al., Biotechnol. Adv.21: 695-713 (2003). VI. Exemplary Linker-Drug Compounds and Antibody-Drug Conjugates A. Exemplary Linker-Drug Compounds [0303] In one aspect, provided herein is a compound of Formula (I'):

, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR¹¹; R¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl or a 3 to 6 membered cycloalkyl; R^2a and R^2b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; or R^2a and R^2b, taken together, form oxo; R³ is independently selected from hydrogen, halogen, -OR¹¹, -N(R¹¹R¹¹), -NHR¹¹, - C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, - N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^4a and R^4b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -NHR¹¹ or –OR¹¹; R⁵ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁶ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; wherein two R⁵ and R⁶ substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R¹¹ substituents; R⁷ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C₂-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2,

S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^8a and R^8b are each independently selected from hydrogen, halogen or a -C₁-C₆ alkyl, optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁹ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2, -C(=O)NH(R¹¹), -C(=O)N(R¹¹R¹¹), -S(O)₂R¹¹, -S(=O)R¹¹, -SR¹¹, -S(=O)₂NH₂, - S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C₆ alkoxyalkyl, oxo, hydroxyl or -C₁-C₆ alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C₂- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)₂-, -S(=O)-, -S-, -S(=O)₂N(R¹¹)-, - S(=O)₂N(H)(C₁-C₆ alkylene)-, or -S(=O)₂N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L' is a linker; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. [0304] In another aspect, provided herein is a compound of Formula (II’):

, or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkoxy, C₁-C₆ haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)_n- or -O(CH₂)_n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker. [0305] In some embodiments, A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. In a particular embodiment, A and B are each phenylene. In other embodiments, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. In a particular embodiment, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene. [0306] In some embodiments, b is 0. In a particular embodiment, b is 0 and X is O. In other embodiments, b is 1. In a particular embodiment, b is 1 and X is O. In another particular embodiment, b is 1 and X is N(H) or N(CH₃). In another particular embodiment, b is 1 and X is N(CH₃). [0307] In some embodiments, c is 1. In a particular embodiment, c is 1 and R⁹ is fluoro, chloro, C₁-C3 alkyl, C₁-C3 alkoxy, C₁-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In another embodiment, c is 0. [0308] In some embodiments, d is 1. In a particular embodiment, d is 1 and R⁷ is fluoro, chloro, or methyl. In another embodiment, d is 0. [0309] In some embodiments, e is 1. In a particular embodiment, e is 1 and R³ is fluoro. In another embodiment, e is 0. [0310] In some embodiments, R¹ hydrogen, halogen, or C₁-C₆ alkyl. In some embodiments, R¹ is hydrogen or methyl. In a particular embodiment, R¹ is hydrogen. [0311] In some embodiments, R^2a is hydrogen. In some embodiments, R^2b is hydrogen. In a particular embodiment, R^2a and R^2b are each hydrogen. [0312] In some embodiments, R³ is hydrogen or fluoro. In a particular embodiment, R³ is hydrogen. [0313] In some embodiments, X¹ and X² are C(R⁷); or X¹ is C(R⁷) and X² is N; or X¹ and X² are N. In a particular embodiment, X¹ and X² are C(R⁷). In another particular embodiment, X¹ is C(R⁷) and X² is N. In another particular embodiment, X¹ is N and X² is C(R⁷). In another particular embodiment, X¹ and X² are N. [0314] In some embodiments, each R⁷ is independently hydrogen, fluoro, chloro, or methyl. In a particular embodiment, each R⁷ is hydrogen. In another particular embodiment, each R⁷ is independently fluoro, chloro, or methyl. [0315] In some embodiments, X³, X⁴, and X⁵ are C(R⁹); or X³ and X⁵ are N and X⁴ is C(R⁹); or X³ and X⁴ are N and X⁵ is C(R⁹); or X³ is N and X⁴ and X⁵ are C(R⁹); or X³ and X⁵ are C(R⁹) and X⁴ is N. In a particular embodiment, X³, X⁴, and X⁵ are C(R⁹). In another particular embodiment, X³ and X⁵ are N and X⁴ is C(R⁹). In yet another particular embodiment, X³ and X⁴ are N and X⁵ is C(R⁹). In some embodiments, one of X³, X⁴, and X⁵ is N and the remaining are C(R⁹). In a particular embodiment, X³ is N and X⁴ and X⁵ are C(R⁹). [0316] In some embodiments, each R⁹ is independently hydrogen, fluoro, chloro, C₁-C₃ alkyl, C₁-C3 alkoxy, C₁-C3 haloalkoxy, C₁-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In a particular embodiment, each R⁹ is hydrogen. In some embodiments, each R⁹ is independently fluoro, chloro, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, C₁- C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. [0317] In some embodiments, Z is *-N(H)(CH₂)_n- or *-O(CH₂)_n-, and * indicates the point of attachment of Z to L. In a particular embodiment, Z is *-N(H)(CH₂)n-. In a more particular embodiment, Z is *-N(H)CH₂-. [0318] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0 or 1. In a particular embodiment, n is 0. In another particular embodiment, n is 1. [0319] In some embodiments,

, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L³ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²³-, -O-, -NR²³-, -(PEG)_mC(O)NR²³-, -C(O)NR²³(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²³ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)_mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²³ is C₁-C₆ alkylene, the alkylene is point of attachment of L³ to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0320] In some embodiments, AA is glycine. In some embodiments, AA is glutamic acid. [0321] In some embodiments, L³ is 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2. In some embodiments, L³ is a 1-25 membered aliphatic comprising -(PEG)_m-, -(PEG)_mC(O)NR²³-, or -C(O)NR²³(PEG)_m-, and further optionally comprising -C(O)NR²³-, -O-, or -NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂. In some embodiments, L³ is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂. [0322] In a particular embodiment,

wherein: X⁶ is C(R²⁴) or N; X⁷ is C(R²⁵) or N; R²⁴ is hydrogen or hydroxy; R²⁵ is hydrogen, hydroxy, or -O(CH₂CH₂O)₇CH₃; and R²⁶ is -C(O)(CH₂CH₂O)8-12CH₃.

, wherein: R²⁰ is hydrogen

Arg is arginine; Lys is lysine; Glu is glutamine; L¹ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)mC(O)NR²¹-, -C(O)NR²¹(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)_mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L¹ to -C(O)-(Glu)_r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)_mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10. [0324] In some embodiments, L¹ is a 1-25 membered aliphatic optionally comprising -C(O)NR²¹-, -(PEG)_mC(O)NR²¹-, or -C(O)NR²¹(PEG)_m-. In a more particular embodiment, L¹ is C₁-C₆ alkyl. [0325] In some embodiments, r is 0. In some embodiments, r is 1. [0326] In some embodiments, p is an integer from 5 to 10. In a particular embodiment, p is 8. [0327] In a particular embodiment,

is:

wherein: L² is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)mC(O)NR²¹-, -C(O)NR²¹(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)_mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L² to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)_mCH_3; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; and R²² is an -O-linked sugar acid. [0329] In some embodiments, the sugar acid is glucuronic acid. [0330] In some embodiments, L² is a 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR²¹-. [0331] In some embodiments, each R²¹ is independently hydrogen, C₁-C₆ alkyl, or - (CH₂CH₂O)mCH₃. [0332] In a particular embodiment,

, . [0334] In some embodiments,

, wherein: Ala is alanine; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0335] In some embodiments, the aliphatic of L¹, L², and/or L³ is a linear or branched aliphatic chain. In some embodiments, the aliphatic of L¹, L², and/or L³ comprises a 3 to 8 membered cycloalkyl. In some embodiments, the aliphatic of L¹, L², and/or L³ comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl. [0336] In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-15 membered. In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-10 membered. In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-5 membered. [0337] In some embodiments, m is an integer from 2 to 24. In some embodiments, m is an integer from 4 to 24. In some embodiments, m is an integer from 8 to 24. In some embodiments, m is an integer from 12 to 24. In some embodiments, m is an integer from 4 to 12. In some embodiments, m is an integer from 8 to 12. [0338] In some embodiments, Cy is piperidinylene, piperazinylene, 2,5- diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃. [0339] In some embodiments, L⁴ is absent. In some embodiments, L⁴ is absent, and Z is *-N(H)(CH₂)_n-. In a particular embodiment, L⁴ is absent, and Z is *-N(H)(CH₂)-. In other embodiments, L⁴ is **-CH₂-N(R⁴⁰)-, **-C(O)CH₂CH₂N(R⁴⁰)-, or **- CH₂-N(R⁴⁰)C(O)CH₂N(R⁴⁰)-. In some embodiments, L⁴ is **-CH₂-N(R⁴⁰)-, **- C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂-N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, and Z is *-O(CH₂)_n-. In a particular embodiment, L⁴ is **-CH₂-N(R⁴⁰)-, **-C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂- N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, and Z is *-O(CH₂)-. [0340] In some embodiments, R⁴⁰ is hydrogen or methyl. In a particular embodiment, R⁴⁰ is hydrogen. [0341] In yet another aspect, provided herein is a compound of Formula (III’):

or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein for a compound of Formula (I’) or (II’), or any embodiment of the foregoing. [0342] In another aspect, provided herein is a compound of Formula (IV’):

, or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein for a compound of Formula (I’) or (II’), or any embodiment of the foregoing. [0343] Examples of GSPT1-degrading compound include the compounds in Table A, or a pharmaceutically acceptable salt thereof. Table A. Exemplary Linker-Payloads (LPs)

[0344] In some embodiments, provided herein is a compound selected from:

,

,

B. Exemplary Antibody-Drug Conjugates [0345] The anti-CD33 antibodies described herein may be included in an antibody-drug conjugate. An antibody-drug conjugate typically comprises three components: Antibody, Payload, and Linker. In some embodiments, the Antibody targets the ADC to a particular cell type and may also elicit a therapeutic response, the Payload elicits a desired therapeutic response, and the Linker attaches the Payload to the Antibody. Often, the Payload is coupled via the Linker to an Antibody that specifically targets a certain tumor antigen (e.g., a protein that is expressed at higher levels on tumor cells compared to normal cells). In some embodiments, an antibody binds its antigen on the surface of a cell, such as a cancer cell, and the ADC is internalized by the cell. In some such embodiments, after the ADC is internalized, the Payload elicits the desired therapeutic response, for example, in the case of a Payload which is an anticancer agent, the Payload inhibits the expansion of, or kills, the cancer cell. [0346] In some embodiments, the Payload is an anticancer drug, such as any of the anticancer drugs described herein in connection with combination therapy. In certain embodiments, the Payload is a GSPT1-degrading compound. [0347] Thus, in some embodiments, an antibody-drug conjugate comprising an anti-CD33 antibody provided herein, a GSPT1-degrading compound described herein (e.g., any of Examples 1-79), and a linker that attaches the GSPT1-degrading compound to the anti-CD33 antibody, is provided. In some embodiments, provided herein is an antibody-drug conjugate comprising an anti-CD33 antibody provided herein and a GSPT1-degrader-linker compound described herein (e.g., any of Examples LP1-78). [0348] In one aspect, provided herein is an antibody-drug conjugate of Formula (I"):

S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹,

-NHR¹¹ or –OR¹¹; R^8a and R^8b are each independently selected from hydrogen, halogen or a -C₁-C₆ alkyl, optionally substituted with –R¹¹,

-NHR¹¹ or –OR¹¹; R⁹ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2,

S(=O)2NH(C₁-C₆ alkyl), or -S(=O)2N(C₁-C₆ alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹,

-NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C6 ^{alkoxyalkyl, oxo, hydroxyl or -C}1^-C6 ^alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C₂- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R¹¹)-, - S(=O)₂N(H)(C₁-C₆ alkylene)-, or -S(=O)₂N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. [0349] In another aspect, provided herein is an antibody-drug conjugate of Formula (II"):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together with the carbon atom to which they are attached, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkoxy, C₁-C₆ haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)n- or -O(CH₂)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; and b is 0 or 1. [0350] In some embodiments, A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. In a particular embodiment, A and B are each phenylene. In other embodiments, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. In a particular embodiment, A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene. [0351] In some embodiments, b is 0. In a particular embodiment, b is 0 and X is O. In other embodiments, b is 1. In a particular embodiment, b is 1 and X is O. In another particular embodiment, b is 1 and X is N(H) or N(CH₃). In another particular embodiment, b is 1 and X is N(CH₃). [0352] In some embodiments, c is 1. In a particular embodiment, c is 1 and R⁹ is fluoro, chloro, C₁-C3 alkyl, C₁-C3 alkoxy, C₁-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In another embodiment, c is 0. [0353] In some embodiments, d is 1. In a particular embodiment, d is 1 and R⁷ is fluoro, chloro, or methyl. In another embodiment, d is 0. [0354] In some embodiments, e is 1. In a particular embodiment, e is 1 and R³ is fluoro. In another embodiment, e is 0. [0355] In some embodiments, R¹ hydrogen, halogen, or C₁-C₆ alkyl. In some embodiments, R¹ is hydrogen or methyl. In a particular embodiment, R¹ is hydrogen. [0356] In some embodiments, R^2a is hydrogen. In some embodiments, R^2b is hydrogen. In a particular embodiment, R^2a and R^2b are each hydrogen. [0357] In some embodiments, R³ is hydrogen or fluoro. In a particular embodiment, R³ is hydrogen. [0358] In some embodiments, X¹ and X² are C(R⁷); or X¹ is C(R⁷) and X² is N; or X¹ and X² are N. In a particular embodiment, X¹ and X² are C(R⁷). In another particular embodiment, X¹ is C(R⁷) and X² is N. In another particular embodiment, X¹ is N and X² is C(R⁷). In another particular embodiment, X¹ and X² are N. [0359] In some embodiments, each R⁷ is independently hydrogen, fluoro, chloro, or methyl. In a particular embodiment, each R⁷ is hydrogen. In another particular embodiment, each R⁷ is independently fluoro, chloro, or methyl. [0360] In some embodiments, X³, X⁴, and X⁵ are C(R⁹); or X³ and X⁵ are N and X⁴ is C(R⁹); or X³ and X⁴ are N and X⁵ is C(R⁹); or X³ is N and X⁴ and X⁵ are C(R⁹); or X³ and X⁵ are C(R⁹) and X⁴ is N. In a particular embodiment, X³, X⁴, and X⁵ are C(R⁹). In another particular embodiment, X³ and X⁵ are N and X⁴ is C(R⁹). In yet another particular embodiment, X³ and X⁴ are N and X⁵ is C(R⁹). In some embodiments, one of X³, X⁴, and X⁵ is N and the remaining are C(R⁹). In a particular embodiment, X³ is N and X⁴ and X⁵ are C(R⁹). [0361] In some embodiments, each R⁹ is independently hydrogen, fluoro, chloro, C₁-C3 alkyl, C₁-C3 alkoxy, C₁-C3 haloalkoxy, C₁-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. In a particular embodiment, each R⁹ is hydrogen. In some embodiments, each R⁹ is independently fluoro, chloro, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁-C₃ haloalkoxy, C₁- C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. [0362] In some embodiments, Z is *-N(H)(CH₂)_n- or *-O(CH₂)_n-, and * indicates the point of attachment of Z to L. In a particular embodiment, Z is *-N(H)(CH₂)_n-. In a more particular embodiment, Z is *-N(H)CH₂-. [0363] In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0 or 1. In a particular embodiment, n is 0. In another particular embodiment, n is 1. [0364] In some embodiments, L comprises

, wherein

indicates point of attachment to Ab. [0365] For example, in some embodiments, L is , wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L³ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²³-, -O-, -NR²³-, -(PEG)_mC(O)NR²³-, -C(O)NR²³(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²³ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²³ is C₁-C₆ alkylene, the alkylene is point of attachment of L³ to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0366] In some embodiments, AA is glycine. In some embodiments, AA is glutamic acid. [0367] In some embodiments, L³ is 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂. In some embodiments, L³ is a 1-25 membered aliphatic comprising -(PEG)_m-, -(PEG)_mC(O)NR²³-, or -C(O)NR²³(PEG)_m-, and further optionally comprising -C(O)NR²³-, -O-, or -NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂. In some embodiments, L³ is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂. [0368] In a particular embodiment,

, wherein: X⁶ is C(R²⁴) or N; X⁷ is C(R²⁵) or N; R²⁴ is hydrogen or hydroxy; R²⁵ is hydrogen, hydroxy, or -O(CH₂CH₂O)7CH₃; and R²⁶ is -C(O)(CH₂CH₂O)8-12CH₃. [0369] In some embodiments,

wherein: R²⁰ is hydrogen

Arg is arginine; Lys is lysine; Glu is glutamine; L¹ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)_mC(O)NR²¹-, -C(O)NR²¹(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L¹ to -C(O)-(Glu)_r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10. [0370] In some embodiments, L¹ is a 1-25 membered aliphatic optionally comprising -C(O)NR²¹-, -(PEG)_mC(O)NR²¹-, or -C(O)NR²¹(PEG)_m-. In a more particular embodiment, L¹ is C₁-C₆ alkyl. [0371] In some embodiments, r is 0. In some embodiments, r is 1. [0372] In some embodiments, p is an integer from 5 to 10. In a particular embodiment, p is 8.

attachment to Ab. [0374] In some embodiments,

, wherein: L² is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)_mC(O)NR²¹-, -C(O)NR²¹(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)_mCH₃, or -CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L² to phenylene; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; and R²² is an -O-linked sugar acid. [0375] In some embodiments, the sugar acid is glucuronic acid. [0376] In some embodiments, L² is a 1-25 membered aliphatic optionally comprising 1 or 2 - C(O)NR²¹-. [0377] In some embodiments, each R²¹ is independently hydrogen, C₁-C₆ alkyl, or - (CH₂CH₂O)_mCH₃. [0378] In a particular embodiment, L is:

_{attachment to Ab.} [0379] In some embodiments,

, _{wherein indicates point of attachment to Ab.} [0380] In some embodiments,

, wherein: indicates point of attachment to Ab; Ala is alanine; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0381] In some embodiments, the aliphatic of L¹, L², and/or L³ is a linear or branched aliphatic chain. In some embodiments, the aliphatic of L¹, L², and/or L³ comprises a 3 to 8 membered cycloalkyl. In some embodiments, the aliphatic of L¹, L², and/or L³ comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl. [0382] In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-15 membered. In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-10 membered. In some embodiments, the aliphatic of L¹, L², and/or L³ is 1-5 membered. [0383] In some embodiments, m is an integer from 2 to 24. In some embodiments, m is an integer from 4 to 24. In some embodiments, m is an integer from 8 to 24. In some embodiments, m is an integer from 12 to 24. In some embodiments, m is an integer from 4 to 12. In some embodiments, m is an integer from 8 to 12. [0384] In some embodiments, Cy is piperidinylene, piperazinylene, 2,5- diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)_mCH₃. [0385] In some embodiments, L⁴ is absent. In some embodiments, L⁴ is absent, and Z is *- N(H)(CH₂)n-. In a particular embodiment, L⁴ is absent, and Z is *-N(H)(CH₂)-. In other embodiments, L⁴ is **-CH₂-N(R⁴⁰)-, **-C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂- N(R⁴⁰)C(O)CH₂N(R⁴⁰)-. In some embodiments, L⁴ is **-CH₂-N(R⁴⁰)-, **- C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂-N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, and Z is *-O(CH₂)n-. In a particular embodiment, L⁴ is **-CH₂-N(R⁴⁰)-, **-C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂- N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, and Z is *-O(CH₂)-. [0386] In some embodiments, R⁴⁰ is hydrogen or methyl. In a particular embodiment, R⁴⁰ is hydrogen. [0387] In some embodiments, the antibody or antigen-binding portion thereof binds CD33. In some embodiments, the antibody or antigen-binding portion thereof is an antibody or antigen- binding portion thereof described herein. [0388] In some embodiments, a is 1-20, or 1-15, or 1-12, or 1-10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10. In some embodiments, a is 1-4. In some embodiments, a is 1-3. In some embodiments, a is 1-2. [0389] In yet another aspect, provided herein is an antibody-drug conjugate of Formula III”:

, or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein with respect to Formula I" or II", or any embodiment of the foregoing. [0390] In another aspect, provided herein is an antibody-drug conjugate of Formula IV":

or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein with respect to Formula I" or II", or any embodiment of the foregoing. [0391] Another aspect provides a compound of Formula V":

, or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., R¹, R^2a, R^2b, R³, R⁷, R⁹, L³, Ab, a) are as described herein with respect to Formula I" or II", or any embodiment of the foregoing. [0392] Nonlimiting examples of antibody-drug conjugates are described herein. For example, provided in an aspect is an antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in yet another aspect is an antibody drug conjugate of the following formula:

or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. Provided in another aspect is an antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein values for variables (e.g., a, Ab) are as described herein. [0393] In some embodiments, a is 1-20. In some embodiments, a is 1-15, or 1-12, or 1-10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10. In some embodiments, a is 6-10. [0394] In some embodiments, Ab is an antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding portion thereof binds CD33. In some embodiments, the antibody or antigen-binding portion thereof binds CD33 and is any of the antibodies or antigen-binding portions thereof described herein. In a particular embodiment, Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0395] In another particular embodiment: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0396] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 69 may be replaced with a pyroglutamic acid (pE). [0397] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 83 may be replaced with a pyroglutamic acid (pE). [0398] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0399] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0400] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 71 may be replaced with a pyroglutamic acid (pE). [0401] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 85 may be replaced with a pyroglutamic acid (pE). [0402] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0403] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE). [0404] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0405] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE). [0406] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0407] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0408] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0409] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88. [0410] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78. [0411] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92. [0412] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78. [0413] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92. [0414] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79. [0415] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93. [0416] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80. [0417] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94. [0418] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81. [0419] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95. [0420] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82. [0421] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96. VII. Therapeutic Compositions and Methods A. Methods of Treating Diseases [0422] In one embodiment, provided herein is a method of treating and/or preventing cancer, which comprises administering to a patient a compound, antibody, or antibody-drug conjugate provided herein. [0423] In another embodiment, provided herein is method of managing cancer, which comprises administering to a patient a compound, antibody, or antibody-drug conjugate provided herein. [0424] Also provided herein are methods of treating patients who have been previously treated for cancer but are non-responsive to standard therapies, as well as those who have not previously been treated. Also encompassed are methods of treating patients regardless of patient's age, although some diseases or disorders are more common in certain age groups. Further encompassed are methods of treating patients who have undergone surgery in an attempt to treat the disease or condition at issue, as well as those who have not. Because patients with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a patient may vary, depending on his/her prognosis. The skilled clinician will be able to readily determine without undue experimentation specific secondary agents, types of surgery, and types of non-drug based standard therapy that can be effectively used to treat an individual patient with cancer. [0425] As used herein, the term “cancer” includes, but is not limited to, solid tumors and blood borne tumors. The term “cancer” refers to disease of skin tissues, organs, blood, and vessels, including, but not limited to, cancers of the bladder, bone, blood, brain, breast, cervix, chest, colon, endometrium, esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth, neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat, and uterus. Specific cancers include, but are not limited to, advanced malignancy, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforms, glioblastoma, brain stem glioma, poor prognosis malignant brain tumor, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D colorectal cancer, unresectable colorectal carcinoma, metastatic hepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma, malignant melanoma, malignant mesothelioma, malignant pleural effusion mesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressive, hormone refractory prostate cancer, resected high-risk soft tissue sarcoma, unresectable hepatocellular carcinoma, Waldenstrom's macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen independent prostate cancer, androgen dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, urachal cancer, papillary thyroid carcinoma, follicular thyroid carcinoma, medullary thyroid carcinoma, and leiomyoma. [0426] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the solid tumor is metastatic. In certain embodiments, the solid tumor is drug-resistant. In certain embodiments, the solid tumor is hepatocellular carcinoma, prostate cancer, ovarian cancer, or glioblastoma. [0427] In certain embodiments, the cancer is a blood borne tumor. In certain embodiments, the blood borne tumor is metastatic. In certain embodiments, the blood borne tumor is drug resistant. In certain embodiments, the cancer is leukemia. [0428] In one embodiment, methods provided herein encompass treating, preventing or managing various types of leukemias such as chronic lymphocytic leukemia (CLL), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and acute myeloblastic leukemia (AML) by administering a therapeutically effective amount of a compound, antibody, or antibody-drug conjugate provided herein. [0429] In some embodiments, the methods provided herein encompass treating, preventing or managing acute leukemia in a subject. In some embodiments, the acute leukemia is acute myeloid leukemia (AML), which includes, but is not limited to, undifferentiated AML (M0), myeloblastic leukemia (M1), myeloblastic leukemia (M2), promyelocytic leukemia (M3 or M3 variant [M3V]), myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]), monocytic leukemia (M5), erythroleukemia (M6), and megakaryoblastic leukemia (M7). In one embodiment, the acute myeloid leukemia is undifferentiated AML (M0). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M1). In one embodiment, the acute myeloid leukemia is myeloblastic leukemia (M2). In one embodiment, the acute myeloid leukemia is promyelocytic leukemia (M3 or M3 variant [M3V]). In one embodiment, the acute myeloid leukemia is myelomonocytic leukemia (M4 or M4 variant with eosinophilia [M4E]). In one embodiment, the acute myeloid leukemia is monocytic leukemia (M5). In one embodiment, the acute myeloid leukemia is erythroleukemia (M6). In one embodiment, the acute myeloid leukemia is megakaryoblastic leukemia (M7). Thus, the methods of treating, preventing or managing acute myeloid leukemia in a subject comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage acute myeloid leukemia alone or in combination. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage acute myeloid leukemia. [0430] In some embodiments, the methods provided herein encompass treating, preventing or managing acute lymphocytic leukemia (ALL) in a subject. In some embodiments, acute lymphocytic leukemia includes leukemia that originates in the blast cells of the bone marrow (B-cells), thymus (T-cells), and lymph nodes. The acute lymphocytic leukemia can be categorized according to the French-American-British (FAB) Morphological Classification Scheme as L1—Mature-appearing lymphoblasts (T-cells or pre-B-cells), L2—Immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells), and L3— Lymphoblasts (B-cells; Burkitt’s cells). In one embodiment, the acute lymphocytic leukemia originates in the blast cells of the bone marrow (B-cells). In one embodiment, the acute lymphocytic leukemia originates in the thymus (T-cells). In one embodiment, the acute lymphocytic leukemia originates in the lymph nodes. In one embodiment, the acute lymphocytic leukemia is L1 type characterized by mature-appearing lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L2 type characterized by immature and pleomorphic (variously shaped) lymphoblasts (T-cells or pre-B-cells). In one embodiment, the acute lymphocytic leukemia is L3 type characterized by lymphoblasts (B- cells; Burkitt’s cells). In certain embodiments, the acute lymphocytic leukemia is T-cell leukemia. In one embodiment, the T-cell leukemia is peripheral T-cell leukemia. In another embodiment, the T-cell leukemia is T-cell lymphoblastic leukemia. In another embodiment, the T-cell leukemia is cutaneous T-cell leukemia. In another embodiment, the T-cell leukemia is adult T-cell leukemia. Thus, the methods of treating, preventing or managing acute lymphocytic leukemia in a subject comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage acute lymphocytic leukemia alone or in combination with a second active agent. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage acute lymphocytic leukemia. [0431] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic myelogenous leukemia (CML) in a subject. The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage chronic myelogenous leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage chronic myelogenous leukemia. [0432] In some embodiments, the methods provided herein encompass treating, preventing or managing chronic lymphocytic leukemia (CLL) in a subject. The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage chronic lymphocytic leukemia. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage chronic lymphocytic leukemia. [0433] In some embodiments, the methods provided herein encompass treating, preventing or managing myelodysplastic syndrome (MDS) in a subject. MDS is characterized by immature blood cells in the bone marrow that do not mature and may progress to AML. In some embodiments, the subject has very low, low, intermediate, high, or very high risk MDS according to the International Prognostic Scoring System (IPSS-R). The methods comprise the step of administering to the subject an amount of a compound, antibody, or antibody-drug conjugate provided herein effective to treat, prevent or manage MDS. In some embodiments, the methods comprise the step of administering to the subject a compound, antibody, or antibody-drug conjugate provided herein in combination with a second active agent in amounts effective to treat, prevent or manage MDS. [0434] In certain embodiments, provided herein are methods of treating, preventing, and/or managing disease in patients with impaired renal function. In certain embodiments, provided herein are method of treating, preventing, and/or managing cancer in patients with impaired renal function. In certain embodiments, provided herein are methods of providing appropriate dose adjustments for patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors. [0435] In certain embodiments, provided herein are methods of treating, preventing, and/or managing lymphoma, including non-Hodgkin's lymphoma. In some embodiments, provided herein are methods for the treatment or management of non-Hodgkin's lymphoma (NHL), including but not limited to, diffuse large B-cell lymphoma (DLBCL), using prognostic factors. [0436] In certain embodiments, provided herein are methods of treating, preventing, and/or managing multiple myeloma, including relapsed/refractory multiple myeloma in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of a compound, antibody, or antibody-drug conjugate provided herein to a patient having relapsed/refractory multiple myeloma with impaired renal function. [0437] In certain embodiments, the patient to be treated with one of the methods provided herein has not been treated with anticancer therapy prior to the administration of a compound, antibody, or antibody-drug conjugate provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has been treated with anticancer therapy prior to the administration of a compound, antibody, or antibody-drug conjugate provided herein. In certain embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to the anticancer therapy. [0438] The methods provided herein encompass treating a patient regardless of patient's age, although some diseases or disorders are more common in certain age groups. B. Routes of Administration and Carriers [0439] Provided herein are compositions (e.g., pharmaceutical compositions) comprising a compound, antibody, or antibody-drug conjugate provided herein and one or more pharmaceutically acceptable carriers. [0440] In various embodiments, a compound, antibody, or antibody-drug conjugate provided herein may be administered in vivo by various routes, including, but not limited to, oral, intra- arterial, parenteral (including intravenous and subcutaneous), intranasal, intramuscular, intracardiac, intraventricular, intratracheal, buccal, rectal, intraperitoneal, intradermal, topical, transdermal, and intrathecal, or otherwise by implantation or inhalation. The subject compositions may be formulated into preparations, such as liquid formulations or formulations suitable for injections, inhalations, and the like. Alternatively, in some embodiments, the composition may be provided as a lyophilized powder that may be reconstituted upon addition of an appropriate liquid or carrier, for example, sterile water. The appropriate formulation and route of administration may be selected according to the intended application. [0441] In various embodiments, compositions comprising a compound, antibody, or antibody-drug conjugate provided herein are provided in formulations with a wide variety of pharmaceutically acceptable carriers (see, e.g., Gennaro, Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed., Lippencott Williams and Wilkins (2004); Kibbe et al., Handbook of Pharmaceutical Excipients, 3rd ed., Pharmaceutical Press (2000)). Various pharmaceutically acceptable carriers, which include vehicles, adjuvants, and diluents, are available. Moreover, various pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are also available. VIII. NUMBERED EMBODIMENTS [0442] Embodiment 1. A compound of Formula (I'):

, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR¹¹; R¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl or a 3 to 6 membered cycloalkyl; R^2a and R^2b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; or R^2a and R^2b, taken together, form oxo; R³ is independently selected from hydrogen, halogen, -OR¹¹, -N(R¹¹R¹¹), -NHR¹¹, - C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, - N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^4a and R^4b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -NHR¹¹ or –OR¹¹; R⁵ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁶ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; wherein two R⁵ and R⁶ substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R¹¹ substituents; R⁷ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2, -C(=O)NH(R¹¹), -C(=O)N(R¹¹R¹¹), -S(O)₂R¹¹, -S(=O)R¹¹, -SR¹¹, -S(=O)₂NH₂, - S(=O)2NH(C₁-C₆ alkyl), or -S(=O)2N(C₁-C₆ alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^8a and R^8b are each independently selected from hydrogen, halogen or a -C₁-C₆ alkyl, optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁹ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH₂,

S(=O)2NH(C₁-C₆ alkyl), or -S(=O)2N(C₁-C₆ alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C2-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C₆ alkoxyalkyl, oxo, hydroxyl or -C₁-C₆ alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C₂- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)₂-, -S(=O)-, -S-, -S(=O)₂N(R¹¹)-, - S(=O)2N(H)(C₁-C₆ alkylene)-, or -S(=O)2N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L' is a linker; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. [0443] Embodiment 2. The compound of embodiment 1, wherein A and B are independently selected from phenylene, pyridylene, pyrimidinylene, or pyridazinylene. [0444] Embodiment 3. The compound of embodiment 2, wherein A and B are each phenylene. [0445] Embodiment 4. The compound of embodiment 1, wherein A is phenylene and B is cyclohexylene, or A is cyclohexylene and B is phenylene. [0446] Embodiment 5. The compound of any one of embodiments 1-4, wherein b is 0. [0447] Embodiment 6. The compound of embodiment 5, wherein X is O. [0448] Embodiment 7. The compound of any one of embodiments 1-4, wherein b is 1. [0449] Embodiment 8. The compound of embodiment 7, wherein X is O. [0450] Embodiment 9. The compound of embodiment 7, wherein X is N(H) or N(CH₃). [0451] Embodiment 10. The compound of any one of embodiments 1-9, wherein c is 1. [0452] Embodiment 11. The compound of any one of embodiments 1-10, wherein d is 1. [0453] Embodiment 12. The compound of any one of embodiments 1-11, wherein e is 1. [0454] Embodiment 13. The compound of embodiment 1, of Formula (II'):

, or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkyl, C₁-C₆ haloalkoxy, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)n- or -O(CH₂)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker. [0455] Embodiment 14. The compound of any one of embodiments 1-13, wherein R¹ is hydrogen or methyl. [0456] Embodiment 15. The compound of embodiment 14, wherein R¹ is hydrogen. [0457] Embodiment 16. The compound of any one of embodiments 1-15, wherein R^2a and R^2b are each hydrogen. [0458] Embodiment 17. The compound of any one of embodiments 1-16, wherein R³ is hydrogen or fluoro. [0459] Embodiment 18. The compound of embodiment 17, wherein R³ is hydrogen. [0460] Embodiment 19. The compound of any one of embodiments 1-18, wherein X¹ and X² are C(R⁷); or X¹ is C(R⁷) and X² is N; or X¹ and X² are N. [0461] Embodiment 20. The compound of embodiment 19, wherein X¹ and X² are C(R⁷). [0462] Embodiment 21. The compound of any one of embodiments 1-20, wherein each R⁷ is independently hydrogen, fluoro, chloro, or methyl. [0463] Embodiment 22. The compound of embodiment 21, wherein each R⁷ is hydrogen. [0464] Embodiment 23. The compound of any one of embodiments 1-22, wherein X³, X⁴, and X⁵ are C(R⁹); or X³ and X⁵ are N and X⁴ is C(R⁹); or X³ and X⁴ are N and X⁵ is C(R⁹); or X³ is N and X⁴ and X⁵ are C(R⁹); or X³ and X⁵ are C(R⁹) and X⁴ is N. [0465] Embodiment 24. The compound of embodiment 23, wherein X³, X⁴, and X⁵ are C(R⁹). [0466] Embodiment 25. The compound of any one of embodiments 1-24, wherein each R⁹ is independently hydrogen, fluoro, chloro, C₁-C3 alkyl, C₁-C3 alkoxy, C₁-C3 haloalkyl, C₁- C3 haloalkoxy, 3 or 4 membered cycloalkyl, or oxetanyloxy. [0467] Embodiment 26. The compound of embodiment 25, wherein each R⁹ is hydrogen. [0468] Embodiment 27. The compound of any one of embodiments 1-26, wherein Z is *- N(H)(CH₂)n- or *-O(CH₂)n-, and * indicates the point of attachment of Z to L'. [0469] Embodiment 28. The compound of embodiment 27, wherein Z is *-N(H)(CH₂)_n-. [0470] Embodiment 29. The compound of any one of embodiments 1-28, wherein n is 0, 1, 2, or 3. [0471] Embodiment 30. The compound of embodiment 29, wherein n is 0 or 1. [0472] Embodiment 31. The compound of any one of embodiments 1-30, wherein Z is *- N(H)CH₂-. [0473] Embodiment 32. The compound of any one of embodiments 1-31, having Formula (III'):

, or a pharmaceutically acceptable salt thereof, wherein: [0474] Embodiment 33. The compound of any one of embodiments 1-32, having Formula IV':

or a pharmaceutically acceptable salt thereof. [0475] Embodiment 34. The compound of any one of embodiments 1-33, wherein

, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L³ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²³-, -O-, -NR²³-, -(PEG)_mC(O)NR²³-, -C(O)NR²³(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²³ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)_mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²³ is C₁-C₆ alkylene, the alkylene is point of attachment of L³ to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; and L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0476] Embodiment 35. The compound of embodiment 34, wherein L³ is 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or - NH2. [0477] Embodiment 36. The compound of embodiment 34, wherein L³ is a 1-25 membered aliphatic comprising -(PEG)m-, -(PEG)mC(O)NR²³-, or -C(O)NR²³(PEG)m-, and further optionally comprising -C(O)NR²³-, -O-, or -NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or - NH₂. [0478] Embodiment 37. The compound of embodiment 34, wherein L³ is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from - OH, -COOH, or -NH2. [0479] Embodiment 38. The compound of embodiment 34 or 37, wherein Cy is piperidinylene, piperazinylene, 2,5-diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃. [0480] Embodiment 39. The compound of any one of embodiments 34-38, wherein the aliphatic of L³ is a linear or branched aliphatic chain. [0481] Embodiment 40. The compound of any one of embodiments 34-38, wherein the aliphatic of L³ comprises a 3 to 8 membered cycloalkyl. [0482] Embodiment 41. The compound of any one of embodiments 34-38 and 40, wherein the aliphatic of L³ comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl. [0483] Embodiment 42. The compound of embodiment 34, wherein

is:

wherein: X⁶ is C(R²⁴) or N; X⁷ is C(R²⁵) or N; R²⁴ is hydrogen or hydroxy; R²⁵ is hydrogen, hydroxy, or -O(CH₂CH₂O)7CH₃; and R²⁶ is -C(O)(CH₂CH₂O)8-12CH₃. [0484] Embodiment 43. The compound of any one of embodiments 1-33, wherein

Arg is arginine; Val is valine; Glu is glutamic acid; L¹ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)mC(O)NR²¹-, -C(O)NR²¹(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)_mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L¹ to -C(O)-(Glu)_r-; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)_mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10. [0485] Embodiment 44. The compound of embodiment 43, wherein L¹ is a 1-25 membered aliphatic optionally comprising -C(O)NR²¹-, -(PEG)_mC(O)NR²¹-, or -C(O)NR²¹(PEG)_m-. [0486] Embodiment 45. The compound of embodiment 43 or 44, wherein the aliphatic of L¹ is a linear or branched aliphatic chain. [0487] Embodiment 46. The compound of embodiment 43, wherein

[0488] Embodiment 47. The compound of any one of embodiments 1-33, wherein

, wherein: L² is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)mC(O)NR²¹-, -C(O)NR²¹(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)_mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L² to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)_mCH₃ L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; and R²² is an -O-linked sugar acid. [0489] Embodiment 48. The compound of embodiment 47, wherein the sugar acid is glucuronic acid. [0490] Embodiment 49. The compound of embodiment 47 or 48, wherein L² is a 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR²¹-. [0491] Embodiment 50. The compound of any one of embodiments 43-49, wherein each R²¹ is independently hydrogen, C₁-C₆ alkyl, or -(CH₂CH₂O)mCH₃. [0492] Embodiment 51. The compound of embodiment 47, wherein

is:

_. [0493] Embodiment 52. The compound of any one of embodiments 1-33, wherein

. [0494] Embodiment 53. The compound of any one of embodiments 1-33, wherein

, wherein: Ala is alanine; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0495] Embodiment 54. The compound of any one of embodiments 34-41, 43-45, and 47-50, wherein the aliphatic of L¹, L², or L³ is 1-15 membered. [0496] Embodiment 55. The compound of embodiment 54, wherein the aliphatic of L¹, L², or L³ is 1-10 membered. [0497] Embodiment 56. The compound of embodiment 55, wherein the aliphatic of L¹, L², or L³ is 1-5 membered. [0498] Embodiment 57. The compound of any one of embodiments 34-50 and 53-56, wherein L⁴ is absent. [0499] Embodiment 58. The compound of embodiment 57, wherein Z is *-N(H)(CH₂)_n-. [0500] Embodiment 59. The compound of any one of embodiments 34-56, wherein L⁴ is **-

[0501] Embodiment 60. The compound of embodiment 59, wherein Z is *-O(CH₂)n-. [0502] Embodiment 61. The compound of any one of embodiments 34-50, 53-56, 59, and 60, wherein R⁴⁰ is hydrogen. [0503] Embodiment 62. The compound of any one of embodiments 13-42 and 54-56, having Formula IV':

, or a pharmaceutically acceptable salt thereof. [0504] Embodiment 63. A compound having a structure from Table A, or a pharmaceutically acceptable salt thereof. [0505] Embodiment 64. A compound selected from:

,

,

, and pharmaceutically acceptable salts thereof. [0506] Embodiment 65. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) (i) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1; (ii) a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2; (iii) a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3; (iv) a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of any one of SEQ ID NOs: 16, 17, and 18; (v) a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of any one of SEQ ID NOs: 19-26; and (vi) a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27 or 28; b) (i) a HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 29, 30, and 31; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 32-39; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40 or 41; c) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42; (v) an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43 or 44; and (vi) LCDR3 comprising the amino acid sequence of SEQ ID NO: 45 or 46; d) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO:10; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12; (iv) an LCDR1 comprising the amino acid sequence of any one of SEQ ID NOs: 47-49; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 50-57; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58 or 59; or e) (i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13; (ii) an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14; (iii) an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15; (iv) an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60; (v) an LCDR2 comprising the amino acid sequence of any one of SEQ ID NOs: 61-66; and (vi) an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67 or 68. [0507] Embodiment 66. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 19, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28. [0508] Embodiment 67. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 32, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 34, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 39, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 31, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 29, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 38, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 40; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 37, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 35, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41. [0509] Embodiment 68. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; or c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 44, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 45. [0510] Embodiment 69. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 50, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 52, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 57, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 49, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 47, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 56, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 58; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 54, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 53, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59. [0511] Embodiment 70. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 63, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 61, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 64, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 66, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 67; or h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 65, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0512] Embodiment 71. The isolated antibody or antigen-binding portion thereof of embodiment 65, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. [0513] Embodiment 72. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0514] Embodiment 73. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0515] Embodiment 74. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; b) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; c) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 71 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; d) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; e) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 77; f) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; g) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; h) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; i) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; j) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 79; k) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 80; l) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 81; or m) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 73 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0516] Embodiment 75. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0517] Embodiment 76. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0518] Embodiment 77. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-71, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0519] Embodiment 78. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-77, wherein the antibody or antigen-binding portion thereof is a monoclonal antibody. [0520] Embodiment 79. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-78, wherein the antibody or antigen-binding portion thereof is a human antibody, chimeric antibody, or a humanized antibody. [0521] Embodiment 80. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-79, wherein the antibody is a full-length antibody. [0522] Embodiment 81. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-80, wherein the antibody or antigen-binding portion thereof is an IgG antibody. [0523] Embodiment 82. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-81, wherein the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region. [0524] Embodiment 83. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-82, wherein the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. [0525] Embodiment 84. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 83-87, and a light chain (LC) comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to an amino acid sequence selected from SEQ ID NOs: 88-96, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE). [0526] Embodiment 85. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises a heavy chain (HC) comprising an amino acid sequence selected from SEQ ID NOs: 83-87, and a light chain (LC) comprising an amino acid sequence selected from SEQ ID NOs: 88-96, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE). [0527] Embodiment 86. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises: a) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89; c) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 85, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 88; h) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 92; j) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 86, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 83, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 87, and a light chain (LC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE). [0528] Embodiment 87. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising an amino acid sequence having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 84, and a light chain (LC) sequence comprising an amino acid having at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0529] Embodiment 88. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises: a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; c) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; h) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; j) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE). [0530] Embodiment 89. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-83, wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0531] Embodiment 90. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-79, wherein the antibody or antigen-binding portion thereof is an antibody fragment selected from an Fv, single-chain Fv (scFv), Fab, Fab’, or (Fab’)₂. [0532] Embodiment 91. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-90, wherein the antibody or antigen-binding portion thereof binds human CD33. [0533] Embodiment 92. The isolated antibody or antigen-binding portion thereof of embodiment 91, wherein human CD33 comprises the amino acid sequence of SEQ ID NO: 97 or SEQ ID NO: 99. [0534] Embodiment 93. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-92, wherein the antibody or antigen-binding portion thereof binds the monomeric form of human CD33 and/or the dimeric form of human CD33. [0535] Embodiment 94. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-93, wherein the antibody or antigen-binding portion thereof binds cynomolgus monkey CD33. [0536] Embodiment 95. The antibody or antigen-binding portion thereof of embodiment 94, wherein cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO: 98. [0537] Embodiment 96. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-95, wherein the antibody or antigen-binding portion thereof binds the monomeric form of cynomolgus monkey CD33 and/or the dimeric form of cynomolgus monkey CD33. [0538] Embodiment 97. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-96, wherein the antibody or antigen-binding portion thereof binds to human CD33 with an affinity (KD) of less than 1.5 nM. [0539] Embodiment 98. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-97, wherein the antibody or antigen-binding portion thereof binds to cynomolgus monkey CD33 with an affinity (KD) of less than 10 nM. [0540] Embodiment 99. The isolated antibody or antigen-binding portion thereof of embodiment 97 or 98, wherein affinity is determined using biolayer interferometry. [0541] Embodiment 100. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-99, wherein the antibody or antigen-binding portion thereof does not bind to human Siglec 6 or human Siglec 8. [0542] Embodiment 101. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-100, wherein the antibody or antigen-binding portion thereof internalizes after binding to CD33+ cells. [0543] Embodiment 102. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-101, wherein the antibody or antigen-binding portion thereof has a Tregitope-adjusted EpiMatrix Score equal to or less than 0, equal to or less than -25, or equal to or less than -45. [0544] Embodiment 103. The isolated antibody or antigen-binding portion thereof of any one of embodiments 65-101, wherein the antibody or antigen-binding portion thereof is a bispecific antibody. [0545] Embodiment 104. The isolated antibody of antigen-binding portion thereof of embodiment 103, wherein the bispecific antibody binds CD33 and a second antigen. [0546] Embodiment 105. The isolated antibody or antigen-binding portion thereof of embodiment 104, wherein the second antigen is expressed on the surface of T cells or NK cells. [0547] Embodiment 106. The isolated antibody or antigen-binding portion thereof of embodiment 104 or 105, wherein the second antigen is selected from CD3, CD16, CD16A, NKG2C, and NKG2D. [0548] Embodiment 107. A pharmaceutical composition comprising the isolated antibody or antigen-binding portion thereof of any one of embodiments 65-106 and a pharmaceutically acceptable carrier. [0549] Embodiment 108. An isolated nucleic acid encoding the antibody or antigen-binding portion thereof of any one of embodiments 65-106. [0550] Embodiment 109. A vector comprising the nucleic acid of embodiment 108. [0551] Embodiment 110. A host cell comprising the nucleic acid of embodiment 108 or the vector of embodiment 109. [0552] Embodiment 111. A host cell that produces the antibody or antigen-binding portion thereof of any one of embodiments 65-106. [0553] Embodiment 112. A method for making an anti-CD33 antibody or antigen-binding portion thereof, comprising culturing the host cell of embodiment 110 or 111 under conditions suitable for expression of the antibody or antigen-binding portion thereof. [0554] Embodiment 113. The method of embodiment 112, further comprising recovering the antibody or antigen-binding portion thereof produced by the host cell. [0555] Embodiment 114. An antibody-drug conjugate comprising the antibody or antigen- binding portion thereof of any one of embodiments 65-106 and a cytotoxic agent. [0556] Embodiment 115. An antibody-drug conjugate of Formula (I"):

, or a pharmaceutically acceptable salt thereof, wherein: A is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl, or a 5 to 12 membered heteroaryl ring; B is independently selected from an unsubstituted or substituted 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; X is independently selected from O or -NR¹¹; R¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl or a 3 to 6 membered cycloalkyl; R^2a and R^2b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, wherein the alkyl or cycloalkyl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; or R^2a and R^2b, taken together, form oxo; R³ is independently selected from hydrogen, halogen, -OR¹¹, -N(R¹¹R¹¹), -NHR¹¹, - C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, - N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^4a and R^4b are each independently selected from hydrogen, halogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -NHR¹¹ or –OR¹¹; R⁵ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁶ is selected from hydrogen, -C₁-C₆ alkyl, a 3 to 6 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, wherein the alkyl, cycloalkyl, heterocyclic and heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; wherein two R⁵ and R⁶ substituents together with the carbon atoms they are attached to, may join to form a 5 or 6 membered ring that may be saturated, partially saturated, and may further optionally be substituted with 1 or 2 R¹¹ substituents; R⁷ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH₂, -C(=O)NH(R¹¹), -C(=O)N(R¹¹R¹¹), -S(O)₂R¹¹, -S(=O)R¹¹, -SR¹¹, -S(=O)₂NH₂, - S(=O)2NH(C₁-C₆ alkyl), or -S(=O)2N(C₁-C₆ alkyl)2, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^8a and R^8b are each independently selected from hydrogen, halogen or a -C₁-C₆ alkyl, optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁹ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C₂-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2,

S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH₂, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C₆ alkoxyalkyl, oxo, hydroxyl or -C₁-C₆ alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C2- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R¹¹)-, - S(=O)2N(H)(C₁-C₆ alkylene)-, or -S(=O)2N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. [0557] Embodiment 116. The antibody-drug conjugate of embodiment 115, wherein A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. [0558] Embodiment 117. The antibody-drug conjugate of embodiment 116, wherein A and B are each phenylene. [0559] Embodiment 118. The antibody-drug conjugate of embodiment 115, wherein A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. [0560] Embodiment 119. The antibody-drug conjugate of any one of embodiments 115-118, wherein b is 0. [0561] Embodiment 120. The compound or antibody-drug conjugate of embodiment 119, wherein X is O. [0562] Embodiment 121. The antibody-drug conjugate of any one of embodiments 115-118, wherein b is 1. [0563] Embodiment 122. The compound or antibody-drug conjugate of embodiment 121, wherein X is O. [0564] Embodiment 123. The compound or antibody-drug conjugate of embodiment 121, wherein X is N(H) or N(CH₃). [0565] Embodiment 124. The antibody-drug conjugate of any one of embodiments 115-123, wherein c is 1. [0566] Embodiment 125. The antibody-drug conjugate of any one of embodiments 115-124, wherein d is 1. [0567] Embodiment 126. The antibody-drug conjugate of any one of embodiments 115-125, wherein e is 1. [0568] Embodiment 127. The antibody-drug conjugate of embodiment 115, of Formula (II"):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together with the carbon atom to which they are attached, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)n- or -O(CH₂)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; and b is 0 or 1. [0569] Embodiment 128. The antibody-drug conjugate of any one of embodiments 115-127, wherein R¹ is hydrogen or methyl. [0570] Embodiment 129. The antibody-drug conjugate of embodiment 128, wherein R¹ is hydrogen. [0571] Embodiment 130. The antibody-drug conjugate of any one of embodiments 115-129, wherein R^2a and R^2b are each hydrogen. [0572] Embodiment 131. The antibody-drug conjugate of any one of embodiments 115-130, wherein R³ is hydrogen or fluoro. [0573] Embodiment 132. The antibody-drug conjugate of embodiment 131, wherein R³ is hydrogen. [0574] Embodiment 133. The antibody-drug conjugate of any one of embodiments 115-132, wherein X¹ and X² are C(R⁷); or X¹ is C(R⁷) and X² is N; or X¹ and X² are N. [0575] Embodiment 134. The antibody-drug conjugate of embodiment 133, wherein X¹ and X² are C(R⁷). [0576] Embodiment 135. The antibody-drug conjugate of any one of embodiments 115-134, wherein each R⁷ is independently hydrogen, fluoro, chloro, or methyl. [0577] Embodiment 136. The antibody-drug conjugate of embodiment 135, wherein each R⁷ is hydrogen. [0578] Embodiment 137. The antibody-drug conjugate of any one of embodiments 115-136, wherein X³, X⁴, and X⁵ are C(R⁹); or X³ and X⁵ are N and X⁴ is C(R⁹); or X³ and X⁴ are N and X⁵ is C(R⁹); or X³ is N and X⁴ and X⁵ are C(R⁹); or X³ and X⁵ are C(R⁹) and X⁴ is N. [0579] Embodiment 138. The antibody-drug conjugate of embodiment 137, wherein X³, X⁴, and X⁵ are C(R⁹). [0580] Embodiment 139. The antibody-drug conjugate of any one of embodiments 115-138, wherein each R⁹ is independently hydrogen, fluoro, chloro, C₁-C₃ alkyl, C₁-C₃ alkoxy, C₁- C₃ haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. [0581] Embodiment 140. The antibody-drug conjugate of embodiment 139, wherein each R⁹ is hydrogen. [0582] Embodiment 141. The antibody-drug conjugate of any one of embodiments 115-140, wherein Z is *-N(H)(CH₂)n- or *-O(CH₂)n-, and * indicates the point of attachment of Z to L. [0583] Embodiment 142. The antibody-drug conjugate of embodiment 141, wherein Z is *- N(H)(CH₂)_n-. [0584] Embodiment 143. The antibody-drug conjugate of any one of embodiments 115-142, wherein n is 0, 1, 2, or 3. [0585] Embodiment 144. The antibody-drug conjugate of embodiment 143, wherein n is 0 or 1. [0586] Embodiment 145. The antibody-drug conjugate of any one of embodiments 115-144, wherein Z is *-N(H)CH₂-. [0587] Embodiment 146. The antibody-drug conjugate of any one of embodiments 115 and 127-145, of Formula (III"):

or a pharmaceutically acceptable salt thereof. [0588] Embodiment 147. The antibody-drug conjugate of any one of embodiments 115 and 127-146, having Formula IV":

or a pharmaceutically acceptable salt thereof. [0589] Embodiment 148. The antibody-drug conjugate of any one of embodiments 115-147, wherein L comprises

, wherein indicates point of attachment to Ab. [0590] Embodiment 149. The antibody-drug conjugate of embodiment 148, wherein L is

, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L³ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²³-, -O-, -NR²³-, -(PEG)_mC(O)NR²³-, -C(O)NR²³(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²³ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)_mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²³ is C₁-C₆ alkylene, the alkylene is point of attachment of L³ to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0591] Embodiment 150. The antibody-drug conjugate of embodiment 149, wherein L³ is 1- 25 membered aliphatic optionally comprising 1 or 2 -C(O)NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, - COOH, or -NH2. [0592] Embodiment 151. The antibody-drug conjugate of embodiment 149, wherein L³ is a 1-25 membered aliphatic comprising -(PEG)m-, -(PEG)mC(O)NR²³-, or -C(O)NR²³(PEG)m-, and further optionally comprising -C(O)NR²³-, -O-, or -NR²³-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, - COOH, or -NH₂. [0593] Embodiment 152. The antibody-drug conjugate of embodiment 149, wherein L³ is a 1-25 membered aliphatic comprising -Cy- and further optionally comprising -(PEG)_m-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2. [0594] Embodiment 153. The antibody-drug conjugate of embodiment 149 or 152, wherein Cy is piperidinylene, piperazinylene, 2,5-diazabicyclo[2.2.1]heptanylene, azetidinylene, dioxanylene, wherein Cy is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃. [0595] Embodiment 154. The antibody-drug conjugate of any one of embodiments 149-153, wherein the aliphatic of L³ is a linear or branched aliphatic chain. [0596] Embodiment 155. The antibody-drug conjugate of any one of embodiments 149-153, wherein the aliphatic of L³ comprises a 3 to 8 membered cycloalkyl. [0597] Embodiment 156. The antibody-drug conjugate of any one of embodiments 149-153 and 155, wherein the aliphatic of L³ comprises a linear or branched, aliphatic chain, and a 3 to 8 membered cycloalkyl. [0598] Embodiment 157. The antibody-drug conjugate of embodiment 149, wherein

. ,

_,

wherein: X⁶ is C(R²⁴) or N; X⁷ is C(R²⁵) or N; R²⁴ is hydrogen or hydroxy; R²⁵ is hydrogen, hydroxy, or -O(CH₂CH₂O)7CH₃; and R²⁶ is -C(O)(CH₂CH₂O)8-12CH₃. [0599] Embodiment 158. The antibody-drug conjugate of embodiment 148, wherein L is

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10. [0600] Embodiment 159. The antibody-drug conjugate of embodiment 158, wherein L¹ is a 1-25 membered aliphatic optionally comprising -C(O)NR²¹-, -(PEG)_mC(O)NR²¹-, or - C(O)NR²¹(PEG)m-. [0601] Embodiment 160. The antibody-drug conjugate of embodiment 154 or 155, wherein the aliphatic of L¹ is a linear or branched aliphatic chain. [0602] Embodiment 161. The antibody-drug conjugate of embodiment 158, wherein

point of attachment to Ab. [0603] Embodiment 162. The antibody-drug conjugate of embodiment 148, wherein L is

, wherein: L² is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)_mC(O)NR²¹-, -C(O)NR²¹(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH2; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)_mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L² to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; and R²² is an -O-linked sugar acid. [0604] Embodiment 163. The antibody-drug conjugate of embodiment 162, wherein the sugar acid is glucuronic acid. [0605] Embodiment 164. The antibody-drug of embodiment 162 or 163, wherein L² is a 1-25 membered aliphatic optionally comprising 1 or 2 -C(O)NR²¹-. [0606] Embodiment 165. The antibody-drug conjugate of any one of embodiments 158-164, wherein each R²¹ is independently hydrogen, C₁-C₆ alkyl, or -(CH₂CH₂O)_mCH₃. [0607] Embodiment 166. The antibody-drug conjugate of embodiment 162, wherein L is:

or

_{, indicates point of attachment to Ab.} [0608] Embodiment 167. The antibody-drug conjugate of embodiment 148, wherein

_{indicates point of} attachment to Ab. [0609] Embodiment 168. The antibody-drug conjugate of embodiment 148, wherein

, wherein: indicates point of attachment to Ab; Ala is alanine; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. [0610] Embodiment 169. The antibody-drug conjugate of any one of embodiments 149-156, 158-160, and 162-165, wherein the aliphatic of L¹, L², or L³ is 1-15 membered. [0611] Embodiment 170. The antibody-drug of embodiment 169, wherein the aliphatic of L¹, L², or L³ is 1-10 membered. [0612] Embodiment 171. The antibody-drug of embodiment 170, wherein the aliphatic of L¹, L², or L³ is 1-5 membered. [0613] Embodiment 172. The antibody-drug conjugate of any one of embodiments 149-156, 158-160, 162-165, and 168-171, wherein L⁴ is absent. [0614] Embodiment 173. The antibody-drug conjugate of embodiment 172, wherein Z is *- N(H)(CH₂)_n-. [0615] Embodiment 174. The antibody-drug conjugate of any one of embodiments 149-156, 158-160, 162-165, and 168-171, wherein L⁴ is **-CH₂-N(R⁴⁰)-, **-C(O)CH₂CH₂N(R⁴⁰)-, or **-CH₂-N(R⁴⁰)C(O)CH₂N(R⁴⁰)-. [0616] Embodiment 175. The antibody-drug conjugate of embodiment 174, wherein Z is *- O(CH₂)n-. [0617] Embodiment 176. The antibody-drug conjugate of any one of embodiments 149-156, 158-160, 162-165, 168-171, 174, and 175, wherein R⁴⁰ is hydrogen. [0618] Embodiment 177. The antibody-drug conjugate of any one of embodiments 127-157 and 169-171, having Formula V":

, or a pharmaceutically acceptable salt thereof. [0619] Embodiment 178. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0620] Embodiment 179. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0621] Embodiment 180. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0622] Embodiment 181. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0623] Embodiment 182. An antibody drug conjugate of the following formula:

or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0624] Embodiment 183. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0625] Embodiment 184. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0626] Embodiment 185. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0627] Embodiment 186. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0628] Embodiment 187. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. [0629] Embodiment 188. The antibody-drug conjugate of any one of embodiments 115-187, wherein a is 1-15, or 1-12, or 1-10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10. [0630] Embodiment 189. The antibody-drug conjugate of any one of embodiments 115-188, wherein the antibody or antigen-binding portion thereof binds CD33. [0631] Embodiment 190. The antibody-drug conjugate of embodiment 189, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 65-106. [0632] Embodiment 191. The antibody-drug conjugate of embodiment 190, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 71, 75, 77, 87, and 89. [0633] Embodiment 192. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: n) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; o) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; p) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; q) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; r) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; s) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; t) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; u) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; v) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; w) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; x) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; y) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or z) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0634] Embodiment 193. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0635] Embodiment 194. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0636] Embodiment 195. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0637] Embodiment 196. An antibody drug conjugate of the following formula:

or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0638] Embodiment 197. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0639] Embodiment 198. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0640] Embodiment 199. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0641] Embodiment 200. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0642] Embodiment 201. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 6-10; and Ab is an antibody or antigen-binding portion thereof that binds CD33 and comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). [0643] Embodiment 202. The antibody-drug conjugate of any one of claims 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 69 may be replaced with a pyroglutamic acid (pE). [0644] Embodiment 203. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 83 may be replaced with a pyroglutamic acid (pE). [0645] Embodiment 204. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0646] Embodiment 205. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0647] Embodiment 206. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 71 may be replaced with a pyroglutamic acid (pE). [0648] Embodiment 207. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 85 may be replaced with a pyroglutamic acid (pE). [0649] Embodiment 208. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0650] Embodiment 209. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE). [0651] Embodiment 210. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0652] Embodiment 211. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 86 may be replaced with a pyroglutamic acid (pE). [0653] Embodiment 212. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). [0654] Embodiment 213. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88, optionally wherein the glutamic acid (E) at the N- terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). [0655] Embodiment 214. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 72 may be replaced with a pyroglutamic acid (pE). [0656] Embodiment 215. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88. [0657] Embodiment 216. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78. [0658] Embodiment 217. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92. [0659] Embodiment 218. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78. [0660] Embodiment 219. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92. [0661] Embodiment 220. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79. [0662] Embodiment 221. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93. [0663] Embodiment 222. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80. [0664] Embodiment 223. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94. [0665] Embodiment 224. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81. [0666] Embodiment 225. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95. [0667] Embodiment 226. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82. [0668] Embodiment 227. The antibody-drug conjugate of any one of embodiments 192-201, wherein the antibody or antigen-binding portion thereof comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96. [0669] Embodiment 228. A pharmaceutical composition comprising the antibody-drug conjugate of any one of embodiments 114-227 and a pharmaceutically acceptable carrier. [0670] Embodiment 229. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated antibody or antigen-binding portion thereof of any one of embodiments 65-106, the pharmaceutical composition of embodiment 103 or 228, or the antibody-drug conjugate of any one of embodiments 114-227. [0671] Embodiment 230. The method of embodiment 229, wherein the cancer is leukemia. [0672] Embodiment 231. The method of embodiment 230, wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, or acute myeloid leukemia. [0673] Embodiment 232. The method of any one of embodiments 229-231, wherein the subject is a human. [0674] Embodiment 233. Use of the isolated antibody or antigen-binding portion thereof of any one of claims 65-106, the pharmaceutical composition of embodiment 107 or 228, or the antibody-drug conjugate of any one of embodiments 114-227 for the preparation of a medicament for treating cancer in a subject in need thereof. [0675] Embodiment 234. The isolated antibody or antigen-binding portion thereof of any one of claims 65-106, the pharmaceutical composition of embodiment 107 or 228, or the antibody-drug conjugate of any one of embodiments 114-227 for use in treating cancer in a subject in need thereof. IX. SYNTHETIC EXAMPLES Example 1: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3- (4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea

[0676] Step 1-1: (4-((4-nitrophenoxy)methyl)phenyl)methanol

[0677] To a solution of (4-(bromomethyl)phenyl)methanol (0.500 g, 2.49 mmol, 1 eq) in DMF (10 mL) were added 4-nitrophenol (0.415 g, 2.98 mmol, 1.2 eq) and cesium carbonate (1.620 g, 4.97 mmol, 2 eq), then the reaction was stirred at 25 °C for 12 h. TLC showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated. It was then diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. It was used directly into the next step without further purification. (2-((4-Nitrophenoxy)methyl)phenyl)methanol (0.620 g, 2.39 mmol, 96.2% yield) was obtained as a white solid.¹H NMR (400MHz DMSO-d6) δ 8.23 - 8.17 (m, 2H), 7.45 - 7.39 (m, 2H), 7.35 - 7.31 (m, 2H), 7.23 - 7.17 (m, 2H), 5.24 (s, 2H), 5.18 (t, J = 5.6 Hz, 1H), 4.49 (d, J = 5.6 Hz, 2H) [0678] Step 1-2: 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline

[0679] To a solution of (3-((4-nitrophenoxy)methyl)phenyl)methanol (0.620 g, 2.39 mmol, 1 eq) in DMF (15 mL) were added tert-butylchlorodimethylsilane (0.721 g, 4.78 mmol, 2 eq) and 1H-imidazole (0.488 g, 7.17 mmol, 3 eq), then the reaction was stirred at 25 °C for 12 h. TLC showed the reaction was completed. The reaction was dissolved with water (10 mL), extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. It was used directly into the next step without further purification. tert- Butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane (0.800 g, 2.14 mmol, 89.6% yield) was obtained as a white oil. [0680] To a solution of tert-butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane (0.800 g, 2.14 mmol, 1 eq) in water (5 mL) were added iron (0.598 g, 10.71 mmol, 5 eq), ammonium chloride (1.150 g, 21.42 mmol, 10 eq) and ethanol (10 mL), then the reaction was stirred at 80 °C for 2 h. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated. It was hen diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuum. The reaction was purified by silica gel column chromatography (2-10% Ethyl acetate in Petroleum ether). 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (0.500 g, 1.46 mmol, 68.0% yield) was obtained as a yellow solid. [0681] Step 1-3: 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)

[0682] To a solution of 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (0.209 g, 0.61 mmol, 1.5 eq) and bis(2,5-dioxopyrrolidin-1-yl) carbonate (0.156 g, 0.61 mmol, 1.5 eq) in acetonitrile (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.105 g, 0.81 mmol, 2 eq), after stirred at 0 °C for 0.1 h, 3-(5-(aminomethyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione methanesulfonate (0.150 g, 0.41 mmol, 1 eq, mesylate) was added to the reaction and it was stirred at 25 °C for 11.9 h. LCMS showed the reaction was completed. The reaction mixture was filtered, and the residue was concentrated. It was used directly into the next step without further purification. 1-(4-((4-(((tert- butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea (0.200 g, 0.31 mmol, 76.6% yield) was obtained as a white solid. LCMS (ESI) m/z: 643.2 [M+1]⁺, ¹H NMR (400MHz DMSO-d6) δ 10.98 (s, 1H), 8.47 (s, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7.52 (s, 1H), 7.35 - 7.27 (m, 6H), 6.89 (d, J = 8.8 Hz, 3H), 6.72 - 6.69 (m, 1H), 5.17 - 5.08 (m, 2H), 5.02 (s, 3H), 4.71 (s, 2H), 4.52 - 4.30 (m, 7H), 2.90 (d, J = 12.0 Hz, 1H), 2.62 (s, 1H), 2.39 (dd, J = 4.4, 13.2 Hz, 1H), 2.02 - 1.98 (m, 1H), 0.95 - 0.94 (m, 1H), 0.91 (s, 8H), 0.09 (s, 6H) [0683] Step 1-4: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4- (hydroxymethyl)benzyl)oxy)phenyl)urea

[0684] A mixture of 1-(4-((3-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (0.150 g, 0.23 mmol, 1 eq) in hydrogen chloride /dioxane (3 mL, 4M) was stirred at 25 °C for 1 h. LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. The reaction was purified by semi-preparative reverse phase HPLC (25-55% acetonitrile + 0.225%formic acid in water, over 10 min), then the collected fraction was concentrated to remove most of the acetonitrile, and it was lyophilized to afford the desired compound. 1- ((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((3- (hydroxymethyl)benzyl)oxy)phenyl)urea (0.012 g, 0.02 mmol, 9.2% yield, 96.0% purity) was obtained as a white solid. LCMS (ESI) m/z: 529.2 [M+1]⁺, ¹H NMR (400MHz DMSO-d6) δ 10.97 (s, 1H), 8.41 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.33 - 7.26 (m, 4H), 6.88 (d, J = 8.8 Hz, 2H), 6.62 (t, J = 5.6 Hz, 1H), 5.19 - 5.07 (m, 2H), 5.01 (s, 2H), 4.52 - 4.28 (m, 6H), 2.97 - 2.85 (m, 1H), 2.60 (d, J = 16.0 Hz, 1H), 2.41 - 2.31 (m, 1H), 2.07 - 1.94 (m, 1H). Example 2: Synthesis of 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6- dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea

[0685] Step 2-1: tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate

[0686] To a solution of tert-butyl N-[[4-(bromomethyl)phenyl]methyl]carbamate (10 g, 33.3 mmol) in MeCN (150 mL) was added 4-nitrophenol (4.82 g, 34.6 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80°C for 16 h. TLC (petroleum ether/ethyl acetate, 2:1, Rf_#1=0.76 Rf_#2=0.6) showed the starting material was consumed and main a new spot formed. The reaction mixture was cooled to r.t and concentrated. The residue was diluted with ethyl acetate/H2O (200 mL/200 mL), the organic layer was washed with brine (250 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to give tert-butyl N-[[4- [(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (12 g, crude) as a light yellow solid.¹H NMR: (400 MHz, DMSO-d6) δ 8.27 (d, J = 9.2 Hz, 2H), 7.48 (d, J = 7.6 Hz, 3H), 7.34-7.27 (m, 4H), 5.30 (s, 2H), 4.19 (d, J = 6.0 Hz, 1H), 1.45 (s, 9H). [0687] Step 2-2: tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl] methyl]carbamate

[0688] To a solution of tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (12 g, 33.5 mmol) in EtOH (150 mL) and H₂O (30 mL) was added Fe powder (9.35 g, 167 mmol) and NH₄Cl (17.9 g, 335 mmol). The mixture was stirred at 80 °C for 2 h. TLC (2:1 petroleum ether/ethyl acetate) showed the reaction was finished. The reaction mixture was cooled to rt and filtered. The cake was washed with ethyl acetate (400 mL), the combined filtrate was concentrated. The residue was diluted with water and ethyl acetate (400 mL/400mL), the organic layer was washed with brine (400 mL), dried over anhydrous Na₂SO₄, filtrated and concentrated to give tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl] methyl]carbamate (9 g, 81.9% yield) as a gray solid. This material was used in the next step without further purification. [0689] Step 2-3: tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate

[0690] To a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (5.65 g, 17.2 mmol) in MeCN (200 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (5.64 g, 22.0 mmol) and Et3N (6.16 g, 60.9 mmol) at -20 °C under nitrogen. The mixture was stirred at -20 °C for 1 h. 3-[5-(Aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6.80 g, 18.4 mmol, MsOH salt) was added to the mixture. The mixture was stirred at 20 °C for 15 h. TLC (2:1 petroleum ether/ethyl acetate) showed the reaction was finished. The reaction mixture was filtered, the cake was washed with MeCN (50 mL) and dried to give tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5-yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (9 g, crude) as a gray solid.¹H NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.43 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53- 7.23 (m, 9H), 6.88 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 6.0 Hz, 1H), 5.14-5.09 (m, 1H), 5.09 (s, 2H), 4.47-4.29 (m, 4H), 4.12 (d, J = 6.0 Hz, 2H), 2.92-2.91 (m, 1H), 2.62-2.51 (m, 1H), 2.41- 2.37 (m, 1H), 1.40 (s, 9H). [0691] Step 2-4: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3- piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea

[0692] A solution of tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (9.0 g, 14.3 mmol) and HCl (30 mL,12 N in dioxane) was stirred at 0°C for 1 h. LCMS showed the staring material was consumed. MeCN (500 mL) was added into the mixture slowly at 0-10 °C. After stirring for 30 minutes, the resulting solid was filtered and dried to give 1-[4-[[4- (aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl]urea (7.12 g, 88.0% yield, HC salt) as an off-white solid.¹H NMR: (400 MHz, DMSO-d6 ) δ 10.98 (s, 1H), 8.66 (s, 1H), 9.30 (s, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 6H), 7.31-7.29 (m, 2H), 6.89 (d, J = 2.0 Hz, 2H), 6.88 (s, 1H), 5.13-5.07 (m, 3H), 4.47-4.29 (m, 4H), 4.01 (t, J = 5.6 Hz, 2H), 2.95-2.87 (m, 1H), 2.62-2.52 (m, 1H), 2.50-2.38 (m, 1H), 2.01-1.94 (m, 1H). [0693] The examples listed in Table 1 were prepared by following similar procedures to those described in Example 1 and Example 2 from the appropriate commercially available starting materials. Table 1.

Example 32: Synthesis of 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3- methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea

[0694] Step 32-1: (S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile

[0695] A solution of methyl 2-(bromomethyl)-4-cyano-benzoate (1500 mg, 5.900 mmol, 1.00 equiv) in DMF (15.0 mL) were added (3S)-3-amino-3-methyl-piperidine-2,6-dione (839 mg, 5.900 mmol, 1.00 equiv) and TEA (2.0 mL). The mixture was stirred overnight at 100 ºC. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford (S)-2-(3-methyl- 2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (1570 mg, 5.542 mmol, 93% yield) as a light yellow solid. LCMS (ESI, m/z): 284 [M+H] ⁺. [0696] Step 32-2: tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)carbamate

[0697] To a solution of (S)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5- carbonitrile (780 mg, 2.750 mmol, 1.00 equiv) in a mixed solvent of DMF (10.0 mL) and THF (10.0 mL) were added di-tert-butyl dicarbonate (120 mg, 5.500 mmol, 2.00 equiv) and 6.0 g Raney Ni. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The solid was filtered out and the filter cake was washed with 30.0 mL MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10:1) to afford tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (247.0 mg, 0.637 mmol, 23% yield) as a white solid. LCMS (ESI, m/z): 388 [M+H] ⁺. [0698] Step 32-3: (S)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6- dione

[0699] To a stirred mixture of tert-butyl (S)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)carbamate (247 mg, 0.640 mmol, 1.00 equiv) in 1,4-Dioxane (3.0 mL) was added 3.0 mL HCl in 1,4-Dioxane. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure to afford (S)-3- (5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione (200 mg, crude, HCl salt) as a light yellow solid. LCMS (ESI, m/z): 288 [M+H] ⁺. [0700] Step 32-4: methyl 4-[(tert-butoxycarbonylamino)methyl]benzoate

[0701] To a stirred mixture of methyl 4-(aminomethyl)benzoate (1000 mg, 6.050 mmol) in Methanol (10.0 mL) was added di-tert-butyl dicarbonate (1387 mg, 6.360 mmol). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure to afford methyl 4-[(tert- butoxycarbonylamino)methyl]benzoate (1640 mg, 5.810 mmol, 95% yield) as a light yellow solid. LCMS (ESI, m/z): 266 [M+H] ⁺. [0702] Step 32-5: tert-butyl N-[[4-(hydroxymethyl)phenyl]methyl]carbamate

[0703] To a stirred solution of methyl 4-[(tert-butoxycarbonylamino)methyl]benzoate (900 mg, 3.390 mmol, 1.00 equiv) in a mixed solvent of 1,4-dioxane (5.0 mL) and water (5.0 mL) was added NaBH₄ (645 mg, 17.000 mmol, 5.00 equiv) in portions at room temperature. The resulting mixture was stirred for overnight at room temperature. The reaction was quenched with 50 mL water. The resulting mixture was extracted with 50.0 mL EtOAc. After combination of the organic phase and dried over anhydrous Na2SO4, filtration was performed and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions ( Spherial C18, 120 g, 20~40 μm; Mobile Phase A: water(0.05% NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 9.0 min ) to afford tert-butyl N- [[4-(hydroxymethyl)phenyl]methyl]carbamate (400.0 mg, 1.685 mmol, 49% yield) as a light yellow solid. LCMS (ESI, m/z): 238 [M+H] ⁺. [0704] Step 32-6: tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate

[0705] To a stirred mixture of tert-butyl N-[[4-(hydroxymethyl)phenyl]methyl]carbamate (400 mg, 1.690 mmol, 1.00 equiv) in DMF (8.0 mL) was added 1-fluoro-4-nitro-benzene (475 mg, 3.370 mmol, 2.00 equiv). To the above mixture was added K₂CO₃ (697 mg, 5.060 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 100 °C. Filtration was performed and the filter cake was washed with 15.0 mL MeCN. The filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions (Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water(0.05% TFA ), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 8.5 min) to afford tert-butyl N-[[4-[(4- nitrophenoxy)methyl]phenyl]methyl]carbamate (410.0 mg, 1.144 mmol, 67% yield) as a yellow solid. LCMS (ESI, m/z): 359 [M+H] ⁺. [0706] Step 32-7: tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate

[0707] To a stirred mixture of tert-butyl N-[[4-[(4- nitrophenoxy)methyl]phenyl]methyl]carbamate (390 mg, 1.090 mmol, 1.00 equiv) in mixed solvent of ethanol (5.0 mL) and water (1.0 mL) were added Fe (303 mg, 5.450 mmol, 5.00 equiv) and NH4Cl (587 mg, 10.880 mmol, 10.00 equiv). The above mixture was stirred for 2 h at 80°C.20 mL ethanol was added to dilute to reaction and the solid was filtered out. The filtrate was concentrated under reduced pressure. He residue was re-dissolved in 20.0 mL EtOAc and filtered. The filtrate was concentrated under vacuum to afford tert-butyl N-[[4- [(4-aminophenoxy)methyl]phenyl]methyl]carbamate (342.0 mg, 1.041 mmol, 95% yield) as a brown solid. LCMS (ESI, m/z): 329 [M+H] ⁺. [0708] Step 32-8: tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate

[0709] To a stirred mixture of tert-butyl N-[[4-[(4- aminophenoxy)methyl]phenyl]methyl]carbamate (109 mg, 0.330 mmol, 1.00 equiv) in DCE (3.0 mL) was added carbonyl diimidazole (59 mg, 0.370 mmol, 1.12 equiv). The resulting mixture was stirred for 4 h at 60 °C. It was concentrated under reduced pressure and the residue was dissolved in 3.0 mL MeCN. To the above mixture was added (S)-3-(5- (aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6-dione HCl salt (107 mg, 0.330 mmol, 1.00 equiv) and 0.3 mL TEA in 1.0 mL DMF. The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions (Spherial C18, 40 g, 20~40 μm; Mobile Phase A: water (0.05% TFA ), Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 7min) to afford tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (100.0 mg, 0.155 mmol, 46% yield) as a light brown solid. LCMS (ESI, m/z): 642 [M+H] ⁺. [0710] Step 32-9: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[1-oxo-2-[rac-(3S)-3- methyl-2,6-dioxo-3-piperidyl]isoindolin-5-yl]methyl]urea

[0711] To a stirred mixture of tert-butyl (S)-(4-((4-(3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (95 mg, 0.150 mmol, 1.00 equiv) in 1,4-dioxane (2.0 mL) was added HCl in 1,4-Dioxane (3.0 mL). The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was dissolved in 1.0 ml ACN, and then added 1.0 ml saturated NaHCO₃ solution to adjust the pH value to 8. It was concentrated and the crude product was purified directly by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 32% B in 10 min, 32% B; Wave Length: 254 nm; RT1(min): 9.32;) to afford 1-(4-{[4- (aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3S)-3-methyl-2,6-dioxopiperidin-3-yl]-1- oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea (40.0 mg, 49% yield, TFA salt) as a white solid. LCMS (ESI, m/z): 542 [M+H] ⁺.¹H NMR (400 MHz, Methanol-d4) δ 7.68 (d, J = 7.9 Hz, 1H), 7.57 – 7.42 (m, 6H), 7.28 – 7.20 (m, 2H), 6.93 – 6.87 (m, 2H), 5.09 (s, 2H), 4.68 (s, 2H), 4.49 (s, 2H), 4.11 (s, 2H), 2.88 – 2.73 (m, 2H), 2.73 – 2.61 (m, 1H), 2.04 – 1.93 (m, 1H), 1.77 (s, 3H). Example 33: Synthesis of 1-(4-{[4-(aminomethyl)phenyl]methoxy}phenyl)-3-({2-[(3R)-3- methyl-2,6-dioxopiperidin-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea

[0712] Step 33-1: (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile

[0713] To a stirred mixture of (3R)-3-amino-3-methyl-piperidine-2,6-dione; hydrobromide (1000 mg, 4.483 mmol, 1.00 equiv) in DMF (10.0 mL) was added methyl 2-(bromomethyl)- 4-cyano-benzoate (1139 mg, 4.483 mmol, 1.00 equiv) and TEA (0.8 mL). The resulting mixture was stirred for 12h at 110 °C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20/1) to afford (R)-2-(3-methyl-2,6- dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (320.0 mg, 1.130 mmol, 25% yield) as a yellow solid. LCMS (ESI, m/z): 284 [M+H]⁺. [0714] Step 33-2: tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)carbamate

[0715] To a stirred mixture of 2.0 g Raney Ni and (R)-2-(3-methyl-2,6-dioxopiperidin-3-yl)- 1-oxoisoindoline-5-carbonitrile (200 mg, 0.706 mmol, 1.00 equiv) in a mixed solvent of DMF (8.0 mL) in THF (12.0 mL) was added Boc2O (308 mg, 1.411 mmol, 2.00 equiv) at room temperature. The resulting mixture was stirred for 12h at room temperature under H₂ atmosphere. Desired product could be detected by LCMS. The solid was filtered out, the filter cake was washed with 60.0 mL MeCN. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC [MeOH/DCM (1/20)] to afford tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)carbamate (92.0 mg, 0.237 mmol, 34% yield) as a colorless oil. LCMS (ESI, m/z): 388 [M+H]⁺. [0716] Step 33-3: (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3-methylpiperidine-2,6- dione

[0717] To a stirred mixture of tert-butyl (R)-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)carbamate (92 mg, 0.237 mmol, 1.00 equiv) in DCM (10.0 mL) was added TFA (3.0 mL). The resulting mixture was stirred for 1h at room temperature and then concentrated under vacuum to afford (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3- methylpiperidine-2,6-dione (107.0 mg, crude, TFA salt) as a yellow oil. LCMS (ESI, m/z): 288 [M+H]⁺. [0718] Step 33-4: (R)-1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(3-methyl-2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea

[0719] To a stirred mixture of (R)-3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)-3- methylpiperidine-2,6-dione trifluoroacetic acid salt (100 mg, 0.249 mmol, 1.00 equiv) and 0.5 mL TEA in DCE (4.0 mL) was added carbonyl diimidazole (48 mg, 0.298 mmol, 1.20 equiv) at room temperature. The resulting mixture was stirred at 60°C for 1 h and then concentrated under reduced pressure. The residue was re-dissolved in 4.0 mL MeCN and add a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (98 mg, 0.298 mmol, 1.20 equiv). The resulting mixture was stirred for 2h at room temperature and concentrated under vacuum. The above crude Boc-protected intermediate was dissolved in 5.0 mL 1,4-dioxane and 5.0 mL 4 M HCl in dioxane and then stirred for 2h at room temperature. After the mixture was concentrated under reduced pressure, the crude product was dissolved in 1.0 ml ACN, and then added 1.0 ml saturated NaHCO₃ solution to adjust the PH value to 8. The resulting solution of the crude product was purified by directly Prep- HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 25% B in 10 min, 25% B; Wave Length: 254 nm; RT1(min): 9.37) to afford (R)-1-(4-((4- (aminomethyl)benzyl)oxy)phenyl)-3-((2-(3-methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)urea (34.5 mg, 0.054 mmol, 15% , 100% ee) (TFA salt) as a white solid. LCMS (ESI, m/z): 542 [M+H]⁺.¹H NMR: (400 MHz, Methanol-d4) δ 7.68 (d, J = 7.9 Hz, 1H), 7.57 – 7.49 (m, 3H), 7.49 – 7.42 (m, 3H), 7.28 – 7.21 (m, 2H), 6.94 – 6.87 (m, 2H), 5.09 (s, 2H), 4.68 (s, 1H), 4.49 (s, 2H), 4.11 (s, 2H), 2.89 – 2.73 (m, 2H), 2.73 – 2.61 (m, 1H), 2.04 – 1.93 (m, 1H), 1.77 (s, 3H). Example 34: Synthesis of 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol- 5-yl]methyl}-1-(4-{[(1r,4r)-4-(aminomethyl)cyclohexyl]methoxy}phenyl)urea

[0720] Step 34-1: tert-butyl N-[[4-[(4-nitrophenoxy)methyl]cyclohexyl]methyl]carbamate

[0721] To a stirred mixture of tert-butyl (((1r,4r)-4- (hydroxymethyl)cyclohexyl)methyl)carbamate (300 mg, 1.234 mmol, 1.00 equiv) in THF (6.0 mL) were added 4-nitrophenol (171 mg, 1.230 mmol, 1.00 equiv) and Triphenylphosphine (355 mg, 1.360 mmol, 1.10 equiv). To the above mixture was added DIAD (0.3 mL, 1.360 mmol, 1.10 equiv) dropwise at 0°C and then stirred for 2h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions ( Spherial C18, 120 g, 20~40 μm; Mobile Phase A: water(0.05% NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 90 mL/min; Gradient: 0% B to 100% B in 30 min, 210 nm; RT: 15.0 min) to afford tert-butyl (((1r,4r)-4- ((4-nitrophenoxy)methyl)cyclohexyl)methyl)carbamate (340.0 mg, 0.932 mmol, 75% yield) as a light yellow solid. LCMS (ESI, m/z): 365 [M+H] ⁺. [0722] Step 34-2: tert-butyl (((1r,4r)-4-((4- aminophenoxy)methyl)cyclohexyl)methyl)carbamate

[0723] A stirred solution of tert-butyl (((1r,4r)-4-((4- nitrophenoxy)methyl)cyclohexyl)methyl)carbamate (330 mg, 0.910 mmol) in mixed solvent of Ethanol (5.0 mL) and Water (1.0 mL) were added NH4Cl (484 mg, 9.070 mmol, 10.00 equiv) and Fe (253 mg, 4.530 mmol, 5.00 equiv). The resulting mixture was stirred for 2h at 80°C and then diluted with 20.0 mL ethanol. The solid was filtered out and the filtrate was concentrated under reduced pressure.30.0 mL EA was added to the above residue and once more filtration again. The filtrate was concentrated under vacuum to afford tert-butyl (((1r,4r)-4-((4-aminophenoxy)methyl)cyclohexyl)methyl)carbamate (225.0 mg, 0.672 mmol, 74% yield) as a light brown solid. LCMS (ESI, m/z): 335 [M+H] ⁺. [0724] Step 34-3: tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate

[0725] To a stirred mixture of tert-butyl (((1r,4r)-4-((4- aminophenoxy)methyl)cyclohexyl)methyl)carbamate (50 mg, 0.150 mmol) in DCE (2.0 mL) was added carbonyl diimidazole (26 mg, 0.160 mmol, 1.07 equiv). The resulting mixture was stirred for 2h at 60°C. The resulting mixture was concentrated under reduced pressure. To the above residue was added 2.0 mL MeCN and then a solution of 3-[5-(aminomethyl)-1- oxo-isoindolin-2-yl]piperidine-2,6-dione trifluoroacetic acid salt (58 mg, 0.1500 mmol, 1.00 equiv) and 0.5 mL TEA in 1.0 mL DMF was added. The resulting mixture was stirred for additional 2h at rt. This was purified by reverse flash chromatography with the following conditions (Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water(0.05% TFA ), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 10 min, 210 nm; RT: 12 min) to afford tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate (33.0 mg, 0.052 mmol, 34% yield) as a light yellow solid. LCMS (ESI, m/z): 634 [M+H] ⁺. [0726] Step 34-4: 1-(4-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)phenyl)-3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea

[0727] To a stirred mixture of tert-butyl (((1r,4r)-4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)cyclohexyl)methyl)carbamate (28 mg, 0.040 mmol) in 1,4-Dioxane (2.0 mL) was added HCl in 1,4-Dioxane (2.0 mL) dropwise at room temperature. The resulting mixture was stirred for 2h at room temperature and then concentrated under reduced pressure. The crude product was dissolved in 1.0 ml ACN, and then added 1.0 ml saturated NaHCO3 solution to adjust the PH value to 8. The resulting solution was purified Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min, 20% B; Wave Length: 254 nm; RT1(min): 10.57;) to afford 1-(4-(((1r,4r)-4-(aminomethyl)cyclohexyl)methoxy)phenyl)-3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (12.0 mg, 0.022 mmol, 50% yield) as a white solid. LCMS (ESI, m/z): 534 [M+H] ⁺.¹H NMR (300 MHz, Methanol-d4) δ 8.85 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.58 – 7.45 (m, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.00 (s, 1H), 6.82 (d, J = 9.0 Hz, 2H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.58 – 4.39 (m, 4H), 3.77 (d, J = 6.2 Hz, 2H), 3.00 – 2.90 (m, 1H), 2.70 – 2.60 (m, 4H), 2.59 – 2.40 (m, 2H), 2.00 (m, 1H), 1.99 – 1.75 (m, 4H), 1.70 – 1.55 (s, 1H), 1.50 – 1.42 (s, 1H), 1.10 – 0.85 (m, 4H). Example 35: Synthesis of 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol- 5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea

[0728] Step 35-1: (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexan-1-ol

[0729] To a stirred mixture of (1r,4r)-4-aminocyclohexan-1-ol (240 mg, 2.080 mmol, 1.00 equiv) in Methanol (5.0 mL) was added hexane-2,5-dione (0.3 mL, 2.080 mmol, 1.00 equiv). The above mixture was added p-toluenesulfonic acid (86 mg, 0.500 mmol, 2.40 equiv) and stirred for 4h at 60^oC. The resulting mixture was concentrated under reduced pressure. The residue was dissolved 50.0 mL EA and washed with 15 mL 1M HCl aq and then 15 mL saturated NaHCO3 aq solution. After dried over anhydrous Na2SO4 and filtration the filtrate was concentrated under reduced pressure to afford (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1- yl)cyclohexan-1-ol (230mg, 1.189 mmol, 57% yield) as a yellow solid. LCMS (ESI, m/z): 194 [M+H] ⁺. [0730] Step 35-2: 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl-1H-pyrrole

[0731] To a stirred mixture of (1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclohexan-1-ol (332 mg, 1.720 mmol, 1.00 equiv) in THF (5.0 mL) was added NaH (82 mg, 3.440 mmol, 2.00 equiv) in portions at room temperature. To the above mixture was added a solution of 1- bromo-4-(bromomethyl)benzene (430 mg, 1.720 mmol) in 5.0 mL THF. The resulting mixture was stirred overnight at 60 ^oC. The reaction was quenched with 20.0 mL H2O. The resulting mixture was extracted with 50.0 mL * 3 EA. The combined organic layers was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions ( Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water(0.05% TFA ), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 10 min, 210 nm; RT: 6 min) to afford 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl-1H-pyrrole (420.0 mg, 1.159 mmol, 67% yield) as a yellow solid. LCMS (ESI, m/z): 362 [M+H] ⁺. [0732] Step 35-3: tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1-

[0733] To a stirred mixture of 1-((1r,4r)-4-((4-bromobenzyl)oxy)cyclohexyl)-2,5-dimethyl- 1H-pyrrole (420 mg, 1.160 mmol, 1.00 equiv) in mixed solvent of 1,4-Dioxane (3.0 mL) and Water (0.3 mL) was added potassium; potassium N-Boc-aminomethyl trifluoroborate (273 mg, 1.160 mmol, 1.16 equiv). To the above mixture was added Cs2CO3 (1130 mg, 3.480 mmol, 3.48 equiv) and XPhos Pd G3 (106 mg, 0.120 mmol, 0.12 equiv). The resulting mixture was stirred overnight at 110°C under nitrogen atmosphere. The reaction was quenched with 10.0 mL water and then extracted with 40.0 mL * 3 EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The above residue was purified by reverse flash chromatography with the following conditions (Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water(0.05% NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 10 min) to afford tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl- 1H-pyrrol-1-yl)cyclohexyl)oxy)methyl)benzyl)carbamate (125.0 mg, 0.303 mmol, 26% yield) as a yellow oil. LCMS (ESI, m/z): 413 [M+H] ⁺. [0734] Step

To a stirred mixture of tert-butyl (4-((((1r,4r)-4-(2,5-dimethyl-1H-pyrrol-1- yl)cyclohexyl)oxy)methyl)benzyl)carbamate (102 mg, 0.250 mmol, 1.00 equiv) in IPA (4.3 mL) and Water (1.1 mL) was added hydroxylamine;hydrochloride (257 mg, 3.710 mmol, 1.50 equiv). To the above mixture was added TEA (0.4 mL) and then stirred overnight at 80^oC. The crude product was purified by reverse flash chromatography with the following conditions ( Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water (0.05% NH4HCO3 ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 0% B to 100% B in 10 min, 210 nm; RT: 9 min) to afford tert-butyl (4-((((1r,4r)-4-aminocyclohexyl)oxy)methyl)benzyl)carbamate (65.0 mg, 0.194 mmol, 78% yield) as a yellow solid. LCMS (ESI, m/z): 335 [M+H] ⁺. [0735] Step 35-5: tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate

[0736] To a stirred mixture of tert-butyl (4-((((1r,4r)-4- aminocyclohexyl)oxy)methyl)benzyl)carbamate (44 mg, 0.130 mmol, 1.00 equiv) in DCE (2.0 mL) was added carbonyl diimidazole (23 mg, 0.140 mmol, 1.08 equiv). The resulting mixture was stirred for 2h at 60^oC.The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 2.0 mL MeCN and then added a solution 3-[5-(aminomethyl)-1- oxo-isoindolin-2-yl]piperidine-2,6-dione;2,2,2-trifluoroacetaic acid salt (51 mg, 0.130 mmol, 1.00 equiv) and 1.0 mL TEA in DMF. The resulting mixture was stirred for 2h at room temperature. The crude product was purified by reverse flash chromatography with the following conditions ( Spherial C18, 48 g, 20~40 μm; Mobile Phase A: water(0.05% TFA ), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 11.0 min) to afford tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate (21.0 mg, 0.033 mmol, 25% yield) as a light yellow solid. LCMS (ESI, m/z): 634 [M+H] ⁺. [0737] Step 35-6: 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5- yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea

[0738] To a stirred mixture of tert-butyl (4-((((1r,4r)-4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)cyclohexyl)oxy)methyl)benzyl)carbamate (16 mg, 0.030 mmol, 1.00 equiv) in DCM (1.8 mL) was added TFA (0.6 mL). The resulting mixture was stirred for 2h at room temperature. After the mixture was concentrated under reduced pressure, the crude product was dissolved in 1.0 ml ACN, and then added 1.0 ml saturated NaHCO₃ solution to adjust the PH value to 8. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 2% B to 20% B in 10 min, 20% B; Wave Length: 254 nm; RT1(min): 10.57; Number Of Runs: 0) to afford 3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-2,3-dihydro-1H- isoindol-5-yl]methyl}-1-[(1r,4r)-4-{[4-(aminomethyl)phenyl]methoxy}cyclohexyl]urea (7.6 mg, 0.014 mmol, 56% yield) as a white solid. LCMS (ESI, m/z): 534 [M+H] ⁺.¹H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.49 (s, 1H), 7.47 – 7.37 (m, 1H), 7.42 (s, 4H), 5.14 (dd, J = 13.3, 5.2 Hz, 1H), 4.57 (s, 2H), 4.55 – 4.39 (m, 4H), 4.09 (s, 2H), 3.44 – 3.35 (m, 1H), 2.91 (ddd, J = 17.6, 13.5, 5.4 Hz, 1H), 2.78 (ddd, J = 17.5, 4.7, 2.4 Hz, 1H), 2.49 (qd, J = 13.2, 4.6 Hz, 1H), 2.21 – 2.08 (m, 1H), 2.07 (s, 2H), 1.97 (d, J = 12.7 Hz, 2H), 1.47 – 1.39 (m, 1H), 1.37 (d, J = 10.6 Hz, 1H), 1.31 – 1.16 (m, 2H). Example 36: Synthesis of 1-(4-((1s,3s)-3-(aminomethyl)cyclobutoxy)phenyl)-3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureatrifluroacetic acid salt

[0739] Step 36-1: tert-butyl (((cis-1,3)-3-hydroxycyclobutyl)methyl)carbamate

[0740] To a stirred mixture of (cis-1,3 )-3-(aminomethyl)cyclobutan-1-ol HCl salt (I-1) (200 mg, 1.459 mmol) in 5.0 mL MeOH was added TEA (295 mg, 2.918 mmol). The resulting mixture was stirred for 1 min at room temperature. To the above mixture was added di-tert- butyl dicarbonate (350 mg, 1.605 mmol). The resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford tert- butyl (((1s,3s)-3-hydroxycyclobutyl)methyl)carbamate (I-2) (280 mg, 1.393 mmol, 95.5% yield) as a white solid. LCMS (ESI, m/z): 202 [M+H] ⁺. [0741] Step 36-2: tert-butyl (((1s,3s)-3-(4-nitrophenoxy)cyclobutyl)methyl)carbamate

[0742] To a stirred mixture of tert-butyl (((1s,3s)-3-hydroxycyclobutyl)methyl)carbamate (I- 2) (83 mg, 0.413 mmol) in 4.0 mL DMF was added NaH (60 mg, 2.478 mmol) at 0°C and stirred for 10 min at room temperature. To the above mixture was added 1-fluoro-4-nitro- benzene (I-3) (64 mg, 0.454 mmol). The resulting mixture was stirred for 1 h at room temperature. The reaction was quenched with 10.0 mL water at 0°C. The resulting mixture was extracted with ethylacetate (3X10.0 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (Spherial C18, 90 g, 20~40 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 220 nm; RT: 14 min) to afford tert- butyl (((1s,3s)-3-(4-nitrophenoxy)cyclobutyl)methyl)carbamate (I-4)(95 mg, 0.295 mmol, 71.4% yield) as a light yellow solid. LCMS (ESI, m/z): 323 [M+H] ⁺. [0743] Step 36-3: tert-butyl (((1s,3s)-3-(4-aminophenoxy)cyclobutyl)methyl)carbamate

[0744] To a stirred mixture of tert-butyl (((1s,3s)-3-(4- nitrophenoxy)cyclobutyl)methyl)carbamate (I-4) (100 mg, 0.310 mmol) in 3.0 mL THF was added NH4Cl (233 mg, 4.402 mmol) in 1.0 mL water . To the above mixture was added Zn (121 mg, 1.860 mmol). The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered. The filter cake was washed with THF (3X5.0 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 5.0 mL EA. The resulting mixture was filtered and the filter cake was washed with EA (3X10.0 mL). The filtrate was concentrated under reduced pressure to afford tert-butyl (((1s,3s)-3-(4- aminophenoxy)cyclobutyl)methyl)carbamate (I-5) (90 mg, 0.308 mmol, 99.4% yield) as a light yellow solid. LCMS (ESI, m/z): 293 [M+H] ⁺. [0745] Step 36-4: tert-butyl (((1s,3s)-3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)ureido)phenoxy)cyclobutyl)methyl)carbamate

[0746] To a stirred mixture of carbonyl diimidazole (1996 mg, 12.320 mmol) in 13.0 ml DCE was added tert-butyl (((1s,3s)-3-(4-aminophenoxy)cyclobutyl)methyl)carbamate (I-5) (90 mg, 0.308 mmol) in 1.0 mL DCE dropwise slowly. The resulting mixture was stirred for 1 h at room temperature. The resulting mixture was washed with water (3x30.0 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in 3.0 mL MeCN. To the above mixture was added 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione HCl salt (I-6)(95 mg, 0.308 mmol) and TEA (94 mg, 0.924 mmol) in 1.0 mL MeCN. The resulting mixture was stirred 1 h at room temperature. The crude product was purified by reverse phase flash with the following conditions (Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: I; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 220 nm; RT: 8.0 min) to afford tert-butyl (((1s,3s)-3-(4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)cyclobutyl)methyl)carbamate (I-7) (120 mg, 0.203 mmol, 65.9% yield) as a light yellow solid. LCMS (ESI, m/z): 592 [M+H] ⁺. [0747] Step 36-5: 1-(4-((1s,3s)-3-(aminomethyl)cyclobutoxy)phenyl)-3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea TFA salt

[0748] To a stirred mixture of tert-butyl (((1s,3s)-3-(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)cyclobutyl)methyl)carbamate (I-7) (100 mg, 0.1700 mmol) in 6.0 mL DCM was added 2.0 mL TFA. The resulting mixture was stirred for 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 7.5 min, 50% B; Wave Length: 254/210 nm; RT: 8 min) to afford 1-(4-((1s,3s)-3- (aminomethyl)cyclobutoxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)urea (Ex.1) TFA salt (33.3 mg, 0.055 mmol, 32.4% yield) as a white solid. LCMS (ESI, m/z):492 [M+H] ⁺. [0749] LCMS Analytic Conditions: Column: HALO C18, Column 3.0*30 mm, 2.7 um; Mobile phase A: water/0.05%TFA, Mobile phase B: ACN/0.05%TFA; Flow rate: 1.5000 mL/min; Gradient: 5% B to 40% B in 1.69 min; 40% B to 100% B in 0.60 min;100% B to 100% B in 0.50 min ;100% B to 5 % B in 0.03 min;254 nm; RT: 0.970 min. [0750] 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.48 (s, 1H), 7.73 – 7.66 (m, 3H), 7.51 (s, 1H), 7.44 (dd, J = 7.8, 1.4 Hz, 1H), 7.34 – 7.23 (m, 2H), 6.73 (dd, J = 7.5, 5.3 Hz, 3H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.53 (p, J = 7.1 Hz, 1H), 4.45 (d, J = 17.4 Hz, 1H), 4.40 (d, J = 5.9 Hz, 2H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 – 2.85 (m, 3H), 2.59 (tdd, J = 12.2, 6.6, 3.3 Hz, 4H), 2.47 – 2.32 (m, 1H), 2.17 (hept, J = 7.8 Hz, 1H), 2.00 (dtd, J = 10.6, 5.4, 2.7 Hz, 1H), 1.80 (tdd, J = 9.6, 7.5, 2.8 Hz, 2H). [0751] The examples listed in Table 2 were prepared using similar procedures to those described in Example 36, with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry.

.

Example 50: Synthesis of 1-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)- 3-(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)urea

[0752] Step 50-1: ((1s,4s)-cyclohexane-1,4-diyl)dimethanol

[0753] A mixture of (1s,4s)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (I-8)(2.000 g, 10.74 mmol) in tetrahydrofuran (40 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. After 0.5 h lithium aluminum hydride (0.898 g, 23.63 mmol) was added slowly and the mixture was stirred at 25 °C for 4 h under nitrogen atmosphere. TLC showed one new spot was detected. The reaction mixture was quenched by sodium hydroxide solution (0.5 M 8 mL) at 0 °C, and then dried (Na2SO4), filtered and concentrated under reduced pressure to give the crude product ((1s,4s)-cyclohexane-1,4-diyl)dimethanol (I-9)(0.700 g, 4.85 mmol, 45.2% yield) as a colorless oil. The crude product was used into the next step without further purification. [0754] Step 50-2: ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate

[0755] To a solution of ((1s,4s)-cyclohexane-1,4-diyl)dimethanol (I-9)(0.600 g, 4.16 mmol), 4-methylbenzene-1-sulfonyl chloride (0.634 g, 3.33 mmol) in dichloromethane (30 mL) was added triethylamine (2.2 mL, 12.48 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 12 h. TLC showed three new spots were detected. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (2X50 mL). The combined organic layers were washed with sat. aq. NaCl solution (50 mL), dried (Na₂SO₄), filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford the product ((1s,4s)-4- (hydroxymethyl)cyclohexyl)methyl 4-methylbenzenesulfonate (I-10)(0.470 g, 1.57 mmol, 37.8% yield) as a yellow solid, which was confirmed by ¹H NMR. ¹H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.33 (t, J = 5.2 Hz, 1H), 3.91 (d, J = 7.2 Hz, 2H), 3.22 (dd, J = 5.2, 6.8 Hz, 2H), 2.42 (s, 3H), 1.83 - 1.66 (m, 1H), 1.48 (td, J = 3.2, 6.4z, 1H), 1.40 - 1.19 (m, 8H). [0756] Step 50-3: ((1s,4s)-4-((4-Nitrophenoxy)methyl)cyclohexyl)methanol

[0757] To a solution of ((1s,4s)-4-(hydroxymethyl)cyclohexyl)methyl 4- methylbenzenesulfonate (I-10)(0.470 g, 1.57 mmol), 4-nitrophenol (I-11) (0.307 g, 2.21 mmol) in DMF (10 mL) was added potassium carbonate (0.508 g, 3.69 mmol). The mixture was stirred at 80 °C for 12 h. TLC showed one new spot was detected. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL X 2). The combined organic layers were washed with aq. Sat. NaCl solution (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (10~50% ethyl acetate in petroleum ether) to afford the product ((1s,4s)-4-((4-nitrophenoxy)methyl)cyclohexyl)methanol (I-12) (0.450 g, 1.69 mmol, 92.0% yield) as a yellow solid, which was confirmed by ¹H NMR. ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 9.2 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H), 4.02 (d, J = 7.2 Hz, 2H), 3.32 (s, 2H), 1.96 (s, 1H), 1.59 - 1.32 (m, 10H). [0758] Step 50-4: ((1s,4s)-4-((4-Aminophenoxy)methyl)cyclohexyl)methanol

[0759] A mixture of ((1s,4s)-4-((4-nitrophenoxy)methyl)cyclohexyl)methanol (I-12)(0.500 g, 1.88 mmol) in tetrahydrofuran (10 mL) was degassed and purged with nitrogen for 3 times, Then palladium active/carbon catalyst (0.200 g, 0.19 mmol) was added and the mixture was stirred at 25 °C for 12 h under hydrogen (15 psi) atmosphere. TLC showed one new spot was detected. The mixture was filtered with diatomite to give the filtrate. The filtrate was concentrated under reduced pressure and purified by prep-TLC to afford the product ((1s,4s)- 4-((4-aminophenoxy)methyl)cyclohexyl)methanol (I-13)(0.264 g, 1.12 mmol, 59.5% yield) as a yellow solid, which was confirmed by ¹H NMR. ¹H NMR (400 MHz, DMSO-d6) δ 6.63 (d, J = 6.8 Hz, 2H), 6.54 - 6.44 (m, 2H), 4.56 (s, 2H), 4.36 (s, 1H), 3.70 (d, J = 5.2 Hz, 2H), 3.30 (s, 2H), 1.84 (s, 1H), 1.65 - 1.24 (m, 9H). [0760] Step 50-5: 4-nitrophenyl (4-(((1s,4s)-4- (hydroxymethyl)cyclohexyl)methoxy)phenyl)carbamate

[0761] To a solution of ((1s,4s)-4-((4-aminophenoxy)methyl)cyclohexyl)methanol (I- 13)(0.100 g, 0.42 mmol) in tetrahydrofuran (2 mL) was added (4-nitrophenyl) carbonochloridate (I-14) (0.102 g, 0.51 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.2 mL, 1.27 mmol) at 0 °C. The mixture was stirred at 25 °C for 1 h. TLC showed one new spot was detected. The mixture was concentrated under reduced pressure to give the product 4-nitrophenyl (4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)carbamate (I- 15)(0.120 g, 0.30 mmol, 70.5% yield) as a yellow solid. [0762] Step 50-6: 1-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4- (((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)urea

[0763] To a solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione;methanesulfonic acid (I-16) (0.101 g, 0.27 mmol) in DMF (2 mL) was added N-ethyl- N-isopropylpropan-2-amine (0.04 mL, 0.25 mmol) at 25 °C. After addition, the mixture was stirred at this temperature for 0.5 h and then 4-nitrophenyl (4-(((1s,4s)-4- (hydroxymethyl)cyclohexyl)methoxy)phenyl)carbamate (I-15) (0.100 g, 0.25 mmol) was added at 25 °C. The resulting mixture was stirred at 25 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was filtered to give the filtrate. The filtrate was purified by semi-preparative reverse phase-HPLC (20-50% acetonitrile in water + 0.225% formic acid, over 10 min). Then the collected fraction was lyophilized to afford the product 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-3-(4-(((1s,4s)-4-(hydroxymethyl)cyclohexyl)methoxy)phenyl)urea (EX.50) (0.020 g, 0.03 mmol, 14.7% yield, 97.2% purity) as a white solid, which was confirmed by ¹H NMR and QC-LCMS. MS (ESI) m/z: 535.4 [M+1]⁺ [0764] ¹H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.42 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 9.2 Hz, 2H), 6.68 - 6.60 (m, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.48 - 4.28 (m, 5H), 3.79 (d, J = 7.2 Hz, 2H), 3.31 - 3.29 (m, 2H), 2.96 - 2.87 (m, 1H), 2.61 (s, 1H), 2.38 (dd, J = 4.4, 13.6 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.92 - 1.83 (m, 1H), 1.57 - 1.34 (m, 9H). Example 51: Synthesis of Enantiomer 1-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-3-(4-(((1R,3R)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea (Absolute stereochemistry not defined)

[0765] Step 51-1: Methyl 3-(4-nitrophenoxy)cyclopentane-1-carboxylate

[0766] To a mixture of methyl 3-hydroxycyclopentane-1-carboxylate (I-17) (0.500 g, 3.47 mmol) and 4-nitrophenol (I-11) (0.579 g, 4.16 mmol) and triphenylphosphine (1.092 g, 4.16 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (0.842 g, 4.16 mmol) at 0 °C under nitrogen. The mixture was stirred at 70 °C for another 12 h. TLC showed one new spot was detected and the starting material was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column to afford product methyl 3-(4-nitrophenoxy)cyclopentane-1-carboxylate (I- 18) (0.563g, 2.24 mmol, 64.6% yield), which was confirmed by ¹H NMR.¹H NMR (400 MHz, CDCl3) δ 8.22 - 8.17 (m, 2H), 6.93 - 6.86 (m, 2H), 4.96 (s, 1H), 3.71 (s, 3H), 3.17 - 3.05 (m, 1H), 2.29 - 2.12 (m, 4H), 2.01 - 1.90 (m, 2H). [0767] Step 51-2: (3-(4-nitrophenoxy)cyclopentyl)methanol

[0768] To a mixture of methyl methyl 3-(4-nitrophenoxy)cyclopentane-1-carboxylate (I-18) (0.550 g, 2.07 mmol) in THF (10 mL) was added lithium borohydride (0.473 g, 12.44 mmol) at 0 °C under nitrogen. The mixture was stirred at 25 °C for another 2 h. TLC showed the reaction was consumed completely and one new spot was detected. The reaction mixture was quenched by hydrochloric acid (1 M, 10 mL) at 0 °C. The mixture was filtered. The filtrate was extracted with ethyl acetate (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to give a residue. The residue was purified by flash silica gel column (0-30% ethyl acetate in petroleum ether) to afford the product (3-(4-nitrophenoxy)cyclopentyl)methanol (I-19) (0.300 g, 1.27 mmol, 61.0% yield) as a yellow oil, which was confirmed by ¹H NMR.¹H NMR (400 MHz, CDCl3) δ 8.23 - 8.16 (m, 2H), 6.95 - 6.88 (m, 2H), 4.90 (ddd, J = 2.4, 5.6 Hz, 1H), 3.68 - 3.57 (m, 2H), 2.52 - 2.39 (m, 1H), 2.21 - 2.06 (m, 2H), 2.05 - 1.85 (m, 2H), 1.77 - 1.66 (m, 1H), 1.48 - 1.41 (m, 1H). [0769] Step 51-3: (3-(4-aminophenoxy)cyclopentyl)methanol

[0770] A mixture of (3-(4-nitrophenoxy)cyclopentyl)methanol (I-19)(0.300 g, 1.26 mmol) in THF (6 mL) was degassed and purged with nitrogen for 3 times. Then palladium/carbon (0.270 g, 0.13 mmol) was added to the mixture. The reactant mixture was stirred at 25 °C for 12 h under hydrogen atmosphere (15 Psi). TLC showed the reaction was consumed completely and the one new spot was detected. The reaction mixture was filtered. The filtrated was concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford the product (3-(4-aminophenoxy)cyclopentyl)methanol (I-20) (0.252 g, 1.22 mmol, 96.2% yield) as yellow oil, which was confirmed by ¹H NMR. ¹H NMR (400 MHz, CDCl3) δ 6.67 - 6.61 (m, 2H), 6.58 - 6.53 (m, 2H), 4.61 (dd, J = 2.4, 5.6 Hz, 1H), 3.50 (d, J = 6.8 Hz, 2H), 2.42 - 2.29 (m, 1H), 1.99 - 1.86 (m, 3H), 1.83 - 1.76 (m, 1H), 1.47 (ddd, J = 5.6, 8.8, 13.6 Hz, 1H), 1.34 - 1.25 (m, 1H). [0771] Step 51-4: Pure enantiomers ((1R,3R)-3-(4-aminophenoxy)cyclopentyl)methanol and ((1R,3R)-3-(4-aminophenoxy)cyclopentyl)methanol (absolute stereochemistry not defined)

[0772] (3-(4-Aminophenoxy)cyclopentyl)methanol (I-20)(0.250 g, 1.21 mmol) was separated by SFC separation (DAICEL CHIRALPAK IC(250mm*30mm,10um), Mobile phase: Phase A for carbon dioxide, and Phase B for IPA (0.1%ammonium hydroxide isopropanol); Gradient elution: IPA (0.1% ammonium hydroxide) in carbon dioxide from 30% to 30%, Flow rate: 150 mL/min;3.8 min) to afford two fractions. The fraction 1 was concentrated in vacuum to afford the pure enantiomer ((1R,3R)-3-(4-aminophenoxy)cyclopentyl)methanol (I- 20B) (0.122 g, 0.59 mmol, 48.8% yield) as yellow oil, which was confirmed by ¹H NMR and 2D-NMR..¹H NMR (400 MHz, DMSO-d6) δ 6.71 - 6.37 (m, 4H), 4.94 - 4.25 (m, 4H), 3.29 (d, J = 5.2 Hz, 2H), 2.25 - 2.11 (m, 1H), 1.94 - 1.71 (m, 3H), 1.69 - 1.57 (m, 1H), 1.54 - 1.42 (m, 1H), 1.37 - 1.22 (m, 1H). Absolute stereochemistry of enantiomer (I-20B) was not assigned. [0773] The fraction 2 was concentrated in vacuum to afford second pure enantiomer ((1S,3S)-3-(4-aminophenoxy)cyclopentyl)methanol (I-20C) (0.125 g, 0.61 mmol, 50.0% yield) as yellow oil.¹H NMR (400 MHz, DMSO-d6) δ 6.71 - 6.37 (m, 4H), 4.94 - 4.25 (m, 4H), 3.29 (d, J = 5.2 Hz, 2H), 2.25 - 2.11 (m, 1H), 1.94 - 1.71 (m, 3H), 1.69 - 1.57 (m, 1H), 1.54 - 1.42 (m, 1H), 1.37 - 1.22 (m, 1H). [0774] Absolute stereochemistry of enantiomer (I-20C) was not assigned. [0775] Step 51-5: 4-nitrophenyl (4-(((1R,3R)-3- (hydroxymethyl)cyclopentyl)oxy)phenyl)carbamate

[0776] To a mixture of pure enantiomer I-20B (0.122 g, 0.59 mmol) and 4-nitrophenyl chloroformate (I-14) (0.142 g, 0.71 mmol) in THF (2 mL) was added N,N- diisopropylethylamine (0.3 mL, 1.77 mmol) at 0 °C under nitrogen. The mixture was stirred at 25 °C for another 1 h. TLC showed one new spot detected and the starting material was consumed completely. The reaction was filtered. The filtrate was concentrated under reduced pressure to afford the crude 4-nitrophenyl (4-(((1R,3R)-3- (hydroxymethyl)cyclopentyl)oxy)phenyl)carbamate (I-21) (0.202 g, 92.2% yield), as a single enantiomer. [0777] Step 51-6: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4- (((1R,3R)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea (absolute stereochemistry not defined)

[0778] To a mixture crude 4-nitrophenyl (4-(((1R,3R)-3- (hydroxymethyl)cyclopentyl)oxy)phenyl)carbamate (I-21)(0.202 g, 0.54 mmol) and 3-(5- (aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonic acid salt (I-16) (0.200 g, 0.54 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.09 mL, 0.54 mmol) at 25 °C under nitrogen. The mixture was stirred at 25 °C for 12 h. LCMS showed the desired mass was detected. The reaction mixture was filtered. The pH of the filtrate was adjusted to 5 with formic acid. The mixture was purified by semi-preparative reverse phase HPLC (15-45% acetonitrile in water + 0.225% formic acid, 15 min). The collected fraction was lyophilized to afford the product 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-3-(4-((( 1R,3R)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea (EX.51)(0.007 g, 0.01 mmol, 2.6% yield 100.0% purity) as a white solid, which was confirmed by ¹H NMR and QC LCMS. Absolute stereochemistry for the enantiomer EX.51 was not established. LCMS: m/z: 507.4 [M+1]⁺ [0779] 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.44 - 8.36 (m, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 - 7.39 (m, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 9.2 Hz, 2H), 6.67 - 6.59 (m, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.71 (td, J = 2.8, 5.6 Hz, 1H), 4.54 - 4.25 (m, 5H), 3.35 - 3.32 (m, 2H), 2.95 - 2.87 (m, 1H), 2.64 - 2.56 (m, 1H), 2.38 (dd, J = 4.4, 13.2 Hz, 1H), 2.20 (td, J = 7.2, 14.8 Hz, 1H), 2.03 - 1.91 (m, 2H), 1.84 - 1.73 (m, 2H), 1.71 - 1.61 (m, 1H), 1.55 (ddd, J = 5.6, 8.4, 14.0 Hz, 1H), 1.38 - 1.27 (m, 1H). Example 52: Synthesis of 1-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3- (4-(((1S,3S)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea (Absolute stereochemistry not defined )

[0780] Step 53-1: rac-Methyl (1R,3S)-3-(4-nitrophenoxy)cyclopentane-1-carboxylate

[0781] A mixture of 4-nitrophenol (I-11 (0.579 g, 4.16 mmol), rac-methyl (1R,3R)-3- hydroxycyclopentane-1-carboxylate (I-22) (0.500 g, 3.47 mmol) and triphenylphosphine (1.368 g, 5.20 mmol) in tetrahydrofuran (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. After 0.5 h, a solution of diisopropyl azodicarboxylate (1.0 mL, 5.2 mmol) in tetrahydrofuran (2 mL) was added and the mixture was stirred at 70 °C for 12 h under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 2), the combined organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated in vacuum to give a residue. The mixture was purified by TLC to afford the product rac-methyl (1R,3S)-3-(4-nitrophenoxy)cyclopentane-1-carboxylate (I-23) (0.260 g, 0.98 mmol, 28.3% yield) as a colorless oil.¹H NMR (400 MHz, DMSO-d6) δ 8.22 - 8.15 (m, 2H), 7.12 - 7.06 (m, 2H), 5.03 - 4.97 (m, 1H), 3.58 (s, 3H), 2.98 - 2.88 (m, 1H), 2.44 - 2.34 (m, 1H), 2.02 - 1.91 (m, 4H), 1.91 - 1.83 (m, 1H), 1.29 - 1.11 (m, 1H). [0782] Step 53-2: rac-((1R,3S)-3-(4-Nitrophenoxy)cyclopentyl)methanol

[0783] A mixture of methyl rac-methyl (1R,3S)-3-(4-nitrophenoxy)cyclopentane-1- carboxylate (I-23) (0.260 g, 0.98 mmol) in tetrahydrofuran (10 mL) was degassed and purged with nitrogen for three times and then the mixture was stirred at 0 °C for 0.5 h under nitrogen atmosphere. After 0.5 h lithium borohydride (0.200 g, 5.26 mmol) was added slowly and the mixture was stirred at 25 °C for 2 h under nitrogen atmosphere. TLC showed one new spot was detected. The reaction mixture was quenched by hydrochloric acid (1M, 10 mL) at 0 °C and then diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC to afford the product rac-((1R,3S)-3-(4- nitrophenoxy)cyclopentyl)methanol (I-24) (0.220 g, 0.93 mmol, 94.6% yield) as a yellow oil, which was confirmed by ¹H NMR and 2D NMR. [0784] ¹H NMR (400 MHz, DMSO-d6) δ 8.21 - 8.16 (m, 2H), 7.14 - 7.07 (m, 2H), 4.97 (dt, J = 3.0, 6.2 Hz, 1H), 4.54 (t, J = 5.2 Hz, 1H), 3.34 - 3.30 (m, 2H), 2.26 - 2.05 (m, 2H), 2.01 - 1.90 (m, 1H), 1.83 - 1.69 (m, 2H), 1.50 - 1.40 (m, 2H). [0785] Step 53-3: rac-((1R,3S)-3-(4-Aminophenoxy)cyclopentyl)methanol

[0786] A mixture of rac-((1R,3S)-3-(4-nitrophenoxy)cyclopentyl)methanol (I-24) (0.220 g, 0.93 mmol) and palladium active/carbon catalyst (0.493 g, 0.46 mmol) in methanol (10 mL) was degassed and purged with nitrogen for 3 times, and then the mixture was stirred at 25 °C for 12 h under hydrogen atmosphere. TLC showed one new spot was detected. The mixture was filtered through pad of Celite to give the filtrate. The filtrate was concentrated under reduced pressure to give the product rac-((1R,3S)-3-(4-aminophenoxy)cyclopentyl)methanol (I-25)(0.190 g, 0.92 mmol, 98.9% yield) as a yellow solid. [0787] ¹H NMR (400 MHz, CDCl₃) δ 6.75 - 6.70 (m, 2H), 6.66 - 6.60 (m, 2H), 4.67 (tt, J = 3.2, 5.6 Hz, 1H), 3.64 (d, J = 6.0 Hz, 2H), 3.42 (s, 2H), 2.31 - 2.21 (m, 1H), 2.19 - 2.10 (m, 1H), 2.01 - 1.92 (m, 1H), 1.85 - 1.77 (m, 2H), 1.67 - 1.61 (m, 2H). [0788] Step 53-4: rac-4-Nitrophenyl (4-((1R,3S)-3- (hydroxymethyl)cyclopentyl)oxy)phenyl)carbamate

[0789] To a solution of N-ethyl-N-isopropylpropan-2-amine (0.3 mL, 1.45 mmol) and rac- ((1R,3S)-3-(4-aminophenoxy)cyclopentyl)methanol (I-25) (0.100 g, 0.48 mmol) in tetrahydrofuran (2 mL) was added 4-nitrophenyl chloroformate(I-14)(0.127 g, 0.63 mmol) at 25 °C and the mixture was stirred at 25 °C for 6 h. TLC showed one new spots were detected. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with sat. aq. NaCl solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude (I-26), which was used into the next step without further purification. [0790] Step 53-5: rac-1-((2-(2,6-Dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4- (((1R,3S)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea

[0791] A solution of rac-4-nitrophenyl (4-((1R,3S)-3- (hydroxymethyl)cyclopentyl)oxy)phenyl)carbamate (I-26) (0.119 g, 0.32 mmol) and N-ethyl- N-isopropylpropan-2-amine (0.06 mL, 0.32 mmol) in DMF(2 mL) was stirred at 25 °C for 6 h. Then a solution of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonic acid salt (I-16)(0.120 g, 0.32 mmol) in tetrahydrofuran (2 mL) was added. The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The residue was purified by semi-preparative reverse phase HPLC (20-50% acetonitrile in water + 0.225% formic acid, over 9 min). Then the collected fraction was lyophilized to afford the crude product. The crude product was purified by semi-preparative reverse phase-HPLC (18-48% acetonitrile in water + 0.1% trifluoroacetic acid, over 9 min). Then the collected fraction was lyophilized to afford the crude product. The crude product was purified by semi-preparative reverse phase-HPLC(12-42% acetonitrile in water +10 Mm ammonium hydrogen carbonate, over 9 min). Then the collected fraction was lyophilized to affordthe product rac-1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-3-(4-((1R,3S)-3-(hydroxymethyl)cyclopentyl)oxy)phenyl)urea (EX.53)(0.008 g, 0.02 mmol, 5.4% yield) as a white solid. LCMS: MS (ESI) m/z: 507.3 [M+1]⁺ [0792] ¹H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.38 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.8 Hz, 2H), 6.62 (t, J = 6.0 Hz, 1H), 5.15 - 5.05 (m, 1H), 4.74 - 4.64 (m, 1H), 4.60 - 4.21 (m, 5H), 3.35 (s, 2H), 2.96 - 2.86 (m, 1H), 2.62 (s, 1H), 2.42 - 2.35 (m, 1H), 2.12 - 1.96 (m, 3H), 1.88 - 1.78 (m, 1H), 1.76 - 1.64 (m, 2H), 1.46 - 1.34 (m, 2H). [0793] The examples listed in Table 3 prepared using procedures modified from those described in EX.50 to 53, with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry. Table 3.

Example 63: Synthesis of N-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)acetamide

[0794] Step 63-1: tert-Butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate

[0795] To a solution of tert-butyl N-[[4-(bromomethyl)phenyl]methyl]carbamate (I-27)(10 g, 33.3 mmol) in MeCN (150 mL) was added 4-nitrophenol (I-11)(4.82 g, 34.6 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80°C for 16 h. The reaction mixture was cooled to r.t and concentrated. The residue was diluted with ethyl acetate/H₂O (200 mL/200 mL), the organic layer was washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered, and concentrated to give tert-butyl N-[[4-[(4- nitrophenoxy)methyl]phenyl]methyl]carbamate (I-28) (12 g, crude) as a light yellow solid.¹H NMR: (400 MHz, DMSO-d6) δ 8.27 (d, J = 9.2 Hz, 2H), 7.48 (d, J = 7.6 Hz, 3H), 7.34-7.27 (m, 4H), 5.30 (s, 2H), 4.19 (d, J = 6.0 Hz, 1H), 1.45 (s, 9H). [0796] Step 63-2: tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl] methyl]carbamate

[0797] To a solution of tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (I-28) (12 g, 33.5 mmol) in EtOH (150 mL) and H2O (30 mL) was added Fe powder (9.35 g, 167 mmol) and NH₄Cl (17.9 g, 335 mmol). The mixture was stirred at 80 °C for 2 h. TLC (2:1 petroleum ether/ethyl acetate) showed the reaction was finished. The reaction mixture was cooled to rt and filtered. The cake was washed with ethyl acetate (400 mL), the combined filtrate was concentrated. The residue was diluted with water and ethyl acetate (400 mL/400mL), the organic layer was washed with brine (400 mL), dried over anhydrous Na2SO4, filtrated and concentrated to give tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl] methyl]carbamate (I-29) (9 g, 81.9% yield) as a gray solid. The material was used in the next step without further purification. [0798] Step 63-3: tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate

[0799] To a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (I-29) (5.65 g, 17.2 mmol) in MeCN (200 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (5.64 g, 22.0 mmol) and Et3N (6.16 g, 60.9 mmol) at -20 °C under nitrogen. The mixture was stirred at -20 °C for 1 h. 3-[5-(Aminomethyl)-1-oxo-isoindolin-2-yl]piperidine- 2,6-dione methanesulfonic acid salt(I-16)(6.80 g, 18.4 mmol) was added to the mixture. The mixture was stirred at 20 °C for 15 h. TLC (2:1 petroleum ether/ethyl acetate) showed the reaction was finished. The reaction mixture was filtered, the cake was washed with MeCN (50 mL) and dried to give tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (I-30) (9 g, crude) as a gray solid.¹H NMR: (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.43 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53-7.23 (m, 9H), 6.88 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 6.0 Hz, 1H), 5.14-5.09 (m, 1H), 5.09 (s, 2H), 4.47-4.29 (m, 4H), 4.12 (d, J = 6.0 Hz, 2H), 2.92-2.91 (m, 1H), 2.62-2.51 (m, 1H), 2.41-2.37 (m, 1H), 1.40 (s, 9H). [0800] Step 63-4: 1-[4-[[4-(aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3- piperidyl)-1-oxo-isoindolin-5-yl]methyl]urea

[0801] A solution of tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (I-30) (9.0 g, 14.3 mmol) and HCl (30 mL,12 N in dioxane) was stirred at 0°C for 1 h. LCMS showed the staring material was consumed. MeCN (500 mL) was added into the mixture slowly at 0-10 °C. After stirring for 30 minutes, the resulting solid was filtered and dried to give 1-[4-[[4- (aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl]urea HCl salt (I-31) (7.12 g, 88.0% yield, HCl salt) as an off-white solid.¹H NMR: (400 MHz, DMSO-d6 ) δ 10.98 (s, 1H), 8.66 (s, 1H), 9.30 (s, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 6H), 7.31-7.29 (m, 2H), 6.89 (d, J = 2.0 Hz, 2H), 6.88 (s, 1H), 5.13-5.07 (m, 3H), 4.47-4.29 (m, 4H), 4.01 (t, J = 5.6 Hz, 2H), 2.95-2.87 (m, 1H), 2.62-2.52 (m, 1H), 2.50-2.38 (m, 1H), 2.01-1.94 (m, 1H). [0802] Step 63-5: N-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)acetamide

[0803] 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea HCl salt (I-31) (50 mg, 0.095 mmol) was dissolved in pyridine (1.0 ml) and treated with acetic anhydride (1.0 ml). The solution was stirred for 12h at room temperature and concentrated under reduced pressure. The solid was triturated from ethylacetate to give N-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)acetamide (EX.63)(47 mg, 0.083 mmol, 87 % yield).LCMS (ESI) m/z: 570.8 [M+1]⁺.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.82 - 11.17 (m, 1 H), 8.27 - 8.53 (m, 2 H), 7.64 - 7.75 (m, 1 H), 7.49 - 7.55 (m, 1 H), 7.42 - 7.49 (m, 1 H), 7.35 - 7.41 (m, 2 H), 7.22 - 7.34 (m, 4 H), 6.82 - 6.95 (m, 2 H), 6.59 - 6.71 (m, 1 H), 5.08 - 5.22 (m, 1 H), 4.95 - 5.08 (m, 2 H), 4.20 - 4.50 (m, 6 H), 2.86 - 3.02 (m, 1 H), 2.58 - 2.69 (m, 1 H), 2.33 - 2.42 (m, 1 H), 1.96 - 2.11 (m, 1 H), 1.78 - 1.91 (m, 3 H) Example 64: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3- (4-((4-(2-hydroxypropan-2-yl)benzyl)oxy)phenyl)urea

[0804] Step 64-1: 2-(4-(bromomethyl)phenyl)propan-2-ol

[0805] To 1-(4-(bromomethyl)phenyl)ethan-1-one (I-32) (500 mg, 2.347 mmol) in THF (2 mL) at -78 °C was added methylmagnesium bromide (1.173 mL, 3.52 mmol). After stirred at-78 °C for 30 min, the reaction was allowed to warmed to rt over 12h and concentrated. The crude residue was purified using silica gel column chromatography (0-50% Ethyl acetate in Hexane) to afford 2-(4-(bromomethyl)phenyl)propan-2-ol (I-33)(250 mg, 1.091 mmol, 46.5 % yield). LCMS (ESI, m/z): 211.0 [M+H-H2O] ⁺. [0806] Step 64-2: 2-(4-((4-nitrophenoxy)methyl)phenyl)propan-2-ol

[0807] To a mixture containing 4-nitrophenol (138 mg, 0.995 mmol), and 2-(4- (bromomethyl)phenyl)propan-2-ol (I-33) (228 mg, 0.995 mmol) in DMF (10 mL) was added Cs₂CO₃ (648 mg, 1.990 mmol) and stirred at rt for 16 h. The reaction was diluted with ethyl acetate/H2O (50 mL/50 mL) and organic layer was isolated and washed with sat. aq.NaCl (25 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified using silica gel column chromatography (0-60% Ethyl acetate in Hexane) to afford 2-(4-((4- nitrophenoxy)methyl)phenyl)propan-2-ol (I-34) (200 mg, 0.696 mmol, 70.0 % yield). LCMS (ESI, m/z): 270.0 [M+H-H2O] ⁺. [0808] Step 64-3: 2-(4-((4-aminophenoxy)methyl)phenyl)propan-2-ol

[0809] To a mixture containing 2-(4-((4-nitrophenoxy)methyl)phenyl)propan-2-ol (I-34) (100 mg, 0.348 mmol) and 4,4'-bipyridine (1.087 mg, 6.96 µmol) in DMF (1 mL) was added hypodiboric acid (94 mg, 1.044 mmol) at rt. The reaction was stirred for 10 min. and treated with sat. aq. NaCl solution (5ml) and extracted with ethyl acetate (15 mL x 2). The organic extracts were combined and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography using ISCO Gemini C18 (30mm x 250mm) with 0-50% (0.1% FA in ACN/0.1% FA in water). The fractions containing the product were combined and lyophilized to give 2-(4-((4-aminophenoxy)methyl)phenyl)propan-2-ol (I-35) (65 mg, 0.253 mmol, 72.2% yield). LCMS (ESI, m/z): 240.2 [M+H-H₂O]⁺. [0810] Step 64-4: 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4-(2- hydroxypropan-2-yl)benzyl)oxy)phenyl)urea [0811] To 2-(4-((4-aminophenoxy)methyl)phenyl)propan-2-ol (I-35) (65 mg, 0.253 mmol) in DMF (1 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (78 mg, 0.303 mmol) followed by dropwise addition of DIEA (0.265 mL, 1.516 mmol). The mixture was stirred at rt for 10 min and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methane sulfonic acid salt (I-16) (90 mg, 0.30 mmol) was added in one portion. The reaction was stirred for an additional 15 min. and filtered through a plug of celite. The filtrate was purified using prep-HPLC with the following conditions (Column: Waters BEH C18, 30 mm x 100 mm, 5 μm particles; Mobile Phase A: H₂O with 10 mM Ammonium Acetate, Mobile Phase B: ACN with 10 mM Ammonium Acetate; Flow rate: 40 mL/min; Gradient: 5% B to 95% B in 26 min; Wave Length: 254 nm). The fractions containing the product were combined and lyophilized to afford 1-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-(4-((4- (2-hydroxypropan-2-yl)benzyl)oxy)phenyl)urea (EX.64)(6.4 mg, 0.011 mmol, 4.51 % yield). LCMS (ESI, m/z): 539.3 [M+H-H2O] ⁺.¹H NMR (500 MHz, DMSO-d6) δ ppm 10.81 - 11.14 (m, 1 H), 8.55 - 8.66 (m, 1 H), 7.65 - 7.74 (m, 1 H), 7.50 - 7.54 (m, 1 H), 7.42 - 7.48 (m, 3 H), 7.26 - 7.38 (m, 4 H), 6.86 - 6.92 (m, 2 H), 6.80 - 6.86 (m, 1 H), 5.05 - 5.21 (m, 1 H), 4.94 -5.02 (m, 3 H), 4.27 - 4.52 (m, 4 H), 2.85 - 3.01 (m, 1 H), 2.58 - 2.67 (m, 1 H), 2.35 - 2.43 (m, 1 H), 1.94 - 2.08 (m, 1 H), 1.35 - 1.47 (m, 6 H). Example 65: Synthesis of 3-(5-((3-(2-((4-(hydroxymethyl)benzyl)oxy)phenyl)-2- oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0812] Step 65-1: (4-((2-nitrophenoxy)methyl)phenyl)methanol

[0813] To a solution of (4-(bromomethyl)phenyl)methanol (I-36)(1.5 g, 7.46 mmol) in MeCN (100 mL) was added 2-nitrophenol (I-37) (1.038 g, 7.46 mmol) and potassium carbonate (3.09 g, 22.38 mmol). The reaction was stirred at 80°C for 16h. The reaction was cooled to rt and concentrated. The residue was diluted with ethyl acetate/H2O (200 mL/200 mL), the organic layer was isolated and washed with sat. aq. NaCl solution (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give (4-((2- nitrophenoxy)methyl)phenyl)methanol (I-38)(1.9 g, 7.33 mmol, 98 % yield), used as such in subsequent reaction. [0814] Step 65-2: triisopropyl((4-((2-nitrophenoxy)methyl)benzyl)oxy)silane

[0815] To a solution containing (4-((2-nitrophenoxy)methyl)phenyl)methanol (I-38) (1.9 g, 7.33 mmol) in anhydrous DMF (10 mL), was added imidazole (1 g, 14.7 mmol) followed by the slow addition of chlorotriisopropylsilane (2.36 ml, 10.99 mmol). The reaction was stirred for 16 h and diluted with diethyl ether (100 mL) and water added (50 mL). The aqueous layer was decanted, and the organic layer was washed with water (40 mL), dried (MgSO₄), filtered and concentrated. The resulting yellow oil was chromatographed on silica gel (Biotage SNAP, 100 g) with ethylacetate/hexanes to afford triisopropyl((4-((2- nitrophenoxy)methyl)benzyl)oxy)silane (I-39) (3 g, 98% yield). [0816] ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.89 - 7.75 (m, 1H), 7.54 - 7.45 (m, 1H), 7.44 - 7.33 (m, 4H), 7.16 - 7.07 (m, 1H), 7.06 - 6.97 (m, 1H), 5.25 - 5.15 (m, 2H), 4.89 - 4.78 (m, 2H), 1.22 - 1.14 (m, 3H), 1.07 (d, J=12.7 Hz, 15H) [0817] Step 65-3: 2-((4-(((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline

[0818] To a solution containing triisopropyl((4-((2-nitrophenoxy)methyl)benzyl)oxy)silane (I-39) (2.96 g, 7.12 mmol) in EtOH (50 mL) and H2O (10 mL) was added iron powder (1.013 g, 18.14 mmol) and ammonium chloride (1.940 g, 36.3 mmol). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was cooled to rt and filtered though pad of Celite. The pad was were rinsed with ethyl acetate (400 mL). The filtrate was washed with water (100 mL) and with sat. aq. NaCl solution (100 mL), dried over anhydrous Na2SO4, filtrated and concentrated. The crude material was chromatographed on silica gel, eluting with ethylacetate/hexanes, to give 2-((4-(((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline (I-40) (2.0 g). [0819] ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.44 - 7.34 (m, 4H), 6.89 - 6.83 (m, 1H), 6.83 - 6.77 (m, 1H), 6.76 - 6.67 (m, 2H), 5.09 - 5.04 (m, 2H), 4.88 - 4.81 (m, 2H), 3.90 - 3.70 (m, 2H), 1.21 - 1.16 (m, 3H), 1.12 - 1.07 (m, 18H). [0820] Step 65-4: 2-((2-((4-(((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethan- 1-ol

[0821] To a solution of 2-((4-(((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline (I-40) (2.0 g, 5.19 mmol) in acetonitrile (10 mL) was added 2-bromoethan-1-ol (I-41) (0.78 g, 6.2 mmol) followed by addition of sodium bicarbonate (0.87 g, 10.37 mmol). The reaction was heated at 90 °C in a microwave reactor for 1 h. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure to give crude product. Purification using silica gel chromatography, eluting with ethyl acetate/hexanes afforded 2-((2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethan-1-ol (I-42) (1000 mg, 2.33 mmol, 45 % yield). ). LCMS (ESI, m/z): 430.2 [M+H]⁺ [0822] Step 65-5: N-(2-bromoethyl)-2-((4-(((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline

[0823] To a solution of 2-((2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethan-1-ol (I-42)(1400 mg, 3.26 mmol) in dichloromethane (15 mL) at 0 °C, was added carbon tetrabromide (1621 mg, 4.89 mmol) followed by addition of triphenylphosphine (1282 mg, 4.89 mmol), and the mixture was stirred for 12 h at room temperature. The reaction mixture was concentrated under reduced pressure and the crude residue was purified using silica gel chromatography, eluting with ethyl acetate/hexanes, to afford N-(2-bromoethyl)-2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline (I-43) (1550 mg, 3.15 mmol, 97 % yield). LCMS (ESI, m/z): 492.2 [M+H]⁺ [0824] Step 65-6: 3-(1-oxo-5-(((2-((2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethyl)amino)methyl)isoindolin-2- yl)piperidine-2,6-dione

[0825] To a solution of N-(2-bromoethyl)-2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)aniline (I-43) (290 mg, 0.589 mmol) in acetonitrile (2 mL) was added 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione;methanesulfonic acid (I-16) (175 mg, 0.60 mmol)) followed by addition of potassium carbonate (163 mg, 1.177 mmol) and sodium iodide (17.65 mg, 0.118 mmol). The reaction was stirred for 12 h at 80 °C. The reaction mixture was diluted with water and extracted with ethyl acetate (3X50 mL). The organic layers were combined, dried over Na₂SO₄ and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography, eluting with ethyl acetate/hexanes to afford 3-(1-oxo-5-(((2-((2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethyl)amino)methyl)isoindolin-2- yl)piperidine-2,6-dione (I-44) (109 mg, 0.159 mmol, 27.0 % yield). LCMS (ESI, m/z): 685.4 [M+H]⁺ [0826] Step 65-7: 3-(1-oxo-5-((2-oxo-3-(2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)imidazolidin-1-yl)methyl)isoindolin-2- yl)piperidine-2,6-dione

[0827] To a stirred solution of 3-(1-oxo-5-(((2-((2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)amino)ethyl)amino)methyl)isoindolin-2- yl)piperidine-2,6-dione (I-44) (100 mg, 0.146 mmol) in DMF (2 mL) was added 1,1′- carbonyldiimidazole (71.0 mg, 0.438 mmol) followed by addition of TEA (20.35 µl, 0.146 mmol). The reaction was stirred at 80 °C for 12 h. DMAP (~10 mg) was added and heated at 80 °C for an additional 4h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3X25 mL). The organic extracts were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified using silica gel chromatography, eluting with ethyl acetate/ hexanes to afford 3-(1-oxo-5-((2-oxo-3-(2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)imidazolidin-1-yl)methyl)isoindolin-2- yl)piperidine-2,6-dione (I-45) (100 mg, 0.141 mmol, 96 % yield); LCMS (ESI, m/z): 711.2 [M+H]⁺ [0828] Step 65-8: 3-(5-((3-(2-((4-(hydroxymethyl)benzyl)oxy)phenyl)-2-oxoimidazolidin-1- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione [0829] To a solution of 3-(1-oxo-5-((2-oxo-3-(2-((4- (((triisopropylsilyl)oxy)methyl)benzyl)oxy)phenyl)imidazolidin-1-yl)methyl)isoindolin-2- yl)piperidine-2,6-dione (I-45)(100 mg, 0.141 mmol) in acetonitrile (2.5 mL) was added 4- methylbenzenesulfonic acid hydrate (80 mg, 0.422 mmol). The resulting solution was stirred at 80 °C for 2 h. The reaction was cooled to rt, treated with water (10 mL) and extracted with ethyl acetate (3X15 mL). The combined organic layers were washed with sat. aq. NaCl solution (2X10 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified via preparative reverse phase HPLC with the following conditions:Column: Xselect CSH C18, 30 mm x 250 mm, 5 μm particles; Flow Rate: 40.00 mL/min; Column Temperature: 25°C. Mobile Phase A: H₂O (0.1% FA), Mobile Phase B: ACN ( 0.1% FA); Gradient: 5% B , hold for 3 min, to 95% B in 23 min; Wave Length: 254 nm). The fractions containing the product were combined and lyophilized Fraction collection was triggered by UV (254 nm) and MS (ESI +) and ELSD. Fractions containing the desired product were combined and dried via centrifugal evaporation to obtain 3-(5-((3-(2-((4- (hydroxymethyl)benzyl)oxy)phenyl)-2-oxoimidazolidin-1-yl)methyl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione (EX.65). LCMS (ESI, m/z): 555.2 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.97 - 10.86 (m, 1H), 7.66 - 7.55 (m, 1H), 7.48 - 7.40 (m, 1H), 7.38 - 7.31 (m, 3H), 7.28 - 7.12 (m, 4H), 7.11 - 7.05 (m, 1H), 6.96 - 6.84 (m, 1H), 5.16 - 4.99 (m, 4H), 4.46 - 4.19 (m, 6H), 3.68 - 3.55 (m, 2H), 2.94 - 2.76 (m, 1H), 2.64 - 2.46 (m, 1H), 2.40 - 2.17 (m, 1H), 2.05 - 1.82 (m, 1H) Example 66: Synthesis of 1-(4-benzyloxyphenyl)-3-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro- 1-oxo-isoindolin-5-yl]methyl]urea

[0830] Step 66-1: (2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindoline-5-carbonitrile

[0831] To a stirred mixture of 3-(5-bromo-4-fluoro-1-oxo-isoindolin-2-yl)piperidine-2,6- dione (I-46) (2 g, 5.862 mmol) in DMF (30.0 mL) was added Zn(CN)₂ (482 mg, 4.104 mmol), X-phos (842 mg, 1.765 mmol) and Pd2(dba)3 (539 mg, 0.588 mmol). The resulting mixture was stirred for 3 h at 80^oC under nitrogen atmosphere. The reaction was cooled to rt and then poured into 60 mL ice water. The solid was collected by filtration. Trituration of the solid was carried out in 30.0 mL ACN. The solid was collected by filtration to afford 2-(2,6- dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindoline-5-carbonitrile (I-47)(1.6 g, 5.570 mmol, 95% yield, 94.4% purity) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ 288. [0832] Step 66-2: tert-Butyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5- yl]methyl]carbamate

[0833] To a stirred mixture containing 2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindoline- 5-carbonitrile (I-47) (1.6 g, 5.57 mmol) in mixed solvent of DMF (30.0 mL) and THF (30.0 mL) were added (Boc)2O (2.4 g, 11.14 mmol) and Raney Ni (10.0 g). The resulting mixture was stirred for 2h at room temperature under hydrogen atmosphere. The reaction was purged with nitrogen gas and the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The concentrate was stirred vigorously in 50.0 mL of ethyl acetate/petroleum ether 1:10). The resulting solid was collected by filtration to afford tert- butyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]methyl]carbamate (I- 48)(1.0 g, 2.558 mmol, 43.2% yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ 392. [0834] Step 66-3: 3-[5-(aminomethyl)-4-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione TFA salt

[0835] To a stirred mixture of tert-butyl N-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo- isoindolin-5-yl]methyl]carbamate (I-48) (1.0 g, 2.558 mmol) in DCM (30.0 mL) was added TFA (10.0 mL). The resulting mixture was stirred for 1h at room temperature. The resulting mixture was concentrated under reduced pressure. The solid were stirred vigorously in 20.0 mL ethyl acetate. The product was collected by filtration to afford 3-[5-(aminomethyl)-4- fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione TFA salt (I-49)(950 mg, 2.346 mmol, 91.7% yield). LCMS (ESI, m/z): [M+H] ⁺ 292. [0836] Step 66-4: 1-(4-benzyloxyphenyl)-3-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo- isoindolin-5-yl]methyl]urea [0837] To a stirred mixture of 4-benzyloxyaniline (I-50) (25 mg, 0.126 mmol) in 1,4-dioxane (3.0 mL) was added triphosgene (12 mg, 0.041 mmol). The resulting mixture was stirred for 2h at 60°C. The reaction mixture was cooled to room temperature. To the cooled reaction was added 3-[5-(aminomethyl)-4-fluoro-1-oxo-isoindolin-2-yl]piperidine-2,6-dione TFA salt (I- 49)(51 mg, 0.126 mmol) and TEA (38 mg, 0.378 mmol) in 1,4-dioxane (2.0 mL). The resulting mixture was stirred for 1h at room temperature and concentrated under reduced pressure. The crude product was purified by reverse flash chromatography with the following conditions (Spherial C18, 90g, 20~40 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 100% B in 20 min, 210 nm; RT: 17 min), removal of the solvent via concentration and lyophilization gave 1-(4- benzyloxyphenyl)-3-[[2-(2,6-dioxo-3-piperidyl)-4-fluoro-1-oxo-isoindolin-5-yl]methyl]urea (EX.66)(50 mg, 0.097 mmol, 77.0% yield) as an off-white solid. LCMS (ESI, m/z): [M+H] ⁺ 517. [0838] 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.46 (s, 1H), 7.61 – 7.48 (m, 2H), 7.45 – 7.28 (m, 7H), 6.94 – 6.86 (m, 2H), 6.65 (t, J = 6.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 5.04 (s, 2H), 4.57 (d, J = 17.4 Hz, 1H), 4.49 – 4.33 (m, 3H), 2.92 (ddd, J = 18.5, 13.5, 5.4 Hz, 1H), 2.61 (d, J = 17.5 Hz, 1H), 2.43 (td, J = 13.2, 4.5 Hz, 1H), 2.05 – 1.97 (m, 1H). Example 67: Synthesis of 1-(4-(benzylamino)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea

[0839] Step 67-1: N-benzyl-4-nitroaniline

[0840] To a solution of benzylamine (I-51) (3 g, 28.0 mmol) in DMF (20 mL) was added 1- fluoro-4-nitrobenzene (3) (3.95 g, 28.0 mmol) and potassium carbonate (5.80 g, 42.0 mmol). The reaction mixture was heated at 50°C for 16h. The reaction mixture was cooled to rt, filtered, and concentrated under reduced pressure. The residue was diluted with ethyl acetate/H₂O (200 mL/200 mL). The organic layer was isolated and washed with sat. aq. NaCl solution (50 mLX2), dried over anhydrous Na₂SO₄, filtered and concentrated to give N- benzyl-4-nitroaniline (I-52) (5.9 g, 25.8 mmol, 92 % yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ 229. [0841] Step 67-2: tert-butyl benzyl(4-nitrophenyl)carbamate

[0842] To a solution containing N-benzyl-4-nitroaniline (I-52) (1 g, 4.38 mmol) in THF (35 mL) at 23° C. were added DMAP (71 mg, 0.58 mmol, 10 mol %), sodium hydride (0.210 g, 5.26 mmol), and Boc-anhydride (1.526 ml, 6.57 mmol). After stirring for 1.5 h at 60° C, the reaction mixture was cooled to rt and water (20 mL) was added dropwise. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2x20 mL). The combined organic phases were washed with sat. aq. NaCl solution (20 mL) and dried (MgSO4). The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography , eluting with ethyl acetate and hexanes to afford tert-butyl benzyl(4- nitrophenyl)carbamate (I-53) (1.2 g, 85%). LCMS (ESI, m/z): [M+H] ⁺ 273(-tert-butyl). [0843] Step 67-3: tert-butyl (4-aminophenyl)(benzyl)carbamate

[0844] To a solution of tert-butyl benzyl(4-nitrophenyl)carbamate (I-53) (1 g, 3.05 mmol) in EtOH (50 mL) and H₂O (10 mL) was added iron powder (0.850 g, 15.23 mmol) and ammonium chloride (1.629 g, 30.5 mmol). The mixture was stirred at 80 °C for 2 h, cooled to rt and filtered through a pad of Celite. The Celite was washed with ethyl acetate (400 mL). The filtrate was concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate (40 mL) and washed with water (40 mL) and with sat. aq. NaCl solution (40 mL), dried Na2SO4, filtrated and concentrated to give tert-butyl (4- aminophenyl)(benzyl)carbamate (I-54) as a gray solid; 800 mg (88%), LCMS (ESI, m/z): [M+H] ⁺ 299. [0845] Step 67-4: tert-butyl benzyl(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenyl)carbamate

[0846] To a solution of tert-butyl (4-aminophenyl)(benzyl)carbamate (I-54) (200 mg, 0.670 mmol) in acetonitrile (2 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (223 mg, 0.871 mmol) and DIEA (0.351 mL, 2.011 mmol) at -20 °C under nitrogen. The mixture was stirred at -20 °C for 1 h. and 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate salt (I-55) (260 mg, 0.670 mmol) was added to the stirring reaction. The reaction was stirred at 20 °C for 15 h. Silica gel chromatography using ethyl acetate and hexanes as the eluting solvents afforded tert-butyl benzyl(4-(3-((2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindolin-5-yl)methyl)ureido)phenyl)carbamate (I-56) (235 mg, 0.393 mmol, 58.7 % yield). [0847] Step 67-5: 1-(4-(benzylamino)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea

[0848] To a suspension of tert-Butyl benzyl(4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenyl)carbamate (I-56) (230 mg, 0.385 mmol) in 10 mL DCM was added TFA (1 mL). The mixture was stirred at 25°C for 16h. The solvent was removed in vacuo and the residue was purified using prepartive HPLC using following conditions: column:( Xselect CSH C18, 30 mm x 100 mm, 5 μm particles; Flow Rate: 40.00 mL/min; Mobile Phase A: Water(0.1%FA), Mobile Phase B: CAN (0.1% FA); Gradient: 5% B to 95% B in 25 min, hold at 95% B for 1 min. Fraction collection was triggered by UV (254 nm) and MS (ESI +) and ELSD. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 1-(4-(benzylamino)phenyl)-3-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (EX.67) (90 mg, 47%). LCMS (ESI, m/z): [M+H] ⁺ 498.7. [0849] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.60 - 11.15 (m, 1 H), 7.95 - 8.32 (m, 1 H), 7.60 - 7.76 (m, 1 H), 7.47 - 7.53 (m, 1 H), 7.40 - 7.45 (m, 1 H), 7.26 - 7.38 (m, 4 H), 7.17 - 7.26 (m, 1 H), 7.01 - 7.09 (m, 2 H), 6.46 - 6.53 (m, 3 H), 5.85 - 5.94 (m, 1 H), 5.06 - 5.16 (m, 1 H), 4.41 - 4.48 (m, 1 H), 4.35 - 4.40 (m, 2 H), 4.27 - 4.34 (m, 1 H), 4.16 - 4.25 (m, 2 H), 2.84 - 2.98 (m, 1 H), 2.55 - 2.65 (m, 1 H), 2.30 - 2.47 (m, 1 H), 1.94 - 2.05 (m, 1 H) Example 68: Synthesis of 1-((2-(2,6-Dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5- yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea

[0850] Step 68-1: (4-((4-Nitrophenoxy)methyl)phenyl)methanol

[0851] To a solution of (4-(bromomethyl)phenyl)methanol (I-37) (1 g, 4.97 mmol) in MeCN (70 mL) was added 4-Nitrophenol (I-11)(0.830 g, 5.97 mmol) and potassium carbonate (2.062 g, 14.92 mmol). The reaction mixture was stirred at 80°C for 16h. The reaction mixture was cooled to rt and concentrated. The residue was diluted with ethyl acetate/H2O (200 mL/200 mL), the organic layer was isolated and washed with sat. aq. NaCl solution (50 mL), dried Na₂SO₄, filtered and concentrated to give (4-((4- nitrophenoxy)methyl)phenyl)methanol (I-57)(1.26 g, 4.86 mmol, 98 % yield) as a light yellow solid. LCMS (ESI, m/z): [M+H] ⁺ 242 (M⁺-OH).¹H NMR (CHLOROFORM-d, 400 MHz) δ 8.2-8.2 (m, 2H), 7.4-7.5 (m, 4H), 7.0-7.1 (m, 2H), 5.1-5.2 (m, 2H), 4.7-4.8 (m, 2H) [0852] Step 68-2. tert-butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane

[0853] To a solution containing (4-((4-nitrophenoxy)methyl)phenyl)methanol (I-57) (1.26 g, 4.86 mmol) in anhydrous DMF (6.94 ml) at 0 °C was added triethylamine (0.745 ml, 5.35 mmol) followed by the addition of tert-butylchlorodimethylsilane (0.806 g, 5.35 mmol), in one portion. The cloudy suspension was stirred at rt for 1 h. Diethyl ether (100 mL) was added to the reaction followed by addition of water (50 mL). The mixture was poured into a separatory funnel and the aqueous layer discarded. The organic layer was washed with water (2X40 mL) and sat. aq. NaCl solution (50 mL), dried MgSO₄, filtered and concentrated under reduced pressure. The yellow oil obtained was chromatographed on silica gel (Biotage SNAP, 50 g) using ethylacetate/hexanes as the eluent to afford tert-butyldimethyl((4-((4- nitrophenoxy)methyl)benzyl)oxy)silane (I-58) is isolated as colorless oil (1.7 g, 94% yield). [0854] Step 68-3: 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline

[0855] To a solution of tert-butyldimethyl((4-((4-nitrophenoxy)methyl)benzyl)oxy)silane (I- 58) (1.5 g, 4.02 mmol) in EtOH (25 mL) and H2O (5 mL) was added iron powder (1.12 g, 20.1 mmol) and ammonium chloride (2.148 g, 40.2 mmol). The mixture was stirred at 80 °C for 2 h. The reaction mixture was cooled to rt. and filtered through a pad of Celite. The Celite pad was rinsed with ethyl acetate (400 mL) and the combined filtrate was concentrated. The residue was dissolved in ethyl acetate (40 mL) and washed with water (40- mL) and sat. aq. NaCl solution (40 mL), dried (Na₂SO₄), filtrated and concentrated to give 4- ((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (I-59), LCMS (ESI, m/z): [M+H] ⁺ 344. Used without further purification in subsequent step. [0856] Step 68-4: 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2- (2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)methyl)urea

[0857] To a solution of 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (I-59) (35.4 mg, 0.103 mmol) in acetonitrile (1 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (34.3 mg, 0.134 mmol) and DIEA (108 µl, 0.618 mmol) under a nitrogen atmosphere, at 0 ^oC, and stirred for 1h. To the mixture was added 3-(5-(aminomethyl)-4- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonic salt (I-60)(40 mg, 0.103 mmol), and stirred at 20 °C for 15 h. The reaction was concentrated and the residue was chromatographed on silica gel (Biotage SNAP, 25g) using ethyl acetate/hexanes as the eluting solvents to give 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3- ((2-(2,6-dioxopiperidin-3-yl)-4-fluoro-1-oxoisoindolin-5-yl)methyl)urea (I-61) (38 mg, 55.8 % yield). [0858] Step 68-5: 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-(4-((4- (hydroxymethyl)benzyl)oxy)phenyl)-1-methylurea

[0859] To a solution containing 1-(4-((4-(((tert- butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-4-fluoro- 1-oxoisoindolin-5-yl)methyl)urea (I-61) (38 mg, 0.058 mmol) in DCM (2 mL) was added hydrochloric acid (144 µl, 0.575 mmol, 4N in dioxane) and stirred for 16 h. The mixture was concentrated under a stream of nitrogen gas, re-dissolved in DMSO (2 mL) and purified via preparative HPLC using following conditions: column:( Xselect CSH C18, 30 mm x 100 mm, 5 μm particles; Flow Rate: 40.00 mL/min; Mobile Phase A: Water(10 mM ammonium acetate), Mobile Phase B: ACN (10 mM ammonium acetate); Gradient: 5% B to 95% B in 25 min, hold at 95% B for 1 min; Wave Length. Fraction collection was triggered by UV (254 nm) and MS (ESI +) and ELSD. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)-1-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)-1-methylurea (Ex 68), LCMS (ESI, m/z): [M+H] ⁺543.7. [0860] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.68 - 11.13 (m, 1 H), 8.25 - 8.59 (m, 1 H), 7.49 - 7.54 (m, 1 H), 7.42 - 7.49 (m, 1 H), 7.28 - 7.34 (m, 2 H), 7.17 - 7.27 (m, 4 H), 6.77 - 6.85 (m, 2 H), 6.53 - 6.68 (m, 1 H), 5.00 - 5.14 (m, 2 H), 4.92 - 4.96 (m, 2 H), 4.46 - 4.53 (m, 1 H), 4.39 - 4.45 (m, 2 H), 4.29 - 4.38 (m, 3 H), 2.78 - 2.90 (m, 1 H), 2.50 - 2.61 (m, 2 H), 2.30 - 2.39 (m, 1 H), 1.88 - 1.98 (m, 1 H). Example 69: Synthesis of 1-((2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5- yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea

[0861] Step 69-1: 3-(5-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0862] To a solution of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (I-62) (7 g, 21.48 mmol) in MeCN (100. mL) was added the N-ethyl-N-isopropylpropan-2-amine (11.90 mL, 64.4 mmol) and 3-aminopiperidine-2,6-dione hydrochloride (I-63) (4.59 g, 27.9 mmol). The mixture was stirred at 90 °C for 12 h. The mixture was concentrated in vacuum to give the crude product. The residue was triturated in DCM and filtered to give 3-(5-bromo-7- fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (I-64) (5.8 g, 16.49 mmol, 77 % yield) as a white solid. LCMS (ESI, m/z): [M+H] ⁺ 343/344. [0863] Step 69-2: 2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindoline-5-carbonitrile

[0864] A stirred mixture containing 3-(5-bromo-7-fluoro-1-oxoisoindolin-2-yl)piperidine- 2,6-dione (I-64) (5.8 g, 17.00 mmol), Zn(CN)2 (1.198 g, 10.20 mmol), Pd2(dba)3 (0.311 g, 0.340 mmol) and dppf (0.377 g, 0.680 mmol) in DMF (100 mL) was evacuated under reduced pressure and backfilled with nitrogen gas, the procedure was repeated and the reaction was heated at 120 °C under nitrogen atmosphere for 6 h. The reaction was cooled to room temperature, diluted with water (200 mL) and ethyl acetate (300 mL), transferred to a separatory funnel and the organic layer isolated. The aqueous layer was extracted with additional ethyl acetate (2x100 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude mixture was purified via flash chromatography using ethyl acetate/hexanes as the eluent to provide 2-(2,6-dioxopiperidin-3- yl)-7-fluoro-1-oxoisoindoline-5-carbonitrile (I-65) (2.1 g, 7.31 mmol, 43.0 % yield), LCMS (ESI, m/z): [M+H] ⁺ 288. [0865] Step 69-3: tert-Butyl ((2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5- yl)methyl)carbamate

[0866] To a solution of 2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindoline-5-carbonitrile (I-65) (2.1 g, 7.31 mmol) in deoxygenated THF (10 mL) and deoxygenated DMF (10 mL) was added di-tert-butyl 257ecarbonate (2.074 g, 9.50 mmol) followed by the addition of Raney-Ni (100 mg). The mixture was evacuated under reduced pressure, backfilled with hydrogen gas and pressurized to 50 psi. The mixture was stirred at 25 °C for 40 h. The reaction was evacuated and backfilled with nitrogen gas. Water (100 mL) was added to the reaction and extracted with ethyl acetate (3X100 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude material was purified via flash chromatography using ethylacetate/hexanes as the eluent to provide tert- butyl ((2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5-yl)methyl)carbamate (I- 66)(1.3 g, 3.32 mmol, 45.4 % yield), LCMS (ESI, m/z): [M+H] ⁺ 392.0. [0867] Step 69-4: 3-(5-(Aminomethyl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione

[0868] To a solution of tert-butyl ((2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5- yl)methyl)carbamate (I-66) (1.3 g, 3.32 mmol) in CH₂Cl₂ (100 mL) was added 4N hydrochloric acid in dioxane (4.15 mL, 16.61 mmol)). The reaction was stirred at room temperature for 4h. The resulting solid were filtered, rinsed with diethyl ether (5x10 mL) and dried under reduced pressure to provide 3-(5-(aminomethyl)-7-fluoro-1-oxoisoindolin-2- yl)piperidine-2,6-dione HCl salt (I-67)(1 g, 92%), LCMS (ESI, m/z): [M+H] ⁺ 292.0. [0869] Step 69-5: 1-(4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2- (2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5-yl)methyl)urea

[0870] To a solution of 4-((4-(((tert-butyldimethylsilyl)oxy)methyl)benzyl)oxy)aniline (I-59) (59.0 mg, 0.172 mmol) in MeCN (1 mL), under nitrogen atmosphere, was added bis(2,5- dioxopyrrolidin-1-yl) carbonate (57.2 mg, 0.223 mmol) and DIEA (90 µl, 0.515 mmol). The mixture was stirred at rt for 1h and treated with 3-(5-(aminomethyl)-7-fluoro-1- oxoisoindolin-2-yl)piperidine-2,6-dione HCl salt (I-67) (50 mg, 0.15 mmol). The reaction was stirred at 20 °C for an additional 15h, treated with sat. aq. NaHCO3 (5 mL) and extracted with ethyl acetate (3x10 mL). The organic extracts were combined, dried (Na₂SO₄), filtered and concentrated. The crude product was and chromatographed on silica gel using ethyl acetate/hexanes to provide 1-(4-((4-(((tert- butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-7-fluoro- 1-oxoisoindolin-5-yl)methyl)urea (I-68) (50 mg, 0.076 mmol, 44.1 % yield), LCMS (ESI, m/z): [M+H] ⁺ 661.2 [0871] Step 69-6: 1-((2-(2,6-dioxopiperidin-3-yl)-7-fluoro-1-oxoisoindolin-5-yl)methyl)-3- (4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea

[0872] To a solution containg 1-(4-((4-(((tert- butyldimethylsilyl)oxy)methyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-7-fluoro- 1-oxoisoindolin-5-yl)methyl)urea (I-68) (50 mg, 0.076 mmol) in DCM (2 mL) was added 4N HCl in dioxane (189 µl, 0.757 mmol) stirred for 16 h. The mixture was concentrated under reduced pressure and purified using preparative HPLC using following conditions: column:( Xselect CSH C18, 30 mm x 100 mm, 5 μm particles; Flow Rate: 40.00 mL/min; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN (0.1% FA); Gradient: 5% B, hold for 3 min, then to 95% B in 17 min, hold at 95% B for 1 min. Fraction collection was triggered by UV (254 nm) and MS (ESI +) and ELSD. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford 1-((2-(2,6-dioxopiperidin-3-yl)-7- fluoro-1-oxoisoindolin-5-yl)methyl)-3-(4-((4-(hydroxymethyl)benzyl)oxy)phenyl)urea (EX. 69) (6 mg, 14%). LCMS (ESI, m/z): [M+H] ⁺ 547.7. [0873] 1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 - 11.09 (m, 1 H), 8.55 - 8.66 (m, 1 H), 7.27 - 7.39 (m, 7 H), 7.15 - 7.22 (m, 1 H), 6.85 - 6.94 (m, 2 H), 6.76 - 6.83 (m, 1 H), 5.13 - 5.24 (m, 1 H), 4.94 - 5.10 (m, 3 H), 4.32 - 4.52 (m, 6 H), 2.80 - 2.95 (m, 1 H), 2.56 - 2.63 (m, 1 H), 2.30 - 2.43 (m, 1 H), 1.95 - 2.09 (m, 1 H) [0874] The examples listed in Table 4 prepared using procedures modified from those described in EX.63 to 69, with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry.

T CP ⁰ ₀-₀ ⁴ ₀ ⁰-⁷ ₇ ² ₁ ^0: _o N_t ^e _k ^c _o D _y ^e _n ^r _o ^t _t A

e _r u_t c_u ^r _t S s_a - n e_r - _c - 6 ⁾ _l -₅ ^e _h ⁱ _o ³- - ) _l ⁾ _l U ^, ₂ ^y- 3^- _n ^p ₎ ^z _n ^{y y}- _l y⁽ _{- -} _{z e} ^{n i} _l ^o _d ^e _n _b ^{e 3} - -₅ n_e ^{m 2} _{( i} ^o a ⁽- ^d _{i d} ⁱ ^{r n} _e ^{r )} _l ^d _{i h} p₎ ⁿ _i -^d _{i n} ^a ⁱ _{l e} ^r ^B _{e i u} ^y _h ^c ^- _a ^{y r} - _u N ³ ₍ ₄ ^p _i ^o _s ⁾ ⁱ _l ^t _{x e} ¹ - ^o _d ⁾ _l (₍ ^p ^- _{o o} ^y 4 ^{x x} _{h e} _o ^t _e m ^o ⁾ _l - ^p y - ^y _z ⁶ _{, i} 2₍ ^p _o ^o _r ⁿ _i ^y ^o _u ^o _h _s ^t ⁱ _e _o - ₁ ^m ₎ ^{x 4} ₍ ⁿ _e ^{- x} _o ^l _{f o} ^m ^{4 i} _d ^l _{y o} - ₁ ^b _{( 2} ^{( i - x} ₎ ^l ^e _{l ( d 7 o y} b_a T ^# _x E ⁰ ₇ ¹ ₇

o n _i - - - 1 -⁾ )^{l -} ₃ m_{a 6} ⁾ ^, _{l -} ⁾ _{l l} ₂ ^y- -₅ ^{y y}- -_{5 y} -_n - _a ^z _n -₂ ⁽ ₍ -_n ⁱ _d - -¹ ₅ ^{- a} _e _e ⁾ _l y⁽- ³ - -_{n n} m_{a h} ^t _e ² ₍ ⁿ ⁽ _i ⁱ _l ^e - ^d _i ^{o a} _e ^r - 4 _h - ³ - n ^p _i ⁱ _l ¹ ) ⁶ _, ^o -⁾ _l ^e _r - ^e _b -⁾ _{l 3} ^{- i} _{r -} o _{r n} ⁱ _l ^r _u 2^d _{i d} ^y _h ^u _l ⁴ ₍ ⁽ ₎ _- ^y _h ^l _y ^e _p ^{i o} _u ^o _d ⁾ _l y N m ^r ⁽ _{e d} _l ³-⁾ _l ^p _i ⁿ _{i u} ⁾ ₍ o _l - ₍ ₃ ^{y - r} _e ⁿ _i o^t _e ^y _h ⁴ ₍ ^t _e ⁿ _{e p} o^l _f ⁿ _{i h} ^t s ^y _{x 2} _h ^o _l ⁽ ₍ ^p _{i s} ⁱ _o ^m ₎ ^t _e - ₁ ^{m h} _{p x} -^o _{i 7} ^{- o} _{s e} i - ^y ⁴ _z ^y _n ^{p i} ( ^{n e} _{o o} ^t ^x _e ^y _z ^p _o ^{x l} ^{n x} _y m _o ⁾ ₎ - _{e h} ^x _o ⁱ _o ^{- m} ₎ ^l _{e o o} ^l _o ^m ₎ ^l ⁱ _d - ₁ ⁿ _{i y} m^{x d} _{- y} _o ⁶ _, ^x _{o y} ₁ ^b ₍ ^p _{) d 1 y} ^b ₍ ^a ₍ ² ₍ #_x _E ² ₇ ³ ₇ ⁴ ₇

e _r u_t c_u ^r _t S e _h - - ^{- -} ^p ₃ ₎ ⁾ ^- _l y^{- 3} _{- 2} ⁽ ₍ -_n - - e - ^y _{x 6} ^, _{- 5} 2 ₂ ³ - - -_n ^a _e ^{r )} _y ^{- i} ^m ₍ ^o ₎ ⁽- ⁿ _i ¹ - ^{i x} _{3 d 5} i_r ¹ - -_n ^a _e ^r a ⁽- ^l _y ^{2 o} _l o _u ⁾ _{l o} ^{l -} ₎ ^l _y ^e _p ^o _r ⁱ _l o _u ⁾ _l z ₍ ⁽- ^d _i ^r _r o _d n^y _{h y} zⁿ _e ⁱ _p ^o _u ^l _d n^y _h N ⁴ ₍- _n ₁ ^e _b ³ _e _- ^p _{i u} ^l _{f i} o_s ^t _{e n} e_b ^h _p ^o _{x f}- _i ₄ ^o _s ^t _e o _r ⁾ _l o_l ^y _n ^p _o - ₄ ⁱ ^x _o ^m ₎ _o ^x _o ^l _y ⁽- 4₍ ^o _r ^o _i o_u ^d- -₎ ^l ⁶ _{, y} ⁱ _o ^m ^x ₎ _o ^l _y h _c ⁱ _d - ₁ ^l _f ² ₍ #_x _E ⁵ ₇ ⁶ ₇

e _r u_t c_u ^r _t S -⁾ _l ^{- e} - ^{- -} ₃ y^- ₂ ⁽ _h p₎ ² _{- 2} ^{( -} _n - - - 3 ₅ _- - - ₍ _n -₄ ^y _x ⁾ _{y (} ^{- i} e ⁶ _, ^x _{3 d} - ₅ i_r ¹ - -_n ^a _e ^r _u m_a ² ₍ ⁿ _i ¹ - ⁱ ^{- o} _l o⁽- 3^o ₎ ^a _{e o} ^{l -} ₎ ^l _y ^e _p ^o _r ⁱ _l o⁾ _l ₂ ^d _i ^r _r o _d n -⁾ _l ^l _y ^r _u ⁾ _y zⁿ _e ⁱ _p ^o _u ^l _d n^y _h N ⁽ _{( e} - ₁ ^p _{i u} ^l ^p _{f i} o_s ^y _h ^z _{n l} _o - ₄ ^{i e y} _n _n ^{e h} _p ^o _{x f}- _i ₄ ^o _s ^t _e x _o ^t _{e b b} ^{( o} _i - o ^{x o} _{r -} ^o _r ^d _{- )} ^l _y ⁱ _o ^m ₎ ^l _y i _o ^m ₎ _d ^l _y ^o _u ⁴ ₍ l _f - ₁ ^o _u ^l _f ⁶ _, ^x _o 2 ₍ #_x _E ⁷ ₇ ⁸ ₇

T CP ⁰ ₀-₀ ⁴ ₀ ⁰-⁷ ₇ ² ₁ ^0: _o N_t ^e _k ^c _o D _y ^e _n ^r _o ^t _t

A ^M m 0⁰ _. ⁽ 0 ^{1 8 –} H 6² _, ^– H _. 2^{1 4} _, ^, ₎ ^. ₎ 4 _{( 1 6} _δ ^. ₃ ₇ ^. ₇ ^m ₂ ₍ ^. ₅ ^m ₍ ^H ₁ ^H ₁ S H M + ₅ C + ⁸ L ^M _{( 5} e _r u_t c_u ^r _t S -⁾ _l ^{- z} ^{y -} ₂ ⁽ _n e^a _e - - 3 - ₅- ₍- _b ₄ ⁾ _l ^r _u 6_{, -} n¹ _{- n} ⁱ _l ⁽- ^{y )} _l _e m_a ² _{( i} -₂ ^d _i ^o ^r _r ^{o 3} ^o _d n _{- h} ^{t y} _n _i ⁾ _{l e} ^e _h N ⁽ _{( e} - ₁ ^p _{i u} ^l ^p _f _o - ₄ ^o _s ^y m i _h ^t _e ^o _r ^p ₎ o^y ^x _o _o ^x _u i _o ^m ₎ ^l _x _f ^o ₎ _d ^l _y ⁱ _r ^t ₍ ^l _y #_x _E ⁹ ₇ GSPT1-Degrader-Linker (LP) Examples: Example LP1: N-((7S,16S)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14- pentaazaheptadecan-17-yl)-2,5,8,11,14,17,20,23-octaoxahexacosan-26-amide

[0875] Step A: (tert-Butoxycarbonyl)glycylglycyl-L-phenylalanylglycine (Compound 1a)

[0876] General procedure for the loading of Fmoc-Gly-OH on resin: 11.1 g resin (0.9 mmol/g, 10 mmol, 1 eq) was swelled in dichloromethane (DCM) for 30 minutes and then washed with 500 mL of DCM. A solution of Fmoc-Gly-OH (12 mmol) and DIPEA (40 mmol) in dry DCM was added to the resin and the resin was gently shaken for 2 h at room temperature under argon atmosphere. The reagents were then washed thoroughly with DCM and DMF and the process was repeated to ensure maximum loading of Fmoc-Gly-OH on the resin. The resin was then shaken in 100 mL capping mixture (17:2:1 DCM:MeOH:DIPEA) for 20 minutes and then washed thoroughly with DCM and DMF. The capping process was repeated one more time to ensure complete capping.1 mg of resin was subjected to shake in 1 mL cleavage mixture (1% TFA in DCM) for 10 minutes and the successful loading of the Fmoc-Gly-OH was confirmed by LCMS monitoring. Fmoc-Gly-OH, M.W= 297.31, observed= 298.48 (M+H⁺). [0877] Fmoc deprotection: 11.1 g resin (0.9 mmol/g, 10 mmol, 1 eq) was swelled in dichloromethane (DCM) for 30 minutes and then washed with 500 mL of DCM. The resin was then shaken gently in 20% piperidine in DMF (150 mL) for at least 10 minutes at room temperature. The reaction mixture was then drained, and the resin was washed thoroughly with DMF. The process was repeated once to ensure complete Fmoc deprotection. [0878] Amino-acid coupling: 11.1 g Fmoc-deprotected resin (0.9 mmol/g, 10 mmol, 1 eqv) The Fmoc/Boc amino acids (30 mmol) were preactivated in 150 mL dry DMF in presence of HATU (28 mmol) and DIPEA (60.5 mmol) for 15 minutes and added to the resin. The resin was then gently shaken for at least 2 h. The reaction mixture was then drained, and the resin was washed thoroughly with DCM and DMF.1 mg of resin was subjected to shake in 1 mL cleavage mixture (1% TFA in DCM) for 10 minutes and the successful coupling was confirmed by LCMS monitoring. LCMS monitoring fragments: Fmoc-Phe-Gly-OH, M.W= 444.5, observed= 298.48 (M+H⁺). M+1: 445.3 and M+ 23: 467.3, Exact mass 444.17, Purity > 99 %. [0879] Resin Cleavage and purification of Boc-GGFG-OH: 11.1 g resin after complete SPPS cycle was shaken in 1% TFA in DCM (150 mL) for 10 minutes and filtered. The process was repeated twice and the combined filtrates were added to cold (0-8 ^oC) diethyl ether. The crude peptide was precipitated, centrifuged, and ether mixture was decanted. The crude product was purified by RP-MPLC using water-acetonitrile gradient. Both the eluent was buffered with 0.05 % acetic acid (Note: The presence of trace TFA from mobile phase modifier will cause Boc deprotection upon extended storage of product at -20 °C). The pure fractions from the preparative RP-MPLC was combined and lyophilized to obtain the product 1a as white solid with 98% UPLC purity. Exact mass: 436.20. MS observe: 437.4 (M+H⁺) and 459.4 (M+Na⁺). [0880] Step B: (S)-3-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoic acid (Compound 1e)

[0881] Maleic Anhydride 1b (1.23 g, 12.5 mmol) and S-Dap(BOC)-OH 1c (2.55 g, 12.5 mmol) were dissolved in acetic acid (12 mL) and stirred at room temperature (25 ^oC) for 3 hours under argon atmosphere. The solvent was evaporated in vacuo by azeotroping with acetonitrile, and the residue was dissolved in water (20 mL), frozen, and lyophilized to afford a white glassy solid, 3.36g (89%), which was used as is in the subsequent step. UPLC: 0.77 min/2.5 min; Exact Mass: 302.11. Observed MS: 325.18 (M+Na⁺) and 203.7 (M+H – BOC)⁺. The product is best visible in negative mode MS, MS:301.34 (M-H⁺) and 603.54 (2M-H⁺). [0882] (S,Z)-4-((2-((tert-butoxycarbonyl)amino)-1-carboxyethyl)amino)-4-oxobut-2-enoic acid 1d (2.31 g, 7.64 mmol), was suspended in toluene (65 mL) and treated with DMA (4.5 mL). The solid was slowly dissolved with stirring at room temperature (r.t, 25 ^oC). DIEA (4.0 mL, 22.9 mmol) and powdered molecular sieves (2.5 g) were added, and the resultant mixture was carefully heated, on an oil bath, under argon, at 77 to 82 ^oC for 16 h. (Note: careful temperature control is required to ensure the chiral center remains intact). The mixture was cooled to r.t, and the molecular sieves were removed by filtration. The solvents were evaporated in vacuo at 40 ^oC azeotroping with acetonitrile then on a high vacuum for 20 minutes. The residue was dissolved in water (buffered with 0.05% TFA) (~1 mL) and applied to a RediSep C18 AQ 250 g cartridge and eluted with acetonitrile (5% step 20% gradient to 70%) in water (TFA 0.05%). The gradient was paused at 33% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid (1e), 1.436 g (66%). UPLC: 0.90 min/5 min, >95%. Chiral Chromatography: Single enantiomer. Exact Mass: 284.10. The product is best visible in negative mode MS, Observed MS:283.14 (M-H⁺). [0883] Step C: 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea (1l)

[0884] To a solution of tert-butyl N-[[4-(bromomethyl)phenyl]methyl]carbamate (10 g, 33.3 mmol) in MeCN (150 mL) was added 4-nitrophenol (4.82 g, 34.6 mmol) and K2CO3 (13.8 g, 100 mmol). The reaction mixture was stirred at 80°C for 16h. TLC (petroleum ether/ethyl acetate, 2:1, Rf_#1=0.76 Rf_#2=0.6) showed the starting material was consumed and main a new spot formed. The reaction mixture was cooled to r.t and concentrated. The residue was diluted with ethyl acetate/H2O (200 mL/200 mL), the organic layer was washed with brine ^{(250 mL), dried over anhydrous Na}2^SO4^{, filtered and concentrated to give tert-butyl N-[[4-} [(4-nitrophenoxy)methyl]phenyl]methyl]carbamate 1g (12 g, crude) as a light yellow solid. ¹H NMR: 400 MHz, DMSO-d6 δ: 8.27 (d, J = 9.2 Hz, 2H), 7.48 (d, J = 7.6 Hz, 3H), 7.34- 7.27 (m, 4H), 5.30 (s, 2H), 4.19 (d, J = 6.0 Hz, 1H), 1.45 (s, 9H). [0885] To a solution of tert-butyl N-[[4-[(4-nitrophenoxy)methyl]phenyl]methyl]carbamate (12 g, 33.5 mmol) in EtOH (150 mL) and H2O (30 mL) was added Fe powder (9.35 g, 167 mmol) and NH4Cl (17.9 g, 335 mmol). The mixture was stirred at 80 °C for 2 hr. TLC (petroleum ether/ethyl acetate, 2:1, Rf_#2=0.6 Rf_#3=0.2) showed the reaction was finished. The reaction mixture was cooled to rt and filtered the cake was washed with ethyl aceate (400 mL), the combined filtrate was concentrated. The residue was diluted with water and ethyl acetate (400 mL/400mL), the organic layer was washed with brine (400 mL), dried over anhydrous Na2SO4, filtrated and concentrated to give tert-butyl N-[[4-[(4- aminophenoxy)methyl]phenyl] methyl]carbamate 1h (9 g, 81.9% yield) as a gray solid. [0886] To a solution of tert-butyl N-[[4-[(4-aminophenoxy)methyl]phenyl]methyl]carbamate (5.65 g, 17.2 mmol) in MeCN (200 mL) was added bis(2,5-dioxopyrrolidin-1-yl) carbonate (5.64 g, 22.0 mmol) and Et3N (6.16 g, 60.9 mmol) at -20 °C under nitrogen. The mixture was stirred at -20 °C for 1 h. 3-[5-(aminomethyl)-1-oxo-isoindolin-2-yl]piperidine-2,6-dione (6.80 g, 18.4 mmol, MsOH salt) was added to the mixture. The mixture was stirred at 20 °C for 15 hours. TLC (petroleum ether/ethyl acetate, 2:1, Rf#4=0 Rf#3=0.2) showed the reaction was finished. The reaction mixture was filtered and cake was washed with MeCN (50 mL) and dried to give tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate 1i (9 g, crude) as a gray solid.¹H NMR: 400 MHz, DMSO-d6 δ: 10.99 (s, 1H), 8.43 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.53-7.23 (m, 9H), 6.88 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 6.0 Hz, 1H), 5.14-5.09 (m, 1H), 5.09 (s, 2H), 4.47-4.29 (m, 4H), 4.12 (d, J = 6.0 Hz, 2H), 2.92-2.91 (m, 1H), 2.62-2.51 (m, 1H), 2.41-2.37 (m, 1H), 1.40 (s, 9H). [0887] A solution of tert-butyl N-[[4-[[4-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl carbamoylamino]phenoxy]methyl]phenyl]methyl]carbamate (9 g, 14.3 mmol) and HCl (30 mL,12 N ) was stirred at 0°C for 1h. LCMS showed the staring material was consumed. MeCN (500 mL) was added into the mixture slowly at 0-10°C, after stirring for 30 mins, the formed solid was filtered and dried to give 1-[4-[[4- (aminomethyl)phenyl]methoxy]phenyl]-3-[[2-(2,6-dioxo-3-piperidyl)-1-oxo-isoindolin-5- yl]methyl]urea 1l (7.12 g, 88.0% yield, HC salt) as a off-white solid.¹H NMR: 400 MHz, DMSO-d6 δ: 10.98 (s, 1H), 8.66 (s, 1H), 9.30 (s, 3H), 7.69 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 6H), 7.31-7.29 (m, 2H), 6.89 (d, J = 2.0 Hz, 2H), 6.88 (s, 1H), 5.13-5.07 (m, 3H), 4.47-4.29 (m, 4H), 4.01 (t, J = 5.6 Hz, 2H), 2.95-2.87 (m, 1H), 2.62-2.52 (m, 1H), 2.50-2.38 (m, 1H), 2.01-1.94 (m, 1H). [0888] Step D: tert-Butyl((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11- tetraazatridecan-13-yl)carbamate (1m).

[0889] 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)urea (446 mg, 0.651 mmol) was weighed in an isolator. The solid was mixed as a slurry in dimethylformamide (DMF) (8 mL) for 15 minutes until chunks was not present. Boc-GGFG-OH 1a (312 mg, 0.716 mmol) and HATU (248 mg, 0.651 mmol) were sequentially added to the reaction mixture, following by DIEA (400 µL, 2.28 mmol). The reaction mixture turns yellow and dissolves over time (~ 5-10 minutes). After 15-30 minutes at room temperature, product is verified with UPLC-MS. Reaction is quenched with glacial Acetic Acid (130 µL 2.28 mmol). Crude reaction mixture is loaded onto RP-MPLC C18 Aq column (Teledyne ISCO) and purified with gradient elution of Water/0.05 % Acetic Acid and Acetonitrile/0.05 % Acetic Acid. Gradient pause at 0 % B until all DMF has eluted. Quick ramp up to 30 % and pause gradient until impurities elute. Gradual ramp up to 40 % B and pause until product completes eluting. HPLC purity > 94 %. Fractions were frozen and lyophilized to a white solid 1m, 396 mg (64 %). UPLC: 1.15 min/2.5 min run, 98 %; MS: 946.4 (M+H⁺). [0890] Step E: (2S)-2-(2-aminoacetamido)-N-(2-((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)amino)-2-oxoethyl)-3- phenylpropanamide (1n).

[0891] Solid tert-butyl((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11- tetraazatridecan-13-yl)carbamate (396 mg, 0.418 mmol) was slurry in anhydrous dioxane (4 mL) and anhydrous acetonitrile (8 mL).4 M HCl in dioxane (6 mL) was added to the slurry and the sample was mixed for 90 minutes at room temperature. The crude reaction mixture was concentrated in vacuo without exceeding a bath temperature of 40 °C to solids. The solids were dissolved in dimethylformamide and loaded onto a C18 Aq RP-MPLC Column. Fractions were checked by UPLC, combined (purity > 95 %), frozen, and lyophilized to a white solid, 349 mg (87 %) as a TFA salt. UPLC: 1.53 min/5 min run, 97 %; MS: 846.8 [0892] Step F: tert-Butyl ((7S,16S)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1- (4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14- pentaazaheptadecan-17-yl)carbamate (1o)

[0893] (S)-3-((tert-Butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoic acid (224 mg, 0.787 mmol) and HATU (293 mg, 0.771 mmol), were dissolved in DMF (4 mL), treated with DIEA (0.365 mL, 2.08 mmol), and held at rt for 5 minutes. The resultant solution was transferred to a vial containing solids (2S)-2-(2-aminoacetamido)-N- (2-((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)amino)-2-oxoethyl)-3-phenylpropanamide TFA- salt (578 mg, 0.602 mmol) and HOAt (catalytic). The resultant solution was held at r.t for one hour, treated with acetic acid (0.180 mL, 3 mmol), diluted with water (3 mL), applied to a RediSep C18 AQ 150 g cartridge and eluted with acetonitrile (5% step 20% gradient to 95%) in water (acetic acid 0.05%). The gradient was paused at 47% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 629 mg (94%). UPLC: 2.06 min/5.0 min run, 99%; MS: 1112.93 (M+H⁺). [0894] Step G: (2S)-3-amino-N-((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11- tetraazatridecan-13-yl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide TFA-salt (1p)

[0895] tert-Butyl ((7S,16S)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazaheptadecan-17-yl)carbamate (629 mg, 0.566 mmol) was suspended in DCM (13 mL) and treated with TFA (6 mL). The resultant solution was held at rt for one hour. The solvents were evaporated in vacuo, then on high vacuum for 30 minutes. The residue was dissolved in DMSO/water (2 mL/1 mL) and applied to a RediSep C18 AQ 100 g cartridge, and eluted with acetonitrile (5% step 10% gradient to 95%) in water (TFA 0.05%). The gradient was paused at 42% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 559 mg (88%). UPLC: 1.44 min/5.0 min run, 99%. MS: 1012.93 (M+H⁺). [0896] Step H: N-((7S,16S)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazaheptadecan-17-yl)- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide (LP1)

[0897] Semi-solid 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-oic acid (589 mg, 0.679 mmol) and solid HATU (254 mg, 0.668 mmol) were dissolved in DMF (6 mL), and treated with DIPEA (0.270 mL, 1.53 mmol) at rt for 6 minutes. The resultant solution was transferred to a vial containing solids (2S)-3-amino-N-((7S)-7-benzyl-1-(4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan-13-yl)- 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide TFA-salt (559 mg, 0.496 mmol) and HOAt (catalytic), and the resultant solution was held at rt for one hour. The solution was treated with acetic acid (0.10 ml, 1.67 mmol), diluted with water (4 mL), applied to a RediSep C18 AQ 150 g cartridge and eluted with acetonitrile (5% step 10% gradient to 95%) in water (acetic acid 0.05%). The gradient was paused at 42% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 668 mg (85%). UPLC 1.84 min/5.0 min, >96%; MS: 1583.26 (M+H⁺).¹H NMR (DMSO-d6, 500 MHz); δ 11.2 (s, 1H), 8.64 (m, 2H), 8.54 (m, 1H), 8.45-8.34 (m, 2H), 8.21-8.16 (m, 2H), 7.95-7.93 (m, 1H), 7.75 (d, J=0.59, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 2H), 7.55-7.42 (m, 8H), 7.27 (s, 1H), 7.17 (m, 2H), 6.8 (t, J= 1.7 Hz, 1H), 5.35 (m, 1H), 5.25 (s, 1H), 4.88 (m, 1H), 4.70 (m, 2H), 4.65 (m, 2H), 4.54 (m, 3H), 4.00 (m, 7H), 3.86-3.81 (m, 48H), 3.48 (s, 3H), 3.29 (m, 1H), 3.14 (m, 1H), 3.04 (1H), 2.85 (m, 1H), 2.63 (m, 1H), 2.43 (td, J= 2.42 and 1.38 Hz), 2.24 (m, 1H). Example LP2: N-((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14- pentaazaheptadecan-17-yl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan- 38-amide

[0898] Step 1: (R)-3-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanoic acid (2c)

[0899] Maleic Anhydride 1b (1.23 g, 12.5 mmol) and S-Dap(BOC)-OH (2.55 g, 12.5 mmol) were dissolved in acetic acid (12 mL) and stirred at room temperature (25 ^oC) for 3 hours under argon atmosphere. The solvent was evaporated in vacuo by azeotroping with acetonitrile, and the residue was dissolved in water (20 mL), frozen, and lyophilized to afford a white solid, 3.5g (92%), which was used as is in the subsequent step. UPLC: 0.77 min/2.5 min. Exact mass: 302.11. MS: 325.16 (M+Na⁺) and 203.67 (M+H – BOC)⁺. The product is best visible in negative mode MS, MS:301.23 (M-H⁺) and 603.48 (2M-H⁺). [0900] Solid sample of 2b, (R,Z)-4-((2-((tert-butoxycarbonyl)amino)-1-carboxyethyl)amino)- 4-oxobut-2-enoic acid (2.31 g, 7.64 mmol), was suspended in toluene (65 mL) and treated with DMA (4.5 mL). The solid slowly dissolved with stirring at room temperature (r.t, 25 ^oC). DIEA (4.0 mL, 22.9 mmol) and powdered molecular sieves (2.5 g) were added, and the resultant mixture was carefully heated, on an oil bath, under argon, at 78 to 80 ^oC for 16 h. (Note: careful temperature control is required to ensure the chiral center remains intact). The mixture was cooled to r.t, and the molecular sieves were removed by filtration. The solvents were evaporated in vacuo at 40 ^oC azeotroping with acetonitrile then on a high vacuum for 20 minutes. The residue was dissolved in water (buffered with 0.05% TFA) (~1 mL) and applied to a RediSep C18 AQ 250 g cartridge and eluted with acetonitrile (5% step 20% gradient to 70%) in water (TFA 0.05%). The gradient was paused at 33% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 1.8 g (85%). NMR(DMSO-d6). UPLC: 0.90 min/5 min, >99%. Chiral Chromatography: Single enantiomer. Exact Mass: 284.10. The product is best visible in negative mode MS, Observed MS:283.18 (M-H+). [0901] Step 2: tert-Butyl ((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1- (4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14- pentaazaheptadecan-17-yl)carbamate (2d)

[0902] Solid sample of (R)-3-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro-1H- pyrrol-1-yl)propanoic acid (224 mg, 0.787 mmol) and HATU (293 mg, 0.771 mmol), were dissolved in DMF (4 mL), treated with DIEA (0.365 mL, 2.08 mmol), and held at rt for 5 minutes. The resultant solution was transferred to a vial containing solids (2S)-2-(2- aminoacetamido)-N-(2-((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)amino)-2-oxoethyl)-3-phenylpropanamide TFA- salt (578 mg, 0.602 mmol) and HOAt (catalytic). The resultant solution was held at r.t for 1 hour, treated with acetic acid (0.180 mL, 3 mmol), diluted with water (3 mL), applied to a RediSep C18 AQ 150 g cartridge and eluted with acetonitrile (5% step 20% gradient to 95%) in water (acetic acid 0.05%). The gradient was paused at 47% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 600 mg (89%). UPLC: 2.07 min/5.0 min run, 98%; MS: 1113.12 (M+H⁺). [0903] Step 3: (2R)-3-amino-N-((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11- tetraazatridecan-13-yl)-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide (2e)

[0904] tert-butyl ((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazaheptadecan-17-yl)carbamate (600 mg, 0.539 mmol) was suspended in DCM (13 mL) and treated with TFA (6 mL). The resultant solution was held at rt for one hour. The solvents were evaporated in vacuo, then on high vacuum for 30 minutes. The residue was dissolved in DMSO/water (2 mL/1 mL) and applied to a RediSep C18 AQ 100 g cartridge, and eluted with acetonitrile (5% step 10% gradient to 95%) in water (TFA 0.05%). The gradient was paused at 42% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 500 mg (91%). UPLC: 1.48 min/5.0 min run, 96%. MS: 1013.01 (M+H⁺). [0905] Step 4: N-((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazaheptadecan-17-yl)- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide (LP2)

[0906] Semi-solid sample of 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38- oic acid (m-Peg12-OH) (96.9 mg, 0.153 mmol) and solid, HATU (64 mg, 0.170 mmol), were dissolved in DMF (1 mL), and treated with DIPEA (0.59 mL, 0.340 mmol) at rt for 6 minutes. The resultant solution was transferred to a vial containing solids (2R)-3-amino-N- ((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan-13-yl)- 2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propenamide (3e) TFA-salt (115 mg, 0.113 mmol) and HOAt (catalytic), and the resultant solution was held at rt for one hour. The solution was treated with acetic acid (0.10 ml) and applied to a RediSep C18 AQ 50 g cartridge and eluted with acetonitrile (5% step 10% gradient to 95%) in water (acetic acid 0.05%). The gradient was paused at 42% acetonitrile as the product eluted. Fractions were combined, frozen and lyophilized to a white solid, 130 mg (72%). UPLC 1.87 min/5.0 min, >99%; MS: 1583.79 (M+H⁺).¹H NMR (DMSO-d6, 500 MHz); δ 11.2 (s, 1H), 8.64 (m, 2H), 8.54 (m, 1H), 8.45- 8.34 (m, 2H), 8.21-8.16 (m, 2H), 7.95-7.93 (m, 1H), 7.75 (d, J=0.59, 1H), 7.69-7.67 (m, 2H), 7.63-7.61 (m, 2H), 7.55-7.42 (m, 8H), 7.27 (s, 1H), 7.17 (m, 2H), 6.8 (t, J= 1.7 Hz, 1H), 5.35 (m, 1H), 5.25 (s, 1H), 4.88 (m, 1H), 4.70 (m, 2H), 4.65 (m, 2H), 4.54 (m, 3H), 4.00 (m, 7H), 3.86-3.81 (m, 48H), 3.48 (s, 3H), 3.29 (m, 1H), 3.14 (m, 1H), 3.04 (1H), 2.85 (m, 1H), 2.63 (m, 1H), 2.43 (td, J= 2.42 and 1.38 Hz), 2.24 (m, 1H). Example LP3: N-((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan- 13-yl)-1-(3-(2,5-dioxo-2,5-dihydro-1N-((7S)-7-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin- 3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo- 2,5,8,11-tetraazatridecan-13-yl)-1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amideH-pyrrol-1- yl)propanamido)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide

[0907] To a solution of (2S)-2-(2-(2-aminoacetamido)acetamido)-N-(2-((4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)amino)-2- oxoethyl)-3-phenylpropanamide (1n, 10.1 mg, 0.012 mmol) and 2,5-dioxopyrrolidin-1-yl 1- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-3-oxo-7,10,13,16,19,22,25,28-octaoxa-4- azahentriacontan-31-oate (3a, 12.35 mg, 0.018 mmol) and in DMF (0.3 mL), DIPEA (6.26 µl, 0.036 mmol) was added. The reaction mixture was stirred at RT for 30 mins. LCMS analysis showed the reaction completed (1.462 min at 3 min acidic run, M+H/z = 1420.9). The reaction mixture was neutralized with acetic acid and purified on Xbridge C185 u 19x150 mm column with 10-50% ACN in water (18.9 mL/min, both with 0.05% TFA). The fractions containing expected product were combined and freeze-dried to yield N-((7S)-7- benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan-13-yl)- 1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3,6,9,12,15,18,21,24- octaoxaheptacosan-27-amide (LP3, 9.1 mg, 6.01 µmol, 50.3 % yield).1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.45 (s, 1H), 8.29 (t, 1H), 8.10 – 8.20 (m, 3H), 8.00 (t, J = 5.7 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.52 (s, 1H), 7.42 – 7.35 (m, 3H), 7.28 – 7.318(m, 10H), 7.02 (s, 2H), 6.90 – 6.86 (m, 2H), 6.68 (t, J = 6.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.2 Hz, 1H), 5.01 (s, 2H), 4.51 – 4.28 (m, 7H), 3.81 – 3.58 (m, 4H), 3.62 – 3.56 (m, 4H), 3.51 – 3.47 (m, 28H), 3.38-3.32 (m, 2H), 3.16 (q, J = 5.8 Hz, 2H), 3.08 (dd, J = 13.9, 4.6 Hz, 1H), 2.99 – 2.77 (m, 3H), 2.60 (dd, J = 13.9, 9.6 Hz, 1H), 2.38 (dt, J = 31.8, 6.8 Hz, 5H), 2.06 (ddq, J = 10.4, 5.3, 2.7 Hz, 1H). Example LP4: N-((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo-2,5,8,11,14- pentaazanonadecan-19-yl)-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38- amide

[0908] Step 1: (R)-5-amino-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid (4e)

[0909] To a stirred mixture of (R)-2-amino-5-((tert-butoxycarbonyl)amino)pentanoic acid, 4a (1.00 g, 4.30 mmol, 1.00 equiv) in 20.0 mL AcOH was added furan-2,5-dione, 4b (423 mg, 4.30 mmol, 1.00 equiv). The resulted mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to afford (R,Z)-5-((tert-butoxycarbonyl)amino)- 2-(3-carboxyacrylamido)pentanoic acid, 4c (1.42 g, 100% yield) as a white solid. LCMS (ESI, m/z): 331 [M+H] ⁺. [0910] A solution of (R,Z)-5-((tert-butoxycarbonyl)amino)-2-(3- carboxyacrylamido)pentanoic acid, 4c (1.42 g, 4.30 mmol, 1.00 equiv) in 100 mL toluene was stirred at 110 ^oC overnight. The solvent was removed under reduced pressure and then purified by reverse flash chromatography ((Spherial C18, 80 g, 20~40 μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 0% B to 60% B in 20 min, 210 nm; RT: 14 min)) to give (R)-5-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid, 4d (800 mg, 59% yield) as a white solid. LCMS (ESI, m/z): 313 [M+H] ⁺. [0911] To a stirred solution of (R)-5-((tert-butoxycarbonyl)amino)-2-(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1-yl)pentanoic acid, 4d (800 mg, 2.56 mmol, 1.00 equiv) in 20.0 mL DCM was added 6.0 mL TFA. The resulted solution was stirred at room temperature for 30 mins. The solvent was removed under reduced pressure and 20.0 mL EA was added to precipitate the final compound. The solid was collected by filtration to give (R)-5-amino-2-(2,5-dioxo-2,5- dihydro-1H-pyrrol-1-yl)pentanoic acid TFA salt, 4e (349 mg, 42% yield, ee 100%) as a white solid. LCMS (ESI, m/z): 213 [M+H] +.1H NMR (400 MHz, DMSO-d6) δ 13.21 (br, 1H), 7.72 (s, 3H), 7.14 (s, 2H), 4.58 (dd, J = 10.8, 4.9 Hz, 1H), 2.76 (m, 2H), 2.19 – 1.76 (m, 2H), 1.47 (m, 2H). [0912] Step 2: (R)-43-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-38-oxo- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxa-39-azatetratetracontan-44-oic acid (4g)

[0913] To a solution of (R)-5-amino-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)pentanoic acid (4e, 20 mg, 0.094 mmol) and 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23,26,29,32,35- dodecaoxaoctatriacontan-38-oate (4f, 64.6 mg, 0.094 mmol) in DMF (0.8 mL), DIPEA(50 uL) was added. The reaction mixture was stirred at RT for 30 min. LCMS analysis showed the reaction completed (1.04 min at 2 min run, M+H/z = 783.4). The reaction mixture was purified on 19x150 mm Xbridge 5u column with 10-30% ACN in water(both with 0.05% TFA, 18.9 mL/min). The fractions containing expected intermediate were combined and freeze-dried to yield 4g (31 mg, 0.040 mmol, 42.13%). [0914] Step 3: N-((7S,16R)-7-benzyl-16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 3,6,9,12,15-pentaoxo-2,5,8,11,14-pentaazanonadecan-19-yl)- 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaoctatriacontan-38-amide (LP4)

[0915] To a solution of 4g (31 mg, 0.040 mmol), (2S)-2-(2-(2-aminoacetamido)acetamido)- N-(2-((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)amino)-2-oxoethyl)-3-phenylpropanamide (1n, 31.9 mg, 0.038 mmol) and HATU (20 mg, 0.053 mmol) in DMF (0.8 mL), DIPEA(30 uL) was added. The reaction mixture was stirred at RT for 15 mins. LCMS analysis showed reaction completed (1.23 min at 2 min run, M+H/Z = 1610.6). The reaction mixture was purified on 19x150 mm Xbridge column with 10-30% ACN in water. The fractions containing expected product were combined and freeze-dried to yield N-((7S,16R)-7-benzyl- 16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12,15-pentaoxo- 2,5,8,11,14-pentaazanonadecan-19-yl)-2,5,8,11,14,17,20,23,26,29,32,35- dodecaoxaoctatriacontan-38-amide (LP4, 20.2 mg, 0.013, 34.21%).1H NMR (400 MHz, DMSO-d6) δ ppm 10.84 - 11.15 (m, 1 H), 8.38 - 8.44 (m, 1 H), 8.24 - 8.34 (m, 2 H), 8.17 - 8.22 (m, 1 H), 8.07 - 8.14 (m, 1 H), 7.94 - 8.03 (m, 1 H), 7.77 - 7.85 (m, 1 H), 7.66 - 7.72 (m, 1 H), 7.49 - 7.53 (m, 1 H), 7.40 - 7.47 (m, 1 H), 7.34 - 7.39 (m, 2 H), 7.14 - 7.32 (m, 9 H), 7.02 - 7.09 (m, 2 H), 6.84 - 6.92 (m, 2 H), 6.59 - 6.67 (m, 1 H), 5.05 - 5.15 (m, 1 H), 4.97 - 5.05 (m, 2 H), 4.46 - 4.58 (m, 2 H), 4.39 - 4.43 (m, 2 H), 4.25 - 4.34 (m, 3 H), 3.67 - 3.82 (m, 4 H), 3.59 - 3.63 (m, 1 H), 3.53 - 3.58 (m, 3 H), 3.40 - 3.52 (m, 45 H), 3.21 - 3.25 (m, 3 H), 2.85 - 3.09 (m, 4 H), 2.74 - 2.84 (m, 1 H), 2.56 - 2.64 (m, 1 H), 2.36 - 2.41 (m, 1 H), 2.22 - 2.29 (m, 2 H), 1.88 - 2.04 (m, 3 H), 1.18 - 1.31 (m, 2 H). [0916] Example LP5: 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)-N-((7S)-7- benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan- 13-yl)-1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)piperidine-4-carboxamide

[0917] Step 1: methyl 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)piperidine-4- carboxylate

[0918] To a solution of compound 5a (120 mg, 0.46 mmol) in DMF (0.5 mL) was added sodium hydride (60% dispersion in mineral oil, 17.7 mg 0.69 mmol) at 0 ^OC. The mixture was stirred for 30 minutes at room temperature. Compound 5b (180 mg, 0.64 mmol) in DMF (0.5 mL) was added dropwise to the above reaction mixture at 0 ^OC. The reaction was stirred overnight at room temperature. Upon completion as monitored by LCMS analysis, the reaction was quenched with saturated aq. NH4Cl solution, filtered and purified by prep- HPLC eluting with 0-100% acetonitrile in water with 0.1% formic acid to afford Boc- protected 5c (44.7 mg, Yield 16%). MS (ES+) m/z 599.3 [M+18]. [0919] To a solution of the above intermediate (39.0 mg, 0.07 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (0.1 mL). The mixture was stirred for 3 hours at room temperature. Upon completion as monitored by LCMS analysis, the reaction was concentrated and the crude was lyophilized overnight to get solid compound 5c (37.1 mg, Yield 115%). MS (ES+) m/z 482.3 [M+H]. [0920] Step 2: methyl 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)-1-(2-(1,3-dioxo- 1,3,3a,4,7,7a-hexahydro-2H-4,7-epoxyisoindol-2-yl)ethyl)piperidine-4-carboxylate

[0921] 2-(2-Hydroxyethyl)-3a,4,7,7a-tetrahydro-1H-4,7-epoxyisoindole-1,3(2H)-dione (2.80 g, 13.4 mmol) was dissolved in 15 ml of dichloromethane under sonication, followed by addition of triphenylphosphine (7.00 g, 26.7 mmol). The mixture was cooled to 0 ^OC, NBS (3.92 g, 22.0 mmol) was added in portions. The reaction mixture was allowed to warm up to room temperature and stirred for 12 h. Upon completion as monitored by LCMS analysis, the reaction was concentrated and the crude was purified by column chromatography giving compound 5d (2.07 g, Yield: 57 %). Compound 5c (37.1 mg, 0.08 mmol), 5d (21.0 mg, 0.08 mmol), KI (0.08 mmol, 12.6 mg) and K²CO3 were taken in acetonitrile (0.5 mL). The mixture was stirred overnight at 60 ^OC. Upon completion as monitored by LCMS analysis, the reaction was filtered, and solvent was evaporated. The crude product was redissolved in 0.5 mL DMF and purified by prep-HPLC eluting with 0-100% acetonitrile in water with 0.1% formic acid to afford the compound 5e (25.4 mg, Yield 49%). MS (ES+) m/z 673.3 [M+H]. [0922] Step 3: 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)-1-(2-(1,3-dioxo- 1,3,3a,4,7,7a-hexahydro-2H-isoindol-2-yl)ethyl)piperidine-4-carboxylic acid

[0923] Compound 5e (25.4 mg, 0.04 mmol) and LiOH (2.7 mg, 0.11 mmol) were taken in 1:3:3 H2O:THF:MeOH. The mixture was stirred overnight at room temperature. Upon completion as monitored by LCMS analysis, the solvent was evaporated. The crude product was redissolved in 1.0 mL H2O and purified by prep-HPLC eluting with 0-50% acetonitrile in water with 0.1% formic acid to afford the corresponding acid (9.7 mg, Yield 39%). MS (ES+) m/z 677.3 [M+H+18]. The acid (9.7 mg, 0.015 mmol) was taken in 0.3 mL toluene. The mixture was stirred for 3 hours at 100 ^oC. Upon completion, the solvent was evaporated. The crude product was redissolved in 1.0 mL H2O and purified by prep-HPLC eluting with 0-50% acetonitrile in water with 0.1% formic acid to afford 5f (4.8 mg, Yield 55%). MS (ES+) m/z 591.3 [M+H]. [0924] Step 4: 4-((2,5,8,11,14,17,20-heptaoxadocosan-22-yl)oxy)-N-((7S)-7-benzyl-1-(4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6,9,12-tetraoxo-2,5,8,11-tetraazatridecan-13-yl)- 1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)piperidine-4-carboxamide (LP5)

[0925] The LP examples listed in Table 5 were prepared using similar procedures described for the synthesis of LP1- LP5 with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry. Table 5. Examples of Linker-Payloads (LPs)

Example LP54: 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)- 3-methylbutanamido)-5-ureidopentanamido)-2-((26-oxo-2,5,8,11,14,17,20,23-octaoxa- 27-azanonacosan-29-yl)carbamoyl)benzyl (4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate

[0926] Step 1: 9H-fluoren-9-yl)methyl ((2S)-1-(((2S)-1-((3-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxo-5- ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (54b)

[0927] To a solution of 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea (1l, 100 mg, 0.190 mmol) and (9H- fluoren-9-yl)methyl ((S)-1-(((S)-1-((3-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4- ((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-1-oxo-5-ureidopentan-2-yl)amino)- 3-methyl-1-oxobutan-2-yl)carbamate (54a, 181 mg, 0.190 mmol) in DMF (1.0 mL), DIPEA (0.099 mL, 0.569 mmol) was added. The reaction mixture was stirred at RT for 30 mins. LCMS analysis showed product formed. The reaction mixture was purified on Xbridge C18 19x150 mm 5U column with 50-90% ACN in water (both with 0.05% TFA, 20 mL/min). The fractions containing expected product were combined and freeze-dried to yield 54b (121 mg, 0.090 mmol, 47.5%). LCMS ESI, M+H-Boc/z = 1241.4). [0928] Step 2: 9H-fluoren-9-yl)methyl ((2S)-1-(((2S)-1-((3-((2-aminoethyl)carbamoyl)-4- ((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenyl)amino)-1-oxo-5- ureidopentan-2-yl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (54c)

[0929] To a solution of 54b (121 mg, 0.090 mmol) in DCM(2 mL), TFA (2 mL) was added. The reaction mixture was stirred at RT for 15 mins. LCMS analysis showed the product formed. The reaction mixture was concentrated and purified on 19x150 mm Xbridge column with 30-70% ACN in water (both with 0.05% TFA, 18.9 mL/min). The fractions containing expected were combined and freeze-dried to yield 54c (60 mg, 0.048 mmol, 53.3% yield). LCMS ESI, M+H/z = 1241.76. [0930] Step 3: 4-((S)-2-((S)-2-amino-3-methylbutanamido)-5-ureidopentanamido)-2-((26- oxo-2,5,8,11,14,17,20,23-octaoxa-27-azanonacosan-29-yl)carbamoyl)benzyl (4-((4-(3-((2- (2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (54f)

[0931] To a solution of 2,5-dioxopyrrolidin-1-yl 2,5,8,11,14,17,20,23-octaoxahexacosan-26- oate (54d, 29.6 mg, 0.058 mmol) and 2c (60 mg, 0.048 mmol) in DMF (1.0 mL), DIPEA (0.025 mL, 0.145 mmol) was added. The reaction mixture was stirred at RT for 30 mins. LCMS analysis showed product formed. The reaction mixture was purified on Xbridge C18 5u 19x150mm column in ACN in water (both with 0.05% TFA, 20 mL/min). The fractions containing product were combined and freeze-dried to yield 54e (51 mg, 0.031 mmol, 64.9%). LCMS ESI, M+H/z = 1636.3. [0932] To a solution of 54e (6, 51 mg, 0.031 mmol in DMF (1.0 mL), piperidine (0.1 mL) was added. The reaction mixture was stirred at RT for 30 mins. LCMS analysis showed product formed. The reaction mixture was concentrated and purified on 19x150 mm Xbridge column with 20-40% ACN in water (both with 0.05% TFA, 18.9 mL/min). The fractions containing expected product were combined and freeze-dried to yield 54f (40 mg, 0.028 mmol, 91.2% yield). LCMD ESI, M+H/z = 1414.2. [0933] Step 4: 4-((S)-2-((S)-2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3- methylbutanamido)-5-ureidopentanamido)-2-((26-oxo-2,5,8,11,14,17,20,23-octaoxa-27- azanonacosan-29-yl)carbamoyl)benzyl (4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (LP54)

[0934] To a solution of 54f (15 mg, 10.61 µmol) and 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)propanoate (54g, 4.24 mg, 0.016 mmol) in DMF (0.5 mL), DIPEA (5.56 µl, 0.032 mmol) was added. The reaction mixture was stirred at RT for 30 mins. LCMS analysis showed product formed. The reaction mixture was purified on Xbridge C185u 19x150mm column with 30-50% ACN in water (both with 0.05% TFA, 20 mL/min). The fractions containing intermediate were combined and freeze-dried to yield 4-((S)-2-((S)- 2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-3-methylbutanamido)-5- ureidopentanamido)-2-((26-oxo-2,5,8,11,14,17,20,23-octaoxa-27-azanonacosan-29- yl)carbamoyl)benzyl (4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamate (LP54, 7 mg, 4.47 µmol, 42.2 % yield). LCMS ESI M+H/z = 1565.3. [0935] The LP examples listed in Table 6 were prepared using similar procedures described for the synthesis of LP54 with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry.

Example LP60: (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0936] Step 1: (2S,3R,4S,5S,6S)-2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4- ((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (60g)

[0937] To a solution of 5-formyl-2-hydroxy-benzoic acid (5.000 g, 30.1 mmol) in DMF (50 mL) was added tert-butyl N-(2-aminoethyl)carbamate (5.786 g, 36.12 mmol), 1-ethyl-(3-(3- dimethylamino)propyl)-carbodiimide hydrochloride (6.903 g, 36.12 mmol) and benzotriazol- 1-ol (4.876 g, 36.12 mmol) at 0°C under nitrogen. Then the mixture was stirred at 25 °C for 12 h under nitrogen. TLC showed the starting material was consumed and new spots were formed. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were dried over anhydrous sodium sulfate solid, filtered and concentrated in vacuum to give the residue. The residue was purified by flash silica gel column (0-50 % ethyl acetate in petroleum ether) to give tert-butyl (2-(5-formyl-2-hydroxybenzamido)ethyl)carbamate, 60b (2.800 g, 9.08 mmol, 30.2% yield) as a white solid.¹H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 9.84 (s, 1H), 9.11 (t, J = 5.2 Hz, 1H), 8.46 (d, J = 1.6 Hz, 1H), 7.94 (dd, J = 1.6, 8.8 Hz, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 5.6 Hz, 1H), 3.43 - 3.43 (m, 1H), 3.37 - 3.33 (m, 2H), 3.14 (q, J = 6.0 Hz, 2H), 1.35 (s, 9H). [0938] To a solution of tert-butyl (2-(5-formyl-2-hydroxybenzamido)ethyl)carbamate, 60b (2.800 g, 9.08 mmol) in acetonitrile (70 mL) was added (2R,3R,4S,6S)-2-bromo-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4-diyl diacetate, 60c (3.967 g, 9.99 mmol) and silver oxide (4.209 g, 18.16 mmol) under nitrogen. Then the mixture was stirred at 25 °C for 12 h under nitrogen. TLC showed the starting material was consumed and one main new spot was formed. The reaction mixture was filtered and filtrate was concentrated in vacuum to give the residue. The residue was purified by flash silica gel column (0-88% ethyl acetate in petroleum ether) to give (2S,3R,4S,5S,6S)-2-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-formylphenoxy)-6-(methoxycarbonyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate, 60d (5.000 g, 8.01 mmol, 88.2% yield) as yellow solid. LCMS: m/z: 625.4 [M+1]+. [0939] To a solution of (2S,3R,4S,5S,6S)-2-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-formylphenoxy)-6-(methoxycarbonyl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate 60d (5.000 g, 8.01 mmol) in dichloromethane (50 mL) was added sodium borohydride (0.363 g, 9.61 mmol) at 0 °C. Then the mixture was stirred at 0 °C for 2h. LCMS showed the starting material was consumed and desired mass was detected. The reaction mixture was quenched with a small amount of water, dried over anhydrous sodium sulfate solid, wash with DCM (20 mL × 2), filtered and concentrated in vacuum to give (2S,3R,4S,5S,6S)-2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4- (hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, 60e (4.650 g, 7.42 mmol, 92.7% yield) as a yellow solid, which was used in the next step directly. LCMS: m/z: 627.4 [M+1]+. [0940] To a solution of (2S,3R,4S,5S,6S)-2-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-(hydroxymethyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 60e (0.370 g, 0.59 mmol, in DMF (5 mL) was added bis(4-nitrophenyl) carbonate (0.215 g, 0.71 mmol) and N-ethyl-N- isopropylpropan-2-amine (0.2 mL, 1.18 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture contained (2S,3R,4S,5S,6S)-2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)- 4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H- pyran-3,4,5-triyl triacetate, 60g (0.400 g, 0.51 mmol) as a yellow oil was used into the next step directly without further purification. LCMS: MS (ESI) m/z: 792.4[M+1]+ [0941] Step 2: (2S,3R,4S,5S,6S)-2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4- ((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (60h)

[0942] To a solution of 1l (0.200 g, 0.35 mmol) in N,N-dimethylformamide (2 mL) was added (2S,3R,4S,5S,6S)-2-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran- 3,4,5-triyl triacetate (60g, 0.281 g, 0.35 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.2 mL, 1.42 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and the desired mass was observed. The mixture was filtered. The residue was purified by semi-preparative reverse phase HPLC (38-68% acetonitrile in water + 0.225% formic acid, over 10 min). Then the collected fraction was concentrated to remove most of the acetonitrile, then the aqueous solution was extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum afford the product 60h (0.250 g, 0.21 mmol, 59.74% yield) as a yellow solid. LCMS: m/z: 1180.6 [M+1]+ [0943] Step 3: (2S,3S,4S,5R,6S)-6-(2-((2-aminoethyl)carbamoyl)-4-((((4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid (60i)

[0944] To a solution of 60h (0.250 g, 0.21 mmol) in tetrahydrofuran (3 mL) was added with hydrochloric acid (6 M, 3 mL). The mixture was stirred at 45 °C for 2 h. LCMS showed the starting material was consumed and the desired mass was observed. The mixture was concentrated. The residue was purified by semi-preparative reverse phase HPLC (8-38% acetonitrile in water + 0.225% formic acid, over 10 min). Then the collected fraction was concentrated to remove most of the acetonitrile, and then lyophilized to afford the product 60i (0.085 g, 0.09 mmol, 42.69% yield) as a white solid. LCMS, m/z: 940.5 [M+1]+ [0945] Step 4: (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)- 3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (LP60)

[0946] To a solution of 60i (0.085 g, 0.09 mmol) in dimethylformamide (1 mL) was added 2,5-dioxopyrrolidin-1-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanoate (60j, 0.033 g, 0.11 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.03 mL, 0.18 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed and the desired mass was observed. The mixture was filtered. The residue was purified by semi- preparative reverse phase HPLC (18-48% acetonitrile in water + 0.225% formic acid, over 10 min). Then the collected fraction was concentrated to afford the product. The residue was purified by semi-preparative reverse phase HPLC (10-40% acetonitrile in water + 0.1% ammonium bicarbonate, over 9 min). Then the collected fraction was concentrated to remove most of the acetonitrile, then lyophilized to afford the product LP60 (0.038 g, 0.03 mmol, 36.09% yield) as a white solid. LCMS: m/z, 1133.4 [M+1]⁺.1H NMR (400 MHz, DMSO-d6) δ 11.03 - 10.92 (m, 1H), 8.55 - 8.42 (m, 1H), 8.26 (s, 1H), 7.91 - 7.86 (m, 1H), 7.83 - 7.77 (m, 2H), 7.71 - 7.63 (m, 1H), 7.51 (s, 1H), 7.48 - 7.41 (m, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.29 (d, J = 9.2 Hz, 2H), 7.24 (d, J = 7.6 Hz, 3H), 6.99 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.80 - 6.65 (m, 1H), 5.75 (d, J = 3.6 Hz, 1H), 5.35 - 5.29 (m, 1H), 5.14 - 5.07 (m, 2H), 5.01 (d, J = 3.2 Hz, 4H), 4.48 - 4.37 (m, 3H), 4.34 - 4.27 (m, 1H), 4.21 - 4.16 (m, 2H), 3.97 - 3.82 (m, 1H), 3.36 (d, J = 6.8 Hz, 4H), 3.27 - 3.16 (m, 3H), 2.97 - 2.84 (m, 1H), 2.67 (td, J = 2.0, 3.6 Hz, 1H), 2.41 - 2.35 (m, 1H), 2.07 - 1.97 (m, 3H), 1.49 - 1.43 (m, 3H), 1.27 - 1.23 (m, 1H), 1.21 - 1.14 (m, 2H). Example LP61: (2S,3S,4S,5R,6S)-6-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)-4-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0947] Step 1: (2S,3R,4S,5S,6S)-2-(4-formyl-2-nitrophenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (61c)

[0948] To a solution of (2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (61a, 1.0 g, 2.52 mmol) and 4-hydroxy-3-nitrobenzaldehyde (61b, 0.421 g, 2.52 mmol) in acetonitrile (10 mL), silver oxide (0.700 g, 3.02 mmol) was added. The reaction mixture was stirred at RT for overnight. The reaction mixture was filtered and worked up with EtOAc, water and brine. The organics were combined, concentrated, purified on 40 g CombiFlash column with 0-50% EtOAc in hexane (40 mL/min). The major containing product was collected, concentrated and dried under high vacuum to yield 61c (681 mg,1.41 mmol, 55.9%).1H NMR (400 MHz, Chloroform-d) δ 10.01 (d, J = 2.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 8.10 (s, 1H), 7.52 (s, 1H), 7.29 (s, 1H), 5.44 (s, 2H), 5.40 – 5.29 (m, 2H), 3.77 – 3.70 (m, 3H), 2.14 – 2.04 (m, 9H). [0949] Step 2: (2S,3R,4S,5S,6S)-2-(2-amino-4-(hydroxymethyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (61e)

[0950] To a solution of 61c (681 mg, 1.41 mmol)) in MeOH (5 ml), sodium borohydride (0.057 g, 1.511 mmol) was added. The reaction mixture was stirred at RT for 30 min. The reaction mixture was worked up with EtOAc, water and brine. The organics were combined, concentrated, and purified on 40 g CombiFlash column with 20-70% EtOAc in hexane. The fractions corresponding to new peak were combined, concentrated and dried under high vacuum to yield (2S,3R,4S,5S,6S)-2-(4-(hydroxymethyl)-2-nitrophenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 61d (275 mg, 0.567 mmol, 40.2% yield). [0951] A solution of 61d (1.0 g, 2.060 mmol) in ethanol (20 mL) and a solution of ammonium chloride (1.102 g, 20.60 mmol) in water (15 mL) was added. The resultant mixture was stirred at RT, and zinc (1.347 g, 20.60 mmol) was added in potions in a period of 2 h. LCMS analysis showed the reaction mostly completed. The reaction mixture was filtered, and the filtrate was worked up with EtOAc, water and brine. The organics were concentrated and purified on 50 g CombiFlash AQ column with 0-35%ACN in water ( both with 0.05% TFA, 60 mL/min). The fractions containing expected product were combined and freeze-dried to yield 61e (378 mg, 0.83 mmol, 40.3%). LCMS ESI, M+H/z = 456.1. [0952] Step 3: (2S,3R,4S,5S,6S)-2-(2-((tert-butoxycarbonyl)amino)-4-((((4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (61h)

[0953] To a solution of 61e (378 mg, 0.83 mmol) and Boc-anhydride (0.574 mL, 2.472 mmol) in DMF (5 mL), DIPEA (0.6 mL) was added. The reaction mixture was stirred at RT overnight. LCMS analysis showed the reaction mostly completed (1.44 min at 2min run, M+H/z = 556.1). The reaction mixture was worked up with EtOAc, water and brine. The organics were combined, concentrated and purified on 40 g CombiFlash column with 30-70% EtOAc in hexane (40 mL/min) to yield (2S,3R,4S,5S,6S)-2-(2-((tert-butoxycarbonyl)amino)- 4-(hydroxymethyl)phenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate, 61f (381 mg, 0.686 mmol, 82.7% yield). LCMS ESI, M+H/z = 556.1. [0954] To a solution of 61f (200 mg, 0.360 mmol) and bis(4-nitrophenyl) carbonate (110 mg, 0.360 mmol) in DMF (2 mL), N-ethyl-N-isopropylpropan-2-amine (0.189 mL, 1.080 mmol) was added. The reaction mixture was stirred at RT for 15 min. LCMS analysis showed the formation of intermediate 55g (1.53 min at 2 min run, M+H-Ac/z = 679.2). To the reaction mixture was added 1-(4-((4-(aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)urea (11, 190 mg, 0.360 mmol). The reaction mixture was stirred at RT for 30 min. LCMS analysis showed the formation of product 61h. The reaction mixture was purified on 19x150 mm BEU Xbridge 5 u column with 40-70% ACN in water (both with 0.05% TFA, 18.9 mL/min). The fraction containing expected product were combined and freeze-dried to yield (2S,3R,4S,5S,6S)-2-(2-((tert-butoxycarbonyl)amino)-4- ((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-6- (methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 61h (105 mg, 0.095 mmol, 26.3 % yield). LCMS ESI, M+H/z = 1109.5. [0955] Step 4: (2S,3S,4S,5R,6S)-6-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)-4-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid (LP61)

[0956] To a solution of 61h (36 mg, 0.032 mmol) in CH₂Cl2 (0.8 mL), TFA (0.8 mL) was added. The reaction mixture was stirred at RT for 15 min. LCMS analysis showed the formation of 61i. The reaction mixture was concentrated and dried under high vacuum to yield intermediate 61i (37 mg). LCMS ESI, M+H/z = 869.3. [0957] To a solution of intermediate 55i (37 mg) and 2,5-dioxopyrrolidin-1-yl 3-(2,5-dioxo- 2,5-dihydro-1H-pyrrol-1-yl)propanoate (8.64 mg, 0.032 mmol) in DMF (0.5 mL), DIPEA(20 µl) was added. The reaction mixture was stirred at RT for 48 h. LCMS analysis showed the reaction 60% completion. The reaction mixture was purified on 19x150 mm Xbridge C18 BET 5u column with 10-40% ACN in water (both with 0.05% TFA, 18.9 mL/min). The fractions containing expected product were combined and freeze-dried to yield (2S,3S,4S,5R,6S)-6-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanamido)-4-((((4-((4- (3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)carbamoyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid (3.2 mg, 3.14 µmol, 9.67 % yield for 2 steps). LCMS ESI, M+H/z = 1020.4.1H NMR (499 MHz, DMSO-d6) δ 10.97 (s, 1H), 8.43 (s, 1H), 7.77 – 7.66 (m, 2H), 7.51 (s, 1H), 7.44 (dd, J = 7.9, 1.4 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.21 (m, 4H), 7.04 – 6.91 (m, 3H), 6.92 – 6.84 (m, 2H), 6.82 (s, 1H), 6.65 (t, J = 6.2 Hz, 2H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.87 (d, J = 7.9 Hz, 1H), 4.80 (dd, J = 10.1, 9.2 Hz, 1H), 4.48 – 4.37 (m, 3H), 4.31 (d, J = 17.3 Hz, 1H), 4.21 – 4.15 (m, 3H), 3.70 – 3.56 (m, 2H), 3.56 (d, J = 9.3 Hz, 1H), 3.41 (dd, J = 9.2, 7.8 Hz, 1H), 2.91 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.71 – 2.54 (m, 4H), 2.48 (s, 1H), 2.38 (qd, J = 13.5, 4.5 Hz, 1H), 2.00 (dtd, J = 12.7, 5.3, 2.3 Hz, 1H). Example LP62: N-((9S)-9-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-5,8,11,14-tetraoxo-2-oxa- 4,7,10,13-tetraazapentadecan-15-yl)-1-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)propanamido)-3,6,9,12,15,18,21,24-octaoxaheptacosan-27-amide

[0958] Step 1: (2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)methyl acetate (62b)

[0959] Compound 62a (1.00 g, 2.82 mmol) and lead (IV) acetate (1.50 g, 3.39 mmol) were taken in a 40 mL reaction vial and dry THF-Toluene solvent mixture (1:1 ratio, 10 mL, 1:10 W/V with respect to compound 1) were added to the solids followed by addition of pyridine (340.0 µL, 4.23 mmol) to the mixture. The reaction mixture was stirred at 65 °C for 2 hours under nitrogen atmosphere. The completion of the reaction was confirmed by LCMS monitoring. The reaction mixture was filtered, and the solid cake was washed 4 times with dichloromethane. The filtrate was evaporated under reduced pressure to get the crude product as a gummy liquid, which was purified by normal phase automated flash chromatography using ethyl acetate (EA) and hexane system. The pure product eluted at 60% EA in Hexane. The pure fractions were combined and concentrated under reduced pressure to afford compound 62b [(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetamido)methyl acetate] as a white solid (840 mg, 80 % yield, Purity > 99%). Calculated exact mass: 368.14, observed mass: 391.44 (M+Na⁺). [0960] Step 2: tert-butyl (4-((4-(hydroxymethyl)benzyl)oxy)phenyl)carbamate (62e)

[0961] Compound 62c [tert-butyl (4-hydroxyphenyl)carbamate, 1.56 g, 7.46 mmol], compound 62d [(4-(bromomethyl)phenyl)methanol 1.5 g, 7.46 mmol] and Cesium carbonate (7.29 g, 22.38 mmol) were taken in dry DMF (2 mL, 1.33 V) and the reaction mixture was stirred at 25 °C for 30 minutes under nitrogen atmosphere. The completion of the reaction was confirmed by LCMS monitoring. The crude reaction mixture was filtered, and the solid cake was washed with DCM. The filtrate was concentrated under reduced pressure to get the crude product as an oil. The product was purified by normal phase automated flash chromatography using ethyl acetate-hexane gradient system as eluent to obtain compound 62e [tert-butyl (4-((4-(hydroxymethyl)benzyl)oxy)phenyl)carbamate] as a white solid (2.69 g, 95 % yield, Purity 87 %). Calculated exact mass: 329.16, observed mass: 352.38 (M+Na+). [0962] Step 3: (9H-fluoren-9-yl)methyl (2-((((4-((4-((tert- butoxycarbonyl)amino)phenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate

[0963] Compound 62f (2.68 g, 7.29 mmol) and 62e (1.35 g, 3.65 mmol) were dissolved in dry THF (5 mL, 1:3.70 W/V with respect to compound 62e) and p-toluene sulfonic acid monohydrate (pTSA) (139 mg, 0.73 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 30 minutes under nitrogen atmosphere. The reaction mixture was loaded directly onto a C18 Aq column pre-equilibrated with 5% acetonitrile in water (without modifier) and purified by RP-MPLC using water-acetonitrile gradient (without modifier). The pure fractions eluted from the column were combined and lyophilized to obtain the compound 62g as a white solid (900 mg, 37% yield, Purity > 80%). UPLC retention time: 3.62 minutes at 5 minutes run method. Calculated exact mass: 637.28, observed mass: 638.8 (M+H⁺). [0964] Step 4: tert-butyl (4-((4-(((2- aminoacetamido)methoxy)methyl)benzyl)oxy)phenyl)carbamate

[0965] Compound 62g (1.40 g, 2.24 mmol) was dissolved in dry DMF (10 mL, 1:7 W/V) and piperidine (2 mL, 16.6%) was added to it. The reaction mixture was stirred at 25 °C for 15 minutes. The completion of the reaction was confirmed by LCMS monitoring. The reaction mixture was loaded directly onto a C18 Aq column pre-equilibrated with 5% acetonitrile in water (without modifier) and purified by RP-MPLC using water-acetonitrile gradient (without modifier). The pure fractions eluted from the column were combined and lyophilized to obtain the compound 62h as a white solid (780 mg, 84% yield, Purity 98 %). UPLC retention time: 1.15 minutes at 2.5 minutes run method. Calculated exact mass: 415.21, observed mass: 416.4 (M+H⁺). [0966] Step 5: Fmoc-GGF-OH, (((9H-fluoren-9-yl)methoxy)carbonyl)glycylglycyl-L- phenylalanine (62j)

[0967] Compound 62i (H₂N-Gly-Gly-Phe-OH, 558 mg, 2.0 mmol) and Fmoc-OSu (1.34 g, 4.0 mmol) were taken in dry DMF (6 mL, 11 V). DIPEA (1.4 mL, 8 mmol) was added to the mixture. The solution was allowed to stir for 1 hour at 25 °C under nitrogen atmosphere. The reaction was quenched with 1.5 mL TFA. The reaction mixture was loaded directly onto a C18 Aq column pre-equilibrated with 5% acetonitrile in water (without modifier) and purified by RP-MPLC using water-acetonitrile gradient (without modifier). The pure fractions eluted from the column were combined and lyophilized to obtain the compound 62j as a white solid (709 mg, 71%yield, Purity > 98%). UPLC retention time: 3.05 minutes at 5 minutes run method. Calculated exact mass: 501.19, observed mass: 502.6 (M+H⁺). [0968] Step 6: (9H-fluoren-9-yl)methyl(S)-(9-benzyl-1-(4-((4-((tert- butoxycarbonyl)amino)phenoxy)methyl)phenyl)-5,8,11,14-tetraoxo-2-oxa-4,7,10,13- tetraazapentadecan-15-yl)carbamate (62k)

[0969] Compound 62j (Fmoc-GGF-OH, 285 mg, 0.570 mmol), HATU (216 mg, 0.570 mmol) and HOAt (4 mg, 0.27 mmol) were taken in dry DMF (4 mL, 18 V) and DIPEA (316 µL, 1.81 mmol) was added to the solution. The solution was allowed to stir for 5 minutes at 25 °C under nitrogen atmosphere. The preactivated solution was then added to another reaction vial with compound 62h (215 mg, 0.518 mmol) and reacted for 1 h at 25 °C under nitrogen atmosphere. The completion of the reaction was confirmed by LCMS monitoring. The reaction mixture was loaded directly onto a C18 Aq column pre-equilibrated with 5% acetonitrile in water (without modifier) and purified by RP-MPLC using water-acetonitrile gradient (without modifier). The pure fractions eluted from the column were combined and lyophilized to obtain the compound 62k as a white solid (320 mg, 70%yield, Purity > 98%). UPLC retention time: 3.82 minutes at 5 minutes run method. Calculated exact mass: 898.39, observed mass: 900.02 (M+H⁺). [0970] Step 7: (9H-fluoren-9-yl)methyl (S)-(1-(4-((4-aminophenoxy)methyl)phenyl)-9- benzyl-5,8,11,14-tetraoxo-2-oxa-4,7,10,13-tetraazapentadecan-15-yl)carbamate (62l)

[0971] Compound 62k (200 mg, 0.22 mmol) was taken 1 mL DCM and the slurry was cooled to -10 °C on a dry ice-IPA bath. A mixture of 2:1 dichloromethane-TFA (2 mL dichloromethane: 1mL TFA) was also cooled to -10 °C. The cooled DCM-TFA (1 mL) mixture was then added to the slurry of compound 62k in DCM dropwise while stirring. The effective concentration of TFA in the reaction mixture is 16.6%. The reaction mixture stirred at -5 °C for 1 hour. The reaction was monitored by LCMS until no starting material remained. The reaction was quenched with MTBE and the precipitated product was isolated by centrifugation (4000 rpm, 5 minutes, 4 °C), followed by decantation of the MTBE. The product was washed with MTBE and centrifugation was repeated twice to ensure complete removal of the TFA. The crude product 62l obtained was dried under reduced pressure and was taken to the next step without any further purification (95% yield, Purity >95%). UPLC retention time: 2.38 minutes at 5 minutes run method. Calculated exact mass:798.34, observed mass: 799.65 (M+H⁺). [0972] Step 8: (9H-fluoren-9-yl)methyl ((9S)-9-benzyl-1-(4-((4-(3-((2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-5,8,11,14-tetraoxo-2-oxa- 4,7,10,13-tetraazapentadecan-15-yl)carbamate

[0973] Compound 62l (220 mg, 0.275 mmol) was taken in 1 mL dry DMF followed by bis(2,5-dioxopyrrolidin-1-yl) carbonate (62m, 112.9 mg, 0.440 mmol). DIPEA (144 µL, 0.826 mmol) was added and the reaction mixture was stirred for an hour at 25 °C (until starting material 62l was fully consumed, determined by LCMS, and converted to Intermediate 62n). The crude reaction mixture was added to Methyl tertiary-butyl ether (MTBE) (35 mL) to precipitate intermediate 62n. The mixture was centrifuged, and MTBE was decanted and discarded. Isolated intermediate 62n was dried for 15 minutes under vacuum and immediately subjected to the next reaction. Intermediate 62n was taken in dry DMF and 62o (90.3 mg, 0.330 mmol) was then added. DIPEA (144 µL, 0.826 mmol) was added and the reaction mixture was stirred for 1 hour at 25 °C. Consumption of intermediate 62n was observed by LCMS and MTBE was added to the reaction mixture to precipitate out the crude product 62p. The mixture was centrifuged, and the MTBE supernatant was discarded. The precipitated product 62p was dried under vacuum and used directly in the next step without further purification. Yield of intermediate 162n: 95%, Purity >90%. UPLC retention time: 3.04 minutes at 5 minutes run method. Calculated exact mass:939.34, observed mass: 940.72 (M+H⁺) and 962.71 (M+Na⁺).Yield of product 62p: 90%, Purity >80%. UPLC retention time: 2.84 minutes at 5 minutes run method. Calculated exact mass:1097.43, observed mass: 1098.86 (M+H⁺) and 1121.88 (M+Na⁺). [0974] Step 9: (2S)-2-(2-(2-aminoacetamido)acetamido)-N-(2-((((4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)-3- phenylpropanamide

[0975] Crude compound 62p (54 mg, 0.049 mmol) was dissolved 20 % piperidine in DMF (0.5 mL total V, 0.4 mL, DMF, 0.1 mL piperidine). The solution was allowed to stir for 15 minutes at 25 °C under nitrogen atmosphere (full consumption of starting material was observed with LCMS). The reaction mixture was quenched with AcOH. Water with 0.05 % AcOH was added to precipitate the product. The reaction mixture was centrifuged (4700 rpm, 30 min) to afford crude intermediate 62q as the pellet. The supernatant was decanted, and the pellet was washed with MTBE (35 mL). The mixture was centrifuged, and supernatant decanted again. The MTBE wash was repeated. The pellet was dried under high vacuum overnight to yield 62q as a white solid (74% yield, Purity > 80%). UPLC retention time: 2.31 minutes at 5 minutes run method. Calculated exact mass: 875.36, observed mass: 876.94 (M+H⁺). [0976] Step 10: (2S)-2-(16-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-4,7,14-trioxo-10-oxa- 3,6,13-triazahexadecanamido)-N-(2-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)-3- phenylpropanamide (LP62)

[0977] Intermediate 62q (150 mg, 0.171 mmol) and 62r (141.73 mg, 0.205 mmol) was taken in dry DMF (1 mL, 6.6 V). Triethylamine (60 µL, 0.428 mmol) was added and the reaction mixture was stirred for 1 h at 25 °C under nitrogen atmosphere. Full starting material consumption was determined by LCMS. The reaction was then quenched with 100 µL acetic acid. The quenched reaction mixture was loaded directly onto a C18 Aq column and purified by RP-MPLC using water-acetonitrile gradient, both eluents were buffered with 0.05% acetic acid. The product elutes between 40%-45% acetonitrile in water. Pure fractions were combined and lyophilized to obtain LP62 as a white solid (17% yield, Purity > 96%). UPLC retention time: 1.91 minutes at 5 minutes run method. Calculated exact mass: 1449.63, observed mass: 1451.10 (M+H⁺).¹H-NMR (500 MHz; DMSO-d6): δ 10.96 (s, 0.3H), 8.58 (s, 1H), 8.42 (s, 1H), 8.31 (s, 1H), 8.15 (s, 2H), 8.00 (s, 2H), 7.68 (s, 1H), 7.51 (s, 1H), 7.39 (s, 3H), 7.32 (dt, J = 78.2, 40.9 Hz, 13H), 7.24 (t, J = 32.2 Hz, 9H), 6.94 (d, J = 56.9 Hz, 3H), 6.59 (d, J = 51.1 Hz, 1H), 5.05 (d, J = 39.4 Hz, 3H), 4.62 (s, 2H), 4.62-4.32 (m, 9H), 4.39 (t, J = 31.6 Hz, 7H), 3.69 (s, 8H), 3.59 (s, 7H), 3.49 (s, 32H), 3.14 (s, 3H), 3.06 (s, 1H), 2.86 (d, J = 46.2 Hz, 4H), 2.38 (s, 5H), 2.00 (s, 1H), 1.23 (s, 1H). Example LP63: N-((9S,18R)-9-benzyl-18-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4- ((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)phenyl)-5,8,11,14,17-pentaoxo-2-oxa-4,7,10,13,16- pentaazahenicosan-21-yl)-2,5,8,11,14,17,20,23-octaoxahexacosan-26-amide

[0978] To (R)-31-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-26-oxo-2,5,8,11,14,17,20,23- octaoxa-27-azadotriacontan-32-oic acid, 63a (20 mg, 0.033 mmol, prepared similar to 4g in Example LP4), and 1-hydroxypyrrolidine-2,5-dione (3.79 mg, 0.033 mmol) in DCM (2 mL) was added dicyclohexylmethanediimine (6.80 mg, 0.033 mmol). After stirred at r. t. for 30 min, the reaction mixture was filtered and concentrated to get the crude intermediate, 2,5- dioxopyrrolidin-1-yl (R)-31-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-26-oxo- 2,5,8,11,14,17,20,23-octaoxa-27-azadotriacontan-32-oate, which was dissolved in DMF (2 mL), and 62q (28.9 mg, 0.033 mmol) was added followed by DIEA (0.012 mL, 0.066 mmol). After stirred at RT for 15 min, the reaction solution was filtered and purified by ISCO C18 prep HPLC (Gemini, 30X250mm, 30ml/min, 10% - 60% 0.1% FA in ACN/0.1% FA in water) to get N-((9S,18R)-9-benzyl-18-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-1-(4-((4-(3- ((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)- 5,8,11,14,17-pentaoxo-2-oxa-4,7,10,13,16-pentaazahenicosan-21-yl)-2,5,8,11,14,17,20,23- octaoxahexacosan-26-amide, LP63 (4.7 mg, 2.99 µmol, 9.08 % yield).1H NMR (500 MHz, DMSO-d6) δ ppm 10.82 - 11.07 (m, 1 H), 8.55 - 8.65 (m, 1 H), 8.39 - 8.46 (m, 1 H), 8.23 - 8.34 (m, 2 H), 8.06 - 8.15 (m, 1 H), 7.95 - 8.04 (m, 1 H), 7.76 - 7.86 (m, 1 H), 7.66 - 7.73 (m, 1 H), 7.49 - 7.55 (m, 1 H), 7.38 - 7.47 (m, 3 H), 7.29 - 7.35 (m, 4 H), 7.22 - 7.27 (m, 4 H), 7.16 - 7.21 (m, 1 H), 7.01 - 7.08 (m, 2 H), 6.86 - 6.92 (m, 2 H), 6.60 - 6.68 (m, 1 H), 5.07 - 5.14 (m, 1 H), 4.98 - 5.06 (m, 2 H), 4.60 - 4.67 (m, 2 H), 4.49 - 4.59 (m, 2 H), 4.37 - 4.48 (m, 5 H), 4.27 - 4.35 (m, 1 H), 3.70 - 3.81 (m, 4 H), 3.42 - 3.64 (m, 31 H), 3.22 - 3.26 (m, 3 H), 2.87 - 3.10 (m, 4 H), 2.75 - 2.86 (m, 1 H), 2.56 - 2.65 (m, 2 H), 2.36 - 2.41 (m, 1 H), 2.23 - 2.29 (m, 2 H), 1.89 - 2.05 (m, 3 H), 1.21 - 1.31 (m, 2 H). LCMS: 1464.4 [M+1]+. Example LP64: (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-(10-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6-dioxo-2,9-dioxa-4,7- diazadecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid

[0979] Step 1: (2-((((4-((4-nitrophenoxy)methyl)benzyl)oxy)methyl)amino)-2- oxoethyl)carbamate (64e)

[0980] To a solution of 4-nitrophenol 64b (8.880 g, 63.85 mmol) in DMF (150 mL) was added (4-(chloromethyl)phenyl)methanol 64a (10.000 g, 63.85 mmol) and potassium carbonate (17.620 g, 127.71 mmol). The mixture was stirred at 80 °C for 12 h. TLC showed one new spot was detected. The reaction mixture was diluted with water 1000 mL and extracted with ethyl acetate (500 mL × 2). The combined organic layers were washed with brine 200 mL, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (4-((4-nitrophenoxy)methyl)phenyl)methanol 64c (15.000 g, 57.86 mmol, 90.6% yield) as a yellow solid. [0981] To a solution of (4-((4-nitrophenoxy)methyl)phenyl)methanol 64c (1.000 g, 3.86 mmol) and 4-methylbenzenesulfonic acid;pyridine (1.939 g, 7.71 mmol) in dichloromethane (10 mL) was added (2-((tert-butoxycarbonyl)amino)acetamido)methyl acetate 64d (1.425 g, 5.79 mmol). Then the mixture was stirred at 45 °C for 12 h under nitrogen. LCMS showed the reaction complete. The mixture was concentrated in vacuum to remove most of dichloromethane, then diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by semi-preparative reverse phase HPLC (40 - 70% acetonitrile in water + 0.225% formic acid, 15 min). The collected fraction was lyophilized to afford tert-butyl (2-((((4-((4- nitrophenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate 64e (0.670 g, 1.50 mmol, 39.0% yield) as a white solid. MS (ESI) m/z: 468.1 [M+23]+. [0982] Step 2: (2-oxo-2-((((4-((4- ((phenoxycarbonyl)amino)phenoxy)methyl)benzyl)oxy)methyl)amino)ethyl)carbamate (64h)

[0983] To a solution of tert-butyl (2-((((4-((4- nitrophenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate 64e (0.670 g, 1.50 mmol), ammonium hydrochloride (0.805 g, 15.0 mmol) in ethanol (10 mL) and water (2 mL) was added iron (0.420 g, 7.52 mmol), then the mixture was stirred at 80 °C for 2 h. TLC showed the starting material was consumed, and a main spot was detected. The mixture was diluted with water (100 mL), extracted with acetate ethyl (30 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel column (0 - 50% acetate ethyl in petroleum ether) to afford tert-butyl (2-((((4-((4- aminophenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate 64f (0.580 g, 1.40 mmol, 92.8% yield) as a yellow oil. [0984] The mixture of tert-butyl (2-((((4-((4- aminophenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate 64f (0.580 g, 1.40 mmol), phenyl carbonochloridate 64g (0.219 g, 1.40 mmol), N-ethyl-N-isopropylpropan-2- amine (0.361 mg, 2.79 mmol) in DMF (8 mL) was stirred at 0 °C for 2 h. TLC showed the starting material was consumed, and a main spot was detected. The mixture was diluted with water (100 mL), extracted with acetate ethyl (50 mL × 2). The combined organic layer was dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated in vacuum to give a residue. The residue was purified by silica gel column (0-60% acetate ethyl in petroleum ether) to afford tert-butyl (2-oxo-2-((((4-((4- ((phenoxycarbonyl)amino)phenoxy)methyl)benzyl)oxy)methyl)amino)ethyl)carbamate 64h (0.740 g, 1.38 mmol, 99.0% yield) as a yellow oil. [0985] Step 3: (2-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate (64j)

[0986] The mixture of tert-butyl (2-oxo-2-((((4-((4- ((phenoxycarbonyl)amino)phenoxy)methyl)benzyl)oxy)methyl)amino)ethyl)carbamate 64h (0.740 g, 1.38 mmol), 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6- dione;hydrochloride 64i (0.428 g, 1.38 mmol), N-ethyl-N-isopropylpropan-2-amine (1.0 mL, 5.53 mmol) in DMF (10 mL) was stirred at 50 °C for 12 h. LCMS showed the starting material was consumed, and the desired mass was detected. The mixture was purified by semi-preparative reverse phase HPLC (30 - 60 % acetonitrile in water + 0.225% formic acid, 15 min). The collected fraction was lyophilized to afford tert-butyl (2-((((4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)amino)-2-oxoethyl)carbamate 64j (0.317 g, 0.44 mmol, 32.1% yield) as a yellow solid, which was confirmed by 1H NMR. [0987] LCMS (ESI) m/z: 715.3 [M+1]+.1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.68 ( t, J = 6.4 Hz, 1H), 8.44 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.45 - 7.37 (m, 3H), 7.30 (dd, J = 5.2, 8.4 Hz, 4H), 7.01 ( t, J = 5.6 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.64 ( t, J = 6.0 Hz, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 5.02 (s, 2H), 4.61 (d, J = 6.6 Hz, 2H), 4.50 - 4.23 (m, 6H), 3.56 (d, J = 6.0 Hz, 2H), 2.94 - 2.89 (m, 1H), 2.65 - 2.56 (m, 1H), 2.43 - 2.34 (m, 1H), 2.05 - 1.94 (m, 1H), 1.38 (s, 9H). [0988] Step 4: 2-Amino-N-(((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)acetamide (64k)

[0989] The mixture of tert-butyl (2-((((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)amino)-2- oxoethyl)carbamate 64j (0.050 g, 0.07 mmol), dibromozinc (0.032 mg, 0.14 mmol) in dichloromethane (3 mL) was stirred at 25 °C for 2 h. LCMS showed the starting material was consumed, and the desired mass was detected. The reaction mixture was concentrated to afford the crude 2-amino-N-(((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)acetamide 64k (0.042 g, 0.07 mmol, 97.7% yield) as a yellow solid, which was used for next step directly. MS (ESI) m/z: 615.2 [M+1]⁺. [0990] Step 5: (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid (64n)

[0991] To a solution of methyl 3,4,5-triacetoxy-6-(2-(2-(tert- butoxycarbonylamino)ethylcarbamoyl)-4-((4- nitrophenoxy)carbonyloxymethyl)phenoxy)tetrahydropyran-2-carboxylate 60g (0.360 g, 0.45 mmol) in THF (5 mL) was added hydrogen chloride (6 M, 5 mL), then the mixture was stirred at 45 °C for 12 h. LCMS showed the starting material was consumed, and the desired mass was detected. The mixture was purified by semi-preparative reverse phase HPLC (5 - 35 % acetonitrile in water + 0.225% formic acid, 15 min). The collected fraction was lyophilized to afford (2S,3S,4S,5R,6S)-6-(2-((2-aminoethyl)carbamoyl)-4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2- carboxylic acid 64l (0.100 g, 0.18 mmol, 39.9% yield) as a white solid. MS (ESI) m/z: 552.2 [M+1]+.1H NMR (400 MHz, DMSO-d6) δ 8.83 - 8.68 (m, 1H), 8.37 - 8.26 (m, 3H), 8.18 - 8.05 (m, 2H), 7.61 - 7.54 (m, 3H), 6.98 - 6.87 (m, 2H), 5.35 - 5.23 (m, 4H), 5.04 - 4.95 (m, 2H), 3.74 - 3.60 (m, 4H), 2.99 ( t, J = 5.2 Hz, 4H). [0992] To a solution of (2S,3S,4S,5R,6S)-6-(2-((2-aminoethyl)carbamoyl)-4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2- carboxylic acid (0.100 g, 0.18 mmol), N-ethyl-N-isopropylpropan-2-amine (23.44 mg, 0.18 mmol) in DMF (2 mL) was added (2,5-dioxopyrrolidin-1-yl) 6-(2,5-dioxopyrrol-1- yl)hexanoate (55.9 mg, 0.18 mmol), then the mixture was stirred at 25 °C for 2 h. LCMS showed the reaction complete. The reaction mixture was used for next step directly. LCMS: MS (ESI) m/z: 745.0 [M+1]⁺. [0993] Step 6: (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-(10-(4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6-dioxo-2,9-dioxa-4,7- diazadecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid (LP64)

[0994] The mixture of 2-amino-N-(((4-((4-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin- 5-yl)methyl)ureido)phenoxy)methyl)benzyl)oxy)methyl)acetamide 64k (0.042 g, 0.07 mmol), (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1- yl)hexanamido)ethyl)carbamoyl)-4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)-3,4,5- trihydroxytetrahydro-2H-pyran-2-carboxylic acid 64n (0.051 g, 0.07 mmol), N-ethyl-N- isopropylpropan-2-amine (0.011 g, 0.08 mmol) in DMF (3 mL) was stirred at 25 °C for 12 h. LCMS showed the starting material was remained, and the desired mass was detected. The mixture purified by semi-preparative reverse phase HPLC (20 - 50 % acetonitrile in water + 0.225% formic acid, 1 min). The collected fraction was lyophilized to afford crude product, then the crude product was purified by semi-preparative reverse phase HPLC (20 - 50 % acetonitrile in water + 0.1% trifluoroacetic acid, 11 min). The collected fraction was lyophilized to afford crude product, then the crude product was purified by semi-preparative reverse phase HPLC (10 - 40 % acetonitrile in water + 10 mM ammonium bicarbonate, 9 min). The collected fraction was lyophilized to afford (2S,3S,4S,5R,6S)-6-(2-((2-(6-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)ethyl)carbamoyl)-4-(10-(4-((4-(3-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)phenoxy)methyl)phenyl)-3,6-dioxo- 2,9-dioxa-4,7-diazadecyl)phenoxy)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxylic acid LP64 (0.004 g, 0.01 mmol, 4.2% yield) as a white solid. MS (ESI) m/z: 1220.5 [M+1]⁺ [0995] ¹H NMR (400 MHz, DMSO-d6) δ 11.05 - 10.92 (m, 1H), 8.79 - 8.70 (m, 1H), 8.65 - 8.54 (m, 1H), 8.45 - 8.30 (m, 1H), 8.06 - 7.92 (m, 1H), 7.76 (s, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.54 - 7.35 (m, 6H), 7.34 - 7.20 (m, 6H), 6.99 (s, 2H), 6.87 ( d, J = 8.8 Hz, 2H), 5.73 ( s, 1H), 5.28 ( s, 1H), 5.16 - 4.93 (m, 6H), 4.61 ( d, J = 6.4 Hz, 2H), 4.50 - 4.36 (m, 5H), 4.34 - 4.24 (m, 1H), 3.63 ( d, J = 6.0 Hz, 2H), 3.28 - 3.09 (m, 8H), 2.96 - 2.86 (m, 2H), 2.63 - 2.56 (m, 1H), 2.44 - 2.39 (m, 1H), 2.10 - 1.93 (m, 4H), 1.52 - 1.34 (m, 6H), 1.18 - 1.10 (m, 2H). [0996] The examples listed in Table 7 were prepared using similar procedures described for the synthesis of LP4, LP60, and LP62-64 with appropriate starting materials and reagents, which are well known and understood by one of ordinary skill in the art of organic chemistry. Table 7. Examples of linker-payloads

Example B1: Evaluation of Biological Activity [0997] Standard physiological, pharmacological and biochemical procedures are available for testing to identify those compounds and/or conjugates that possess the desired anti- proliferative activity. Such assays include, for example, biochemical assays such as binding assays, radioactivity incorporation assays, as well as a variety of cell-based assays. [0998] Using targeted protein degradation, small molecules can be used to induce novel protein–protein interactions and enable destruction of target proteins that drive disease. Induction of protein degradation as a therapeutic strategy has been clinically validated by the class of immunomodulatory drugs developed by Celgene which include lenalidomide and pomalidomide. Removal of disease-driving proteins translates to the therapeutic benefits derived from immunomodulatory drug treatment. Specifically, CELMoDs (including immunomodulatory drugs) have the capacity to induce recruitment followed by ubiquitination of substrate proteins to the CRL4CRBN E3 ubiquitin ligase, after which, ubiquitin tagged proteins are trafficked to and subsequently degraded by the 26S proteasome. GSPT1 (G1 to S Phase Transition protein 1) is a translation termination factor with intrinsic GTPase activity. GSPT1 in complex with eRF1 recognizes the mRNA stop codon and functions to terminate protein translation by catalyzing the cleavage of the nascent protein from the terminal tRNA as well as by releasing the ribosomal subunits from the stop site allowing reformation and translation initiation at a new start site. Thus, GSPT1 plays a key role in protein synthesis and cell proliferation. Targeted degradation of GSPT1 by CELMoDs elicits broad antitumor activity in AML and solid tumor cells. See, e.g., Matyskiela ME, et al. Nature.2016 Jul 14;535(7611):252-7; Surka C, et al., Blood.2021 Feb 4;137(5):661-677. [0999] GSPT1 DiscoverX Degradation Assay. DF15 multiple myeloma cells expressing ePL- tagged GSPT1 were dispensed into a 384-well plate (Corning #3712) pre-spotted with compound. Compounds were dispensed by an acoustic dispenser (ATS Acoustic Transfer System from EDC Biosystems) into a 384-well in a 10 pt dose response curve using 3-fold dilutions starting at 10 uM and going down to 0.0005 uM in DMSO. A DMSO control is added to the assay.25 µL of media (RPMI-1640 + 10% Heat Inactivated FBS +25mM Hepes+1mM Na Pyruvate+1X NEAA + 0.1% Pluronic F-68 + 1x Pen Strep Glutamine) containing 5000 cells was dispensed per well. Assay plates were incubated at 37°C with 5% CO2 for twenty hours. After incubation, 25 µl of the InCELL Hunter™ Detection Reagent Working Solution (DiscoverX, cat #96-0002, Fremont, CA) was added to each well and incubated at room temperature for 30 minutes protected from light. After 30 minutes, luminescence was read on a PHERAstar luminometer (Cary, NC). [1000] To determine EC₅₀ values for GSPT1 degradation, a four parameter logistic model (Sigmoidal Dose-Response Model) (FIT= (A+((B-A)/1+((C/x)^D)))) wherein C is the inflection point (EC50), D is the correlation coefficient, A and B are the low and high limits of the fit respectively) was used to determine the compound’s EC₅₀ value, which represents the half maximum effective concentration. The minimum Y is reference to the Y constant. In the GSPT1 degradation assay, Ataluren^® (luciferase inhibitor) was used as the control with a Y constant = 0. The maximum limit is the Y max DMSO control. All percent of control GSPT1 degradation curves were processed and evaluated using Activity Base (IDBS). Table 8. GSPT1 Degradation Data

X. BIOLOGICAL EXAMPLES Example B1: Generation of CD33 Antibodies [1001] Screening and discovery of fully human immunoglobulin G (IgG) antibodies against CD33 was performed by utilizing yeast display platform. Recombinant human CD33 extracellular domain (ECD), which includes the V and C2 domains, was used as bait in an initial screen to isolate binders from naive human libraries of fully human antibodies expressed by yeast cells. This initial attempt failed to identify antibodies that recognized the CD33 C2 region, as determined using an Octet^® biolayer interferometry (BLI) detection system. A modified screening campaign of the yeast display platform was undertaken that integrated truncated human and cynomolgus CD33 ECDs expressing the C2 domain but lacking the V domain (CD33-C2) and were allowed to form either human/human homodimers or human/cynomolgus heterodimers. Following first-round selection with the full-length human CD33 ECD of a >10⁹ naïve human antibody library and a second-round polyspecificity reagent/Siglec6/8 counterselection, remaining antibodies were sub-binned with either full-length human CD33, full-length cyno CD33, human CD33-C2 or human/cyno CD33-C2. 78 unique antibodies were identified and of these, 72 avidly-bound the full-length human CD33 ECD with 58 recognizing the V domain and 14 binding to truncated human CD33-C2. None of the C2 domain binders cross-reacted in avid assay format with the cynomolgus form of the CD33 ECD while 52/58 V domain binders exhibited cynomolgus CD33 affinities. These results underscore the relative difficulty identifying CD33 C2 selective antibodies from this library, particularly with respect to cynomolgus CD33 cross- reactivity, a highly desirable feature that enables pre-clinical toxicology and PK/PD studies in monkeys. [1002] Of the 14 that recognized human CD33-C2, 10 CD33-C2 antibodies were selected as parents for subsequent affinity maturation. 8 of 10 of these parental antibodies failed after affinity maturation to exhibit improved binding to human CD33 natively-expressed by Molm13 AML cells and showed poor affinity for Hek293 cells engineered to express cynomolgus CD33. [1003] Of the 2 maturation-amenable lineages, the first was subjected to a total of 3 rounds of affinity maturation, however recognition of human CD33 expressed by Molm13 and MV-411 AML cells remained low and could not be progressed without causing Siglec-6 off-target reactivity, as assessed by Octet^® BLI. Since CD33-related Siglec proteins can be detected in healthy tissue (e.g. Siglec-6 in placenta, colon; Siglec-8 in brain, lung, intestine, liver), it is important to avoid potential toxicities resulting from inadvertent antibody cross-reactivity to these proteins. The 2^nd maturation-amenable lineage was advanced through 4 total rounds of maturation, leading to the identification of variations that improved Molm13, MV-411 and cynomolgus CD33 (Hek293 cynomolgus CD33) cell-binding profiles. One particular antibody, CD33-M, was chosen for further development based on cross-reactivity with cynomolgus CD33 and selectivity for CD33 without off-target binding to human Siglec 6 and Siglec 8. By comparison, a published C2 domain binding antibody (WO 2019/224711) exhibited weaker human CD33 avidity, non-selectivity for CD33 binding by virtue of comparable Siglec 6 cross-reactivity, and a lack of cynomolgus CD33 cross-reactivity. Binding affinity to cynomolgus monkey CD33 is an important property because it enables in vivo toxicology, PK/PD and immunogenicity studies in cynomolgus monkey and can provide pre-clinically valuable on-target data if the administered antibody has affinity to the host protein. Altogether, CD33-M exhibited several advantageous properties over the published C2 domain binding antibody, including greater human and cynomolgus CD33 avidity, as well as selectivity for CD33 without Siglec 6 cross-reactivity.

[1004] CD33-M antibody selectively-bound human CD33 in monomeric or dimeric states, bound dimeric cyno CD33 and did not exhibit affinities for Siglec 6 or Siglec 8. In contrast, the published C2 domain binding antibody (WO 2019/224711) failed to bind the monomeric form of human CD33 or cyno CD33 and exhibited significant off-target reactivity with Siglec 6. The antibody was immobilized on the AHC (anti-hIgG capture) tip with human CD33 in solution at 100 nM to monitor monovalent or avid affinities. Cyno CD33, human Siglec 6 and human Siglec 8 in dimeric states were in solution at 100 nM. Example B2: Surface Plasmon Resonance Analysis of Affinity Matured Antibodies [1005] Having created antibody CD33-M, which exhibited greater human and cynomolgus CD33 avidity, as well as selectivity for CD33 without Siglec 6 cross-reactivity compared to other published C2 domain binding antibodies, improvement of its drug-like properties was performed by optimizing the isoelectric point of the light chain and decreasing predicted immunogenicity. Also, further increasing its affinity toward human and cynomolgus CD33 was performed through site-directed mutagenesis, which led to the creation of twelve progeny antibodies (CD33-A to L). Binding kinetics of antibody CD33-M and its progeny antibodies described in Example 1 above was assessed by surface plasmon resonance. A published human anti-CD33 antibody, vadastuximab (VADA) and a non-specific, isotype control were included for comparison. [1006] Surface plasmon resonance measurements were carried out on a Biacore™ 8K (Cytiva). An anti-human capture surface was prepared on a CM5 sensor chip (Cytiva, 29149603) through amine coupling (Cytiva, BR100633) according to the manufacturer’s guidelines (Cytiva, 292346000). Respective antibodies were diluted to 1µg/ml into 1x HBS- EP (10x, Cytiva, BR100669) running buffer and captured onto flow cell two for 60s contact time at a flow rate of 20 µl/min. A seven-point, 3-fold serial dilution of either human (AcroBiosystems, CD3-H5226) or cynomolgus (Sino Biological Cat#90303-C08H) CD33 were prepared, starting at 100 nM, in 1x HBS-EP running buffer. Analyte series followed a 180s contact time followed by a 600s dissociation time at a flow rate 30 µl/min where mid- concentration analytes were performed in duplicate. Data was processed and double referenced using Biacore™ Insight Evaluation (Cytiva) and fit to either a 1:1 (human CD33) or two-state (cynomolgus CD33) model. [1007] The binding data for the antibodies is shown in Table 10 below.

[1008] The data indicated several antibodies have higher affinity for human CD33 and cynomolgus monkey CD33 compared to vadastuximab. Example B3: ELISA Binding Analysis of Affinity Matured Antibodies [1009] The binding of antibody CD33-M and its progeny antibodies described above were investigated by ELISA. [1010] Costar^® half area high-binding ELISA plates (Corning, 3690) were coated overnight with 50µl/well of either Human (AcroBiosystems, CD3-H5226) or cynomolgus (Sino Biological Cat#90303-C08H) CD33 diluted to 1µg/ml in Dulbecco’s Phosphate Buffered Saline (DPBS, Cytiva, SH30028.02). Plates were blocked using 2% bovine serum albumin (BSA, 10%, Thermo Scientific, 37525) in DPBS for two hours. ELISA plates were washed three times with 150µl/well of 1x PBS-Tween^® (PBST, EMD Millipore, 524653) using a BioTek EL405™ platewasher (Agilent). An 11-point, 3-fold serial dilution starting at 1µM was prepared in 1% BSA-DPBS for each respective antibody and 50µl of each dilution was added to the ELISA plate and incubated at room temperature for one hour. Following antibody incubation, plates were washed with PBST and 50µl of a 160 ng/ml peroxidase- conjugated goat anti-Human IgG (Jackson ImmunoResearch, 109-035-098) in 1% BSA-PBS was added to each well and incubated for one hour at room temperature. Plates were washed with PBST and 50µl of 1-Step Ultra TMB-ELISA (Themo Scientific, 34028) was added to each well and incubated for 30s to 1min. Reaction was quenched by the addition of 50µl of 1N sulfuric acid (Fisher Scientific, SA212-1) and absorbance at 450nm was read using a Tecan Spark^® plate reader (Tecan). [1011] The optical density was read on a microplate reader and the EC50 data was obtained from a dose response curve as shown in Table 11 below.

[1012] Antibody CD33-M and its affinity matured progeny antibodies exhibited high affinity for human and cyno CD33. Example B4: Novel C2 antibodies exhibited selective affinity for CD33+ cells [1013] CD33-M and its progeny antibodies described above were tested for selective affinity for CD33+ cells compared to vadastuximab (VADA) or isotype control. [1014] HEK293 cells were engineered to express the full-length coding sequence of cynomolgus CD33 or a truncated form of human CD33 lacking the V-domain by transfection. Serially diluted antibodies were added to cells, followed by washing and additional incubation with a secondary anti-human IgG detection antibody. Levels of antibody binding were analyzed by determining the mean fluorescence intensity (MFI) by flow cytometry. Results in HEK293 cells engineered to express the full-length coding sequence of cynomolgus CD33 are shown in FIG.1A. Results in HEK293 cells engineered to express a truncated form of human CD33 lacking the V-domain are shown in FIG.1B. CD33-M and its progeny antibodies exhibited greater affinity for CD33+ HEK293 cells expressing full length cynomolgus CD33 or human C2 domain compared to vadastuximab. [1015] The antibodies were also tested for binding to CD33+ AML cancer cell lines (Molm13 and MV411), and CD33-negative Pfeiffer cells (FIGS.1C-1E). CD33-M and its affinity matured progeny antibodies exhibited selective affinity for the CD33+ AML cancer cells lines relative to the CD33- cell line. Example B5: Affinity of Antibody CD33-M to Endogenous Human and Cynomolgus Monkey CD33 [1016] CD33-M was compared to vadastuximab or isotype control for binding affinity to endogenous CD33 in human and cynomolgus monocytes. Monocytes were isolated from 3 human peripheral blood mononuclear cell (PBMC) samples and 3 cynomolgus samples by flow cytometry gating with anti-CD14 and anti-CD159a antibodies, excluding doublets and dead cells. CD33-M or vadastuximab were incubated at increasing concentrations (i.e. 32pM-100nM) with monocytes (50,000 cells/data point) and stained with AF647-conjugated anti-CD33, BV421-CD14 and PE-CD159a. The geometric MFI (gMFI) of AF647 at each concentration was graphed on a log scale as non-linear regression curves (FIGS.2A-2F). [1017] The results demonstrated CD33-M has higher binding affinity than VADA to human and cynomolgus endogenous CD33. Example B6: Affinity of Novel C2 antibodies to Endogenous Cynomolgus Monkey CD33 [1018] The progeny antibodies of CD33-M were also tested for binding affinity to endogenous cynomolgus CD33 in neutrophils. PBMCs isolated from three cynomolgus blood donors were stained with AF647-conjugated CD33-C2 antibody and CD33 binding analyzed by flow cytometry. PBMCs were isolated from fresh blood samples using RBC lysis buffer prior staining. The neutrophil population was gated using a side scatter/CD45+ plot after excluding doublets and dead cells. Geometric MFI (gMFI) at each concentration was graphed on a log scale as non-linear regression curves. CD33 expression and antigen density in cynomolgus neutrophils were confirmed by flow cytometry. [1019] The results (FIGS.3A-3F) demonstrated CD33-M and the affinity matured progeny antibodies bind endogenous cynomolgus CD33 in neutrophils from whole blood samples. Example B7: Antibody Mediated Internalization in CD33+ cells [1020] Antibody drug conjugates (ADCs) comprise an antibody and a molecular warhead for targeted cytotoxicity. The ability of the antibody to mediate internalization is an important property for ADC potency. Antibody CD33-M was compared with VADA for ability to mediate internalization. [1021] CD33+ MOLM-13 cells, CD33+ MV-411 cells, or CD33-negative Pfeiffer cells were incubated with various concentrations (32 pM-10 nM) of antibody CD33-M or VADA labeled with acid-sensitive fluorescent Fab fragments that become fluorescent in the endosome. Cells were stained with the Fab-labeled antibody on ice and, after washing off unbound antibody, incubated at 37°C for four hours. Cells were then analyzed by flow cytometry, recording the geometric MFI (gMFI) at each concentration of antibody. [1022] The results (FIGS.4A-4C) demonstrated antibody CD33-M showed greater internalization in CD33+ cells than VADA. Example B8: Novel C2 antibodies exhibited antibody-drug conjugate cytotoxicity in AML cells [1023] CD33-M and its affinity matured progeny antibodies described herein were compared with VADA in an ADC cytotoxicity assay. The antibodies (at concentrations ranging from 0.04pM-80nM) were incubated with an anti-human IgG secondary antibody-MMAE conjugate (monomethyl auristatin E; commercially-available, Moradec LLC) and administered to CD33+ MOLM-13 cells (2000 cells/well). The cytotoxicity IC50 and IC90 values (nM) were determined. Data obtained is shown in Table 12 below.

[1024] Several of the novel C2 antibodies described herein exhibited greater cytotoxicity than VADA when formatted as an ADC. Example B9: Immunogenicity Analysis of Anti-CD33 Antibodies [1025] There are various elements that contribute to immunogenicity of antibodies and proteins. It has been reported that T cell-dependent responses play an important role in the development of anti-drug antibody (ADA) responses to biologics (Jawa V, et al., Clin Immunol.2013 Dec;149(3):534-55). Antibodies and proteins may contain neo-epitopes that bind HLA and elicit an immunogenic T cell effector (Teff) response. Antibodies may also contain Tregitopes (epitopes that activate regulatory T cells (Tregs)) that lead to immunogenicity suppression. [1026] Interactive Screening and Protein Reengineering Interface (ISPRI) developed by EpiVax was employed for assessing potential immunogenicity. EpiVax is known to be a clinically well-established T cell-dependent in silico analysis tool. Using ISPRI, the immunogenic potential of CD33-M and its progeny antibodies described herein were analyzed with EpiMatrix vaccine design technology (EpiVax, Inc). [1027] Heavy chain, light chain, VH, and VL domains of CD33-M and its affinity matured progeny antibodies were analyzed by EpiMatrix, which screens the entire primary amino acid sequences for the presence of putative effector T cell effectors (Teff) and regulatory T cell epitopes (Treg). The results are shown in FIGS.5A-5B. Greater Teff increases the immunogenic potential, while greater Treg decreases the immunogenic potential of each sequence on a normalized scale. Various scores were evaluated: EpiMatrix Score (reflecting Teff and Treg epitope content), Tregitope content (reflecting all Tregitope content), Tregitope-adjusted EpiMatrix Score (EpiMatrix Score excluding Tregitope content), and Predicted Ab Response. The Tregitope-adjusted EpiMatrix Score is considered a strong predictor of ADA response. [1028] The affinity matured progeny antibodies of CD33-M have a superior Tregitope- adjusted EpiMatrix Score and immunogenicity profile compared to the parental CD33-M antibody and two published anti-CD33 antibodies that are reported to bind the C2 domain of CD33 (antibody C33B904 described in WO 2019/224711 and antibody 1H7 described in WO 2018/218207). Example B10: Generation of Anti-CD33 Antibody GSPT1 Degrader Drug Conjugates [1029] General Procedures: Antibody was subjected to mild reduction in 20 mM L-histidine and 250 mM sucrose, pH5.5, 10 mM EDTA at 37 °C by the addition of 12-fold molar (per antibody) excess TCEP for 2 hours until separation of light chain, heavy chain is observed on RP-UPLC (Agilent AdvancedBio Diphenyl 2.1 x 150 mm). The mobile phase consisted of 0.1% TFA in water (A) and 0.1% TFA in acetonitrile (B). The system was operated at a flow rate of 1 ml/min. The gradient condition was as follows: 0-1 min., 20-30%B; 1-6 min, 30- 42%, 6.05-6.5 min, 42-95%. Wavelength 280 nM was used to monitor the reduction. TCEP was removed by Zeba column. Buffer was exchanged to 50 mM sodium acetate, pH 5.0. The maleimide-linked, GSPT1-degrader reagent (12 eq.) was incubated with the activated antibody for 1 hr at 25^C. The antibody conjugate was purified on HiTrap S column to remove excess reagents. [1030] Purification of Conjugate: The conjugate was purified from maleimide-linked GSPT1-degrader reagent and/or GSPT1-degrader via HiTrap SP HP column by AKTA: (1) Equilibrated with 10 CV 50 mM Sodium Acetate, pH 5.2, (2) Loaded samples (samples in formulation buffer were diluted with 2 equal volume of 50 mM Sodium Acetate, pH 5.2), (3) Washed with 30 CV 50 mM Sodium Acetate, pH 5.2, (4) Eluted with 1-100% 50 mM Sodium Acetate + 1 M NaCl pH 5.2 in 20 CV [1031] After purification: The peak fractions were formulated by dialysis into formulation buffer (20 mM histidine-250 mM sucrose pH5.5). Dialysis was performed against formulation buffer overnight. Final product was filtered under sterile conditions. [1032] Formation of conjugates was confirmed by LC-MS analysis. The samples were diluted to 1 mg/mL in 100 mM Tris pH 7.5. Twenty μl of sample was reduced by adding 2 μl of TCEP. The samples were analyzed by LC-MS using Agilent 1290 Infinity UPLC coupled to a 6530 Accurate-Mass Q-TOF. The analytical column used was waters BEH C4 column, 1.7 um, 2.1 mm x 50 mm held at 60 °C. The mobile phase consisted of 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The system was operated at a flow rate of 200 μl/min. The gradient condition was as follows: 0-2 min., held at 27% B; 2-9 min., slow ramp from 27-37% B; 9-9.5 min., linear ramp from 37-90% B; 9.5-12.3 min., held at 90% B. The MS settings were as follows: Polarity = Positive, Capillary Voltage = 4.2 kV, Sample Cone = 40 V, Source Offset = 15 V, Source Temperature = 140 °C, Desolvation Temperature = 325 °C. The data acquisition range was 900-3200 m/z. Deconvolution was done using Agilent MassHunter Walkup. [1033] ADC1 [Antibody CD33-B LP3]: Antibody CD33-B was subjected to mild reduction in PBS pH7.4, 2 mM EDTA at 37^C by the addition of 30-fold molar (per antibody) excess TCEP for 1 hour until separation of light chain, heavy chain is observed on RP-UPLC (Agilent AdvancedBio Diphenyl 2.1 x 150 mm). The mobile phase consisted of 0.1% TFA in water (A) and 0.1% TFA in acetonitrile (B). The system was operated at a flow rate of 1 ml/min. The gradient condition was as follows: 0-1 min., 20-30%B; 1-6 min, 30-42%, 6.05- 6.5 min, 42-95%. Wavelength 280 nM was used to monitor the reduction. TCEP was removed by Zeba column. Buffer was exchanged to 20 mM L-histidine and 250 mM sucrose, pH6.0. LP3 (10 eq.) was incubated with the activated antibody for 1 hr at 25 ^C in the presence of 2 mM EDTA. The ADC was purified on HiTrap S column to remove excess reagents. [1034] ADC2 [Antibody CD33-B LP4]: Antibody CD33-B was subjected to mild reduction in PBS pH7.4, 10 mM EDTA at 37^C by the addition of 12-fold molar (per antibody) excess TCEP for 2 hours until separation of light chain, heavy chain is observed on RP-UPLC (method described above). LP4 (8 eq.) was incubated with the activated antibody for 1 hr at 8 ^C in the presence of 10 mM EDTA. The ADC was purified on HiTrap S column to remove excess reagents. [1035] ADC3 [Antibody CD33-B LP2]: Antibody CD33-B was subjected to mild reduction in 20 mM L-histidine and 250 mM sucrose, pH5.5, 10 mM EDTA at 37^C by the addition of 12-fold molar (per antibody) excess TCEP for 2 hours until separation of light chain, heavy chain is observed on RP-UPLC (method described above). TCEP was removed by Zeba column. Buffer was exchanged to 50 mM Sodium Acetate, pH 5.0. LP2 (12 eq.) was incubated with the activated antibody for 1 hr at 25 ^C. The ADC was purified on HiTrap S column to remove excess reagents. Example B11: CD33-GSPT1-ADCs Demonstrate Tumor Burden Reduction and Prolonged Median-Survial in Disseminated MV4-11-Luc AML Xenograft Model [1036] Novel C2 antibodies CD33-B, CD33-C, CD33-F, and CD33-M described herein were conjugated to payload-linker LP2.

and tested for in vivo potency in a disseminated MV4-11 AML xenograft model. [1037] On day 0, MV4-11tumor cells (1X10⁶) stably transduced with the firefly luciferase gene (MV-411-Luc) were intravenously inoculated into NSG mice. On day 11, the mice were randomized into treatment groups (n = 8 per treatment group). [1038] On days 12, 19, and 26, the mice were treated with 3mg/kg or 10 mg/kg doses of ADC having the indicated antibody and monitored for tumor burden by bioluminescent imaging (BLI) and survival. Results are shown in Table 13 below.

* Tumor Burden Reduction; significance p<0.0001 # Significance p=0.002, log-rank test [1039] All CD33-GSPT1 ADCs exhibited dose-dependent reduction of tumor burden and tumor regression on treatment, and >70% prolonged survival relative to vehicle control. Example B12: Single-Dose Administration of CD33-GSPT1-ADC Results in GSPT1 Degradation and Apoptosis in Subcutaneous MV4-11-Luc AML Xenograft Model [1040] Novel C2 antibody CD33-B described herein was conjugated to payload-linker LP2:

and administered in a single 10 mg/kg dose by IV bolus to MV4-11-Luc AML xenograft mice. Terminal collection of tumor tissue was performed at 0, 6, 24, 48, 72, 168, and 216 hours post-dosing. Tumor tissue was processed for GSPT1 degradation and apoptosis (cleaved Caspase 3) by Western blot analysis (FIG.6). [1041] Single 10 mg/kg IV dose of the ADC led to significant GSPT1 degradation as early as 24 hr (-98.7%; P < 0.0001), up to 9 days (-96.6%; P < 0.0001) post-single IV dosing. Cleaved caspase 3 induction was observed as early as 24 hr post-dosing (+183.5%; P < 0.0001). The results are shown in FIG.7. Example B13: Data set for candidate linker-payload + Antibody CD33-B [1042] Antibody CD33-B described herein was conjugated to payload compound 1-(4-((4- (aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)urea via different linkers and compared for human serum stability in an in vitro cytotoxicity assay in Molm13 or MV-411 cells. The linker-payloads were LP2, LP4, LP32, and LP36. [1043] In vitro human serum stability of various CD33-GSPT1-ADCs having different linkers was tested. Each of the indicated ADCs were incubated in human serum (pooled multidonor) at 0.1 mg/kg for 0-120 hours at 37 °C. ADC samples were then directly administered to Molm13 and MV-411 AML cells (2,000 cells/well) at final concentrations of 0.023pM to 55nM. Cultures were assayed for viability after 3 days by CellTiter –Glo and IC50 values were plotted over time. The results are shown in FIG.8. [1044] In vitro cell potency was maintained at sub-nM IC50 values for >72 hours in Molm- 13 and for >120 hours in MV-411, highlighting the overall stability of the ADC formatted payload after exposure to human serum at elevated temperature. Example B14: Physical properties of CD33-GSPT1-ADCs [1045] ADCs comprising antibody CD33-M or CD33-B and various linker-payloads were evaluated for aggregation and drug antibody ratio (DAR). [1046] Aggregation was assessed by mass photometry using a Refeyn TwoMP instrument to assay sample heterogeneity. ADC conjugates were diluted to 100nM in 1x PBS. Conjugates were analyzed individually at 3 final concentrations by mass photometry: 2 nM, 10 nM, and 25 nM. Each sample was analyzed in normal mode and data was collected for 60 seconds. Urease (trimer & hexamer) and a control antibody were used as mass calibration standards. The mass calibration curve with Urease (MW – 272, 545 kDa) and control mAb (MW -145 kDa) was applied to each of the sample datasets. Counts vs. mass (kDa) plots were generated with DiscoverMP software and gaussian fits provided the measured mass and % total counts for the sample used to quantify the percent desired ADC and oligomer content. [1047] ADC aggregation was not observed with the antibody CD33-M conjugated to linker- payload LP2, LP36, and LP4, suggesting by this criterion that these ADCs exhibit promising developability, immunogenicity and product safety prospects. Conversely, CD33-M LP32 aggregated at a frequency of ~18-23% and did not pass this criterion. [1048] The average drug-to-antibody ratio (DAR) of ADCs comprising antibody CD33-B and various linker payloads was also analyzed. [1049] To determine the DAR, an aliquot of 50 µL of ADC samples at 1.0 mg/mL concentration was incubated with FabRICATOR MagIC (Genovis) for 20min at 37°C to generate subunit species including light chain (LC), Fc, and Fd’. The resulting samples were collected and subjected to reversed phase liquid chromatography-mass spectrometry (LC- MS) analysis for DAR measurement. LC-MS was performed on a Thermo Vanquish LC coupled with Orbitrap Exploris 480 mass spectrometer using water with 0.1% DFA as the mobile phase A (MPA), and acetonitrile with 0.1% DFA as the mobile phase B (MPB). A reversed phase column (ACQUITY Premier Protein BEH C4300Å, 1.7µm, 2.1x100 mm, Waters PN 186010327) was used at column temperature 65°C. A linear gradient at 0.3 mL/min eluting from 15% to 50% MPB in 5.4 minutes was used to spatially separate each subunit species. [1050] The Exploris 480 mass spectrometer was operated in full scan mode under positive polarity, with ion transferring tube temperature at 320°C, vaporizing temperature at 200°C, and spray voltage at 3800V. The resolution was set at 15k, scan range 1000-4000 m/z, AGC target 300%, maximum injection time 160 ms, and source fragment energy was 35V. [1051] Mass range of deconvolution was from 20 kDa to 100 kDa to accommodate all possible moieties. DAR values of Fd’ and LC were measured as weighted averages of the corresponding chains individually by following Equation 1, and the analysis was based on the intensity of corresponding deconvoluted masses. Total DAR value was calculated from DAR of Fd’ and LC: DAR Total = 2 x (DAR Fd’+ DAR LC).

[1052] The DAR of ADCs comprising antibody CD33-B and various linker-payloads fell within DAR 7.8-8.3, confirming uniformity of DAR for each of these ADCs. [1053] ADC aggregation and DAR data are summarized in Table 14.

Example B15: In vitro cytotoxicity in AML cells with CD33-GSPT1-ADCs [1054] CD33 C2 domain-binding ADCs exhibited selective potency in CD33+ AML cells. In vitro potency of the antibodies (CD33-B, CD33-C, CD33-F, CD33-M) when formatted as an ADC using various linker-payload configurations was tested. Molm-13, HL-60, and U-937 AML cells were selected as they exhibit progressively decreasing levels of CD33 expression ranging from 56,700 for Molm-13 to 14,400 for U-937 cell surface CD33 receptor copy expression (Mol Cancer Ther (2014) 13 (6): 1549–1557.) ADCs were administered at concentrations ranging from 0.03pM to 55nM. Unconjugated payload compound 1-(4-((4- (aminomethyl)benzyl)oxy)phenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)methyl)urea, was included for comparison. Potency could not be detected in CD33- Pfeiffer cells. Results are shown in FIGS.9A-9G. In FIG.9A, ADC cytotoxicity is expressed as IC50 values (nM). In FIGS.9B-9G, cytotoxicity is expressed as dose-response curves. Example B16: In vivo ADCs exhibited tumor growth inhibition and improved survival in an AML xenograft model. [1055] MV-411-Luc tumor cells were engrafted by tail vein injection and allowed to acclimatize for approximately 10 days. After day 10, ADCs comprising antibody CD33-B conjugated to linker-payload LP2, LP36, or LP4 were administered at 10 or 3mg/kg, 3-times once per week (QWX3). Alternatively, drug vehicle or a non-conjugated, equimolar mixture (i.e., 1:8) of antibody and payload (Compound 11) were administered as negative controls. The bioluminescent signature of the tumor cells was tracked at the indicated time points for approximately 30 days as indicated in FIG.10A. The administered ADCs at each dosing- level (where applicable) resulted in tumor regression, here defined as >50% tumor burden reduction. FIG.10B shows the Kaplan Meier survival profiles of the animals tracked for 120 days post-engraftment. The results demonstrate dose-dependent (where applicable) improvement in survival. Each experimental group was comprised of 8 animals (n=8, FIG. 10A and FIG.10B). XI. TABLE OF CERTAIN SEQUENCES [1056] The following table provides a listing of certain sequences referenced herein.

Claims

What is Claimed is: 1. A compound of Formula (I'):

S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R^8a and R^8b are each independently selected from hydrogen, halogen or a -C₁-C₆ alkyl, optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R⁹ is independently selected from hydrogen, halogen, -OR¹¹, -C₁-C₆ alkyl, -(C₁- C₆ haloalkyl), -(C₁-C₆ alkyl)-O-(C₁-C₆ alkyl), -NHR¹¹, -N(R¹¹R¹¹), -CN, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring, -C2-C₆ alkenyl, -O-(C₁-C₆ haloalkyl)-O-(C₁- C₆ alkyl), -C(=O)-(C₁-C₆ alkyl), -C(=O)OH, -C(=O)-O-(C₁-C₆ alkyl), -C(=O)NH2, -C(=O)NH(R¹¹), -C(=O)N(R¹¹R¹¹), -S(O)₂R¹¹, -S(=O)R¹¹, -SR¹¹, -S(=O)₂NH₂, - S(=O)₂NH(C₁-C₆ alkyl), or -S(=O)₂N(C₁-C₆ alkyl)₂, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may be optionally substituted with –R¹¹, -N(R¹¹R¹¹), -NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C₆ alkoxyalkyl, oxo, hydroxyl or -C₁-C₆ alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C₂- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)₂-, -S(=O)-, -S-, -S(=O)₂N(R¹¹)-, - S(=O)₂N(H)(C₁-C₆ alkylene)-, or -S(=O)₂N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L' is a linker; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. 2. The compound of claim 1, wherein A and B are independently selected from phenylene, pyridylene, pyrimidinylene, or pyridazinylene. 3. The compound of claim 2, wherein A and B are each phenylene.

4. The compound of claim 1, wherein A is phenylene and B is cyclohexylene, or A is cyclohexylene and B is phenylene. 5. The compound of any one of claims 1-4, wherein b is 0. 6. The compound of claim 5, wherein X is O. 7. The compound of any one of claims 1-4, wherein b is 1. 8. The compound of claim 7, wherein X is O. 9. The compound of claim 7, wherein X is N(H) or N(CH₃). 10. The compound of any one of claims 1-9, wherein c is 1. 11. The compound of any one of claims 1-10, wherein d is 1. 12. The compound of any one of claims 1-11, wherein e is 1. 13. The compound of claim 1, of Formula (II'):

, or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkyl, C₁-C₆ haloalkoxy, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)n- or -O(CH₂)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; b is 0 or 1; and L' is a linker.

14. The compound of any one of claims 1-13, having Formula (III'):

, or a pharmaceutically acceptable salt thereof, wherein: 15. The compound of any one of claims 1-14, having Formula IV':

or a pharmaceutically acceptable salt thereof. 16. The compound of any one of claims 1-15, wherein is

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. 17. The compound of claim 16, wherein

is:

18. The compound of any one of claims 1-15, wherein

is:

_. 19. The compound of any one of claims 1-15, wherein

. 20. The compound of any one of claims 1-15, wherein

, wherein: Ala is alanine; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl. 21. The compound of any one of claims 13-17, having Formula IV':

, or a pharmaceutically acceptable salt thereof.

22. A compound having a structure from Table A, or a pharmaceutically acceptable salt thereof. ,

,

,

, and pharmaceutically acceptable salts thereof. 24. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 1, a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 3, a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 16, a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 19, and a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 27; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 21, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 26, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 18, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; f) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 16, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 25, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 27; g) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 24, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; h) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 23, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; or i) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 22, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28.

25. An isolated antibody or antigen-binding portion thereof that specifically binds to CD33, wherein the antibody or antigen-binding portion thereof comprises: a) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 17, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 20, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 28; b) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 5, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 6, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 30, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 33, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 41; c) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 42, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 43, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 46; d) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 10, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 11, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 12, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 48, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 51, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 59; e) an HCDR1 comprising the amino acid sequence of SEQ ID NO: 13, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 14, an HCDR3 comprising the amino acid sequence of SEQ ID NO: 15, an LCDR1 comprising the amino acid sequence of SEQ ID NO: 60, an LCDR2 comprising the amino acid sequence of SEQ ID NO: 62, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 68. 26. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from SEQ ID NOs: 74-82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). 27. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising an amino acid sequence selected from SEQ ID NOs: 69-73, and a light chain variable region (VL) comprising an amino acid sequence selected from SEQ ID NOs: 74- 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). 28. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; b) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; c) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 71 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; d) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; e) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 77; f) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; g) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; h) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; i) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 78; j) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 79; k) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 72 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 80; l) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 69 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 81; or m) the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, identical to the amino acid sequence of SEQ ID NO: 73 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). 29. The isolated antibody or antigen-binding portion thereof of acclaim 24 or 25, wherein the VH is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70 and the VL is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). 30. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, which comprises a heavy chain variable region (VH) and a light chain variable region (VL) wherein: a) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 74; b) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 75; c) the VH comprises the amino acid sequence of SEQ ID NO: 71 and the VL comprises the amino acid sequence of SEQ ID NO: 76; d) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 75; e) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 77; f) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 74; g) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 74; h) the VH comprises the amino acid sequence of SEQ ID NO: 70 and the VL comprises the amino acid sequence of SEQ ID NO: 78; i) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 78; j) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 79; k) the VH comprises the amino acid sequence of SEQ ID NO: 72 and the VL comprises the amino acid sequence of SEQ ID NO: 80; l) the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 81; or m) the VH comprises the amino acid sequence of SEQ ID NO: 73 and the VL comprises the amino acid sequence of SEQ ID NO: 82; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 69-73 may be replaced with a pyroglutamic acid (pE). 31. The isolated antibody or antigen-binding portion thereof of claim 24 or 25, wherein the antibody or antigen-binding portion thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 70, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 75, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 70 may be replaced with a pyroglutamic acid (pE). 32. The isolated antibody or antigen-binding portion thereof of any one of claims 24-31, wherein the antibody or antigen-binding portion thereof is a monoclonal antibody. 33. The isolated antibody or antigen-binding portion thereof of any one of claims 24-32, wherein the antibody or antigen-binding portion thereof is a human antibody, chimeric antibody, or a humanized antibody. 34. The isolated antibody or antigen-binding portion thereof of any one of claims 24-33, wherein the antibody is a full-length antibody. 35. The isolated antibody or antigen-binding portion thereof of any one of claims 24-34, wherein the antibody or antigen-binding portion thereof is an IgG antibody. 36. The isolated antibody or antigen-binding portion thereof of any one of claims 24-35, wherein the antibody is an IgG antibody lacking a C-terminal lysine in the heavy chain constant region. 37. The isolated antibody or antigen-binding portion thereof of any one of claims 24-36, wherein the antibody is an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. 38. The isolated antibody or antigen-binding portion thereof of any one of claims 24-37, wherein the antibody comprises: a) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; b) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; c) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 85 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 90; d) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89; e) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 91; f) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; g) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 88; h) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; i) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 92; j) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 93; k) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 86 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 94; l) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 83 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 95; or m) a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 87 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 96; optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NOs: 83-87 may be replaced with a pyroglutamic acid (pE). 39. The isolated antibody or antigen-binding portion thereof of any one of claims 24-37, wherein the antibody comprises a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 84 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 89, optionally wherein the glutamic acid (E) at the N-terminus of SEQ ID NO: 84 may be replaced with a pyroglutamic acid (pE). 40. The isolated antibody or antigen-binding portion thereof of any one of claims 24-33, wherein the antibody or antigen-binding portion thereof is an antibody fragment selected from an Fv, single-chain Fv (scFv), Fab, Fab’, or (Fab’)2. 41. The isolated antibody or antigen-binding portion thereof of any one of claims 24-40, wherein the antibody or antigen-binding portion thereof binds human CD33.

42. The isolated antibody or antigen-binding portion thereof of claim 41, wherein human CD33 comprises the amino acid sequence of SEQ ID NO: 97 or SEQ ID NO: 99. 43. The isolated antibody or antigen-binding portion thereof of any one of claims 24-42, wherein the antibody or antigen-binding portion thereof binds the monomeric form of human CD33 and/or the dimeric form of human CD33. 44. The isolated antibody or antigen-binding portion thereof of any one of claims 24-43, wherein the antibody or antigen-binding portion thereof binds cynomolgus monkey CD33. 45. The antibody or antigen-binding portion thereof of claim 44, wherein cynomolgus monkey CD33 comprises the amino acid sequence of SEQ ID NO: 98. 46. The isolated antibody or antigen-binding portion thereof of any one of claims 24-45, wherein the antibody or antigen-binding portion thereof binds the monomeric form of cynomolgus monkey CD33 and/or the dimeric form of cynomolgus monkey CD33. 47. The isolated antibody or antigen-binding portion thereof of any one of claims 24-46, wherein the antibody or antigen-binding portion thereof does not bind to human Siglec 6 or human Siglec 8. 48. A pharmaceutical composition comprising the isolated antibody or antigen-binding portion thereof of any one of claims 24-47 and a pharmaceutically acceptable carrier. 49. An isolated nucleic acid encoding the antibody or antigen-binding portion thereof of any one of claims 24-47. 50. An antibody-drug conjugate comprising the antibody or antigen-binding portion thereof of any one of claims 24-47 and a cytotoxic agent. 51. An antibody-drug conjugate of Formula (I"):

-NHR¹¹ or –OR¹¹; R¹¹ is independently selected from hydrogen, halogen, -C₁-C₆ alkyl, -C₂-C₆ alkenyl, - C₁-C₆ haloalkyl, a 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 5 to 12 membered aryl or a 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹¹ are each independently unsubstituted or substituted with 1, 2, or 3 R¹² substituents; R¹² in each instance is independently selected from hydrogen, -C₁-C₆ alkyl, halogen, - OH, -O-(C₁-C₆ alkyl), -NH2, a 3 to 12 membered alkyl, 5 to 12 membered heterocyclic, 5 to 12 membered aryl or 5 to 12 membered heteroaryl ring; wherein the alkyl, alkenyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl ring in R¹² are each independently unsubstituted or substituted with R¹³; R¹³ is independently hydrogen, halo, -C₁-C₆ alkyl, -C₁-C₆ haloalkyl, -C₁- C6 ^{alkoxyalkyl, oxo, hydroxyl or -C}1^-C6 ^alkoxy; Z is independently selected from -O-, -N(R¹¹)-, C₁-C₆ alkylene, C₁-C₆ haloalkylene, - O-(C₁-C₆ alkylene)-, -(C₁-C₆ alkylene)-O-(C₁-C₆ alkylene)-, -N(R¹¹)-(C₁-C₆ alkylene)-, 3 to 12 membered cycloalkylene, 4 to 12 membered heterocyclene, 5 to 12 membered arylene or a 5 to 12 membered heteroarylene ring, C₂- C₆ alkenylene, -O-(C₁-C₆ haloalkylene)-O-(C₁-C₆ alkylene)-, -C(=O)-(C₁- C₆ alkylene)-, -C(=O)O-, -C(=O)-O-(C₁-C₆ alkylene)-, -C(=O)N(R¹¹)-, - C(=O)N(R¹¹)(C₁-C₆ alkylene)-, -S(O)2-, -S(=O)-, -S-, -S(=O)2N(R¹¹)-, - S(=O)₂N(H)(C₁-C₆ alkylene)-, or -S(=O)₂N(C₁-C₆ alkyl)(C₁-C₆ alkylene)-, or a bond; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; b is 0 or 1; c is 0, 1, 2, 3, or 4; d is 0, 1, 2, 3, or 4; and e is 0, 1, 2, or 3, and further wherein two R⁹ substituents on adjacent carbon atoms of the B group may join to form a 5 or 6 membered ring that may be saturated, partially saturated, or aromatic; and may further optionally be substituted with 1 or 2 R¹³ substituents and may include an oxo substituent if the ring is not an aromatic ring; and wherein the heterocyclic and heteroaryl cyclic ring in each A, B, R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, R¹² and R¹³ may include 1, 2 or 3 heteroatoms independently selected from O, N or S. 52. The antibody-drug conjugate of claim 115, wherein A and B are independently selected from phenylene, pyridinylene, pyrimidinylene, or pyridazinylene. 53. The antibody-drug conjugate of claim 116, wherein A and B are each phenylene. 54. The antibody-drug conjugate of claim 115, wherein A is phenylene and B is cyclohexylene, cyclopentylene, cyclobutylene, or bicyclo[1.1.1]pentanylene, or A is cyclohexylene and B is phenylene. 55. The antibody-drug conjugate of any one of claims 115-118, wherein b is 0. 56. The compound or antibody-drug conjugate of claim 119, wherein X is O. 57. The antibody-drug conjugate of any one of claims 115-118, wherein b is 1. 58. The compound or antibody-drug conjugate of claim 121, wherein X is O. 59. The compound or antibody-drug conjugate of claim 121, wherein X is N(H) or N(CH₃). 60. The antibody-drug conjugate of any one of claims 115-123, wherein c is 1. 61. The antibody-drug conjugate of any one of claims 115-124, wherein d is 1. 62. The antibody-drug conjugate of any one of claims 115-125, wherein e is 1. 63. The antibody-drug conjugate of claim 115, of Formula (II"):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halogen, or C₁-C₆ alkyl; R^2a and R^2b are each independently hydrogen, halogen, C₁-C₆ alkyl, or 3 to 6 membered cycloalkyl, or R^2a and R^2b, taken together with the carbon atom to which they are attached, form oxo; each R³ is independently hydrogen or halogen; X¹ and X² are each independently C(R⁷) or N; each R⁷ is independently hydrogen, halogen, C₁-C₆ alkyl, or C₁-C₆ haloalkyl; X³, X⁴, and X⁵ are each independently C(R⁹) or N; each R⁹ is independently hydrogen, halogen, -CN, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁- C₆ haloalkyl, 3 to 12 membered cycloalkyl, 4 to 12 membered heterocyclic, 3 to 12 membered cycloalkoxy, or 4 to 12 membered heterocyclyloxy; Z is -N(H)(CH₂)n- or -O(CH₂)n-, or a bond; n is 0, 1, 2, 3, 4, or 5; L is a linker; Ab is an antibody or antigen binding portion thereof; a is 1-20; and b is 0 or 1. 64. The antibody-drug conjugate of any one of claims 51-63, wherein R³ is hydrogen or fluoro. 65. The antibody-drug conjugate of any one of claims 51-64, wherein each R⁷ is independently hydrogen, fluoro, chloro, or methyl. 66. The antibody-drug conjugate of any one of claims 51-65, wherein each R⁹ is independently hydrogen, fluoro, chloro, C₁-C3 alkyl, C₁-C3 alkoxy, C₁-C3 haloalkyl, 3 or 4 membered cycloalkyl, or oxetanyloxy. 67. The antibody-drug conjugate of any one of claims 51 and 63-66, of Formula (III"):

or a pharmaceutically acceptable salt thereof. 68. The antibody-drug conjugate of any one of claims 51 and 63-67, having Formula IV":

or a pharmaceutically acceptable salt thereof. 69. The antibody-drug conjugate of any one of claims 51-68, wherein L comprises

, w eren indicates point of attachment to Ab. 70. The antibody-drug conjugate of claim 69, wherein L is

, wherein: Phe is phenylalanine; Gly is glycine; AA is glycine or glutamic acid; L³ is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)_m-, -C(O)NR²³-, -O-, -NR²³-, -(PEG)_mC(O)NR²³-, -C(O)NR²³(PEG)m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²³ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)mCH₃, provided that when R²³ is C₁-C₆ alkylene, the alkylene is point of attachment of L³ to -C(O)-AA-; m is an integer from 1 to 25; Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl.

, ,

_,

wherein: X⁶ is C(R²⁴) or N; X⁷ is C(R²⁵) or N; R²⁴ is hydrogen or hydroxy; R²⁵ is hydrogen, hydroxy, or -O(CH₂CH₂O)₇CH₃; and R²⁶ is -C(O)(CH₂CH₂O)8-12CH₃. 72. The antibody-drug conjugate of claim 69, wherein L is R

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; and each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; r is 0 or 1; and p is 0 or an integer from 1 to 10. 73. The antibody-drug conjugate of claim 72, wherein

:

point of attachment to Ab. 74. The antibody-drug conjugate of claim 69, wherein

, wherein: L² is a 1-25 membered aliphatic optionally comprising 1, 2 or 3 groups independently selected from -(PEG)m-, -C(O)NR²¹-, -O-, -NR²¹-, -(PEG)mC(O)NR²¹-, -C(O)NR²¹(PEG)_m-, or -Cy-, wherein the aliphatic is unsubstituted or substituted with one or more substituents independently selected from -OH, -COOH, or -NH₂; PEG is CH₂CH₂O; each R²¹ is independently hydrogen, C₁-C₆ alkyl, C₁-C₆ alkylene, -(CH₂CH₂O)mCH₃, or - CH₂CH₂C(O)N(H)(CH₂CH₂O)_mCH₃, provided that when R²¹ is C₁-C₆ alkylene, the alkylene is point of attachment of L² to phenylene; m is an integer from 1 to 25; and Cy is a four to eight-membered heterocyclylene, and is unsubstituted or optionally substituted with -C(O)(PEG)mCH₃; L⁴ is absent

N(R⁴⁰)C(O)CH₂N(R⁴⁰)-, wherein ** indicates point of attachment to Z; each R⁴⁰ is independently hydrogen or C₁-C₆ alkyl; and R²² is an -O-linked sugar acid. 75. The antibody-drug conjugate of claim 74, wherein L is:

or

_{, indicates point of attachment to Ab.} 76. The antibody-drug conjugate of any one of claims 63-71, having Formula V":

, or a pharmaceutically acceptable salt thereof. 77. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 78. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 79. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 80. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 81. An antibody drug conjugate of the following formula:

or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 82. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof.

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 85. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 86. An antibody drug conjugate of the following formula:

, or a pharmaceutically acceptable salt thereof, wherein: a is 1-20; and Ab is an antibody or antigen-binding fragment thereof. 87. The antibody-drug conjugate of any one of claims 51-86, wherein a is 1-15, or 1-12, or 1- 10, or 2-12, or 2-10, or 4-12, or 4-10, or 6-12, or 6-10.

88. The antibody-drug conjugate of any one of claims 51-87, wherein the antibody or antigen-binding portion thereof binds CD33. 89. The antibody-drug conjugate of claim 88, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 24- 47. 90. The antibody-drug conjugate of claim 89, wherein the antibody or antigen-binding portion thereof is the antibody or antigen-binding portion thereof of any one of claims 25, 29, 31, and 39. 91. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 50-90 and a pharmaceutically acceptable carrier. 92. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the isolated antibody or antigen-binding portion thereof of any one of claims 24-47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90. 93. The method of claim 92, wherein the cancer is leukemia. 94. The method of claim 93, wherein the leukemia is chronic lymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblastic leukemia, or acute myeloid leukemia. 95. The method of any one of claims 92-94, wherein the subject is a human. 96. Use of the isolated antibody or antigen-binding portion thereof of any one of claims 24- 47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90 for the preparation of a medicament for treating cancer in a subject in need thereof. 97. The isolated antibody or antigen-binding portion thereof of any one of claims 24-47, the pharmaceutical composition of claim 48 or 91, or the antibody-drug conjugate of any one of claims 50-90 for use in treating cancer in a subject in need thereof.