CN118900846A

CN118900846A - Anti-TREM2 antibodies and uses thereof

Info

Publication number: CN118900846A
Application number: CN202280089650.0A
Authority: CN
Inventors: S·帕帕派特罗珀洛斯; E·A·塔卡伯里; D·K·史提尔斯; A·J·马什; R·奥马拉
Original assignee: Virgil Neuroscience Inc
Current assignee: Virgil Neuroscience Inc
Priority date: 2021-11-22
Filing date: 2022-11-22
Publication date: 2024-11-05

Abstract

The invention provides anti-TREM 2 antibodies, formulations thereof, and methods of their use.

Description

Anti-TREM 2 antibodies and uses thereof

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application 63/381,897 filed on month 1 of 2022, U.S. provisional application 63/264,428 filed on month 11 of 2021, and greek application 20210100820 filed on month 22 of 2021, the contents of which are incorporated herein by reference in their entirety.

Sequence listing

The contents of the electronically submitted sequence Listing XML (title 403433-013WO_SL; size: 331,607 bytes; date of creation: 2022, 11, 18) are incorporated herein by reference in their entirety.

Technical Field

The present invention provides an anti-TREM 2 antibody, a formulation thereof and a method of using the same for treating adult onset leukoencephalopathy with axoglial degeneration and pigmentary glial cells (ALSP) in a human patient.

Background

Trigger receptor 2 (TREM 2) expressed on myeloid cells is a receptor whose expression is limited to microglia in the central nervous system, and mutations thereof increase the risk of neurodegenerative diseases such as alzheimer's disease and frontotemporal dementia (Ulland and Colonna, nature Reviews (Nature Reviews), 14,2018). TREM2 receptors affect microglial Cell status and function through their interaction with various ligands, and such ligands are critical for sensing tissue damage and minimizing the onset of neuropathy (Deczkowsk, cell, 181,2020). In addition, TREM2 receptor agonism is required for microglial progression to a neuroprotective disease-associated (DAM) phenotype (Keren-Shaul, cell 169,2017).

Disclosure of Invention

Disclosed herein are compositions of trigger receptor 2 (TREM 2) antibodies expressed on anti-myeloid cells, and methods of their use. The response of microglial cells to changes in the CNS environment is activated by TREM2 and its related protein kinase complex DAP 12. The TREM2/DAP12 signal acts as a primary regulator, switching microglial cells from homeostasis to a neurological disease-related state, and generating anti-inflammatory responses and neurotrophic factors to protect damaged neurons and achieve neural tissue regeneration. In one embodiment, the anti-TREM 2 antibody is "Ab-1", i.e., a monoclonal antibody that is capable of binding TREM2, also referred to herein as VGL101. The anti-TREM 2 antibody "Ab-1" can be used to modulate the activity of such cells, but without inhibiting or damaging the immune system. Without wishing to be bound by any particular theory, the anti-TREM 2 antibody "Ab-1" activates TREM2, slows disease progression, and enhances microglial cell mediated nerve tissue repair mechanisms.

Thus, in one aspect, the invention provides a liquid formulation of an anti-TREM 2 antibody. In one embodiment, the anti-TREM 2 antibody is "Ab-1", and the liquid formulation further comprises a pharmaceutically acceptable excipient and/or carrier. In some embodiments, the liquid formulation of the present invention comprises sodium acetate. In some embodiments, the liquid formulation of the present invention comprises sucrose. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80.

In another aspect, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of an anti-TREM 2 antibody. In some embodiments, the anti-TREM 2 antibody is anti-TREM 2 antibody "Ab-1". In some embodiments, the methods of the invention comprise administering to a patient in need thereof a liquid formulation comprising an anti-TREM 2 antibody "Ab-1", as described herein.

Drawings

FIG. 1 is a graph showing the average serum concentration (in μg/mL) of anti-TREM 2 antibody "Ab-1" over time in healthy volunteers (receiving 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg, or 30mg/kg single intravenous infusion). Each queue n=6, except for 10mg/kg, n=5. Data for the 30mg/kg dose were available only 28 days after dosing.

FIG. 2 is a graph showing the average serum concentration (in μg/mL) of anti-TREM 2 antibody "Ab-1" over time in healthy volunteers (receiving a dose of 20mg/kg administered intravenously every 28 days for a total of three infusions). N=12

FIG. 3A is a graph showing the effect of the anti-TREM 2 antibody "Ab-1" on sTREM2 in cerebrospinal fluid (CSF) of 18 healthy volunteers administered in single intravenous doses of 3mg/kg, 10mg/kg and 20 mg/kg. The data are plotted as the average change in sTREM2 (in pg/mL) from baseline in CSF over 336 hours (14 days). Each dose n=6. FIG. 3B is a graph showing the effect of anti-TREM 2 antibody "Ab-1" on CSF sTREM2 in 6 healthy volunteers (20 mg/kg administered intravenously every 28 days for a total of three infusions). Average CSF levels of sTREM2 were assessed at baseline (pre-dose), 48 hours and 672 hours (28 days) after the third dose and final dose. * p <0.05.

FIG. 4A is a graph showing the effect of the anti-TREM 2 antibody "Ab-1" on sCSF R in CSF of 18 healthy volunteers administered in single intravenous doses of 3mg/kg, 10mg/kg and 20 mg/kg. The data are plotted as the average change in sCSF R (in pg/mL) in CSF over 336 hours (14 days) from baseline. Each dose n=6. FIG. 4B is a graph showing the effect of anti-TREM 2 antibody "Ab-1" on CSF sCSF R in 6 healthy volunteers (20 mg/kg administered intravenously every 28 days for a total of three infusions). Average CSF levels of sCSF1R were assessed at baseline (pre-dose), 48 hours and 672 hours (28 days) after the third dose and final dose. * p <0.05.

Detailed Description

1. General description of certain embodiments of the invention

Described herein are formulations of anti-TREM 2 antibodies (such as "Ab-1") suitable for administration to a subject (e.g., a human subject). It has been found that at concentrations up to 10 μg/mL, the anti-TREM 2 antibody "Ab-1" has no effect on the release of granulocyte Colony Stimulating Factor (CSF), monocyte chemotactic protein-1 (MCP-1), 10kDa interferon-gamma inducing protein (IP-10), interleukin (IL) -1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-13 and IFN- γ in an in vitro cytokine release assay. The minimal but dose-dependent increase in tumor necrosis factor-alpha release was observed at the two highest concentrations (4. Mu.g/mL and 10. Mu.g/mL). However, this increase was within the scope of reports of other commercially available monoclonal antibodies, and no increase in vivo TNF- α was observed at any dose tested in GLP non-human primate (NHP) studies.

The anti-TREM 2 antibody "Ab-1" was well tolerated in NHP after 1 month of weekly intravenous administration at repeated doses up to 200 mg/kg. No test-related effects on clinical signs, body weight, food consumption, ophthalmic examination, or clinical pathology parameters (serum chemistry, hematology, coagulation, and urinalysis) were observed. Macroscopic and microscopic examination did not reveal any adverse findings or effects on organ weight. The safe pharmacological parameters were incorporated into GLP toxicology studies of NHP according to the international coordination center (ICH) Good Clinical Practice (GCP) three-way guidelines S6 guidance (ICH S6). No CNS effects were observed in the detailed neurobehavioral examination, and no Electrocardiogram (ECG) showed findings related to the anti-TREM 2 antibody "Ab-1".

The no visible adverse reaction level (NOAEL) was considered to be 200mg/kg. The following exposures were observed after a once every 7 days (q 7 d) dose of 200mg/kg 4:

On day 22, for 200mg/kg, the area under the serum curve for the time of quantifiable concentration (AUC 0-168 hr) from pre-dose (time 0) to 168 hours: 838000 h. Mu.g/mL

Maximum serum/cerebrospinal fluid concentration (Cmax) for 200mg/kg on day 22: 8320. Mu.g/mL

In cynomolgus macaques, the dose was administered at q7d for 29 days. The expected dosage regimen for administration to humans as part of the MAD portion of the study is once every 28 days. To calculate NOAEL limit, AUC0-168hr on day 22 was multiplied by 4 (number of doses received by cynomolgus macaques over a 28 day period) based on q7d dosing in cynomolgus macaques; the Cmax NOAEL limit remains unchanged:

NOAEL limit of area under serum or CSF concentration-time curve derived from pre-dose (time 0) to infinite time (auclast+ Clast/λz) (auc0- +%) curve: 838,000h μg/ml×4=3,350,000 h μg/mL

NOAEL limit of Cmax: 8,320 μg/mL

200Mg/kg of NHP NOAEL provided a safety margin 344 and 337 times higher than the expected Cmax and AUC _INF at the initial dose of 1mg/kg in healthy volunteers.

Accordingly, in one aspect, the present invention provides a liquid formulation comprising an anti-TREM 2 antibody "Ab-1", and a pharmaceutically acceptable excipient and/or carrier. In some embodiments, the pharmaceutically acceptable excipients and/or carriers of the present invention are selected from those as described herein.

In another aspect, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of an anti-TREM 2 antibody. In some embodiments, the methods of the invention comprise administering to a patient in need thereof a therapeutically effective amount of a liquid formulation as described herein.

In some embodiments, an anti-TREM 2 antibody comprises a light chain variable region comprising CDRL1 having an amino acid sequence according to SEQ ID No. 2 and a heavy chain variable region; CDRL2 having an amino acid sequence according to SEQ ID NO. 3; and CDRL3 having an amino acid sequence according to SEQ ID No. 4, said heavy chain variable region comprising CDRH1 having an amino acid sequence according to SEQ ID No. 6; CDRH2 having an amino acid sequence according to SEQ ID NO. 7; and CDRH3 having an amino acid sequence according to SEQ ID NO. 8.

In some embodiments, an anti-TREM 2 antibody comprises a light chain variable region having an amino acid sequence according to SEQ ID No. 1 and a heavy chain variable region having an amino acid sequence according to SEQ ID No. 5.

In some embodiments, the anti-TREM 2 antibody is IgG, optionally IgG ₁.

In some embodiments, the anti-TREM 2 antibody comprises a kappa light chain constant region.

In some embodiments, the anti-TREM 2 antibody is IgG ₁, the IgG1 comprising a variant constant region having one or more mutations selected from the group consisting of: R292C, N297G, V302C, D E or L358M according to EU numbering.

In some embodiments, the anti-2 antibody is an anti-TREM 2 antibody "Ab-1".

2. Definition of the definition

As used herein, the term "anti-TREM 2 antibody Ab-1" refers to an anti-TREM 2 antibody "Ab-1" comprising a light chain having the amino acid sequence of SEQ ID No. 9, and a heavy chain having the amino acid sequence of SEQ ID No. 10. "Ab-1" is used interchangeably with VGL101 and describes an antibody having CAS number 2733621-19-5 with the amino acid sequences summarized in Table 1 below.

Table 1: list of amino acid sequences.

In some embodiments, the anti-TREM 2 antibody is an anti-TREM 2 antibody described in one or more of the following patents: WO 2018/195506; U.S. patent 8,231,878; U.S. patent publication 2019/0010230;WO 2017/062672;WO 2019/028292;WO 2018/015573;WO 2019/055841;WO 2019/118513;WO 2020/055975;WO 2020/079580;KR patent publication KR20200048069; each of these patents is incorporated by reference in its entirety. In some embodiments, the anti-TREM 2 antibody is AL002. In some embodiments, the anti-TREM 2 antibody is DNL919. In some embodiments, the anti-TREM 2 antibody is not "Ab-1" (i.e., VGL 101).

As used herein, the term "pharmaceutically acceptable salts" refers to those salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail in J.pharmaceutical Sciences,1977,66,1-19 by S.M. Bere et al, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or with organic acids such as acetic, oxalic, maleic, tartaric, citric, succinic or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulphates, borates, butyrates, camphorites, camphorsulphonates, citrates, cyclopentanepropionates, digluconates, dodecylsulphates, ethanesulphonates, formates, fumarates, glucoheptonates, glycerophosphate, gluconate, hemisulphates, heptanonates, caprates, hydroiodinates, 2-hydroxy-ethanesulphonates, lactoaldehyde, lactates, laurates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulphonates, nicotinates, nitrates, oleates, oxalates, palmates, pamonates, pectinates, persulphates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulphates, tartrates, thiocyanates, p-toluenesulphonates, undecanoates, valerates and the like.

Salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N ⁺(C_1–4 alkyl group ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include nontoxic ammonium, quaternary ammonium and amine cation salts formed using counter ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates, where appropriate.

Unless otherwise indicated, structures described herein are also meant to include all isomeric (e.g., enantiomer, diastereomer, and geometric (or conformational) isomer) structural forms; for example, the R and S configuration, the Z and E double bond isomers, and the Z and E conformational isomers of each asymmetric center. Thus, single stereochemical isomers, enantiomers, diastereomers and geometric (or conformational) mixtures of the compounds of the invention are all within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. In addition, unless otherwise indicated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention, including hydrogen substitution with deuterium or tritium, or carbon substitution with ¹³ C or ¹⁴ C enriched carbon, are within the scope of the present invention. Such compounds may be used, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the invention.

As used herein, reference to "about" or "approximately" has the meaning of being within 20% of a given value or range. In some embodiments, the term "about" means within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

The present invention relates to antibodies that specifically bind to TREM2 (particularly human TREM 2). In humans, the TREM2 gene is located within the TREM gene cluster at 6p21.1 chromosome. The TREM gene cluster encodes four TREM proteins (TREM 1, TREM2, TREM4 and TREM 5) and two TREM-like proteins (TLT-1 and TLT-2). The TREM2 gene encodes a 230 amino acid protein consisting of an extracellular domain, a transmembrane region and a short cytoplasmic tail (Paradowska-Gorycka et al, human Immunology, vol.74:730-737, 2013). The extracellular domain contains a single V-type Ig-superfamily domain with three potential N-glycosylation sites. The wild type human TREM2 amino acid sequence (NCBI reference sequence: NP-061838.1) is provided as SEQ ID NO: 354.

MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRWSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDCGHDPGYQLQTLPGLRDT(SEQ ID NO:354)

Amino acids 1 to 18 of the wild type human TREM2 protein (SEQ ID NO: 354) are signal peptides, which are typically removed from the mature protein. Mature human TREM2 protein comprises the extracellular domain at amino acids 19-174 of SEQ ID NO:354, the transmembrane domain at amino acids 175-195 of SEQ ID NO:354, and the cytoplasmic domain at amino acids 196-230 of SEQ ID NO: 354. The amino acid sequence of the extracellular domain (including the signal peptide) of human TREM2 is provided as SEQ ID NO 355 below.

MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRWSTHNLWLLSFLRRWNGSTAITDDTLGGTL TITLRNLQPHDAGLYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTS(SEQ ID NO:355)

The term "trigger receptor-2 expressed on human myeloid cells" or "human TREM2" may refer to the polypeptide of SEQ ID NO:354, the polypeptide of SEQ ID NO:355, the polypeptide of SEQ ID NO:354 or SEQ ID NO:355 minus the signal peptide (amino acids 1-18), an allelic variant of human TREM2 or a splice variant of human TREM 2. In some embodiments, the term "human TREM2" encompasses naturally occurring variants of TREM2, such as the mutations R47H, Q X (X is a stop codon), Y38C, T66M, D87N, H157Y, R98W and S116C.

3. Description of exemplary embodiments

Antibodies to

In one aspect, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of an antigen-binding protein or antibody or antigen-binding fragment thereof that increases TREM2 activity. In some embodiments, the antibody is an agonist of TREM 2. In some embodiments, the antibody is a TREM2 agonist that specifically binds and activates human TREM 2. In some embodiments, the antibody is the anti-human TREM2 antibody VGL101.

The TREM2 agonist antibody specifically binds human TREM2 (SEQ ID NO: 354) or the extracellular domain (ECD) of human TREM2 (e.g., the ECD shown in SEQ ID NO: 355), e.g., an equilibrium dissociation constant (K _D) of less than 50nM, less than 25nM, less than 10nM, or less than 5nM. In some embodiments, the TREM2 agonist antibody does not cross-react with other TREM proteins (such as human TREM 1). In some embodiments, the TREM2 agonist antibody does not bind to human TREM1.

In some embodiments, the TREM2 antibody specifically binds to human TREM2 residues 19-174 (SEQ ID NO: 354). In some embodiments, the TREM2 antibody specifically binds to an IgV region of human TREM2, e.g., human TREM2 residues 19-140 (SEQ ID NO: 354).

In certain embodiments, the anti-TREM 2 antibodies of the disclosure bind to one or more amino acids within amino acid residues 29-112 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 29-112 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 29-41 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 29-41 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 47-69 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 47-69 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 76-86 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 76-86 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 91-100 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 91-100 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 99-115 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 99-115 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 104-112 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 104-112 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 114-118 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 114-118 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 130-171 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 130-171 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 139-153 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-153 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 130-144 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 130-144 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 158-171 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 158-171 of SEQ ID NO: 354.

In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 43-50 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 49-57 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 354. In some embodiments, an anti-TREM 2 antibody of the disclosure binds to one or more amino acids within amino acid residues 140-153 of human TREM2 (SEQ ID NO: 354) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 140-153 of SEQ ID NO: 354. In some embodiments, the TREM2 antibody specifically binds to a stem region of human TREM2, e.g., amino acid residues 145-174 of human TREM 2.

In some embodiments, the antibody or antigen binding fragment thereof specifically binds TREM2 and prevents degradation or cleavage of TREM 2.

In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody, particularly a fully human antibody. In some embodiments, the antibody is a bispecific or other multivalent antibody. In some embodiments, the antibody is a single chain antibody.

In some embodiments, a TREM 2-activated antibody comprises a light chain variable region comprising the complementarity determining regions CDRL1, CDRL2, and CDRL3 described herein, and a heavy chain variable region comprising the complementarity determining regions CDRH1, CDRH2, and CDRH3.

In certain embodiments, a TREM2 agonist antigen binding protein of the invention comprises at least one light chain variable region comprising CDRL1, CDRL2 and CDRL3 from an anti-TREM 2 agonist antibody described herein, and at least one heavy chain variable region comprising CDRH1, CDRH2 and CDRH 3.

In some embodiments, the TREM2 activated antibody comprises a light chain variable region and a heavy chain variable region as described herein. The light and heavy chain variable regions or CDRs may be from any of the anti-TREM 2 antibodies or variants thereof described herein.

Pct patent application publication No. WO2018/195506A1

In some embodiments, the TREM2 agonist is an antigen binding protein or antibody or antigen binding fragment thereof as described in PCT patent application publication No. WO2018/195506A1 (which application is incorporated herein by reference in its entirety).

In some embodiments, the TREM2 agonist antigen binding protein comprises CDRL1 or a variant thereof having one, two, three or four amino acid substitutions; CDRL2 or a variant thereof having one, two, three or four amino acid substitutions; CDRL3 or a variant thereof having one, two, three or four amino acid substitutions; CDRH1 or variants thereof having one, two, three or four amino acid substitutions; CDRH2 or variants thereof having one, two, three or four amino acid substitutions; and CDRH3 or variants thereof having one, two, three or four amino acid substitutions, wherein the amino acid sequences of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2 and CDRH3, and exemplary light chains and variable regions are provided in tables 1A and 1B below.

Table 1A: exemplary anti-human TREM2 antibody light chain variable region amino acid sequences

TABLE 1B exemplary anti-human TREM2 antibody heavy chain variable region amino acid sequences

As described above, the TREM2 agonist antigen binding protein may comprise one or more of the CDRs present in table 1 (VGL 101), table 1A (light chain CDRs; i.e., CDRL) and table 1B (heavy chain CDRs, i.e., CDRH).

In some embodiments, a TREM2 agonist antigen binding protein comprises one or more light chain CDRs selected from (i) CDRL1 selected from SEQ ID NOs 11 to 18 or 356 to 361, (ii) CDRL2 selected from SEQ ID NOs 19 to 30, and (iii) CDRL3 selected from SEQ ID NOs 31 to 45, and (iv) CDRL containing one or more (e.g., one, two, three, four, or more) amino acid substitutions (e.g., conservative amino acid substitutions), NO more than five, four, three, two, or one amino acid deletions or insertions of (i), (ii), and (iii). In these and other embodiments, the TREM2 agonist antigen binding protein comprises one or more heavy chain CDRs selected from (i) CDRH1 selected from SEQ ID NOs 77 to 86, (ii) CDRH2 selected from SEQ ID NOs 87 to 94, and (iii) CDRH3 selected from SEQ ID NOs 95 to 109, and (iv) CDRH containing one or more (e.g., one, two, three, four or more) amino acid substitutions (e.g., conservative amino acid substitutions), NO more than five, four, three, two or one amino acid deletions or insertions of (i), (ii) and (iii).

In some embodiments, a TREM2 agonist antigen binding protein may comprise 1, 2, 3,4, 5, or 6 variant forms of a CDR listed in tables 1A and 1B, each form having at least 80%, 85%, 90%, or 95% sequence identity to a CDR sequence listed in tables 1A and 1B. In some embodiments, the TREM2 agonist antigen binding protein comprises 1, 2, 3,4, 5, or 6 CDRs listed in tables 1A and 1B, each CDR differing from a CDR listed in these tables by no more than 1, 2, 3,4, or 5 amino acids.

In some embodiments, the TREM2 agonist antigen binding protein comprises CDRL1 comprising a sequence selected from SEQ ID NOS: 11-18 or 356-361 or a variant thereof having one, two, three, or four amino acid substitutions; CDRL2 comprising a sequence selected from the group consisting of SEQ ID NOS.19-30 or variants thereof having one, two, three or four amino acid substitutions; CDRL3 comprising a sequence selected from the group consisting of SEQ ID NOS.31-45 or variants thereof having one, two, three or four amino acid substitutions; CDRH1 comprising a sequence selected from SEQ ID NO. 77-86 or a variant thereof having one, two, three or four amino acid substitutions; CDRH2 comprising a sequence selected from SEQ ID NOs 87-94 or variants thereof having one, two, three or four amino acid substitutions; and CDRH3 comprising a sequence selected from SEQ ID NO 95-109 or a variant thereof having one, two, three or four amino acid substitutions.

In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a CDRL1, the CDRL1 comprising a sequence selected from the group consisting of SEQ ID NOS 11-18 or 356-361; CDRL2, said CDRL2 comprising a sequence selected from the group consisting of SEQ ID NOS.19-30; CDRL3, said CDRL3 comprising a sequence selected from the group consisting of SEQ ID NOS.31-45; CDRH1, said CDRH1 comprising a sequence selected from the group consisting of SEQ ID NOS 77-86; CDRH2, said CDRH2 comprising a sequence selected from the group consisting of SEQ ID NOS: 87-94; and CDRH3, said CDRH3 comprising a sequence selected from the group consisting of SEQ ID NOS 95-109.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, wherein:

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 356, 19 and 31, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 357, 20 and 32, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 357, 21 and 33, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 357, 20 and 33, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 358, 22 and 34, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 359, 22 and 35, respectively;

(g) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 360, 22 and 36, respectively;

(h) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 361, 23 and 37, respectively;

(i) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 11, 23 and 38, respectively;

(j) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 12, 24 and 39, respectively;

(k) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 13, 25 and 40, respectively;

(l) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 14, 26 and 41, respectively;

(m) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 15, 27 and 42, respectively;

(n) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 16, 28 and 43, respectively;

(o) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 17, 29 and 44, respectively; or (b)

(P) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 18, 30 and 45, respectively.

In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein:

(a) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 87 and 95 respectively;

(b) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 88 and 96 respectively;

(c) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 88 and 97 respectively;

(d) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 89 and 96 respectively;

(e) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 90 and 98 respectively;

(f) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 79, 90 and 99 respectively;

(g) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 80, 91 and 100 respectively;

(h) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 91 and 101 respectively;

(i) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 82, 92 and 102 respectively;

(j) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 91 and 103 respectively;

(k) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 91 and 104 respectively;

(l) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 83, 93 and 105 respectively;

(m) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 84, 91 and 106, respectively;

(n) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 107 respectively;

(o) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 86, 94 and 108, respectively; or (b)

(P) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 109, respectively.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein:

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 356, 19 and 31, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 87 and 95, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 357, 20 and 32, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 88 and 96, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 357, 21 and 33, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 78, 88 and 97, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 357, 20 and 33, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 88 and 97, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 357, 20 and 33, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 78, 89 and 96, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 358, 22 and 34, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 87 and 95, respectively;

(g) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 359, 22 and 35, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 90 and 98, respectively;

(h) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 360, 22 and 36, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 79, 90 and 99, respectively;

(i) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 361, 23 and 37, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 80, 91 and 100, respectively;

(j) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 361, 23 and 37, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 81, 91 and 101, respectively;

(k) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 11, 23 and 38, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 82, 92 and 102, respectively;

(l) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 12, 24 and 39, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 81, 91 and 103, respectively;

(m) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 13, 25 and 40, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 81, 91 and 104, respectively;

(n) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 14, 26 and 41, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 83, 93 and 105, respectively;

(o) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 15, 27 and 42, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 84, 91 and 106, respectively;

(p) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS: 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS: 85, 91 and 107, respectively;

(q) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 17, 29 and 44, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 86, 94 and 108, respectively; or (b)

(R) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS: 18, 30 and 45, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS: 85, 91 and 109, respectively.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 361, 23 and 37, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 80, 91 and 100, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 361, 23 and 37, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 91 and 101, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 15, 27 and 42, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 84, 91 and 106, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 107, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 17, 29 and 44, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 86, 94 and 108, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 359, 22 and 35, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 90 and 98, respectively.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence selected from SEQ ID NOS: 46-63 and a heavy chain variable region comprising a sequence selected from SEQ ID NOS: 110-126. In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 46 and a heavy chain variable region comprising the sequence of SEQ ID NO. 110. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 47 and a heavy chain variable region comprising the sequence of SEQ ID NO. 111. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 48 and a heavy chain variable region comprising the sequence of SEQ ID NO. 112. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 49 and a heavy chain variable region comprising the sequence of SEQ ID NO. 113. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 50 and a heavy chain variable region comprising the sequence of SEQ ID NO. 114. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 51 and a heavy chain variable region comprising the sequence of SEQ ID NO. 110. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 53 and a heavy chain variable region comprising the sequence of SEQ ID NO. 116. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 54 and a heavy chain variable region comprising the sequence of SEQ ID NO. 117. in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 55 and a heavy chain variable region comprising the sequence of SEQ ID NO. 118. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 56 and a heavy chain variable region comprising the sequence of SEQ ID NO. 119. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 57 and a heavy chain variable region comprising the sequence of SEQ ID NO. 120. in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 58 and a heavy chain variable region comprising the sequence of SEQ ID NO. 121. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 59 and a heavy chain variable region comprising the sequence of SEQ ID NO. 122. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 60 and a heavy chain variable region comprising the sequence of SEQ ID NO. 123. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 61 and a heavy chain variable region comprising the sequence of SEQ ID NO. 124. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 62 and a heavy chain variable region comprising the sequence of SEQ ID NO. 125. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 63 and a heavy chain variable region comprising the sequence of SEQ ID NO. 126. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 52 and a heavy chain variable region comprising the sequence of SEQ ID NO. 115.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region selected from LV-01、LV-02、LV-03、LV-04、LV-05、LV-06、LV-07、LV-08、LV-09、LV-10、LV-11、LV-12、LV-13、LV-14、LV-15、LV-16、LV-17 and LV-18 as shown in Table 1A, and/or a heavy chain variable region selected from HV-01, HV-02, HV-03, HV-04, HV-05, HV-06, HV-07, HV-08, HV-09, HV-10, HV-11, HV-12, HV-13, HV-14, HV-15, HV-16, and HV-17 as well as functional fragments, derivatives, muteins, and variants of these light and heavy chain variable regions as shown in Table 1B.

In some embodiments, each light chain variable region listed in table 1A can be combined with any heavy chain variable region listed in table 1B to form an anti-TREM 2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to: LV-01 (SEQ ID NO: 46) and HV-01 (SEQ ID NO: 110); LV-02 (SEQ ID NO: 47) and HV-02 (SEQ ID NO: 111); LV-03 (SEQ ID NO: 48) and HV-03 (SEQ ID NO: 112); LV-04 (SEQ ID NO: 49) and HV-04 (SEQ ID NO: 113); LV-05 (SEQ ID NO: 50) and HV-05 (SEQ ID NO: 114); LV-06 (SEQ ID NO: 51) and HV-01 (SEQ ID NO: 110); LV-07 (SEQ ID NO: 52) and HV-06 (SEQ ID NO: 115); LV-08 (SEQ ID NO: 53) and HV-07 (SEQ ID NO: 116); LV-09 (SEQ ID NO: 54) and HV-08 (SEQ ID NO: 117); LV-10 (SEQ ID NO: 55) and HV-09 (SEQ ID NO: 118); LV-11 (SEQ ID NO: 56) and HV-10 (SEQ ID NO: 119); LV-12 (SEQ ID NO: 57) and HV-11 (SEQ ID NO: 120); LV-13 (SEQ ID NO: 58) and HV-12 (SEQ ID NO: 121); LV-14 (SEQ ID NO: 59) and HV-13 (SEQ ID NO: 122); LV-15 (SEQ ID NO: 60) and HV-14 (SEQ ID NO: 123); LV-16 (SEQ ID NO: 61) and HV-15 (SEQ ID NO: 124); LV-17 (SEQ ID NO: 62) and HV-16 (SEQ ID NO: 125); and LV-18 (SEQ ID NO: 63) and HV-17 (SEQ ID NO: 126).

In certain embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-09 (SEQ ID NO: 54) and a heavy chain variable region comprising the sequence of HV-08 (SEQ ID NO: 117). In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-10 (SEQ ID NO: 55) and a heavy chain variable region comprising the sequence of HV-09 (SEQ ID NO: 118). In other embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region comprising the sequence of LV-15 (SEQ ID NO: 60) and a heavy chain variable region comprising the sequence of HV-14 (SEQ ID NO: 123). In still other embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region comprising the sequence of LV-16 (SEQ ID NO: 61) and a heavy chain variable region comprising the sequence of HV-15 (SEQ ID NO: 124). In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-17 (SEQ ID NO: 62) and a heavy chain variable region comprising the sequence of HV-16 (SEQ ID NO: 125). In certain embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-07 (SEQ ID NO: 52) and a heavy chain variable region comprising the sequence of HV-06 (SEQ ID NO: 115).

In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising a contiguous amino acid sequence that differs from the sequence of the light chain variable region in table 1A (i.e., VL selected from LV-01、LV-02、LV-03、LV-04、LV-05、LV-06、LV-07、LV-08、LV-09、LV-10、LV-11、LV-12、LV-13、LV-14、LV-15、LV-16、LV-17 or LV-18) only at 1,2,3, 4,5, 6,7,8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, wherein each such sequence difference is independently a deletion, insertion, or substitution of one amino acid, wherein the deletion, insertion, and/or substitution results in no more than 15 amino acid changes relative to the variable domain sequence described previously. The light chain variable region in some TREM2 agonist antigen binding proteins comprises an amino acid sequence that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NOs 46-63 (i.e., the light chain variable region in table 1A). In one embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence at least 90% identical to a sequence selected from the group consisting of SEQ ID NOS: 46-63. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence at least 95% identical to a sequence selected from the group consisting of SEQ ID NOS: 46-63. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NOS: 46-63. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 54. In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 55. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 60. In still other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 61. In certain embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID No. 62. In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 52.

In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence that differs from the heavy chain variable region in table 1B (i.e., a VH selected from HV-01, HV-02, HV-03, HV-04, HV-05, HV-06, HV-07, HV-08, HV-09, HV-10, HV-11, HV-12, HV-13, HV-14, HV-15, HV-16, or HV-17) by only 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues, wherein each such sequence difference is independently a deletion, insertion, or substitution of one amino acid, wherein the deletion, insertion, and/or substitution results in no more than 15 amino acid changes relative to the variable domain sequence described above. The heavy chain variable region in some TREM2 agonist antigen binding proteins comprises an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% sequence identity to the amino acid sequence of SEQ ID NOs 110-126 (i.e., the heavy chain variable region in table 1B). In one embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence at least 90% identical to a sequence selected from the group consisting of SEQ ID NOS: 110-126. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence at least 95% identical to the sequence selected from SEQ ID NOS: 110-126. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOS 110-126. In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO. 117. In other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO. 118. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO. 123. In still other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO. 124. In certain embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID No. 125. In other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO. 115.

In some embodiments, variants of anti-TREM 2 antibodies can be generated by substituting one or more amino acids in the light or heavy chain variable region to address chemical liabilities (chemical liabilities) (e.g., aspartic acid isomerization, asparagine deamidation, tryptophan, and methionine oxidation) or correct covariance violations (covariance violations) (see, e.g., WO 2012/125495, which is hereby incorporated by reference in its entirety). Such variants may have improved biophysical, expression, and/or stability properties compared to the parent antibody. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and/or a heavy chain variable region having one or more amino acid substitutions listed in tables 2A-2F below.

In some embodiments, additional variants of the anti-TREM 2 antibodies described herein can be produced by affinity modulating any of the anti-TREM 2 antibodies described herein. An "affinity modulating antibody" is an antibody comprising one or more amino acid substitutions in its light chain variable region sequence and/or heavy chain variable region sequence that increases or decreases the affinity of the antibody for a target antigen as compared to a parent antibody that does not comprise an amino acid substitution. Antibody affinity modulation methods are known to those of skill in the art and can include CDR walking mutagenesis (Yang et al, J.mol. Biol.,254,392-403,1995), strand shuffling (Marks et al, bio/Technology,10,779-783,1992), use of E.coli mutant strains (Low et al, J.mol. Biol.,250,350-368,1996), DNA shuffling (Patten et al, curr. Opin. Biotechnol.,1997, 8:724-733), phage display (Thompson et al, J.mol. Biol.,1996, 256:7-88), PCR techniques (Crameri et al, nature,1998, 391:288-291), and other mutagenesis strategies (Barbas et al, proc Nat. Acad. Sci. USA 91:3809-3813,1994; gene:147-155, 1995; yel et al, J.Immunol.155, 1994:226-1997; 1995; J.95:8, 1999-95, J.95:8, J.8:8, J.7-88), and other mutagenesis strategies (Barbas et al, nature,1998, 1999, 1994). Affinity modulation methods are discussed in Hoogenboom, trends in Biotechnology,1995,15:62-70 and Vaughan et al, nature Biotechnology,1998, 16535-539. One specific method of generating affinity-modulating variants of the anti-TREM 2 antibodies described herein is to use a yeast display Fab mutagenesis library.

In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region that is a variant of the light chain variable region of any of the anti-TREM 2 antibodies described herein. Thus, in some embodiments, the light chain variable region of a TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from SEQ ID NOS: 46-63. In some embodiments, the TREM2 agonist antigen binding protein may comprise a light chain variable region from any of the engineered anti-TREM 2 antibody variants listed in tables 2A-2F below.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of SEQ ID NO 54 having a mutation at one or more amino acid positions 64, 79, 80, 85, 94 and/or 100. In some such embodiments, the mutation is V64G、V64A、Q79E、Q79D、S80P、S80A、F85V、F85L、F85A、F85D、F85I、F85L、F85M、F85T、W94F、W94Y、W94S、W94T、W94A、W94H、W94I、W94Q、P100R、P100Q、P100G or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 55 with a mutation at one or more amino acid positions 64, 79, 80, 94 and/or 100. Such mutations may include V64G, V, A, Q, 79, D, S, P, S, A, W, 3825, 94, Y, W, 94 3995, 94T, W, A, W, 94H, W, I, W, Q, P, R, P, 100, Q, P G, or combinations thereof. In certain embodiments, the mutation is V64G, V64A, Q79E, S80P, S A, W94Y, W S, P100R, P Q or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 60 with mutations at one or more amino acid positions 60, 92 and/or 93. The mutation in such embodiments may be selected from L60S, L60P, L60D, L60A, D92E, D Q, D92T, D N, S A, S93N, S93Q, S V or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO 61 with mutations at one or more amino acid positions 56, 57, 92 and/or 93. In such embodiments, the mutation may be N56S, N56T, N56Q, N56E, G A, G V, D92E, D3492 3496 3793 93N, S Q, S V or a combination thereof. In certain embodiments, the mutation is N56S, N Q, G57A, D92E, D3592Q, S93A or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 62 with mutations at amino acid positions 36, 46, 61 and/or 100. Such mutations may include F36Y, S46L, S46R, S V, S46F, K61R, P100Q, P100G, P R or a combination thereof. In a particular embodiment, the mutation is F36Y, K61, 61R, P100,100deg.C or a combination thereof. in another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 52 with a mutation at amino acid position 91, which may be selected from F91V, F91I, F91T, F91L or F91D. In one embodiment, the mutation is F91V.

In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region that is a variant of a heavy chain variable region from any of the anti-TREM 2 antibodies described herein. Thus, in some embodiments, the heavy chain variable region of a TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from the group consisting of SEQ ID NOS: 110-126. For example, the TREM2 agonist antigen binding protein may comprise the heavy chain variable region from any of the engineered anti-TREM 2 antibody variants listed in tables 2A-2F below. In one embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 117 with a mutation at one or more amino acid positions 19, 55, 56, 57, 58 and/or 104. In some such embodiments, the mutation is M19K、M19R、M19T、M19E、M19N、M19Q、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、W104F、W104Y、W104T、W104S、W104A、W104H、W104I、W104Q or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 118 with mutations at one or more amino acid positions 19, 55, 56, 57, 58 and/or 104. such mutations may include M19K、M19R、M19T、M19E、M19N、M19Q、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、W104F、W104Y、W104T、W104S、W104A、W104H、W104I、W104Q or a combination thereof. In certain embodiments, the mutation is M19K, D E, S56A, D57E, T A, W104Y, W T or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of SEQ ID NO. 123 having a mutation at one or more amino acid positions 27, 55, 56, 57, 58, 105 and/or 106. In some embodiments, the mutation is selected from H27Y、H27D、H27F、H27N、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、D105E、D105Q、D105T、D105N、D105G、S106A、S106Q、S106V、S106T or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 124 having a mutation at one or more amino acid positions 55, 56, 57, 58, 105 and/or 106. The mutation in such embodiments may be selected from D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、D105E、D105Q、D105T、D105N、D105G、S106A、S106Q、S106V、S106T or a combination thereof. In certain embodiments, the mutation is D55E, D Q, S56A, D57E, T A, D105E, D105N, S a or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of SEQ ID NO. 125 having a mutation at one or more amino acid positions 43, 76, 85, 99, 100 and/or 116. Such mutations may include L43Q、L43K、L43H、I76T、R85S、R85G、R85N、R85D、D99E、D99Q、D99S、D99T、G100A、G100Y、G100V、T116L、T116M、T116P、T116R or a combination thereof. In certain embodiments, the mutation is L43Q, R85S, D99E, G100A, G100Y, T116L or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 115 with mutations at amino acid positions 62 and/or 63. In such embodiments, the mutation may be selected from D62E, D62Q, D62T, D N, S63A, S Q, S V or a combination thereof. In some embodiments, the mutation is D62E, D62, 62Q, S63A or a combination thereof. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region and/or a heavy chain variable region from any of the anti-TREM 2 variant antibodies listed in tables 2A, 2B, 3A, 3B and 19. Thus, in some embodiments, the light chain variable region of a TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from the group consisting of: SEQ ID NOS: 61, 153-162 and 295-300. In these and other embodiments, the heavy chain variable region of the TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from the group consisting of: SEQ ID NOS 124, 180-190 and 307-312.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of SEQ ID NO 54 having a mutation at one or more amino acid positions 64, 79, 80, 85, 94 and/or 100. Such mutations may include V64G、V64A、Q79E、Q79D、S80P、S80A、F85V、F85L、F85A、F85D、F85I、F85L、F85M、F85T、W94F、W94Y、W94S、W94T、W94A、W94H、W94I、W94Q、P100R、P100Q、P100G or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 117 having a mutation at one or more amino acid positions 19, 55, 56, 57, 58 and/or 104. In certain embodiments, the mutation is selected from M19K、M19R、M19T、M19E、M19N、M19Q、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、W104F、W104Y、W104T、W104S、W104A、W104H、W104I、W104Q or a combination thereof.

In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 55 with mutations at one or more amino acid positions 64, 79, 80, 94 and/or 100. In some embodiments, the mutation is selected from V64G, V64A, Q79E, Q D, S80P, S80A, W94F, W94Y, W94S, W94T, W94A, W94H, W I, W Q, P100R, P100Q, P G or a combination thereof. In certain embodiments, the mutation is selected from V64G, V64A, Q79E, S80P, S A, W94Y, W S, P100R, P Q or a combination thereof. For example, in some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO 55 with one or more mutations selected from the group consisting of V64G, Q79E, S80P, W94Y and P100Q. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 118 with mutations at one or more amino acid positions 19, 55, 56, 57, 58 and/or 104. Such mutations may include M19K、M19R、M19T、M19E、M19N、M19Q、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、W104F、W104Y、W104T、W104S、W104A、W104H、W104I、W104Q or a combination thereof. In certain embodiments, the mutation is selected from M19K, D E, S56A, D57E, T A, W104Y, W T or a combination thereof.

In certain other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of SEQ ID No. 60 having a mutation at one or more amino acid positions 60, 92 and/or 93. The mutation may be selected from L60S, L P, L60D, L A, D92 858 92Q, D3495T, D N, S A, S4293N, S Q, S V or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of SEQ ID NO. 123 having a mutation at one or more amino acid positions 27, 55, 56, 57, 58, 105 and/or 106. In some embodiments, the mutation is selected from H27Y、H27D、H27F、H27N、D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、D105E、D105Q、D105T、D105N、D105G、S106A、S106Q、S106V、S106T or a combination thereof.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of SEQ ID NO 61 with mutations at one or more amino acid positions 56, 57, 92 and/or 93. In certain embodiments, the mutation is selected from N56S, N56T, N56E, G A, G57V, D92E, D3498 3496 3793A, S93N, S Q, S V or a combination thereof. In some embodiments, the mutation is selected from N56S, N Q, G57A, D92E, D3592Q, S93A or a combination thereof. In a particular embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO 61 with one or more mutations selected from N56S, D E and S93A. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 124 having a mutation at one or more amino acid positions 55, 56, 57, 58, 105 and/or 106. The mutation may be selected from D55E、D55Q、D55N、D55T、S56A、S56Q、S56V、D57S、D57E、D57Q、T58A、T58V、D105E、D105Q、D105T、D105N、D105G、S106A、S106Q、S106V、S106T or a combination thereof. In certain embodiments, the mutation is D55E, D Q, S56A, D57E, T A, D105E, D105N, S a or a combination thereof. In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 124 having one or more mutations selected from the group consisting of D55E, S56A, D E, D105E and S106A.

In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 62 with mutations at amino acid positions 36, 46, 61 and/or 100. In a particular embodiment, the mutation is selected from F36Y, S46L, S46R, S46V, S46F, K61R, P100Q, P100G, P R or a combination thereof. In some embodiments, the mutation is F36Y, K61, 61R, P100,100deg.Q or a combination thereof. In some embodiments, the mutation is S46L, P Q or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of SEQ ID No. 125 having a mutation at one or more amino acid positions 43, 76, 85, 99, 100 and/or 116. The mutation may be selected from L43Q、L43K、L43H、I76T、R85S、R85G、R85N、R85D、D99E、D99Q、D99S、D99T、G100A、G100Y、G100V、T116L、T116M、T116P、T116R or a combination thereof. In certain embodiments, the mutation is L43Q, I76T, R85S, D99E, G100A, G100Y, T116L or a combination thereof.

In still other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO. 52 with a mutation at amino acid position 91. The mutation may be selected from F91V, F, I, F, 91T, F, 91L or F91D. In one embodiment, the mutation is F91V. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO 115 with mutations at amino acid positions 62 and/or 63. In a particular embodiment, the mutation is selected from D62E, D62, 62Q, D62 62, 62T, D62 62, 62N, S63, 63A, S63, 63Q, S63V or a combination thereof. In some embodiments, the mutation is selected from D62E, D, Q, S a, or a combination thereof.

Table 2A.10E3 engineered variants of antibodies

Engineered variants of the 13E7 antibodies

Engineered variants of the 2C.4C5 antibodies

Engineering variants of the 2D.6E7 antibodies

Table 2e.5e3 engineered variants of antibodies

Engineering variants of the 24G6 antibody

In some embodiments, the TREM2 agonist antigen binding protein comprises one or more CDRs of a variant of an anti-TREM 2 antibody described herein. In some embodiments, a TREM2 agonist antigen binding protein may comprise one or more CDRs of anti-TREM 2 antibody variants listed in tables 3A, 3B, 3C, 3D and 3E below.

In certain embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and/or a heavy chain variable region from an affinity-modulating variant of a 6E7 antibody. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region and/or a heavy chain variable region with one or more amino acid substitutions listed in table 2G.

Table 2G.6E7 antibody affinity modulating variants

Labeled binding signal values were obtained with a 110nM Ab concentration, whereas the remaining values in the column were obtained with a 10nM Ab concentration.

In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of SEQ ID NO 61 with mutations at one or more amino acid positions 24, 31, 50, 52, 54, 56, 89, 92, 93, 94 and/or 96. In certain embodiments, the mutation is selected from R24A, S R, A50S, A G, S G, L R, N K, N56R, N L, N56T, Q89G, D92V, S R, F94Y, F94L, R96H, R L or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of SEQ ID NO 124 having a mutation at one or more amino acid positions 27, 28, 30, 32, 50, 54, 58, 60, 61, 63, 66, 99, 101, 103, 104 and/or 110. In some embodiments, the mutation is selected from Y27S、S28G、S28H、T30N、T30G、T30E、T30A、Y32E、I50T、G54S、T58V、Y60L、S61A、S63G、S63E、G66D、Q99G、Q99S、Q99M、T101G、Y103R、Y104G、F110S or a combination thereof. The amino acid sequences of the light and heavy chain variable regions and associated CDRs of exemplary 6E7 antibody variants with increased affinity are shown in tables 3A and 3B, respectively, below. The amino acid sequences of the light and heavy chain variable regions and associated CDRs of exemplary 6E7 antibody variants with reduced affinity are shown in tables 3C and 3D, respectively, below. The corresponding sequences of the 6E7 antibodies are listed for comparison.

TABLE 3A light chain variable region amino acid sequences for TREM2 antibodies with improved affinity

TABLE 3 heavy chain variable region amino acid sequences for TREM2 antibodies with improved affinity

In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise one or more CDRs from the affinity-enhanced variants presented in table 3A (light chain CDRs; i.e., CDRL) and 3B (heavy chain CDRs, i.e., CDRH). In some embodiments, the TREM2 agonist antigen binding protein comprises a consensus CDR sequence derived from an affinity-enhanced variant. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises CDRL2 consensus sequence X ₁ASSX₂QX₃ (SEQ ID NO: 139), wherein X ₁ is a or G; X ₂ is L or R; and X ₃ is N, K, R, L or T. In another embodiment, the TREM2 agonist antigen binding protein comprises the CDRL3 consensus sequence X ₁QADX₂X₃PX₄ T (SEQ ID NO: 140), wherein X ₁ is Q or G; X ₂ is S or R; x ₃ is F, L or Y; and X ₄ is R or H. In yet another embodiment, the TREM2 agonist antigen binding protein comprises CDRH2 consensus sequence X ₁IYPGDSDX₂RX₃X₄PX₅FQX₆ (SEQ ID NO: 141), wherein X ₁ is I or T; X ₂ is T or V; x ₃ is Y or L; x ₄ is S or A; x ₅ is S, G or E; And X ₆ is G or D. In some embodiments, the TREM2 agonist antigen binding protein comprises the CDRH3 consensus sequence X ₁RTFYYDSSDYX₂ DY (SEQ ID NO: 142), wherein X ₁ is Q, G, S or M; And X ₂ is F or S.

In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRL1 comprises the sequence of SEQ ID NO:16, CDRL2 comprises the consensus sequence of SEQ ID NO:139, CDRL3 comprises the consensus sequence of SEQ ID NO:140, CDRH1 comprises the sequence of SEQ ID NO:85, CDRH2 comprises the consensus sequence of SEQ ID NO:141, and CDRH3 comprises the consensus sequence of SEQ ID NO: 142.

In some embodiments, the TREM2 agonist antigen binding protein comprises CDRL1 comprising the sequence of SEQ ID No. 16; CDRL2 comprising a sequence selected from the group consisting of SEQ ID NOS.26 and 143-147; CDRL3 comprising a sequence selected from the group consisting of SEQ ID NOs 43 and 148-152; CDRH1 comprising the sequence of SEQ ID NO. 85; CDRH2 comprising a sequence selected from the group consisting of SEQ ID NOs 91 and 170-175; and CDRH3 comprising a sequence selected from SEQ ID NOS: 176-179.

In a particular embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3, wherein:

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 143 and 148, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 144 and 149, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 145 and 43, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 146 and 148, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 26 and 150, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 143 and 151, respectively;

(g) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 145 and 148, respectively;

(h) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 145 and 152, respectively;

(i) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 144 and 43, respectively; or (b)

(J) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 147 and 43, respectively.

In a related embodiment, the TREM2 agonist antigen binding protein of the present invention comprises a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein:

(a) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 170 and 176, respectively;

(b) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 171 and 177, respectively;

(c) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 172 and 177 respectively;

(d) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 171 and 178 respectively;

(e) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 171 and 179 respectively;

(f) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 173 and 177 respectively;

(g) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 176 respectively;

(h) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 174 and 176, respectively;

(i) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 175 and 178 respectively; or (b)

(J) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 85, 91 and 178, respectively.

In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein:

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 143 and 148, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 170 and 176, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 144 and 149, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 171 and 177, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 145 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 172 and 177, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 146 and 148, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 171 and 178, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 26 and 150, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 171 and 179, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 143 and 151, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 173 and 177, respectively;

(g) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 145 and 148, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 176, respectively;

(h) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 145 and 152, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 171 and 178, respectively;

(i) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 143 and 151, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 174 and 176, respectively;

(j) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 144 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 175 and 178, respectively; or (b)

(K) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 147 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 178, respectively.

In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise a light chain variable region selected from LV-101, LV-102, LV-103, LV-104, LV-105, LV-106, LV-107, LV-108, LV-109 and LV-110 as shown in Table 3A, and/or a heavy chain variable region selected from HV-101, HV-102, HV-103, HV-104, HV-105, HV-106, HV-107, HV-108, HV-109, HV-110 and HV-111 as shown in Table 3B, or a sequence that is at least 80% identical, at least 85% identical, at least 90% identical or at least 95% identical to any of the sequences in tables 3A and 3B. For example, in some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising (i) a sequence that is at least 90% identical to a sequence selected from SEQ ID NOs 153-162, (ii) a sequence that is at least 95% identical to a sequence selected from SEQ ID NOs 153-162, or (iii) a sequence selected from SEQ ID NOs 153-162. In related embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising (i) a sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOS 180-190, (ii) a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOS 180-190, or (iii) a sequence selected from the group consisting of SEQ ID NOS 180-190.

Each light chain variable region listed in table 3A can be combined with any of the heavy chain variable regions listed in table 3B to form an anti-TREM 2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to: LV-101 (SEQ ID NO: 153) and HV-101 (SEQ ID NO: 180); LV-102 (SEQ ID NO: 154) and HV-102 (SEQ ID NO: 181); LV-103 (SEQ ID NO: 155) and HV-103 (SEQ ID NO: 182); LV-104 (SEQ ID NO: 156) and HV-104 (SEQ ID NO: 183); LV-105 (SEQ ID NO: 157) and HV-105 (SEQ ID NO: 184); LV-106 (SEQ ID NO: 158) and HV-106 (SEQ ID NO: 185); LV-107 (SEQ ID NO: 159) and HV-107 (SEQ ID NO: 186); LV-108 (SEQ ID NO: 160) and HV-108 (SEQ ID NO: 187); LV-106 (SEQ ID NO: 158) and HV-109 (SEQ ID NO: 188); LV-109 (SEQ ID NO: 161) and HV-110 (SEQ ID NO: 189); and LV-110 (SEQ ID NO: 162) and HV-111 (SEQ ID NO: 190).

TABLE 3C light chain variable region amino acid sequences for reduced affinity TREM2 antibodies

TABLE 3D heavy chain variable region amino acid sequences for reduced affinity TREM2 antibodies

In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise one or more CDRs from the reduced affinity variants presented in table 3C (light chain CDRs; i.e., CDRL) and table 3D (heavy chain CDRs, i.e., CDRH). In some embodiments, the TREM2 agonist antigen binding protein comprises a consensus CDR sequence derived from a variant with reduced affinity. For example, in one embodiment, the TREM2 agonist antigen binding protein comprises the CDRL1 consensus sequence X ₁ASQGISX₂ WLA (SEQ ID NO: 284), wherein X ₁ is R or A; and X ₂ is S or R. In another embodiment, the TREM2 agonist antigen binding protein comprises CDRL2 consensus sequence X ₁AX₂ SLQN (SEQ ID NO: 285), wherein X ₁ is A or S; And X ₂ is S or G. In another embodiment, the TREM2 agonist antigen binding protein comprises CDRL3 consensus sequence QQAX ₁SFPX₂ T (SEQ ID NO: 286), wherein X ₁ is D or V; And X ₂ is R or L. In another embodiment, the TREM2 agonist antigen binding protein comprises the CDRH1 consensus sequence SX ₁ WIA (SEQ ID NO: 287), where X ₁ is Y or E. in yet another embodiment, the TREM2 agonist antigen binding protein comprises CDRH2 consensus sequence IIYPX ₁ DSDTRYSPSFQG (SEQ ID NO: 288), wherein X ₁ is G or S. In yet another embodiment, the TREM2 agonist antigen binding protein comprises the CDRH3 consensus sequence QRX ₁FX₂X₃ DSSDYFDY (SEQ ID NO: 289), wherein X ₁ is T or G; X ₂ is Y or R; and X ₃ is Y or G. In some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising complementarity determining regions CDRL1, CDRL2 and CDRL3, and a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2 and CDRH3, wherein CDRL1 comprises the sequence of SEQ ID NO:284, CDRL2 comprises the consensus sequence of SEQ ID NO:285, CDRL3 comprises the consensus sequence of SEQ ID NO:286, CDRH1 comprises the sequence of SEQ ID NO:287, CDRH2 comprises the consensus sequence of SEQ ID NO. 288, and CDRH3 comprises the consensus sequence of SEQ ID NO. 289.

In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a CDRL1 comprising a sequence selected from the group consisting of SEQ ID NOs 16, 290 and 291; CDRL2 comprising a sequence selected from the group consisting of SEQ ID NOS 28, 292 and 293; CDRL3 comprising a sequence selected from the group consisting of SEQ ID NOs 43, 294 and 271; CDRH1 comprising the sequence of SEQ ID NO. 85 or SEQ ID NO. 302; CDRH2 comprising the sequence of SEQ ID NO. 91 or SEQ ID NO. 303; and CDRH3 comprising a sequence selected from SEQ ID NOS: 107 and 304-306.

In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3, wherein:

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 28 and 43, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 292 and 43, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 28 and 294, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 290, 28 and 43, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 293 and 43, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 28 and 271, respectively; or (b)

(G) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 291, 28 and 43, respectively.

(a) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 304 respectively;

(b) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 107 respectively;

(c) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 305 respectively;

(d) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 303 and 107, respectively;

(e) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 91 and 306 respectively; or (b)

(F) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 302, 91 and 107, respectively.

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 304, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 292 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 294, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively;

(d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively;

(e) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 305, respectively;

(f) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 303 and 107, respectively;

(g) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 290, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively;

(h) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 306, respectively;

(i) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 293 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively;

(j) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 28 and 271, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 91 and 107, respectively; or (b)

(K) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 291, 28 and 43, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 302, 91 and 107, respectively.

In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise a light chain variable region selected from LV-16, LV-201, LV-202, LV-203, LV-204, LV-205 and LV-206 as shown in Table 3C, and/or a heavy chain variable region selected from HV-15, HV-201, HV-202, HV-203, HV-204, HV-205 and HV-206 as shown in Table 3D, or a sequence at least 80% identical, at least 85% identical, at least 90% identical or at least 95% identical to any of the sequences in tables 3C and 3D. For example, in certain embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising (i) a sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOs 61 and 295-300, (ii) a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOs 61 and 295-300, or (iii) a sequence selected from the group consisting of SEQ ID NOs 61 and 295-300. In related embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising (i) a sequence that is at least 90% identical to a sequence selected from the group consisting of SEQ ID NOS: 124 and 307-312, (ii) a sequence that is at least 95% identical to a sequence selected from the group consisting of SEQ ID NOS: 124 and 307-312, or (iii) a sequence selected from the group consisting of SEQ ID NOS: 124 and 307-312.

In some embodiments, each light chain variable region listed in table 3C can be combined with any heavy chain variable region listed in table 3D to form an anti-TREM 2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to: LV-16 (SEQ ID NO: 61) and HV-201 (SEQ ID NO: 307); LV-201 (SEQ ID NO: 295) and HV-15 (SEQ ID NO: 124); LV-202 (SEQ ID NO: 296) and HV-15 (SEQ ID NO: 124); LV-16 (SEQ ID NO: 61) and HV-202 (SEQ ID NO: 308); LV-16 (SEQ ID NO: 61) and HV-203 (SEQ ID NO: 309); LV-16 (SEQ ID NO: 61) and HV-204 (SEQ ID NO: 310); LV-203 (SEQ ID NO: 297) and HV-15 (SEQ ID NO: 124); LV-16 (SEQ ID NO: 61) and HV-205 (SEQ ID NO: 311); LV-204 (SEQ ID NO: 298) and HV-15 (SEQ ID NO: 124); LV-205 (SEQ ID NO: 299) and HV-15 (SEQ ID NO: 124); and LV-206 (SEQ ID NO: 300) and HV-206 (SEQ ID NO: 312).

In some embodiments, the TREM2 agonist antigen binding protein comprises one or more CDRs of an anti-TREM 2 antibody variant listed in table 3E. In some embodiments, the TREM2 agonist antigen binding proteins comprise the light chain variable region and heavy chain variable region of the anti-TREM 2 antibody variants listed in table 3E.

TABLE 3E exemplary variable region amino acid sequences of engineered antibodies

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 16, 369 and 370, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 361, 23 and 372, respectively; or (b)

(C) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 357, 21 and 33, respectively; (d) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 357, 20 and 33, respectively.

(a) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 77, 368 and 98 respectively;

(b) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 85, 371 and 107 respectively;

(c) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 373 and 374 respectively; or (b)

(D) CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 86, 94 and 375, respectively.

(a) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 359, 22 and 35, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 77, 368 and 98, respectively;

(b) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID nos. 16, 369 and 370, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID nos. 85, 371 and 107, respectively;

(c) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOS 361, 23 and 372, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOS 81, 373 and 374, respectively; or (b)

(D) CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 17, 29 and 44, respectively, and CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 86, 94 and 375, respectively.

Thus, in some embodiments, a TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2 and CDRL3 and a heavy chain variable region comprising CDRH1, CDRH2 and CDRH3, wherein the CDRL1, CDRL2 and CDRL3 have the sequences of SEQ ID NOs 361, 23 and 372, respectively, and the CDRH1, CDRH2 and CDRH3 have the sequences of SEQ ID NOs 81, 373 and 374, respectively.

Accordingly, in some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising CDRL1, CDRL2 and CDRL3 having the sequences of SEQ ID NOs 361, 23 and 372, respectively, and CDRH1, CDRH2 and CDRH3 having the sequences of SEQ ID NOs 81, 373 and 374, respectively. In certain embodiments, the antibody is human. In some embodiments, the TREM2 agonist antigen binding protein comprises

(A) A light chain variable region comprising the amino acid sequence of SEQ ID NO. 326 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 327;

(b) A light chain variable region comprising the amino acid sequence of SEQ ID NO. 328 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 329;

(c) A light chain variable region comprising the amino acid sequence of SEQ ID NO. 330 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 331; or (b)

(D) A light chain variable region comprising the amino acid sequence of SEQ ID NO. 332 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 333.

In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO. 330 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO. 331.

Accordingly, in some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:330 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 331. In certain embodiments, the antibody is human.

In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the light chain variable region consisting of the amino acid sequence of SEQ ID NO. 326, 328, 330 or 332. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the heavy chain variable region consisting of the amino acid sequence of SEQ ID NO 327, 329, 331 or 333. In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 326 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 327. In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 328 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 329. In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 330 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 331. In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 332 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID No. 333.

In some embodiments, each of the light chain variable regions disclosed in tables 1A, 3C, and 3E and each of the heavy chain variable regions disclosed in tables 1B, 3D, and 3E can be linked to a light chain constant region (table 4) and a heavy chain constant region (table 5), respectively, to form a complete antibody light chain and heavy chain, as discussed further below. In addition, each of the generated heavy and light chain sequences may be combined to form a complete antibody structure. It is to be understood that the heavy and light chain variable regions provided herein can also be linked to other constant domains having sequences different from the exemplary sequences listed herein.

In some embodiments, exemplary TREM2 agonist antibodies having a light chain variable region with a light chain constant region and a heavy chain variable region with a heavy chain constant region are disclosed in table 3F.

TABLE 3F light and heavy chain amino acid sequences of exemplary antibodies

In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO. 334 and a heavy chain comprising the sequence of SEQ ID NO. 335. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO. 334 and a heavy chain comprising the sequence of SEQ ID NO. 336. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain comprising the sequence of SEQ ID No. 337 and a heavy chain comprising the sequence of SEQ ID No. 338. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain comprising the sequence of SEQ ID No. 339 and a heavy chain comprising the sequence of SEQ ID No. 340. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain comprising the sequence of SEQ ID No. 341 and a heavy chain comprising the sequence of SEQ ID No. 342. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO. 343 and a heavy chain comprising the sequence of SEQ ID NO. 344. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO. 343 and a heavy chain comprising the sequence of SEQ ID NO. 345. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO. 346 and a heavy chain comprising the sequence of SEQ ID NO. 347. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain comprising the sequence of SEQ ID No. 348 and a heavy chain comprising the sequence of SEQ ID No. 349. In some embodiments, a TREM2 agonist antigen binding protein of the present invention comprises a light chain comprising the sequence of SEQ ID No. 350 and a heavy chain comprising the sequence of SEQ ID No. 351.

In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:334 and a heavy chain comprising the sequence of SEQ ID NO: 335. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:334 and a heavy chain comprising the sequence of SEQ ID NO: 336. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:337 and a heavy chain comprising the sequence of SEQ ID NO: 338. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:339 and a heavy chain comprising the sequence of SEQ ID NO: 340. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:341 and a heavy chain comprising the sequence of SEQ ID NO: 342. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID No. 343 and a heavy chain comprising the sequence of SEQ ID No. 344. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID No. 343 and a heavy chain comprising the sequence of SEQ ID No. 345. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID No. 346 and a heavy chain comprising the sequence of SEQ ID No. 347. Accordingly, in some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:348 and a heavy chain comprising the sequence of SEQ ID NO: 349. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:350 and a heavy chain comprising the sequence of SEQ ID NO: 351. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO:352 and a heavy chain comprising the sequence of SEQ ID NO: 353.

In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the light chain consisting of the amino acid sequence of SEQ ID NO. 334, 337, 339 or 341. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the light chain consisting of the amino acid sequence of SEQ ID NO. 343, 346, 348 or 350. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the heavy chain consisting of the amino acid sequence of SEQ ID NO 335, 336, 338, 340 or 342. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises or consists essentially of the heavy chain consisting of the amino acid sequence of SEQ ID NO. 344, 345, 347, 349 or 351. In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain and a heavy chain, wherein:

(a) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 334 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 335;

(b) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 334 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 336;

(c) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 337 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 338;

(d) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 339 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 340; or (b)

(E) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 341 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 342.

In a specific embodiment, a TREM2 agonist antigen binding protein of the present invention comprises a light chain and a heavy chain, wherein:

(a) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 343 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 344;

(b) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 343 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 345;

(c) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 346 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 347;

(d) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 348 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 349;

(e) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 350 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 351; or (b)

(F) The light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 352 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO. 353.

Unless otherwise indicated, references to specific sequences in tables 1A, 1B, 3A, 3B, 3C, 3D, 3E and in the related discussion refer to numbering of amino acid residues in immunoglobulin heavy or light chains according to the numbering of Kabat-EU as described in the following documents: kabat et al Sequences of Proteins of Immunological Interest th edition USDepartment of HEALTH AND Human Services, NIH publication No. 91-3242, pages 662, 680, 689 (1991), and Edelman et al Proc.Natl.Acad.USA, volume 63:78-85 (1969). When referring to the position of an amino acid within a variable region, the Kabat numbering scheme is generally used, whereas when referring to the position of an amino acid within an immunoglobulin constant region, the EU numbering scheme is generally used.

In some embodiments, the TREM2 antigen binding protein comprises an antibody that competes with an antibody comprising the CDRL1, CDRL2, CDRL3, or light chain variable region disclosed in tables 1A, 3C, and 3E and the heavy chain variable region disclosed in tables 1B, 3D, and 3E. In some embodiments, suitable assays for detecting competitive binding employ a binding assayA kinetic sensor for use with the system (Pall ForteBio) which measures binding interactions using a biological layer interference measurement method. A set of antibodies (i.e., antibodies 10E3, 13E7, 24F4, 4C5, 4G10, 32E3, and 6E 7) competed with each other for binding to human TREM2, indicating that they share the same or similar epitopes on human TREM 2. Antibodies 16B8, 26a10, 26C10, 26F2, 33B12, and 5E3 compete with each other for TREM2 binding, but do not compete with antibodies in the first group or antibodies 24a10, 24G6, or 25F12, indicating that the antibodies of the second group bind different epitopes on human TREM 2. Antibodies 24a10 and 24G6 share a similar epitope on human TREM2, as both antibodies compete with each other for human TREM2 binding, but do not compete with any other antibodies. Antibody 25F12 did not compete with any other tested antibodies for binding to human TREM2, indicating that this antibody binds to yet another epitope.

In some embodiments, a TREM2 agonist antigen binding protein competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from SEQ ID NOS: 46-63 and a heavy chain variable region comprising a sequence selected from SEQ ID NOS: 110-126. In other embodiments, a TREM2 agonist antigen binding protein of the invention competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from SEQ ID NOs 153-162 and a heavy chain variable region comprising a sequence selected from SEQ ID NOs 180-190. In still other embodiments, the TREM2 agonist antigen binding proteins of the present invention compete for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs 61 and 295-300 and a heavy chain variable region comprising a sequence selected from the group consisting of SEQ ID NOs 124 and 307-312. In certain embodiments, a TREM2 agonist antigen binding protein of the invention competes with one or more anti-TREM 2 antibodies described herein (including 12G10、26A10、26C10、26F2、33B12、24C12、24G6、24A10、10E3、13E7、14C12、25F12、32E3、24F4、16B8、4C5、6E7、5E3、4G10、V3、V9、V10、V23、V24、V27、V30、V33、V40、V44、V48、V49、V52、V57、V60、V68、V70、V73、V76、V83、V84 and V90) for binding to human TREM2.

In some embodiments, a TREM2 agonist antigen binding protein competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID No. 61 and a heavy chain variable region comprising the sequence of SEQ ID No. 124. In such embodiments, an antigen binding protein that competes with the reference antibody for binding to human TREM2 will bind to the same or similar epitope as antibody 6E7 or any other antibodies 10E3, 13E7, 24F4, 4C5, 4G10 and 32E 3.

In some embodiments, a TREM2 agonist antigen binding protein competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID No. 62 and a heavy chain variable region comprising the sequence of SEQ ID No. 125. In such embodiments, an antigen binding protein that competes with the reference antibody for binding to human TREM2 will bind to the same or similar epitope as antibody 5E3 or any other antibodies 16B8, 26a10, 26C10, 26F2 and 33B 12.

In some embodiments, a TREM2 agonist antigen binding protein competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID No. 52 and a heavy chain variable region comprising the sequence of SEQ ID No. 115. In such embodiments, an antigen binding protein that competes with the reference antibody for binding to human TREM2 will bind to the same or similar epitope as antibody 24G6 or antibody 24a 10.

In some embodiments, a TREM2 agonist antigen binding protein competes for binding to human TREM2 with a reference antibody, wherein the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID No. 56 and a heavy chain variable region comprising the sequence of SEQ ID No. 119. In such embodiments, an antigen binding protein that competes with the reference antibody for binding to human TREM2 will bind to the same or similar epitope as antibody 25F 12.

In some embodiments, isolated nucleic acids encoding the anti-TREM 2 binding domains of the antigen binding proteins of the invention can be used to synthesize antigen binding proteins or to generate variants. In some embodiments, the polynucleotide may comprise a nucleotide sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to any of the nucleotide sequences listed in table 3G.

TABLE 3G exemplary anti-TREM 2 antibody variable region nucleic acid sequences

In some embodiments, the isolated nucleic acid encoding an anti-TREM 2 antibody light chain variable region comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to a sequence selected from the group consisting of SEQ ID NOS: 208-236 and 313-318. In certain embodiments, the isolated nucleic acid encoding the light chain variable region of an anti-TREM 2 antibody comprises a sequence selected from the group consisting of SEQ ID NOS 208-236 and 313-318. In related embodiments, the isolated nucleic acid encoding the heavy chain variable region of the anti-TREM 2 antibody comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to a sequence selected from the group consisting of SEQ ID NOS 237-264 and 319-325. In other related embodiments, the isolated nucleic acid encoding the heavy chain variable region of the anti-TREM 2 antibody comprises a sequence selected from the group consisting of SEQ ID NOS 237-264 and 319-325.

In some embodiments, the polynucleotide encodes a full length light chain and a full length heavy chain. Exemplary polynucleotide sequences are provided in table 3F.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody, e.g., anti-TREM 2 antibody "Ab-1". In some embodiments, the methods of the invention comprise administering to a human patient a liquid formulation as described herein.

As used herein, the terms "treat," "treating" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, or one or more symptoms of a disease or disorder, as described herein. In some embodiments, the treatment may be administered after one or more symptoms have developed. In other embodiments, the treatment may be administered without symptoms. For example, treatment may be administered to a susceptible individual prior to onset of symptoms (e.g., based on a history of symptoms and/or based on genetic or other susceptibility factors). Treatment may also be continued after the symptoms subside, for example, to prevent or delay recurrence thereof.

As used herein, a patient or subject in need of prevention, in need of treatment, or in need of treatment refers to a patient or subject that is able to reasonably benefit from a particular treatment or therapy at the discretion of an appropriate medical practitioner (e.g., doctor, nurse, or practitioner for humans; veterinarian for non-human mammals).

By "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent (such as an anti-TREM 2 antibody "Ab-1") is meant any amount of the drug, alone or in combination with another therapeutic agent, that is capable of protecting a patient or subject from the onset of a disease (such as ALSP), or promoting regression of the disease (as evidenced by a decrease in severity of symptoms of the disease, an increase in frequency and duration of periods of disease-free symptoms, or prevention of injury or disability due to the disease). The ability of a therapeutic agent to promote regression of a disease can be assessed using a variety of methods known to the skilled practitioner, such as a human subject during a clinical trial, an animal model system that predicts efficacy in humans, or by assaying the activity of the agent in an in vitro assay.

In preferred embodiments, a therapeutically effective amount of a drug (such as anti-TREM 2 antibody "Ab-1"), alone or in combination with another agent, can reduce the severity of at least one disease symptom, increase the frequency and duration of disease-free symptom periods, or prevent injury or disability due to the disease. Furthermore, the terms "effective" and "effectiveness" in relation to treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to reduce the severity of at least one symptom of a disease, increase the frequency and duration of periods of disease free symptoms, or prevent damage or disability caused by the disease in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse reactions) that develop at the cellular, organ and/or organism level following drug administration.

As used herein, the term "therapeutic benefit" or "benefit from therapy" refers to decreasing the severity of disease symptoms, increasing the frequency and duration of disease-free symptoms periods, or preventing injury or disability from the disease.

In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient by intravenous infusion. In some embodiments, intravenous infusion of anti-TREM 2 antibody "Ab-1" is up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2 hours, or up to about 60 minutes. In some embodiments, the intravenous infusion of the anti-TREM 2 antibody "Ab-1" is from about 5 minutes to about 5 hours, from about 5 minutes to about 4 hours, from about 5 minutes to about 3 hours, from about 5 minutes to about 2 hours, or from about 5 minutes to about 60 minutes. In some embodiments, the intravenous infusion of the anti-TREM 2 antibody "Ab-1" is about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 70 minutes, about 80 minutes, or about 90 minutes.

In some embodiments, the anti-TREM 2 antibody is administered to a human patient at a dose of up to about 200 mg/kg. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient at a dose of up to about 200 mg/kg. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient at a dose of up to about 150 mg/kg. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient at a dose of up to about 100 mg/kg. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient at a dose of about 1mg/kg to about 100mg/kg, about 1mg/kg to about 90mg/kg, about 1mg/kg to about 80mg/kg, about 1mg/kg to about 70mg/kg, or about 1mg/kg to about 60 mg/kg. In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient at a dose of about 10mg/kg to about 100mg/kg, about 10mg/kg to about 90mg/kg, about 10mg/kg to about 80mg/kg, about 10mg/kg to about 70mg/kg, about 10mg/kg to about 60mg/kg, about 10mg/kg to about 50mg/kg, about 10mg/kg to about 40mg/kg, about 10mg/kg to about 30mg/kg, or about 10mg/kg to about 20 mg/kg. In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient at a dose of about 20mg/kg to about 100mg/kg, about 20mg/kg to about 90mg/kg, about 20mg/kg to about 80mg/kg, about 20mg/kg to about 70mg/kg, about 20mg/kg to about 60mg/kg, about 20mg/kg to about 50mg/kg, about 20mg/kg to about 40mg/kg, or about 20mg/kg to about 30 mg/kg. In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient at a dose of about 30mg/kg to about 100mg/kg, about 30mg/kg to about 90mg/kg, about 30mg/kg to about 80mg/kg, about 30mg/kg to about 70mg/kg, about 30mg/kg to about 60mg/kg, about 30mg/kg to about 50mg/kg, or about 30mg/kg to about 40 mg/kg. In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient at a dose of about 40mg/kg to about 100mg/kg, about 40mg/kg to about 90mg/kg, about 40mg/kg to about 80mg/kg, about 40mg/kg to about 70mg/kg, about 40mg/kg to about 60mg/kg, or about 40mg/kg to about 50 mg/kg. In some embodiments, an anti-TREM 2 antibody (e.g., "Ab-1") is administered to a human patient at a dose of about 50mg/kg to about 100mg/kg, about 50mg/kg to about 90mg/kg, about 50mg/kg to about 80mg/kg, about 50mg/kg to about 70mg/kg, or about 50mg/kg to about 60 mg/kg. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient at a dose of about 1mg/kg, about 2mg/kg, about 3mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 55mg/kg, or about 60 mg/kg.

In some embodiments, the anti-TREM 2 antibody is administered to a human patient once daily, 1, 2,3 or 4 times weekly, or 1, 2,3 or 4 times monthly. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient once daily. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient 1, 2,3, or 4 times per week. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient 1, 2,3, or 4 times per month. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient once every 2 days, every 3 days, every 4 days, every 5 days, every 6 days, every 7 days, every 8 days, every 9 days, every 10 days, or every 14 days. In some embodiments, the anti-TREM 2 antibody "Ab-1" is administered to a human patient once a week.

In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of up to about 300 mg/mL. In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of up to about 250 mg/mL. In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of up to about 200 mg/mL. In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of up to about 150 mg/mL. In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of about 300mg/mL, about 250mg/mL, about 200mg/mL, about 180mg/mL, about 170mg/mL, about 160mg/mL, about 150mg/mL, about 140mg/mL, about 130mg/mL, about 120mg/mL, about 110mg/mL, or about 100 mg/mL. In some embodiments, the invention provides a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of about 140 mg/mL. In some embodiments, the methods of the invention comprise administering to a human patient a liquid formulation as described herein. In some embodiments, the methods of the invention comprise administering to a human patient a liquid formulation comprising anti-TREM 2 antibody "Ab-1" at a concentration of about 140 mg/mL.

In some embodiments, the patient is between 18 and 55 years old (inclusive). In some embodiments, the patient is between 18 and 42 years of age. In some embodiments, the patient is between 42 and 55 years of age. In some embodiments, the patient is 42 years of age or less. In some embodiments, the patient is 42 years old or older.

In some embodiments, the patient is not WOCBP (gestational women). In some embodiments, the patient is WOCBP using an effective contraceptive method during the course of treatment with an anti-TREM 2 antibody and for at least 10 weeks after treatment.

In some embodiments, the patient is a non-smoker (or other smoker of nicotine/tobacco (including e-cigarettes)) determined from a medical history (non-smoked nicotine in the past year). In some embodiments, the patient is negative for the urine cotinine test shortly before or at the time of receiving administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient has a Body Mass Index (BMI) between 18.5kg/m2 and 30.0kg/m2 (inclusive). In some embodiments, the patient is assessed for vital signs (systolic and diastolic blood pressure and pulse rate) shortly before or at the time of administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient is a first generation japanese ethnicity. In some embodiments, the patient is born in japan. In some embodiments, the patient's parents and grandparents are japanese ethnic and are born in japan. In some embodiments, the patient does not undergo a significant change in lifestyle since his departure from japan. In some embodiments, the patient resides outside of japan for less than 10 years.

In some embodiments, the patient has no history or evidence of cardiovascular, respiratory, liver, kidney, gastrointestinal, endocrine, neurological, immune, or psychiatric disorders in a clinical sense. In some embodiments, the patient does not receive monoclonal antibody therapy administration within 120 days prior to receiving anti-TREM 2 antibody "Ab-1". In some embodiments, the patient has no history of alcohol and/or illegal drug addiction within 2 years prior to receiving anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the patient is not positive for hepatitis b surface antigen (HBsAg), hepatitis c antibody, or Human Immunodeficiency Virus (HIV) antibody test.

In some embodiments, the patient does not test positive for urine ethanol shortly before or at the time of receiving administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient receives a urine drug (e.g., cocaine, amphetamines, barbiturates, opioids, benzodiazepines) shortly before or at the time of administration of the anti-TREM 2 antibody "Ab-1Class drugs and cannabinoids) or cotinine test to be non-positive.

In some embodiments, the patient is not a female patient who is nursing shortly before or at the time of receiving administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient is not a female patient who is positive for a serum pregnancy test shortly before or at the time of receiving administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient has no donated blood (> 500 mL) or blood product for 2 months (56 days) prior to receiving anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the patient does not receive any study drug administration within 30 days or 5 half-lives (whichever is longer) prior to receiving the anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the patient does not have a history of allergy to any therapeutic monoclonal antibody, or any excipient, or to a drug having a similar chemical structure.

In some embodiments, the patient is not positive for reverse transcription polymerase chain reaction (RT-PCR) test of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shortly before or at the time of administration of anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient does not have any clinical signs and symptoms consistent with a SARS-CoV-2 infection, e.g., fever, dry cough, dyspnea, sore throat, fatigue, or laboratory-confirmed acute SARS-CoV-2 infection, shortly before or at the time of receiving administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient does not have a severe course of 2019 coronavirus disease (COVID-19; extracorporeal membrane oxygenation, mechanical ventilation, intensive care unit hospitalization).

In some embodiments, the patient has not been recently exposed (within 14 days prior to receiving administration of anti-TREM 2 antibody "Ab-1") to a person with COVID-19 symptoms or positive for the SARS-CoV-2 test.

In some embodiments, the patient does not receive any COVID-19 treatment shortly before or at the time of receiving the anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the patient does not receive a final dose of COVID-19 vaccine within 14 days prior to administration of the anti-TREM 2 antibody "Ab-1" (i.e., they must complete vaccination at least 14 days prior to inclusion).

In some embodiments, the patient receives gene detection prior to administration of the anti-TREM 2 antibody "Ab-1". In some embodiments, the patient does not have an alanyl-tRNA synthetase 2 (AARS 2) gene mutation, e.g., as demonstrated by gene detection. In some embodiments, the patient has a colony stimulating factor 2 (CSF 1R) gene mutation, e.g., as confirmed by gene detection. In some embodiments, the patient has a mutation in an exon (e.g., exons 1-21) in the CSF1R gene. In some embodiments, the patient has a mutation in an exon (e.g., exons 2-17 or 18-21) in the CSF1R gene. In some embodiments, the patient has a sign or symptom of ALSP. Exemplary signs or symptoms of ALSP include cognitive impairment, frontal lobe dysfunction, psychotic symptoms, extrapyramidal symptoms, pyramidal symptoms, involuntary movements, gait disturbances, seizures, pathological reflexes, speech disturbances, swallowing disorders, speech disuse, sensory disturbances, autonomic symptoms, headaches, strokes, dementia, encephalitis, memory loss, depression, executive function loss, bradykinesia, stiffness, and cerebellar symptoms.

In some embodiments, the patient exhibits a ALSP reduction in symptoms following administration of the anti-TREM 2 antibody "Ab-1". In some embodiments, for example, the patient exhibits a decrease in severity of ALSP symptoms after administration of the anti-TREM 2 antibody "Ab-1", e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, compared to the severity of symptoms without administration of the anti-TREM 2 antibody "Ab-1".

In some embodiments, the patient receives CSF collection by lumbar puncture shortly before, at the time of, or after receiving anti-TREM 2 antibody "Ab-1" administration. In some embodiments, the patient receives CSF collection by lumbar puncture shortly before, at the time of, or after receiving the first dose of anti-TREM 2 antibody "Ab-1". In some embodiments, the patient receives CSF collection by lumbar puncture shortly before, at the time of, or after receiving the second dose of anti-TREM 2 antibody "Ab-1". In some embodiments, the patient receives CSF collection by lumbar puncture shortly before, at the time of, or after receiving the third dose of anti-TREM 2 antibody "Ab-1". In some embodiments, the patient does not receive CSF collection by lumbar puncture, wherein the patient is allergic to anesthetic or derivative used during CSF collection or any drug used to perform the lumbar puncture region. In some embodiments, the patient does not receive CSF collection by lumbar puncture, wherein the patient has already performed CSF collection within 30 days prior to receiving anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the patient does not receive CSF collection by lumbar puncture, wherein the patient has a history of spinal deformity, significant lumbar back surgery, clinically significant back pain, clinically significant abnormal X-rays, and/or injury.

In some embodiments, the patient does not receive CSF collection by lumbar puncture, wherein the patient has a persistent skin infection at the lumbar puncture injection site.

In some embodiments, the patient does not receive CSF collection by lumbar puncture, wherein the patient has a clinically significant coagulation test value outside of the normal reference range (prothrombin time/international normalized ratio, partial thromboplastin time) shortly before or at the time of receiving anti-TREM 2 antibody "Ab-1" administration.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 60 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 50 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 45 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 40 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 35 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 30 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 25 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 20 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 15 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 10 minutes.

In some embodiments, the invention provides a method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 60mg/kg, about 50mg/kg, about 40mg/kg, about 30mg/kg, about 20mg/kg, about 10mg/kg, about 5mg/kg, about 3mg/kg, about 2mg/kg, or about 1mg/kg, wherein the duration of the intravenous infusion is about 5 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 60 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 50 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 45 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 40 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 35 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 30 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 25 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 20 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 15 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 10 minutes.

In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient an anti-TREM 2 antibody "Ab-1" by intravenous infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700mg, about 350mg, about 210mg, about 140mg, or about 70mg, wherein the duration of the intravenous infusion is about 5 minutes.

In some embodiments, the invention provides a method of reducing the level of sTREM2 in a subject, the method comprising administering to the subject an anti-sTREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg. In some embodiments, the level of sTREM2 is assessed prior to administration of VGL101. In some embodiments, the level of sTREM2 is a level in cerebrospinal fluid (CSF). In some embodiments, the level of sTREM2 is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

In some embodiments, the method comprises administering to the subject a dose of about 1mg/kg to 75mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering to the human patient a dose of about 1mg/kg to 60mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering to the human patient a dose of about 1mg/kg to 50mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-40 mg/kg. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient once a week.

In some embodiments, the invention provides a method of reducing the level of sCSF R in a subject, the method comprising administering to the subject an anti-TREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg. In some embodiments, the level of sCSF R is assessed prior to administration of VGL101. In some embodiments, the level of sCSF R is a level in cerebrospinal fluid (CSF). In some embodiments, the level of sCSF R is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

In some embodiments, the invention provides a method of binding or stimulating TREM2 in a subject, the method comprising administering to the subject an anti-TREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg. In some embodiments, the method comprises administering to the subject a dose of about 1mg/kg to 75mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering to the human patient a dose of about 1mg/kg to 60mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering to the human patient a dose of about 1mg/kg to 50mg/kg of the anti-TREM 2 antibody. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-40 mg/kg. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg. In some embodiments, the method comprises administering the anti-TREM 2 antibody to the human patient once a week.

Liquid preparation

In some embodiments, the invention provides a liquid formulation comprising an anti-TREM 2 antibody "Ab-1" and a pharmaceutically acceptable excipient (e.g., buffer) and/or carrier (e.g., water). The amount of anti-TREM 2 antibody "Ab-1" in the liquid formulation of the invention is such that the antibody is effective to measurably inhibit TREM2 or a mutant thereof in a patient. In certain embodiments, the liquid formulations of the present invention are formulated for administration to a patient in need of such compositions. In some embodiments, the compositions of the invention are formulated for parenteral (e.g., intravenous) administration to a patient.

In some embodiments, the liquid formulations of the present invention comprise anti-TREM 2 antibody "Ab-1" at a concentration of about 50mg/mL to about 250 mg/mL. In some embodiments, the liquid formulations of the present invention comprise anti-TREM 2 antibody "Ab-1" at a concentration of about 70mg/mL to about 230mg/mL, about 90mg/mL to about 210mg/mL, about 100mg/mL to about 200mg/mL, about 120mg/mL to about 180mg/mL, about 120mg/mL to about 160mg/mL, or about 130mg/mL to about 150 mg/mL. In some embodiments, the liquid formulations of the present invention comprise anti-TREM 2 antibody "Ab-1" at a concentration of about 80mg/mL, about 90mg/mL, about 100mg/mL, about 110mg/mL, about 120mg/mL, about 130mg/mL, about 140mg/mL, about 150mg/mL, about 160mg/mL, about 170mg/mL, about 180mg/mL, about 190mg/mL, or about 200 mg/mL. In some embodiments, the liquid formulation of the present invention comprises anti-TREM 2 antibody "Ab-1" at a concentration of about 135mg/mL, about 136mg/mL, about 137mg/mL, about 138mg/mL, about 139mg/mL, about 140mg/mL, about 141mg/mL, about 142mg/mL, about 143mg/mL, about 144mg/mL, or about 145 mg/mL.

In some embodiments, the liquid formulation of the present invention comprises sodium acetate. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 5mM to about 25 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 6mM to about 24mM, about 7mM to about 23mM, about 8mM to about 22mM, about 9mM to about 21mM, about 10mM to about 20mM, about 11mM to about 19mM, about 12mM to about 18mM, about 13mM to about 17mM, or about 14mM to about 16 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 10mM, about 11mM, about 12mM, about 13mM, about 14mM, about 15mM, about 16mM, about 17mM, about 18mM, about 19mM, or about 20 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 14.5mM, about 14.6mM, about 14.7mM, about 14.8mM, about 14.9mM, about 15mM, about 15.1mM, about 15.2mM, about 15.3mM, about 15.4mM, or about 15.5 mM.

In some embodiments, the liquid formulation of the present invention comprises sucrose. In some embodiments, the liquid formulation of the present invention comprises sucrose at a concentration of about 4% to about 14% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise sucrose at a concentration of about 5% to about 13%, about 6% to about 12%, about 7% to about 11%, or about 8% to about 10% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulation of the present invention comprises sucrose at a concentration of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulation of the present invention comprises sucrose at a concentration of about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, or about 9.5% (w/v) of the total liquid formulation volume.

In some embodiments, the liquid formulations of the present invention comprise polysorbate 80. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80 at a concentration of about 0.005% to about 0.015% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80 at a concentration of about 0.006% to about 0.014%, about 0.007% to about 0.013%, about 0.008% to about 0.012%, or about 0.009% to about 0.011% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulation of the present invention comprises polysorbate 80 at a concentration of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, or about 0.015% (w/v) of the total liquid formulation volume.

In some embodiments, the liquid formulation of the present invention has a pH of about 4.4 to about 6.0. In some embodiments, the liquid formulations of the present invention have a pH of about 4.4 to about 6.0, about 4.5 to about 5.9, about 4.6 to about 5.8, about 4.7 to about 5.7, about 4.8 to about 5.6, about 4.9 to about 5.5, about 5.0 to about 5.4, or about 5.1 to about 5.3. In some embodiments, the liquid formulation of the present invention is about pH4.8, about pH 4.9, about pH 5.0, about pH 5.1, about pH 5.2, about pH 5.3, about pH 5.4, about pH 5.5, or about pH 5.6. In some embodiments, the liquid formulation of the present invention is about pH 5.16, about pH 5.17, about pH 5.18, about pH 5.19, about pH 5.20, about pH 5.21, about pH 5.22, about pH 5.23, or about pH 5.24.

In certain embodiments, the liquid formulations of the present invention comprise anti-TREM 2 antibody "Ab-1" at a concentration of about 140 mg/mL. In some embodiments, the liquid formulation of the present invention comprises sodium acetate at a concentration of about 15 mM. In some embodiments, the liquid formulation of the present invention comprises sucrose at a concentration of about 9% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulation of the present invention comprises polysorbate 80 at a concentration of about 0.01% (w/v) of the total liquid formulation volume. In some embodiments, the liquid formulation of the present invention is at about pH 5.2.

In certain embodiments, the present invention provides a liquid formulation comprising:

anti-TREM 2 antibody "Ab-1" at a concentration of about 140 mg/mL;

sodium acetate at a concentration of about 15 mM;

sucrose at a concentration of about 9% (w/v) of the total liquid formulation volume;

polysorbate 80 at a concentration of about 0.01% (w/v) of the total liquid formulation volume; and

PH of about 5.2.

The liquid formulations of the present invention may be administered parenterally in the form of liquid formulations by injection, infusion or implantation (intravenous, intramuscular, subcutaneous, etc.), or by suitable delivery devices or implants containing conventional, non-toxic pharmaceutically acceptable carriers and adjuvants.

If necessary, the liquid formulation may further comprise a solubilizing agent. The components of the formulation may be present alone or mixed together in unit dosage form, for example in dry lyophilized powder (which may be reconstituted with a carrier such as saline prior to use) or in concentrated solution in a sealed container such as an ampoule or sachet, and the amount of active agent indicated. If the composition is administered by infusion, an infusion bottle or bag containing sterile pharmaceutical grade water or saline may be used to dispense the composition. When the formulation is administered by injection, an ampoule of sterile water or saline may be provided so that the ingredients may be mixed prior to injection.

The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils (such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. Proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size of the dispersion and/or by the use of surfactants. In many cases, it will be preferable to include an isotonic agent, for example, sugar or sodium chloride. In a preferred aspect, water is added to the liquid formulation of the present invention.

Solutions and dispersions of the active compounds can be prepared as the free acid or free base or a pharmacologically acceptable salt thereof in water or another solvent or dispersion medium suitably mixed with one or more pharmaceutically acceptable excipients including, but not limited to, buffers, surfactants, dispersants, emulsifiers, viscosity modifiers and combinations thereof.

Suitable surfactants may be anionic, cationic, zwitterionic or nonionic. Suitable anionic surfactants include, but are not limited to, anionic surfactants containing carboxylate, sulfonate, and sulfate ions. Examples of the anionic surfactant include sodium, potassium, ammonium salts of long-chain alkyl sulfonic acids and alkylaryl sulfonic acids, such as sodium dodecylbenzene sulfonate; sodium dialkylsulfosuccinates, such as sodium dodecylbenzenesulfonate; sodium dialkylsulfosuccinates, such as sodium bis- (2-ethylsulfinyl) -sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and cocoamine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glycerol monostearate, glycerol stearate, polyglycerol-4-oleate, sorbitan acylate, sucrose acylate PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether,401. Stearoyl monoisopropanolamide and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl- β -alanine, sodium N-dodecyl- β -iminodipropionate, myristoyl amphoacetate, lauryl betaine, and lauryl sulfobetaine. The formulation may contain a preservative to prevent microbial growth. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain antioxidants to prevent degradation of the active agent.

Water-soluble polymers are commonly used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethyl cellulose, and polyethylene glycol.

Sterile injectable solutions can be prepared by: the desired amount of active compound is incorporated with one or more of the excipients listed above in an appropriate solvent or dispersion medium, if desired, and then filter sterilized. Generally, the dispersion is prepared by: the various sterilized active ingredients are incorporated into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those listed above. For sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any desired additional ingredient from a previously sterile-filtered solution thereof. The powder may be prepared in such a way that the particles are porous in nature, which may increase the dissolution of the particles. Methods for preparing porous particles are well known in the art.

In some embodiments, the liquid formulation of the present invention is mixed with an intravenous infusion vehicle. In some embodiments, the liquid formulation is mixed with a medium for injection, such as physiological saline (0.9% sodium chloride), 5% glucose (D5W), and ringer's lactate injection. In some embodiments, the present invention provides a liquid pharmaceutical composition prepared by: the liquid formulation of the present invention is mixed with water and then diluted with saline or 5% dextrose. In some embodiments, the liquid pharmaceutical composition is diluted into saline or 5% dextrose intravenous bag for intravenous administration. In some embodiments, the saline or the liquid pharmaceutical composition in a 5% dextrose intravenous bag may be stored at room temperature (about 20 ℃ -25 ℃) for up to about 4 hours prior to intravenous administration. In some embodiments, the saline or the liquid pharmaceutical composition in the 5% dextrose intravenous bag may be stored under refrigerated (about 2 ℃ -8 ℃) conditions for up to about 20 hours prior to intravenous administration. In some embodiments, the liquid pharmaceutical composition in a saline or 5% dextrose intravenous bag is administered intravenously, and may be stored for up to about 20 hours under refrigerated (about 2℃ -8℃) conditions, followed by up to about 4 hours at room temperature (about 20℃ -25℃).

It will also be appreciated that the specific dosage and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the particular compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the particular disease undergoing therapy.

Detailed description of the illustrated embodiments

The disclosure herein is further provided in a non-limiting list of numbered embodiments.

1. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 1mg/kg to 100 mg/kg.

2. The method of embodiment 1, wherein the anti-TREM 2 antibody comprises a light chain variable region comprising CDRL1 having an amino acid sequence according to SEQ ID No.2 and a heavy chain variable region; CDRL2 having an amino acid sequence according to SEQ ID NO. 3; and CDRL3 having an amino acid sequence according to SEQ ID No. 4, said heavy chain variable region comprising CDRH1 having an amino acid sequence according to SEQ ID No. 6; CDRH2 having an amino acid sequence according to SEQ ID NO. 7; and CDRH3 having an amino acid sequence according to SEQ ID NO. 8.

3. The method of any one of the preceding embodiments, wherein the anti-TREM 2 antibody comprises a light chain variable region having an amino acid sequence according to SEQ ID No.1 and a heavy chain variable region having an amino acid sequence according to SEQ ID No. 5.

4. The method of any one of the preceding embodiments, wherein the anti-TREM 2 antibody is IgG, optionally IgG ₁.

5. The method of any one of the preceding embodiments, wherein the anti-TREM 2 antibody comprises a kappa light chain constant region.

6. The method of any one of the preceding embodiments, wherein the anti-TREM 2 antibody is IgG ₁, the IgG1 comprising a variant constant region having one or more mutations selected from the group consisting of: R292C, N297G, V302C, D E or L358M according to EU numbering.

7. The method of any one of the preceding embodiments, wherein the anti-TREM 2 antibody is an anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID No. 9, and a heavy chain having the amino acid sequence of SEQ ID No. 10.

8. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 1mg/kg-75mg/kg of the anti-TREM 2 antibody.

9. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 1mg/kg-60mg/kg of the anti-TREM 2 antibody.

10. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 1mg/kg-50mg/kg of the anti-TREM 2 antibody.

11. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 1mg/kg-40mg/kg of the anti-TREM 2 antibody.

12. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 10mg/kg-60mg/kg of the anti-TREM 2 antibody.

13. The method of any one of embodiments 1-7, comprising administering to the human patient a dose of about 20mg/kg-40mg/kg of the anti-TREM 2 antibody.

14. The method of any one of embodiments 1-7, wherein the method comprises administering to the human patient a dose of the anti-TREM 2 antibody of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

15. The method of any one of embodiments 1 to 14, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once a week.

16. The method of any one of embodiments 1 to 14, wherein the method comprises administering the anti-TREM 2antibody to the human patient once every two weeks.

17. The method of any one of embodiments 1 to 14, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once a month.

18. The method of any one of embodiments 1 to 17, wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion.

19. The method of embodiment 18, wherein the intravenous infusion of the anti-TREM 2 antibody is between 1 and 4 hours, e.g., about 4 hours, 3 hours, 2 hours, about 60 minutes, about 45 minutes, about 30 minutes.

20. A liquid formulation comprising anti-TREM 2 antibody VGL101 at a concentration of about 140mg/mL, and a pharmaceutically acceptable excipient and/or carrier.

21. The liquid formulation of embodiment 20, further comprising sodium acetate at a concentration of about 15mM.

22. The liquid formulation of embodiment 20 or embodiment 21, further comprising sucrose at a concentration of about 9% (w/v) of the total liquid formulation volume.

23. The liquid formulation of any one of embodiments 20-22, further comprising polysorbate 80 at a concentration of about 0.01% (w/v) of the total liquid formulation volume.

24. The liquid formulation of any one of embodiments 20-23, wherein the liquid formulation is about pH 5.2.

25. A liquid formulation at about pH 5.2, the liquid formulation comprising:

anti-TREM 2 antibody VGL101 at a concentration of about 140 mg/mL;

sodium acetate at a concentration of about 15 mM;

sucrose at a concentration of about 9% (w/v) of the total liquid formulation volume; and

Polysorbate 80 at a concentration of about 0.01% (w/v) of the total liquid formulation volume.

26. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a liquid formulation as in any one of embodiments 20-25.

27. The method of embodiment 26, wherein the method comprises administering to the human patient a dose of about 1mg/kg to 60mg/kg of anti-TREM 2 antibody VGL101.

28. The method of embodiment 26, wherein the method comprises administering to the human patient a dose of about 20mg/kg to 40mg/kg of anti-TREM 2 antibody VGL101.

29. The method of embodiment 26, wherein the method comprises administering to the human patient a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40mg/kg of anti-TREM 2 antibody VGL101.

30. The method of any one of embodiments 26-29, wherein the method comprises administering to the human patient the anti-TREM 2 antibody VGL101 once a week.

31. The method of any one of embodiments 26-29, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once every two weeks.

32. The method of any one of embodiments 26-29, wherein the method comprises administering the anti-TREM 2antibody to the human patient once a month.

33. The method of any one of embodiments 26 to 32, wherein the method comprises administering an anti-TREM 2 antibody VGL101 to the human patient by intravenous infusion.

34. The method of embodiment 33, wherein the intravenous infusion of anti-TREM 2 antibody VGL101 is about 60 minutes.

35. A method of reducing the level of sTREM2 in a subject, the method comprising administering to the subject an anti-sTREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg.

36. The method of embodiment 35, wherein the level of sTREM2 is assessed prior to administration of VGL 101.

37. The method of embodiment 35 or embodiment 36, wherein the level of sTREM2 is a level in cerebrospinal fluid (CSF).

38. The method of embodiment 35 or embodiment 36, wherein said level of sTREM2 is a level in serum.

39. The method of any one of embodiments 35 to 38, wherein the level of sTREM2 is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

40. The method of any one of embodiments 35 to 39, wherein the method comprises administering to the subject a dose of about 1mg/kg-75mg/kg of the anti-TREM 2 antibody.

41. The method of any one of embodiments 35 to 39, comprising administering to the human patient a dose of about 1mg/kg-60mg/kg of the anti-TREM 2 antibody.

42. The method of any one of embodiments 35 to 39, comprising administering to the human patient a dose of about 1mg/kg-50mg/kg of the anti-TREM 2 antibody.

43. The method of any one of embodiments 35 to 39, comprising administering to the human patient a dose of about 1mg/kg-40mg/kg of the anti-TREM 2 antibody.

44. The method of any one of embodiments 35 to 39, comprising administering to the human patient a dose of about 10mg/kg-60mg/kg of the anti-TREM 2 antibody.

45. The method of any one of embodiments 35 to 39, comprising administering to the human patient a dose of about 20mg/kg-40mg/kg of the anti-TREM 2 antibody.

46. The method of any one of embodiments 35 to 39, wherein the method comprises administering to the human patient a dose of the anti-TREM 2 antibody of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

47. The method of any one of embodiments 35 to 46, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once a week.

48. The method of any one of embodiments 35 to 46, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once every two weeks.

49. The method of any one of embodiments 35 to 46, wherein the method comprises administering the anti-TREM 2antibody to the human patient once a month.

50. The method of any one of embodiments 35 to 49, wherein the method comprises administering an anti-TREM 2 antibody VGL101 to the human patient by intravenous infusion.

51. The method of embodiment 50, wherein the intravenous infusion of anti-TREM 2 antibody VGL101 is about 60 minutes.

52. A method of reducing the level of sCSF R in a subject, the method comprising administering to the subject an anti-TREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg.

53. The method of embodiment 52, wherein the level of sCSF R is assessed prior to administration of VGL 101.

54. The method of embodiment 52 or embodiment 53, wherein said level of sCSF R is a level in cerebrospinal fluid (CSF).

55. The method of embodiment 52 or embodiment 53, wherein said level of sCSF R is a level in serum.

56. The method of any one of embodiments 52 to 55, wherein the level of sCSF R is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

57. The method of any one of embodiments 52 to 56, wherein the method comprises administering to the subject a dose of about 1mg/kg-75mg/kg of the anti-TREM 2 antibody.

58. The method of any one of embodiments 52 to 56, comprising administering to the human patient a dose of about 1mg/kg-60mg/kg of the anti-TREM 2 antibody.

59. The method of any one of embodiments 52 to 56, comprising administering to the human patient a dose of about 1mg/kg-50mg/kg of the anti-TREM 2 antibody.

60. The method of any one of embodiments 52 to 56, comprising administering to the human patient a dose of about 1mg/kg-40mg/kg of the anti-TREM 2 antibody.

61. The method of any one of embodiments 52 to 56, comprising administering to the human patient a dose of about 10mg/kg-60mg/kg of the anti-TREM 2 antibody.

62. The method of any one of embodiments 52 to 56, comprising administering to the human patient a dose of about 20mg/kg-40mg/kg of the anti-TREM 2 antibody.

63. The method of any one of embodiments 52 to 56, wherein the method comprises administering to the human patient a dose of the anti-TREM 2 antibody of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

64. The method of any one of embodiments 52 to 63, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once a week.

65. The method of any one of embodiments 52 to 63, wherein the method comprises administering the anti-TREM 2 antibody to the human patient once every two weeks.

66. The method of any one of embodiments 52 to 63, wherein the method comprises administering the anti-TREM 2antibody to the human patient once a month.

67. The method of any one of embodiments 52 to 66, wherein the method comprises administering an anti-TREM 2 antibody VGL101 to the human patient by intravenous infusion.

68. The method of embodiment 67, wherein the intravenous infusion of anti-TREM 2 antibody VGL101 is about 60 minutes.

69. A method of binding or stimulating TREM2 in a subject, the method comprising administering an anti-TREM 2 antibody VGL101 to the subject at a dose of about 1mg/kg to 100 mg/kg.

70. The method of embodiment 69, wherein the method comprises administering to the subject a dose of about 1mg/kg to 75mg/kg of the anti-TREM 2 antibody.

71. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-60 mg/kg.

72. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-50 mg/kg.

73. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-40 mg/kg.

74. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 10mg/kg-60 mg/kg.

75. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 20mg/kg-40 mg/kg.

76. The method of embodiment 69, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

77. The method of any one of embodiments 69 to 76 wherein the method comprises administering the anti-TREM 2 antibody to the human patient weekly.

78. The method of any one of embodiments 69 to 76 wherein the method comprises administering the anti-TREM 2 antibody to the human patient once every two weeks.

79. The method of any one of embodiments 69 to 76 wherein the method comprises administering the anti-TREM 2antibody to the human patient once a month.

80. The method of any one of embodiments 69 to 79, wherein the method comprises administering to the human patient an anti-TREM 2 antibody VGL101 by intravenous infusion.

81. The method of embodiment 80, wherein the intravenous infusion of anti-TREM 2 antibody VGL101 is about 60 minutes.

82. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof an anti-TREM 2 antibody at a dose of about 20mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID NO 9 and a heavy chain having the amino acid sequence of SEQ ID NO 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

83. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof an anti-TREM 2 antibody at a dose of about 30mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID NO 9 and a heavy chain having the amino acid sequence of SEQ ID NO 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

84. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof an anti-TREM 2 antibody at a dose of about 40mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID NO 9 and a heavy chain having the amino acid sequence of SEQ ID NO 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

85. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof an anti-TREM 2 antibody at a dose of about 50mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID NO 9 and a heavy chain having the amino acid sequence of SEQ ID NO 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

86. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof an anti-TREM 2 antibody at a dose of about 60mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID NO 9 and a heavy chain having the amino acid sequence of SEQ ID NO 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

87. A method of reducing the level of sCSF R in a subject, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 20mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprises a light chain having the amino acid sequence of SEQ ID NO:9 and a heavy chain having the amino acid sequence of SEQ ID NO:10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

88. A method of reducing the level of sCSF R in a subject, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 30mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprises a light chain having the amino acid sequence of SEQ ID NO:9 and a heavy chain having the amino acid sequence of SEQ ID NO:10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

89. A method of reducing the level of sCSF R in a subject, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 40mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprises a light chain having the amino acid sequence of SEQ ID NO:9 and a heavy chain having the amino acid sequence of SEQ ID NO:10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

90. A method of reducing the level of sCSF R in a subject, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 50mg/kg, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprises a light chain having the amino acid sequence of SEQ ID NO:9 and a heavy chain having the amino acid sequence of SEQ ID NO:10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

91. A method of reducing the level of sCSF R in a subject, wherein the anti-TREM 2 antibody is anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID No. 9, and a heavy chain having the amino acid sequence of SEQ ID No. 10, and wherein the method comprises administering the anti-TREM 2 antibody to the human patient by intravenous infusion once every 28 days.

Example(s)

Anti-TREM 2 antibodies, such as "Ab-1", may be prepared by any method known to those of ordinary skill in the art, for example, as described in WO2018/195506A1, the contents of which are incorporated herein by reference in their entirety.

Abbreviation form

Λz: terminal elimination rate constant

AE: adverse events

AL: p alkaline phosphatase

ALSP: axonal globular degeneration and pigmentary glial cells

ALT: alanine aminotransferase

APOE: apolipoprotein E

AST: aspartate aminotransferase

AUC0-inf: area under serum or CSF concentration-time curve derived from pre-dose (time 0) to infinite time (auclast+ Clast/λz)

AUC0-last: area under the serum or CSF concentration-time curve from pre-dose (time 0) to time of last quantifiable concentration (tlast)

Aucta: area under serum or CSF concentration-time curve over dosing interval

AUMC: area under first moment curve

BMI: body mass index

CCL2: chemokine ligand 2

CFR: federal regulation assembly

CL: systemic clearance rate

Cmax is as follows: maximum serum/cerebrospinal fluid concentration

CNS: central nervous system

COVID-19:2019 coronavirus disease

CSF: cerebrospinal fluid

CSF1R: colony stimulating factor-1 receptor

CTR: report of clinical trial

C-SSRS: columbia suicide severity rating scale

Ctrough: concentration prior to dose administration

CV%: coefficient of variation%

ECG: electrocardiogram

ECRF: electronic case report form

ER: emergency room

EOS: end of study

FDA: united states food and drug administration

FIH: first time human body

FSH: follicle stimulating hormone

GCP: excellent clinical specifications

GLP: good laboratory specifications

HBsAg: hepatitis B surface antigen

HIV: human immunodeficiency virus

HSCT: hematopoietic stem cell transplantation

IB: manual of researcher

ICF: informed consent form

ICH: international coordination Condition

IL: interleukin

IMP: research medicine

IND: research of new drugs

IP-10:10kDa Interferon-gamma-inducible protein

IRB: institutional review board

IV: intravenous injection

MAD: multiple incremental doses

MCP-1: monocyte chemotactic protein-1

MDM: monocyte-derived macrophages

MedDRA: supervision activity medical dictionary

MRT: average residence time

N: number of observations

NfL: neurofilament light chain

NHP: non-human primate

NOAEL: no visible adverse reaction level

And (2) PCR: polymerase chain reaction

PD: pharmacodynamics of medicine

PI: first researcher

PK: pharmacokinetics of

PT: preferred terminology

Q7d: once every 7 days

RR: respiration rate

RoAUC0-tau: rate of accumulation, AUC0-tau (last dose) divided by AUC0-tau (first dose)

RoCmax: accumulation rate, cmax of the last dose divided by Cmax on day 1.

RT-PCR: reverse transcription polymerase chain reaction

SAD: single increment dose

SAE: serious adverse events

SAP (SAP): statistical analysis plan

SARS-CoV-2: severe acute respiratory syndrome coronavirus 2

SD: standard deviation of

SID: subject identification

SM: safety range

SOP: standard operating program

SRC: safety examination committee

T ¹/₂: terminal elimination half-life

Tmax: time to maximum serum/cerebrospinal fluid concentration

TREM2: trigger receptor 2 expressed on myeloid cells

Vss: steady state distribution volume

Vz: distribution volume

WHO: world health organization

WOCBP: pregnant women

Example 1A phase 1, first human, randomized, double-blind, placebo-controlled, single-and multiple-escalated intravenous dose study to evaluate the safety, tolerability and pharmacokinetics of the anti-TREM 2 antibody "Ab-1" in healthy adults

1. The object is:

mainly:

Determining safety and tolerability of anti-TREM 2 antibody "Ab-1" in healthy adult participants at single and multiple increasing Intravenous (IV) doses

Secondary:

Characterization of Single and Multi-dose serum Pharmacokinetic (PK) of intravenous anti-TREM 2 antibody "Ab-1" in healthy adult participants

Evaluating the immunogenicity of single and multiple increasing intravenous doses of anti-TREM 2 antibody "Ab-1" in healthy adult participants

The pharmacokinetics of the anti-TREM 2 antibody "Ab-1" in cerebrospinal fluid (CSF) was evaluated after single and multiple doses.

Exploratory:

research of Pharmacodynamic (PD) biomarkers in serum and CSF, providing a reference for the mechanism of action of the anti-TREM 2antibody "Ab-1" for future development

Investigation of whether the apolipoprotein E4 genotype produces a differential response against the anti-TREM 2 antibody "Ab-1

Determining safety and tolerability of the anti-TREM 2 antibody "Ab-1" in healthy Japanese adult participants at single increasing intravenous doses

Characterization of single dose pharmacokinetics of intravenous anti-TREM 2 antibody "Ab-1" in healthy japanese adult participants.

2. And (3) design:

This is a2 part, first human (FIH), phase 1, randomized, single-center, double-blind (sponsored open), placebo-controlled, dose escalation study that evaluates the safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics of the anti-TREM 2 antibody "Ab-1" administered intravenously to healthy adult participants.

Part a is a single incremental dose (SAD) study performed in approximately 40 healthy adult participants. The study included 5 queues (queue 1A to queue 5A). Part a evaluates single doses of anti-TREM 2 antibody "Ab-1" administered as intravenous infusion over 60 minutes at 5 different dose levels. Doses from cohorts 1A to 5A were 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg and 40mg/kg; the dosage may be adjusted based on the continuous evaluation. Two optional additional queues (queue 6A and queue 7A) may be optionally included, with the dose of queue 6A being below the maximum allowable exposure of 60mg/kg and queue 7A being a japanese queue. The dose during this portion of the study was determined by the sponsor as the study progressed. Safety, pharmacokinetic and pharmacodynamic data were assessed.

(A) Whistle dosing was planned for all SAD queues. The first 2 participants of each cohort will be randomly assigned and administered study treatment such that 1 participant receives the anti-TREM 2 antibody "Ab-1" and the other 1 participant receives placebo. The remaining 6 healthy adult participants were randomly assigned at a ratio of 5:1 (anti-TREM 2 antibody "Ab-1": placebo). The remaining 6 participants in the cohort were not administered study treatment until the investigator reviewed safety data up to 48 hours after dosing of the first 2 participants in each cohort. The cohorts were tested sequentially in dose escalation and the available pharmacokinetic/pharmacodynamic data and safety data for at least 7 days were reviewed before escalation to the next cohort. At least 6 participants per cohort should complete the last dose for at least 7 days to trigger an up-dosing safety audit; participants who stop or exit halfway will be decided by sponsors to replace.

(B) (optionally) for 36 hours of continuous CSF sample collection, participants of cohorts 2A-5A and optionally cohort 6A were indwelling catheter implanted in the lumbar subarachnoid space. The time points of CSF collection correspond to pharmacokinetic time points.

(C) The total study duration for each participant was approximately 113 days, including screening up to 28 days, inclusion (day-2) and baseline evaluation times, treatment period of 1 day, and 84 day follow-up period following day 1 visit until study End (EOS) visit.

Part B is a multiple increasing dose (MAD) study performed in approximately 16 healthy adult participants. Part B of the study plan included two queues (queue 1B and queue 2B). Cohorts 1B and 2B randomly distributed 8 healthy adult participants, receiving three intravenous administrations of anti-TREM 2 antibody "Ab-1" or placebo at a ratio of 6:2 during the study. Dosing of the anti-TREM 2 antibody "Ab-1" or placebo in part B was performed every 28 days, assuming a total of 3 infusions were required to reach steady state. Optional cohort 3B may be included concurrently with cohort 2B, including 6 participants, all receiving intravenous administration of anti-TREM 2 antibody "Ab-1" (at or below the dose selected for cohort 2B). Participants in cohort 3B received prolonged CSF collection by lumbar puncture on day 1 (pre-dose), 58/59, 64 (day 63 inclusion), 85 (day 84 inclusion) and 103 (day 102 inclusion). An additional cohort (cohort 4B) may be optionally included, wherein 8 participants received intravenous administration of anti-TREM 2 antibody "Ab-1" or placebo (60 mg/kg) at a 6:2 ratio. The dose during this portion of the study was determined as the study progressed. Safety, pharmacokinetic and pharmacodynamic data were assessed.

(A) Whistle dosing will not be used in part B of the study. The expected exposure levels in MAD have previously been shown in part a to be safe and well tolerated by healthy adult participants as a single dose. The cohorts were tested sequentially in dose escalation and the available pharmacokinetic/pharmacodynamic data and safety data for at least 7 days were reviewed before escalation to the next cohort. At least 6 participants per cohort should complete the last dose for at least 7 days to trigger an up-dosing safety audit; participants who stop or exit halfway will be decided by sponsors to replace.

(B) For CSF sample collection, all panellists received lumbar puncture on day 1 (pre-dose CSF collection) and on day 58/59 (between 24 and 48 hours after dose 3). Participants in cohort 3B received prolonged CSF collection by lumbar puncture,

As described above.

(C) The total study duration for each participant was approximately 169 days, including screening up to 28 days, inclusion (day-2) and baseline evaluation times, treatment period of 57 days, and 84 day follow-up period after the last dose visit (day 57) up to EOS visit.

Number of participants

Approximately 54 to 96 healthy adult participants were enrolled.

Part a:40 to 56 healthy adult participants

Approximately 40 healthy adult participants were divided into 5 dose cohorts. Another 16 healthy adult participants may be included in two additional optional queues. Including 8 japanese participants in queue 7A.

Part B:16 to 30 healthy adult participants

Approximately 16 healthy adult participants were divided into 2 dose cohorts. Another 14 healthy adult participants may be included in two additional optional queues.

Inclusion criteria:

participants meeting the following criteria were considered eligible to participate in the clinical study:

1. the participants voluntarily agree to participate in the study, and sign Institutional Review Board (IRB) -approved informed consent prior to any screening visit procedures.

2. At the screening visit, men and women between 18 and 55 years of age (inclusive).

3. Female participants were considered eligible if they met the reproductive inclusion criteria.

4. Urine cotinine detection negative is determined to be a non-smoker (or smoker using other nicotine/tobacco (including e-cigarettes)) based on medical history (no nicotine used in the past year) and screening visit and/or inclusion (day-2).

5. At the screening visit, the Body Mass Index (BMI) was between 18.5kg/m2 and 30.0kg/m2 (inclusive).

6. Health was determined by pre-study medical evaluations (medical history, physical examination, vital signs, 12 lead electrocardiogram [ ECG ] and clinical laboratory evaluations) as judged by the chief investigator (PI).

7. Vital signs (systolic and diastolic blood pressure and pulse rate) were assessed at screening visit and inclusion (day-2). If vital signs are out of range (at screening visit and inclusion [ day-2 ]), the researcher may obtain two additional vital sign groups. If each vital sign in these 3 consecutive assessments is out of range and the researcher decides to have clinical relevance, the participant is not eligible to participate in the study.

8. The following applies to the optional japanese participants in queue 7A: to meet the qualification of Japanese participants, the participants must meet the following criteria:

First generation japanese ethnic group:

Birth in Japan

Parents and grandparents are japanese ethnic and are born in japan

No significant change in lifestyle since leaving japan

Residing outside Japan for less than 10 years

Exclusion criteria

Participants meeting one or more of the following criteria were considered ineligible for participation in clinical studies:

1. the participant has a history or evidence of cardiovascular, respiratory, liver, kidney, gastrointestinal, endocrine, neurological, immune, or psychiatric disorders in a clinical sense as determined by PI or a designated person.

2. Participants had received monoclonal antibody therapy administration within 120 days prior to inclusion (day-2).

3. The participants suffer from any concurrent diseases or disorders that, from the PI point of view, render the participants unsuitable for participation in clinical studies.

4. Participants had a history of alcohol and/or illegal drug addiction within 2 years prior to inclusion.

5. The hepatitis B surface antigen (HBsAg), hepatitis C antibody or Human Immunodeficiency Virus (HIV) antibody of the participants tested positive.

6. Participants were positively tested for urine ethanol at screening visit or inclusion (day-2).

7. Participants on screening visit or inclusion (day-2) of urine drugs (e.g., cocaine, amphetamines, barbiturates, opioids, benzodiazepines)Class drug and cannabinoid) and cotinine tested positive.

8. Female participants who were lactating at screening visit or inclusion (day-2) or female participants who were positive for serum pregnancy test.

9. Participants donated blood (> 500 mL) or blood products within 2 months (56 days) prior to inclusion (day-2).

10. Participants had received study drug administration within 30 days or 5 half-lives (whichever is longer) prior to inclusion (day-2).

11. The participants had a history of allergy to the study drug, other therapeutic monoclonal antibodies or any excipients or to drugs with similar chemical structures.

12. The participants were unable to understand the protocol requirements, description and study-related limitations, nature, scope and possible consequences of the clinical study.

13. Participants are unlikely to comply with protocol requirements, description and study-related constraints, such as uncooperative attitudes, inability to return to follow-up, and impossibility to complete clinical studies.

14. Participants have previously included this clinical study.

15. The weaknesses of the participants defined as individuals willing to voluntarily participate in the clinical study may be unduly affected for the following reasons: the benefits associated with participation, whether rational or not, or the return to sexual response by higher-level members in the event of refusal of participation (e.g., by the caretaker, minor, and persons unable to give informed consent).

16. Participants were tested positive for reverse transcription polymerase chain reaction (RT-PCR) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prior to inclusion (day-2).

17. Participants had clinical signs and symptoms consistent with SARS-CoV-2 infection, e.g., fever, dry cough, dyspnea, sore throat, fatigue, or laboratory-confirmed acute SARS-CoV-2 infection.

18. Participants had severe courses of 2019 coronavirus disease (COVID-19; extracorporeal membrane oxygenation, mechanical ventilation, intensive care unit hospitalization).

19. Participants were recently exposed (within 14 days prior to inclusion in the [ day-2 ] clinical ward) to persons with COVID-19 symptoms or positive for SARS-CoV-2 detection.

20. Participants have recently (within 14 days prior to inclusion in the [ day-2 ] clinical ward) arrived at the medical facility for treating COVID-19 patients.

21. Participants had received the final dose of COVID-19 vaccines within 14 days prior to inclusion in the clinical ward (i.e., they had to complete vaccination at least 14 days prior to inclusion).

Exclusion criteria for CSF participants:

Participants meeting one or more of the following criteria are considered ineligible for CSF assessment:

22. Allergy to anesthetic or derivative used during CSF collection or any drug used to perform lumbar puncture area.

23. CSF collection was performed within 30 days prior to inclusion (day-2) in the clinical ward.

24. Have medical histories of spinal deformity, major lumbar back surgery, clinically significant back pain, clinically significant abnormal X-rays and/or injury that, from the point of view of the investigator, would prevent participants from participating in the study or CSF collection during the study.

25. There is a persistent skin infection at the lumbar puncture injection site.

26. At the time of screening, the blood coagulation test values of clinical significance are outside the normal reference range (prothrombin time/international normalized ratio, partial thromboplastin time).

Evaluation criteria:

the main end point is:

safety and tolerability of the anti-TREM 2 antibody "Ab-1", as assessed by Adverse Events (AEs), clinical laboratory tests, and vital sign measurements.

Secondary endpoint:

Single and multi-dose anti-TREM 2 antibody "Ab-1" serum pharmacokinetic parameters: for example, the area under the serum or CSF concentration-time curve (AUC 0-last) from the time before dosing (time 0) to the time of last quantifiable concentration (tlast), the area under the serum or CSF concentration-time curve (AUC 0-inf), maximum serum/cerebrospinal fluid concentration (Cmax), time of maximum serum/cerebrospinal fluid concentration (Tmax), terminal elimination half-life (t 1/2), systemic clearance, steady-state volume of distribution, mean residence time, area under the serum or CSF concentration-time curve within the dosing interval, concentration before dose administration, cumulative rate (Cmax of last dose divided by Cmax on day 1, and AUC0-tau [ last dose ] divided by AUC0-tau [ first dose ])

Shan Jiliang anti-TREM 2 antibody "Ab-1" csf pharmacokinetic parameters: for example, cmax, tmax, AUC0-inf, AUC0-last, λz, t1/2, and anti-TREM 2 antibody "Ab-1" CSF concentration at or after day 1 and day 58/59 after multi-dose administration

Characterization of anti-drug antibody levels following single and multiple dose administration of anti-TREM 2 antibody "Ab-1

Exploratory endpoint:

exploratory pharmacodynamic biomarkers in CSF and serum (e.g., trigger receptor 2[ sTREM2] biomarker expressed on soluble myeloid cells, 10kDa Interferon-gamma Induction protein [ IP-10], monocyte chemotactic protein-1 [ MCP-1], colony stimulating factor-1 receptor [ sCSF R ]), and change in neurofilament light chain [ NfL ]) from baseline

Reporting number and proportion of Japanese participants of AE/Serious Adverse Event (SAE) in dose cohorts receiving single doses

Single dose serum pharmacokinetic parameters of anti-TREM 2 antibody "Ab-1" of Japanese participants

The statistical method comprises the following steps:

Sample size considerations

The sample amount is selected according to clinical judgment, not based on statistical power calculation. No formal sample size calculation was performed. The number of participants was chosen based on feasibility and was considered sufficient to meet the study objectives.

Data presentation/descriptive statistics

All demographic, safety and pharmacokinetic/pharmacodynamic data are listed and appropriately tabulated using descriptive statistics by cohort, race and visit/time. Pharmacokinetic data (serum and CSF) are also suitably graphically displayed. The number and percentage of AEs are shown by system organ category and list of preferred terms and are subdivided by queue and race.

The result of the period:

SUMMARY

To date, the trial has included 82 healthy volunteers who received doses of 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg, 30mg/kg or 40mg/kg of the anti-TREM 2 antibody "Ab-1" (n=68) or placebo (n=14). The anti-TREM 2 antibody "Ab-1" was found to be safe and well tolerated in both SAD and MAD cohorts of administration.

All Adverse Events (AEs) were mild in severity except for one moderate AE, and all AEs were resolved without intervention. To date, no serious adverse events have been reported.

The anti-TREM 2 antibody "Ab-1" shows dose-proportional pharmacokinetics with good half-life and brain permeability.

The anti-TREM 2 antibody "Ab-1" achieved a dose-dependent, sustained decrease in the level of sTREM2 in cerebrospinal fluid (CSF), demonstrating evidence of target binding. Repeated dosing of 20mg/kg correlated with a substantial decrease in the levels of sTREM2, and a decrease was still observed 28 days after the third and final doses. The anti-TREM 2 antibody "Ab-1" is the first antibody reported to exhibit TREM2 binding persistence in a clinical setting.

Anti-TREM 2 antibody "Ab-1" showed a persistent increase in sCSF R levels in CSF following repeated dosing.

Dose escalation was continued in phase 1 trials conducted in healthy volunteers and was approved to initiate a 60mg/kg cohort in australia.

In each double blind cohort, 8 subjects were randomly assigned to receive a single intravenous administration of 1mg/kg, 3mg/kg, 10mg/kg, 20mg/kg, 30mg/kg, or 40mg/kg of anti-TREM 2 antibody "Ab-1" or placebo in the SAD fraction, and 20mg/kg of anti-TREM 2 antibody "Ab-1" or placebo every 28 days in the MAD cohort for a total of three administrations. In addition, for collection of CSF, the open label portion of the assay is in progress. There are preliminary safety and tolerability data for one CSF SAD cohort (single intravenous dose of VGL101 receiving 3mg/kg, 10mg/kg or 20 mg/kg) and one CSF MAD cohort (VGL 101 receiving 20mg/kg once every 28 days for a total of three drug administrations).

Safety and tolerability

In each queue, all AEs were mild except one moderate AE, and all AEs were resolved without intervention. There is no report of Severe AE (SAE) or clinically significant abnormalities in vital signs, ECG or laboratory parameters.

Single increment dose Pharmacokinetics (PK)

Figure 1 shows serum pharmacokinetic data for SAD cohorts. Dosages up to 30mg/kg over 28 days and 1mg/kg, 3mg/kg, 10mg/kg and 20mg/kg over 84 days have been evaluated. All available doses up to 30mg/kg showed linear and dose-proportional pharmacokinetics with low variation.

Multiple ascending dose Pharmacokinetics (PK)

FIG. 2 shows serum pharmacokinetic data from the first MAD cohort, with 20mg/kg of the anti-TREM 2 antibody "Ab-1" administered once every 28 days for a total of three infusions. The data indicate that half-life is about 27 days and that steady state is achieved between dose 3 and dose 4, which supports a monthly dosing regimen.

The brain permeability of the anti-TREM 2 antibody "Ab-1" was between 0.1% and 0.2%.

Pharmacodynamics of medicine

From preclinical studies, reduced levels of soluble TREM2 (sTREM 2) (a proximal biomarker for TREM2 receptor binding) were predicted. FIG. 3A shows the effect of anti-TREM 2 antibody "Ab-1" on CSF sTREM2 in 18 healthy volunteers (receiving a single intravenous dose of 3mg/kg, 10mg/kg and 20mg/kg of anti-TREM 2 antibody "Ab-1"). sTREM2 exhibited a dose-dependent decrease relative to baseline, and the sTREM2 decrease was statistically significant 2 weeks after the single doses of 10mg/kg and 20mg/kg of the anti-TREM 2 antibody "Ab-1".

FIG. 3B shows the effect of anti-TREM 2 antibody "Ab-1" on sTREM2 after 3 intravenous doses of 20mg/kg (administered once every 28 days). CSF levels of sTREM2 were assessed at baseline (pre-dose), at dose 3, and 48 hours and 28 days post-final dose. These data show that following repeated dosing of 20mg/kg of anti-TREM 2 antibody "Ab-1", the reduction in sTREM2 from the pre-dosing baseline was statistically significant, and notably the reduction was greater in magnitude and less variable than the single dose at the 48 hour time point. Similarly, the sTREM2 reduction was maintained for 28 days after dose 3 and final dose, and the change was smaller compared to single dose. These data can be used as persistence of target binding in humans after repeated dosing of the anti-TREM 2 antibody "Ab-1" for 28 days.

Soluble CSF1R (sCSF R) is another biomarker of target engagement downstream of sTREM2 and microglial activation. From preclinical data, increased sCSF R levels in CSF are expected. Figures 4A-4B show the increase in sCSF R and target binding by the anti-TREM 2 antibody "Ab-1" after single and repeated dosing, respectively, as observed for sTREM 2. A decrease in the change was again observed after repeated dosing.

***

While we have described various embodiments of the application, it is apparent that our basic examples can be varied to provide other embodiments that utilize the compounds and methods of the application. It should be understood, therefore, that the scope of the application is defined by the application and the claims, rather than by the particular embodiments shown by way of example.

Claims

1. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to a patient in need thereof an anti-TREM 2 antibody at a dose of about 1mg/kg to 100mg/kg, wherein the anti-TREM 2 antibody comprises:

(a) A light chain variable region comprising CDRL1 having an amino acid sequence according to SEQ ID No. 2 and a heavy chain variable region; CDRL2 having an amino acid sequence according to SEQ ID NO. 3; and CDRL3 having an amino acid sequence according to SEQ ID No. 4, said heavy chain variable region comprising CDRH1 having an amino acid sequence according to SEQ ID No. 6; CDRH2 having an amino acid sequence according to SEQ ID NO. 7; and CDRH3 having an amino acid sequence according to SEQ ID NO. 8; or alternatively

(B) A light chain variable region having an amino acid sequence according to SEQ ID NO. 1 and a heavy chain variable region having an amino acid sequence according to SEQ ID NO. 5.

2. The method of claim 1, wherein the anti-TREM 2 antibody:

(i) Is IgG, optionally IgG ₁;

(ii) Is an IgG1, the IgG ₁ comprising a variant constant region having one or more mutations selected from the group consisting of: according to EU numbering, R292C, N297G, V302C, D E or L358M; and/or

(Iii) Comprising a kappa light chain constant region.

3. The method of claim 1, wherein the anti-TREM 2 antibody is an anti-TREM 2 antibody VGL101, the anti-TREM 2 antibody VGL101 comprising a light chain having the amino acid sequence of SEQ ID No. 9, and a heavy chain having the amino acid sequence of SEQ ID No. 10.

4. The method of claim 1, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg-60 mg/kg.

5. The method of claim 1, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

6. The method of claim 1, wherein the method comprises administering the anti-TREM 2 antibody to the human patient weekly by intravenous infusion, optionally wherein the intravenous infusion is about 60 minutes.

7. A liquid formulation comprising anti-TREM 2 antibody VGL101 at a concentration of about 140mg/mL, and a pharmaceutically acceptable excipient and/or carrier.

8. The liquid formulation of claim 7, further comprising one or more of:

(a) Sodium acetate at a concentration of about 15mM;

(b) Sucrose at a concentration of about 9% (w/v) of the total liquid formulation volume;

(c) Polysorbate 80 at a concentration of about 0.01% (w/v) of the total liquid formulation volume; and/or

(D) pH of about 5.2.

9. A liquid formulation at about pH 5.2, the liquid formulation comprising:

anti-TREM 2 antibody VGL101 at a concentration of about 140 mg/mL;

sodium acetate at a concentration of about 15 mM;

10. A method for treating adult onset leukoencephalopathy with axoglycemia and pigmentary glial cells (ALSP) in a human patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of the liquid formulation of claim 9.

11. The method of claim 10, wherein the method comprises administering to the human patient a dose of about 1mg/kg-60mg/kg of anti-TREM 2 antibody VGL101, optionally a dose of about 20mg/kg-40mg/kg of the anti-TREM 2 antibody.

12. The method of claim 10, wherein the method comprises administering to the human patient a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40mg/kg of anti-TREM 2 antibody VGL101.

13. The method of claim 10, wherein the method comprises administering anti-TREM 2 antibody VGL101 to the human patient once a week by intravenous infusion, optionally wherein the intravenous infusion is about 60 minutes.

14. A method of reducing the level of sTREM2 or sCSF R in a subject, the method comprising administering to the subject an anti-TREM 2 antibody VGL101 at a dose of about 1mg/kg to 100 mg/kg.

15. The method of claim 14, wherein the level of sTREM2 or sCSF R is assessed prior to administration of VGL 101.

16. The method of claim 14, wherein the level of sTREM2 or sCSF R is a level in cerebrospinal fluid (CSF).

17. The method of any one of claims 14, wherein the level of sTREM2 or sCSF R is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

18. The method of claim 14, wherein the method comprises administering to the human patient a dose of about 1mg/kg to 60mg/kg of anti-TREM 2 antibody VGL101, optionally a dose of about 20mg/kg to 40mg/kg of the anti-TREM 2 antibody.

19. The method of claim 14, wherein the method comprises administering the anti-TREM 2 antibody VGL101 to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

20. The method of claim 14, wherein the method comprises administering the anti-TREM 2 antibody to the human patient weekly by intravenous infusion, optionally wherein the intravenous infusion is about 60 minutes.

21. A method of binding or stimulating TREM2 in a subject, the method comprising administering an anti-TREM 2 antibody VGL101 to the subject at a dose of about 1mg/kg to 100 mg/kg.

22. The method of claim 21, wherein the method comprises administering to the human patient a dose of about 1mg/kg to 60mg/kg of the anti-TREM 2 antibody, optionally a dose of about 20mg/kg to 40mg/kg of the anti-TREM 2 antibody.

23. The method of claim 21, wherein the method comprises administering the anti-TREM 2 antibody to the human patient at a dose of about 1mg/kg, about 3mg/kg, about 10mg/kg, about 20mg/kg, or about 40 mg/kg.

24. The method of claim 21, wherein the method comprises administering the anti-TREM 2 antibody to the human patient weekly by intravenous infusion, optionally wherein the intravenous infusion is about 60 minutes.