WO2026030311A1 - Use of semaphorin-4d inhibitory molecules to treat cognitive impairment - Google Patents

Abstract

The disclosure relates to methods for treating cognitive decline or selecting subjects for treatment with an anti-semaphorin-4D antibody using the subject's Mini-Mental State Exam (MMSE) score and/or an equivalent cognitive assessment test score as a patient biomarker.

Description

USE OF SEMAPHORING INHIBITORY MOLECULES TO TREAT COGNITIVE IMPAIRMENT

FIELD OF THE DISCLOSURE

[0001] The disclosure relates to methods for treating subjects having cognitive impairment indicated by a Mini Mental State Examination (MMSE) and having, suspected of having or at risk for Alzheimer’s disease (AD) and methods of selecting subjects having cognitive impairment and having, suspected of having or at risk of Alzheimer’s disease (AD) for treatment with a semaphorin-4D (SEMA4D) binding molecule.

BACKGROUND

[0002] Semaphorin 4D (SEMA4D), also known as CD 100, is a transmembrane protein that belongs to the semaphorin gene family. SEMA4D is expressed on the cell surface as a homodimer, but upon cell activation SEMA4D can be released from the cell surface via proteolytic cleavage to generate sSEMA4D, a soluble form of the protein, which is also biologically active. See Suzuki et al., Nature Rev. Immunol. 3:159-167 (2003); Kikutani et al., Nature Immunol. 9: 17-23 (2008)

[0003] SEMA4D is expressed at high levels in lymphoid organs, including the spleen, thymus, and lymph nodes, and in non-lymphoid organs, such as the brain, heart, and kidney. In lymphoid organs, SEMA4D is abundantly expressed on resting T cells but only weakly expressed on resting B cells and antigen-presenting cells (APCs), such as dendritic cells (DCs). Its expression, however, is upregulated in these cells following activation by various immunological stimuli. The release of soluble SEMA4D from immune cells is also increased by cell activation. SEMA4D has been implicated in the development of neurodegenerative disorders, autoimmune diseases, demyelinating diseases, and certain cancers. However, the effect of blocking SEMA4D signaling on the organization and function of the central nervous system (CNS) including brain and spinal cord and on behaviors controlled by the CNS remains to be elucidated. This is important because changes in the CNS have a profound influence on a subject's behavior and quality of life. In particular, such changes can impact a subject's neuropsychiatric behavior, cognitive behavior, and motor skills.

[0004] The present disclosure addresses a need in the art for additional methods of defining populations of subjects having cognitive impairment and having, suspected of having, or at risk of having a neurodegenerative disorder, such as Alzheimer’s disease that are likely to benefit from early treatment with an anti-SEMA4D antibody or antigen binding fragment thereof, for example, pepinemab.

SUMMARY OF THE DISCLOSURE

[0005] The present disclosure relates to the use of a subject’s Mini-Mental State Examination (MMSE) score in the range of 22-26 and/or an equivalent cognitive assessment test score, for example, a Montreal Cognitive Assessment (MoCA) score in the range of 20-25 or 19-25 as a biomarker to select subjects for treatment and to treat subjects with cognitive impairment that have AD, are suspected of having AD, or are at risk of having AD with an anti-SEMA4D antibody or antigen-binding fragment thereof.

[0006] In one aspect, the embodiments of the disclosure provide for a use of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) for treating a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), wherein the subject has a level of cognitive impairment indicated by a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

[0007] In another aspect, the embodiments of the disclosure provide for a method of selecting subjects having, suspected of having, or at risk of having Alzheimer’s disease for treatment with an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D), said method comprising (a) determining the cognitive impairment status of the subject by administering a standardized cognitive test to the subject; and (b) selecting the subject for treatment if the subject has a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

[0008] In another aspect of the disclosure, the embodiments of the disclosure provide a method of slowing cognitive decline in a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), said method comprising (a) determining the cognitive impairment status of the subject by administering at least one standardized cognitive test, such as the MiniMental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) test, or Clinical Dementia Rating - Global Score (CDR-GS), to the subject; and (b) administering a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) to the subject if the subject has an MMSE score in the range of 22-26, a MoCA score in the range of 20-25 or 19-25 and/or a CDR-GS score of 0.5.

[0009] In another aspect of the disclosure, the embodiments provide a method of treating cognitive decline in a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), said method comprising (a) determining the cognitive impairment status of the subject by administering a standardized cognitive test to the subject; and (b) administering a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) to the subject if the subject has a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

[0010] In some embodiments of each aspect of the disclosure, the anti-SEMA4D antibody or antigen-binding fragment thereof inhibits SEMA4D interaction with its receptor; the receptor may be Plexin-Bl, Plexin-B2, CD72, or any combination thereof. In certain embodiments the antibody or antigen-binding fragment thereof inhibits SEMA4D-mediated signal transduction. The antibody or antigen-binding fragment thereof used in the methods of the disclosure may be selected from the group consisting of:

[0011] (i) an antibody or antigen binding fragment thereof comprising a variable heavy chain (VH) region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 1, 2, and 3, respectively, and a variable light chain (VL) region comprising VL CDRs 1-3 comprising SEQ ID NOS: 4, 5, and 6, respectively;

[0012] (ii) the antibody of (i), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 7 and SEQ ID NO: 8 (human), or SEQ ID NO: 9 and SEQ ID NO: 10 (mouse);

[0013] (iii) an antibody or antigen binding fragment thereof comprising a VH region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 11, 12, and 13, respectively; and a VL region comprising VL CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 14, 15, and 16, respectively; and

[0014] (iv) the antibody of (ii), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 17 and SEQ ID NO: 18.

[0015] In certain embodiments of each aspect of the disclosure, administration of the isolated antibody or antigen-binding fragment thereof results in enhanced therapeutic efficacy relative to administration of the isolated antibody or antigen-binding fragment thereof to a subject with an MMSE score in the range of 17-21 or other standardized cognitive assessment test score indicative of equivalent cognitive impairment status.

[0016] In some embodiments of each aspect of the disclosure, the standardized cognitive assessment test score is obtained by administration of the Mini Mental State Exam (MMSE) Montral Cognitive Assessment (MoCA) or Clinical Dementia Rating - Global Score (CDR- GS) to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Fig.1 A-C shows the difference in change of FDG-Pet SUVR in amyloid-positive subjects treated with placebo and amyloid-positive subjects treated with pepinemab in total modified intent to treat (mITT) population which includes subjects with a CDR-GS score of 0.5 and subjects and subjects with a CDR-GS score of 1-2 (All) (Fig. 1 A), and subjects having a CDR- GS score of 0.5 (Fig. IB) or a CDR-GS score of 1 (Fig. 1C). SUVR = standardized uptake value ratio; RO 1= region of interest.

[0018] Fig. 2A and Fig. 2B are graphs showing the effects of pepinemab treatment on the plasma level of GFAP for the subjects in Fig. 1, including ALL (Fig. 2A), and those having a CDR- GS score of 0.5 (Fig. 2B). The top lines of the graphs indicate the number of subjects tested (placebo+ top line; pepinemab+ second line).

[0019] Fig. 3A-F is a series of graphs showing the change from baseline in various cognitive assessment tests in subjects with an MMSE score 22-26 (Figs. 3A, 3B and 3C) or an MMSE score of 17-21 (Figs. 3D, 3E and 3F) that were treated with pepinemab for 48 weeks. Fig. 3 A is the change from baseline in CDR-SB; Fig.3B is the change from baseline in iADRS; Fig. 3C shows the change from baseline in ADAS-Cogl3. Fig. 3D is the change from baseline in CDR-SB; Fig.3E is the change from baseline in iADRS; Fig. 3F shows the change from baseline in ADAS-Cogl3.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0020] It has now been found from an interim analysis of results for treatment of Alzheimer’s disease in the SIGNAL-AD study (NCT04381468), that there is a significant increase in FDG- PET Standardized Uptake Value Ratio (SUVR) for subjects treated with an anti-SEMA4D antibody that have a score of 0.5 on the Clinical Dementia Rating-Global Scale (CDR-GS), which is indicative of mild cognitive impairment (MCI) in comparison to those treatment subjects having a CDR-GS score of 1 or greater, which indicates a more severe cognitive impairment. It has also been found that subjects who have an MMSE score in the range of 22- 26 respond to treatment with an anti-SEMA4D antibody with a significantly enhanced slowing of cognitive decline compared to subjects having, suspected of having or at risk of AD and who have an MMSE score in the range of 17-21. A slowing of cognitive decline refers to a decline in the rate at which memory, thinking speed, executive functions and other cognitive functions deteriorate. These findings provide a new and unexpected biomarker for selecting patients who have, are suspected of having or are at risk for Alzheimer’s disease who will benefit most from 18 months treatment, Q4W, with anti-SEMA4D antibodies or antigenbinding fragments thereof. Subjects who present with moderately elevated (e.g. above normal but less than 225 ng/ml) levels of Glial Fibrillary Acidic Protein (GFAP) in the blood (Kim et al., GFAP as a Potential Biomarker for Alzheimer ’s Disease: A Systematic Review and MetaAnalysis), Cells, 2023, 12(9): 1309; incorporated herein by reference), or p-tau 217 (Janelidze, et a., Associations of Plasma Phospho-Tau217 levels With Tau Positron Emission Tomography in Early Alzheimer Disease,” JAMA Neurol., 2021, 78(2): 149-156; incorporated herein by reference), or an elevated above normal ratio of AP42/AP40 in the cerebral spinal fluid (CSF) (Lehmann et al., Relevance of Af42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLMR Scale, Front Aging Neurosci., 2018, 10: 138; incorporated herein by reference) or the presence of elevated low or medium levels of amyloid plaque in the brain as shown by positron emission tomography (PET) imaging (Betthauser et al., Multi -method investigation of factors influencing amyloid onset and impairment in three cohorts, Brain, 2022, 145(11), 4065-4079; incorporated herein by reference) may also be included among those subjects that are at an early stage of disease progression and will benefit from treatment with an anti-SEMA4D antibody or antigen-binding fragment thereof.

[0021] In order that the present disclosure may be more readily understood, certain terms are defined below. Additional definitions may be found within the detailed description of the disclosure. [0022] It is to be noted that the term “a” or “an” entity refers to one or more of that entity; for example, “a polynucleotide,” is understood to represent one or more polynucleotides. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0023] Furthermore, "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0024] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0025] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not limitations of the various aspects or embodiments of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0026] Wherever embodiments are described with the language "comprising," otherwise analogous embodiments described in terms of "consisting of' and/or "consisting essentially of' are also provided.

[0027] Amino acids are referred to herein by their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, are referred to by their commonly accepted single-letter codes. Cognitive Assessment

[0028] The terms “determining the cognitive impairment assessment score” and “determining the cognitive impairment status” are used herein to mean that testing of the cognitive ability of a subject is carried out using a standardized screening test for cognitive ability, e.g., the MiniMental State Exam (MMSE) or the MoCA exam.

[0029] As used herein, the term “Mini-Mental State Examination” (MMSE) refers to a test used to check for cognitive impairment. The MMSE is an 11 -question measure that tests five areas of cognitive function: orientation, registration, attention and calculation, recall, and language. The MMSE can help identify potential cognitive issues and track changes over time. The MMSE can be used to stage the severity of cognitive decline associated with AD. MMSE is used extensively in clinical and research settings to measure cognitive function in adults, particularly for screening for cognitive impairment or cognitive decline over time. The MMSE test includes simple questions and problems in a number of areas: the time and place of the test, repeating lists of words, arithmetic such as the serial sevens, language use and comprehension, and basic motor skills. The test is scored out of 30, with lower scores generally indicating greater cognitive impairment.

[0030] The “Montreal Cognitive Assessment” (MoCA) test was designed as a rapid screening instrument for mild cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and orientation. The total possible score is 30 points; a score of 26 or above is considered normal.

[0031] As referred to herein the “Clinical Dementia Rating Scale Sum of Boxes” (CDR-SB) is a test used to stage the severity of AD. A Texas Alzheimer’s Research Consortium Study (Sid E. O'Bryant, PhD, Stephen C. Waring, DVM, PhD, C. Munro Cullum, PhD, James Hall, PhD, Laura Lacritz, PhD, Paul J. Massman, PhD, Philip J. Lupo, MPH, Joan S. Reisch, PhD, Rachelle Doody, MD, PhD, and Texas Alzheimer's Research Consortium, Arch Neurol. 2008;65(8): 1091-1095. doi: 10.1001/archneur.65.8.1091) concluded that mild AD spans CDR- SB scores from 4.5 to 9.0, and moderate AD spans CDR-SB scores from 9.5 to 15.5.

[0032] As used herein, the term “Clinical Dementia Rating - Global Score” (CDR-GS) refers to a widely used standardized tool in dementia research and clinical trials to assess and stage the severity of cognitive impairment. The CDR-GS is a widely used scale in both Alzheimer disease centers and dementia research. CDR is calculated on the basis of testing six different cognitive and behavioral domains such as memory, orientation, judgment and problem solving, community affairs, home and hobbies performance, and personal care. Subjects who score 0.5 on the CDR-GS are considered herein to have some cognitive impairment. Subjects who score >0.5 on the CDR-GS are considered herein to have an advanced to later stage of AD-related dementia (a score of 1.0 indicates mild dementia; 2.0 indicates moderate dementia; 3.0 indicates severe dementia).

[0033] As used herein, the term “Alzheimer's Disease Assessment Scale-Cognitive Subscale” (ADAS-Cogl3 Test) is in reference to one of the most frequently used tests to measure cognition in research studies and clinical trials for new drugs and other interventions. The test primarily measures language, memory and praxis. The ADAS-Cogl3 helps evaluate cognition and differentiates between normal cognitive functioning and impaired cognitive functioning. It is especially useful for determining the extent of cognitive decline and can help evaluate which stage of Alzheimer's disease a person is in, based on a subject’s answers and score. The ADAS-Cogl3 is often used in clinical trials because it can determine incremental improvements or declines in cognitive functioning.

[0034] As used herein, the term “iADRS” refers to a tool used in clinical trials to measure the severity of AD by combining a person's cognitive abilities and their capacity to perform daily activities. It incorporates parts of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study -Activities of Daily Living subscale (ADCS-ADL).

[0035] The term “Mild Cognitive Impairment” (MCI) is used herein to indicate patients who may be in the prodromal stage of Alzheimer's disease if confirmed by one or more other markers of disease or another dementia. Patients with mild cognitive impairment are not functionally impaired enough to meet the criteria for dementia, but still show cognitive problems.

[0036] Cognitive testing is generally done by a qualified and/or certified healthcare provider. It is not necessary and is often not the case that the individual(s) who carries out testing and/or scoring also treats the subject. For the purposes of the methods of the disclosure, test scores such as the MMSE score for example can be obtained from a person, such as a qualified and/or certified healthcare provider for assessing whether to administer treatment. Definitions

[0037] Terms such as "treating" or "treatment" or “to treat” or "alleviating" or “to alleviate” refer to both 1) therapeutic measures that cure, slow down, lessen symptoms of, reverse, and/or halt progression of a diagnosed pathologic condition or disorder and 2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0038] By "therapeutically effective dose or amount" or "effective amount" is intended an amount of anti-SEMA4D antibody or antigen binding fragment, variant, or derivative thereof that when administered brings about a positive therapeutic response with respect to treatment of a patient with a condition to be treated, e.g., an inhibition, delay, or reduction of cognitive impairment associated with Alzheimer’s disease in the patient.

[0039] By "subject" or "individual" or "animal" or "patient" or "mammal," is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include humans, domestic animals, farm animals, and zoo, sports, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, bears, and so on.

[0040] As used herein, phrases such as "a subject that would benefit from administration of an anti-SEMA4D antibody or antigen-binding fragment thereof’ and "an animal in need of treatment" includes subjects, such as mammalian subjects, that would benefit from administration of an anti-SEMA4D antibody or antigen-binding fragment thereof alone or in combination with another therapeutic agent for treatment of cognitive decline and/or an underlying neurodegenerative disorder, e.g., Alzheimer’s disease. [0041] As used herein, "human" or "fully human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from animals transgenic for one or more human immunoglobulins, as described infra and, for example, in U.S. Pat. No. 5,939,598 by Kucherlapati et al. "Human" or "fully human" antibodies also include antibodies comprising at least the variable domain of a heavy chain, or at least the variable domains of a heavy chain and a light chain, where the variable domain(s) have the amino acid sequence of human immunoglobulin variable domain(s).

[0042] "Human" or "fully human" antibodies also include "human" or "fully human" antibodies, as described above, that comprise, consist essentially of, or consist of, variants (including derivatives) of antibody molecules (e.g., the VH regions and/or VL regions) described herein, which antibodies or fragments thereof immunospecifically bind to a SEMA4D polypeptide or fragment or variant thereof. Standard techniques known to those of skill in the art can be used to introduce mutations in the nucleotide sequence encoding a human anti-SEMA4D antibody, including, but not limited to, site-directed mutagenesis and PCR-mediated mutagenesis which result in amino acid substitutions. In certain aspects, the variants (including derivatives) encode less than 50 amino acid substitutions, less than 40 amino acid substitutions, less than 30 amino acid substitutions, less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the reference VH region, VHCDR1, VHCDR2, VHCDR3, VL region, VLCDR1, VLCDR2, or VLCDR3.

[0043] In certain embodiments, the amino acid substitutions are conservative amino acid substitutions, discussed further below. Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity (e.g., the ability to bind a SEMA4D polypeptide, e.g., human, murine, or both human and murine SEMA4D). Such variants (or derivatives thereof) of "human" or "fully human" antibodies can also be referred to as human or fully human antibodies that are "optimized" or "optimized for antigen binding" and include antibodies that have improved affinity to antigen. [0044] The terms "antibody" and "immunoglobulin" are used interchangeably herein. An antibody or immunoglobulin comprises at least the variable domain of a heavy chain and normally comprises at least the variable domains of a heavy chain and a light chain. Basic immunoglobulin structures in vertebrate systems are relatively well understood. See, e.g., Harlow et al. (1988) Antibodies: A Laboratory Manual (2nd ed.; Cold Spring Harbor Laboratory Press).

[0045] As used herein, the term “immunoglobulin” comprises various broad classes of polypeptides that can be distinguished biochemically. Those skilled in the art will appreciate that heavy chains are classified as gamma, mu, alpha, delta, or epsilon, (y, p, a, 5, s) with some subclasses among them (e.g., yl-y4). It is the nature of this chain that determines the "class" of the antibody as IgG, IgM, IgA IgD, or IgE, respectively. The immunoglobulin subclasses (isotypes) e.g., IgGl, IgG2, IgG3, IgG4, IgAl, etc. are well characterized and are known to confer functional specialization. Modified versions of each of these classes and isotypes are readily discernable to the skilled artisan in view of the instant disclosure and, accordingly, are within the scope of the instant disclosure. All immunoglobulin classes are clearly within the scope of the present disclosure, the following discussion will generally be directed to the IgG class of immunoglobulin molecules. With regard to IgG, a standard immunoglobulin molecule comprises two identical light chain polypeptides of molecular weight approximately 23,000 Daltons, and two identical heavy chain polypeptides of molecular weight 53,000-70,000. The four chains are typically joined by disulfide bonds in a "Y" configuration wherein the light chains bracket the heavy chains starting at the mouth of the "Y" and continuing through the variable region.

[0046] Light chains are classified as either kappa or lambda (K, L). Each heavy chain class can be bound with either a kappa or lambda light chain. In general, the light and heavy chains are covalently bonded to each other, and the "tail" portions of the two heavy chains are bonded to each other by covalent disulfide linkages or non-covalent linkages when the immunoglobulins are generated either by hybridomas, B cells or genetically engineered host cells. In the heavy chain, the amino acid sequences run from an N-terminus at the forked ends of the Y configuration to the C-terminus at the bottom of each chain.

[0047] Both the light and heavy chains are divided into regions of structural and functional homology. The terms "constant" and "variable" are used functionally. In this regard, it will be appreciated that the variable domains of both the light (VL or VK) and heavy (VH) chain portions determine antigen recognition and specificity. Conversely, the constant domains of the light chain (CL) and the heavy chain (CHI, CH2 or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, and the like. By convention the numbering of the constant region domains increases as they become more distal from the antigen binding site or amino-terminus of the antibody. The N- terminal portion is a variable region and at the C-terminal portion is a constant region; the CH3 and CL domains actually comprise the carboxy-terminus of the heavy and light chain, respectively.

[0048] As indicated above, the variable region allows the antibody to selectively recognize and specifically bind epitopes on antigens. That is, the VL domain and VH domain, or subset of the complementarity determining regions (CDRs) within these variable domains, of an antibody combine to form the variable region that defines a three-dimensional antigen binding site. This quaternary antibody structure forms the antigen binding site present at the end of each arm of the Y. More specifically, the antigen binding site is defined by three CDRs on each of the VH and VL chains. In some instances, e.g., certain immunoglobulin molecules derived from camelid species or engineered based on camelid immunoglobulins, a complete immunoglobulin molecule can consist of heavy chains only, with no light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993).

[0049] In naturally occurring antibodies, the six "complementarity determining regions" or "CDRs" present in each antigen binding domain are short, non-contiguous sequences of amino acids that are specifically positioned to form the antigen binding domain as the antibody assumes its three-dimensional configuration in an aqueous environment. The remainder of the amino acids in the antigen binding domains, referred to as "framework" regions, show less inter-molecular variability. The framework regions largely adopt a P-sheet conformation and the CDRs form loops that connect, and in some cases form part of, the P-sheet structure. Thus, framework regions act to form a scaffold that provides for positioning the CDRs in correct orientation by inter-chain, non-covalent interactions. The antigen binding domain formed by the positioned CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes the non-covalent binding of the antibody to its cognate epitope. The amino acids comprising the CDRs and the framework regions, respectively, can be readily identified for any given heavy or light chain variable domain by one of ordinary skill in the art, since they have been precisely defined (see below).

[0050] In the case where there are two or more definitions of a term that is used and/or accepted within the art, the definition of the term as used herein is intended to include all such meanings unless explicitly stated to the contrary. A specific example is the use of the term "complementarity determining region" ("CDR") to describe the non-contiguous antigen combining sites found within the variable region of both heavy and light chain polypeptides. This particular region has been described by Kabat et al. (1983) U.S. Dept, of Health and Human Services, "Sequences of Proteins of Immunological Interest" and by Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987), which are incorporated herein by reference, where the definitions include overlapping or subsets of amino acid residues when compared against each other. Nevertheless, application of either definition to refer to a CDR of an antibody or variants thereof is intended to be within the scope of the term as defined and used herein. The appropriate amino acid residues that encompass the CDRs as defined by each of the above cited references are set forth below in Table 1 as a comparison. The exact residue numbers that encompass a particular CDR will vary depending on the sequence and size of the CDR. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.

Table 1. CDR Definitions¹

’Numbering of all CDR definitions in Table 1 is according to the numbering conventions set forth by Kabat et al. (see below). [0051] Kabat et al. also defined a numbering system for variable domain sequences that is applicable to any antibody. One of ordinary skill in the art can unambiguously assign this system of "Kabat numbering" to any variable domain sequence, without reliance on any experimental data beyond the sequence itself. As used herein, "Kabat numbering" refers to the numbering system set forth by Kabat et al. (1983) U.S. Dept, of Health and Human Services, "Sequence of Proteins of Immunological Interest." Unless otherwise specified, references to the numbering of specific amino acid residue positions in an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof of the present disclosure are according to the Kabat numbering system.

[0052] Antibodies or antigen-binding fragments, variants, or derivatives thereof of the disclosure include, but are not limited to, polyclonal, monoclonal, multispecific, bispecific, human, humanized, primatized, or chimeric antibodies, single-chain antibodies, epitopebinding fragments, e.g., Fab, Fab' and F(ab')2, Fd, Fvs, single-chain Fvs (scFv), disulfide- linked Fvs (sdFv), fragments comprising either a VL or VH domain, fragments produced by a Fab expression library, and anti-idiotypic (anti-Id) antibodies (including, e.g., anti-Id antibodies to anti-SEMA4D antibodies disclosed herein). ScFv molecules are known in the art and are described, e.g., in U.S. Pat. No. 5,892,019. Immunoglobulin or antibody molecules of the disclosure can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl, and IgA2, etc ), or subclass of immunoglobulin molecule.

[0053] As used herein, the term "heavy chain portion" includes amino acid sequences derived from an immunoglobulin heavy chain. In certain embodiments, a polypeptide comprising a heavy chain portion comprises at least one of a VH domain, a CHI domain, a hinge (e.g., upper, middle, and/or lower hinge region) domain, a CH2 domain, a CH3 domain, or a variant or fragment thereof. For example, a binding polypeptide for use in the disclosure can comprise a polypeptide chain comprising a CHI domain; a polypeptide chain comprising a CHI domain, at least a portion of a hinge domain, and a CH2 domain; a polypeptide chain comprising a CHI domain and a CH3 domain; a polypeptide chain comprising a CHI domain, at least a portion of a hinge domain, and a CH3 domain, or a polypeptide chain comprising a CHI domain, at least a portion of a hinge domain, a CH2 domain, and a CH3 domain. In another embodiment, a polypeptide of the disclosure comprises a polypeptide chain comprising a CH3 domain. Further, a binding polypeptide for use in the disclosure can lack at least a portion of a CH2 domain (e.g., all or part of a CH2 domain). As set forth above, it will be understood by one of ordinary skill in the art that these domains (e.g., the heavy chain portions) can be modified such that they vary in amino acid sequence from the naturally occurring immunoglobulin molecule.

[0054] In certain anti-SEMA4D antibodies, or antigen-binding fragments, variants, or derivatives thereof disclosed herein, the heavy chain portions of one polypeptide chain of a multimer are identical to those on a second polypeptide chain of the multimer. Alternatively, heavy chain portion-containing monomers of the disclosure are not identical. For example, each monomer can comprise a different target binding site, forming, for example, a bispecific antibody. A bispecific antibody is an artificial protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen. Variations on the bispecific antibody format are contemplated within the scope of the present disclosure. Bispecific antibodies can be generated using techniques that are well known in the art for example, see, for example, Ghayur et al., Expert Review of Clinical Pharmacology 3.4 (July 2010): p. 491; Lu et al., J. Biological Chemistry Vol. 280, No. 20, p. 19665-19672 (2005); Marvin et al., Acta Pharmacologic Sinica 26(6):649-658 (2005); and Milstein C et al., Nature 1983; 305: 537-40; 30 Brennan M et al., Science 1985; 229: 81-3; Thakur et al., Curr Opin Mol Ther. 2010 Jun;12(3):340-9; and U.S. Patent Publication No. 2007/0004909.

[0055] The heavy chain portions of a binding molecule for use in the methods disclosed herein can be derived from different immunoglobulin molecules. For example, a heavy chain portion of a polypeptide can comprise a CHI domain derived from an IgGl molecule and a hinge region derived from an IgG3 molecule. In another example, a heavy chain portion can comprise a hinge region derived, in part, from an IgGl molecule and, in part, from an IgG3 molecule. In another example, a heavy chain portion can comprise a chimeric hinge derived, in part, from an IgGl molecule and, in part, from an IgG4 molecule.

[0056] As used herein, the term “light chain portion” includes amino acid sequences derived from an immunoglobulin light chain, e.g., a kappa or lambda light chain. In certain aspects, the light chain portion comprises at least one of a VL or CL domain.

[0057] Anti-SEMA4D antibodies, or antigen-binding fragments, variants, or derivatives thereof disclosed herein can be described or specified in terms of the epitope(s) or portion(s) of an antigen, e g., a target polypeptide disclosed herein (e.g., SEMA4D) that they recognize or specifically bind. The portion of a target polypeptide that specifically interacts with the antigen binding domain of an antibody is an "epitope," or an "antigenic determinant." A target polypeptide can comprise a single epitope, but typically comprises at least two epitopes, and can include any number of epitopes, depending on the size, conformation, and type of antigen. Furthermore, it should be noted that an "epitope" on a target polypeptide can be or can include non-polypeptide elements, e.g., an epitope can include a carbohydrate side chain.

[0058] The minimum size of a peptide or polypeptide epitope for an antibody is thought to be about four to five amino acids. Peptide or polypeptide epitopes can contain at least seven, at least nine and, in some cases, between at least about 15 to about 30 amino acids. Since a CDR can recognize an antigenic peptide or polypeptide in its tertiary form, the amino acids comprising an epitope need not be contiguous, and in some cases, may not even be on the same peptide chain. A peptide or polypeptide epitope recognized by anti-SEMA4D antibodies of the present disclosure can contain a sequence of at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20, at least 25, or between about 15 to about 30 contiguous or non-contiguous amino acids of SEMA4D.

[0059] By "specifically binds," it is generally meant that an antibody binds to an epitope via its antigen binding domain, and that the binding entails some complementarity between the antigen binding domain and the epitope. According to this definition, an antibody is said to "specifically bind" to an epitope when it binds to that epitope, via its antigen binding domain more readily than it would bind to a random, unrelated epitope. The term "specificity" is used herein to qualify the relative affinity by which a certain antibody binds to a certain epitope. For example, antibody "A" can be deemed to have a higher specificity or affinity for a given epitope than antibody "B," or antibody "A" can be said to bind to epitope "C" with a higher specificity or affinity than it has for related epitope "D."

[0060] By "preferentially binds," it is meant that the antibody specifically binds to an epitope more readily than it would bind to a related, similar, homologous, or analogous epitope. Thus, an antibody that "preferentially binds" to a given epitope would more likely bind to that epitope than to a related epitope, even though such an antibody can cross-react with the related epitope.

[0061] By way of non-limiting example, an antibody can be considered to bind a first epitope preferentially if it binds said first epitope with a dissociation constant (KD) that is less than the antibody's KD for the second epitope. In another non-limiting example, an antibody can be considered to bind a first antigen preferentially if it binds the first epitope with an affinity that is at least one order of magnitude less than the antibody's KD for the second epitope. In another non-limiting example, an antibody can be considered to bind a first epitope preferentially if it binds the first epitope with an affinity that is at least two orders of magnitude less than the antibody's KD for the second epitope.

[0062] In another non-limiting example, an antibody can be considered to bind a first epitope preferentially if it binds the first epitope with an off rate (k(off)) that is less than the antibody's k(off) for the second epitope. In another non-limiting example, an antibody can be considered to bind a first epitope preferentially if it binds the first epitope with an affinity that is at least one order of magnitude less than the antibody's k(off) for the second epitope. In another nonlimiting example, an antibody can be considered to bind a first epitope preferentially if it binds the first epitope with an affinity that is at least two orders of magnitude less than the antibody's k(off) for the second epitope.

[0063] An antibody is said to competitively inhibit binding of a reference antibody to a given epitope if it preferentially binds to that epitope to the extent that it blocks, to some degree, binding of the reference antibody to the epitope. Competitive inhibition can be determined by any method known in the art, for example, competition ELISA assays. An antibody can be said to competitively inhibit binding of the reference antibody to a given epitope by at least 90%, at least 80%, at least 70%, at least 60%, or at least 50%.

[0064] As used herein, the term "affinity" refers to a measure of the strength of the binding of an individual epitope with the CDR of an immunoglobulin molecule. See, e.g., Harlow et al. (1988) Antibodies: A Laboratory Manual (Cold Spring Harbor Laboratory Press, 2nd ed.) pages 27-28. As used herein, the term "avidity" refers to the overall stability of the complex between a population of immunoglobulins and an antigen, that is, the functional combining strength of an immunoglobulin mixture with the antigen. See, e.g., Harlow at pages 29-34. Avidity is related to both the affinity of individual immunoglobulin molecules in the population with specific epitopes, and also the valencies of the immunoglobulins and the antigen. For example, the interaction between a bivalent monoclonal antibody and an antigen with a highly repeating epitope structure, such as a polymer, would be one of high avidity. [0065] Anti-SEMA4D antibodies or antigen-binding fragments, variants, or derivatives thereof of the disclosure can also be described or specified in terms of their cross-reactivity. As used herein, the term "cross-reactivity" refers to the ability of an antibody, specific for one antigen, to react with a second antigen; a measure of relatedness between two different antigenic substances. Thus, an antibody is cross reactive if it binds to an epitope other than the one that induced its formation. The cross-reactive epitope generally contains many of the same complementary structural features as the inducing epitope, and in some cases, can actually fit better than the original.

[0066] For example, certain antibodies have some degree of cross-reactivity, in that they bind related, but non-identical epitopes, e.g., epitopes with at least 95%, at least 90%, at least 85%, at least 80%, at least 75%, at least 70%, at least 65%, at least 60%, at least 55%, and at least 50% identity (as calculated using methods known in the art and described herein) to a reference epitope. An antibody can be said to have little or no cross-reactivity if it does not bind epitopes with less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, less than 70%, less than 65%, less than 60%, less than 55%, and less than 50% identity (as calculated using methods known in the art and described herein) to a reference epitope. An antibody can be deemed "highly specific" for a certain epitope, if it does not bind any other analog, ortholog, or homolog of that epitope.

[0067] Anti-SEMA4D binding molecules, e.g., antibodies or antigen-binding fragments, variants or derivatives thereof of the disclosure can also be described or specified in terms of their binding affinity to a polypeptide of the disclosure, e.g., SEMA4D, e.g., human, murine, or both human and murine SEMA4D. In certain aspects, binding affinities include those with a dissociation constant or Kd less than 5 x 10-2 M, 10-2 M, 5 x 10-3 M, 10-3 M, 5 x 10-4 M, 10-4 M, 5 x 10-5 M, 10-5 M, 5 x 10-6 M, 10-6 M, 5 x 10-7 M, 10-7 M, 5 x 10-8 M, 10-8 M, 5 x 10-9 M, 10-9 M, 5 x 10-10 M, 10-10 M, 5 x 10-11 M, 10-11 M, 5 x 10-12 M, 10-12 M, 5 x 10-13 M, 10-13 M, 5 x 10-14 M, 10-14 M, 5 x 10-15 M, or 10-15 M. In certain embodiments, the anti-SEMA4D binding molecule, e.g., an antibody or antigen binding fragment thereof, of the disclosure binds human SEMA4D with a Kd of about 5 x 10-9 to about 6 x 10-9. In another embodiment, the anti-SEMA4D binding molecule, e.g., an antibody or antigen binding fragment thereof, of the disclosure binds murine SEMA4D with a Kd of about 1 x 10-9 to about 2 x 10-9. [0068] As used herein, the term "chimeric antibody" will be held to mean any antibody wherein the immunoreactive region or site is obtained or derived from a first species and the constant region (which can be intact, partial or modified) is obtained from a second species. In some embodiments the target binding region or site will be from a non-human source (e.g., mouse or primate) and the constant region is human.

[0069] As used herein, the term "engineered antibody" refers to an antibody in which the variable domain in either the heavy or light chain or both is altered by at least partial replacement of one or more CDRs from an antibody of known specificity and, if necessary, by partial framework region replacement and sequence changing. Although the CDRs can be derived from an antibody of the same class or even subclass as the antibody from which the framework regions are derived, it is envisaged that the CDRs will be derived from an antibody of different class or from an antibody from a different species. An engineered antibody in which one or more "donor" CDRs from a non-human antibody of known specificity is grafted into a human heavy or light chain framework region is referred to herein as a "humanized antibody." In certain aspects it is not necessary to replace all of the CDRs with the complete CDRs from the donor variable domain to transfer the antigen binding capacity of one variable domain to another. Rather, only those residues that are necessary to maintain the activity of the binding site against the targeted antigen can be transferred.

[0070] It is further recognized that the framework regions within the variable domain in a heavy or light chain, or both, of a humanized antibody can comprise solely residues of human origin, in which case these framework regions of the humanized antibody are referred to as "fully human framework regions" (for example, MAb VX15/2503, disclosed in U.S. Patent Appl. Publication No. U.S. 2010/0285036 Al as MAb 2503, incorporated herein by reference in its entirety). Alternatively, one or more residues of the framework region(s) of the donor variable domain can be engineered within the corresponding position of the human framework region(s) of a variable domain in a heavy or light chain, or both, of a humanized antibody if necessary to maintain proper binding or to enhance binding to the SEMA4D antigen. A human framework region that has been engineered in this manner would thus comprise a mixture of human and donor framework residues and is referred to herein as a "partially human framework region." [0071] For example, humanization of an anti-SEMA4D antibody can be essentially performed following the method of Winter and co-workers (Jones et al., Nature 321 :522-525 (1986); Riechmann et al., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536 (1988)), by substituting rodent or mutant rodent CDRs or CDR sequences for the corresponding sequences of a human anti-SEMA4D antibody. See also U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205; herein incorporated by reference. The resulting humanized anti-SEMA4D antibody would comprise at least one rodent or mutant rodent CDR within the fully human framework regions of the variable domain of the heavy and/or light chain of the humanized antibody. In some instances, residues within the framework regions of one or more variable domains of the humanized anti-SEMA4D antibody are replaced by corresponding non-human (for example, rodent) residues (see, for example, U.S. Pat. Nos. 5,585,089; 5,693,761; 5,693,762; and 6,180,370), in which case the resulting humanized anti-SEMA4D antibody would comprise partially human framework regions within the variable domain of the heavy and/or light chain.

[0072] Furthermore, humanized antibodies can comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications are made to further refine antibody performance (e.g., to obtain desired affinity). In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the framework regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details see Jones et al., Nature 331 :522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); herein incorporated by reference. Accordingly, such "humanized" antibodies can include antibodies wherein substantially less than an intact human variable domain has been substituted by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some CDR residues and possibly some framework residues are substituted by residues from analogous sites in rodent antibodies. See, for example, U.S. Pat. Nos. 5,225,539; 5,585,089; 5,693,761; 5,693,762; 5,859,205. See also U.S. Pat. No. 6,180,370, and International Publication No. WO 01/27160, where humanized antibodies and techniques for producing humanized antibodies having improved affinity for a predetermined antigen are disclosed.

Determination of Cognitive Impairment Status and Methods of Selecting Subjects for Treatment

[0073] The present disclosure relates to use of cognitive impairment status of a subject, and in particular, an MMSE score in the range of 22-26 and/or an equivalent score on another standardized screening test that assesses cognitive impairment, e.g., the Clinical Dementia Rating-Global Scale (CDR-GS) or Montreal Cognitive Assessment (MoCA) test score in the range of 20-25 or 19-25 to select subjects who will benefit from treatment with an anti- SEMA4D antibody of the disclosure. It has been found that subjects having an MMSE score in the range of 22-26 respond to treatment with an anti-SEMA4D antibody with a significantly greater slowing of cognitive decline (99% to 70% decrease in cognitive decline) compared to subjects having a lower MMSE score, e.g., MMSE score of 17-21.

[0074] One aspect of this disclosure provides a method of selecting subjects having, at risk of having, or suspected of having Alzheimer’s disease for treatment of cognitive decline with an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin- 4D (SEMA4D), which method comprises (a) determining the cognitive impairment status of the subject; and (b) selecting the subject for treatment if the subject has an MMSE score in the range of 22-26 and/or other standardized cognitive test score indicative of the same or similar degree of cognitive impairment, e.g., a MoCA test score in the range of 20-25 or 19-25 or a Clinical Dementia Rating-Global Scale (CDR-GS) score of 0.5. In some embodiments, the subject has a moderately elevated plasma level of Glial Fibrillary Acidic Protein (GFAP) or p- tau 217, or p-tau 181, an elevated ratio of A[342/Ap40 in the cerebral spinal fluid (CSF) or p- tau 217/AP1-42 plasma ratio using the FDA approved Lumipulse” G system, and/or the presence of amyloid plaque in the brain as evidence by positron emission tomography, for example.

[0075] Methods for determining the plasma level of GFAP, p-tau 217, p-tau 181, the CSF level of Ap42 and Ap40, and the presence or absence and amount of amyloid plaque in the brain are well known in the relevant art. Normal and elevated levels of plasma GFAP, p-tau peptides, and CSF AP42/AP40 ratio in CSF, and amyloid plaque in the brain are well known in the relevant art. [0076] Methods for determining the presence or absence of cognitive impairment and degree of cognitive impairment are well known in the art. For example, the MMSE is used herein to assay the degree of impairment of a subject having, suspected of having, or at risk of AD, with an MMSE score in the range of 22-26 indicating that further cognitive decline in the subject can be significantly slowed or reduced by treatment with an anti-SEMA4D antibody of the disclosure or antigen-binding fragment thereof, particularly in comparison to subjects with an MMSE score of 17-21 who are similarly treated.

[0077] Nonlimiting examples of other standardized tests that may be used in the methods of the disclosure to identify subjects with a degree of cognitive impairment equivalent to the level of cognitive impairment associated with an MMSE score in the range of 22-26 include the “Montreal Cognitive Assessment” (MoCA) score in the range of 20-25 or 19-25, Clinical Dementia Rating -Global Scale score of 0.5(CDR-GS), Mini-Cog™, Quick Mild Cognitive Impairment screen (Qmci), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog Test), Clinical Dementia Rating Scale Sum of Boxes (CDR-SB), Addenbrooke's Cognitive Examination III” (ACE-III), and Rowland Universal Dementia Assessment Scale” (RUDAS).

Anti-SEMA4D Antibodies

[0078] Antibodies that bind SEMA4D have been described in the art. See, for example, U.S. Patent No. 8,496,938; U.S. Patent No. 11,427,634, U.S. Publ. Nos. 2008/0219971, U.S. 2010/0285036, and U.S. 2006/0233793, U.S. Publ. No. 2021/0032329, International Patent Applications WO 93/14125, WO 2008/100995, and WO 2010/129917, and Herold et al., Int. Immunol. 7(1): 1-8 (1995), each of which is herein incorporated in its entirety by reference.

[0079] In certain embodiments, the antibody blocks the interaction of SEMA4D with one or more of its receptors, e.g., Plexin-Bl, Plexin-B2, and CD72. In certain embodiments the cancer cells and tumor infiltrating immune cells express Plexin-Bl, Plexin-B2 and/or CD72. Anti-SEMA4D antibodies having these properties can be used in the methods provided herein. Antibodies that can be used include but are not limited to MAbs VX15/2503 (pepinemab), 67, 76, 2282, VX18, D2517, or D2585, and antigen-binding fragments, variants, or derivatives thereof which are fully described in U.S. 2010/0285036, U.S. 2008/0219971 and U.S. Patent No. 11,427,634. The amino acid sequences of the VH and VL regions, as well as the associated CDRs for pepinemab (with VH/VL SEQ ID NOS: 7 and 8) and VX18 are provided in Table 2A and Table 2B, respectively.

Table 2A

Table 2B

[0080] Additional antibodies which can be used in the methods provided herein include the BD16 antibody described in U.S. 2006/0233793 Al as well as antigen-binding fragments, variants, or derivatives thereof; or any of MAb 301, MAb 1893, MAb 657, MAb 1807, MAb 1656, MAb 1808, Mab 59, MAb 2191, MAb 2274, MAb 2275, MAb 2276, MAb 2277, MAb 2278, MAb 2279, MAb 2280, MAb 2281, MAb 2282, MAb 2283, MAb 2284, and MAb 2285, as well as any fragments, variants or derivatives thereof as described in U.S. 2008/0219971 Al . In certain embodiments an anti-SEMA4D antibody for use in the methods provided herein binds human, murine, or both human and murine SEMA4D. Also useful are antibodies which bind to the same epitope as any of the aforementioned antibodies and/or antibodies which competitively inhibit binding or activity of any of the aforementioned antibodies.

[0081] In certain embodiments, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein has an amino acid sequence that has at least about 80%, about 85%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, or about 95% sequence identity to the amino acid sequence for a reference anti-SEMA4D antibody molecule, for example, those described above. In a further embodiment, the binding molecule shares at least about 96%, about 97%, about 98%, about 99%, or 100% sequence identity to a reference antibody.

[0082] In another embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of an immunoglobulin heavy chain variable domain (VH domain), where at least one of the CDRs of the VH domain has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or identical to any CDR1, CDR2 or CDR3 set forth in Tables 2A and 2B.

[0083] In another embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of an immunoglobulin heavy chain variable domain (VH domain), where at least one of the CDRs of the VH domain has an amino acid sequence identical, except for 1, 2, 3, 4, or 5 conservative amino acid substitutions, to any CDR1, CDR2 or CDR3 set forth in Tables 2 A and 2B.

[0084] In another embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of a VH domain that has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identical to those VH domains set forth in Tables 2A and 2B, wherein an anti-SEMA4D antibody comprising the encoded VH domain specifically or preferentially binds to SEMA4D.

[0085] In another embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of an immunoglobulin light chain variable domain (VL domain), where at least one of the CDRs of the VL domain has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, or identical to any CDR1, CDR2 or CDR3 set forth in Tables 2A and 2B.

[0086] In another embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of an immunoglobulin light chain variable domain (VL domain), where at least one of the CDRs of the VL domain has an amino acid sequence identical, except for 1, 2, 3, 4, or 5 conservative amino acid substitutions, to any CDR1, CDR2 or CDR3 set forth in Tables 2A and 2B.

[0087] In a further embodiment, an anti-SEMA4D antibody or antigen-binding fragment, variant, or derivative thereof useful in the methods provided herein comprises, consists essentially of, or consists of a VL domain that has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% identical to those VL domains set forth in Tables 2A and 2B, wherein an anti-SEMA4D antibody comprising the encoded VL domain specifically or preferentially binds to SEMA4D.

[0088] Suitable biologically active variants of the anti-SEMA4D antibodies of the disclosure can be used in the methods of the present disclosure. Such variants will retain the desired binding properties of the parent anti-SEMA4D antibody. Methods for making antibody variants are generally available in the art.

[0089] Methods for mutagenesis and nucleotide sequence alterations are well known in the art. See, for example, Walker and Gaastra, eds. (1983) Techniques in Molecular Biology (MacMillan Publishing Company, New York); Kunkel, Proc. Natl. Acad. Sci. USA 82:488- 492 (1985); Kunkel et al., Methods Enzymol. 154:367-382 (1987); Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (Cold Spring Harbor, N.Y.); U.S. Pat. No. 4,873,192; and the references cited therein; herein incorporated by reference. Guidance as to appropriate amino acid substitutions that do not affect biological activity of the polypeptide of interest can be found in the model of Dayhoff et al. (1978) in Atlas of Protein Sequence and Structure (Natl. Biomed. Res. Found., Washington, D.C.), pp. 345-352, herein incorporated by reference in its entirety. The model of Dayhoff et al. uses the Point Accepted Mutation (PAM) amino acid similarity matrix (PAM 250 matrix) to determine suitable conservative amino acid substitutions. In certain aspects, conservative substitutions, such as exchanging one amino acid with another having similar properties are used. Examples of conservative amino acid substitutions as taught by the PAM 250 matrix of the Dayhoff et al. model include, but are not limited to, Gly«->Ala, Val«->Ile«-^Leu, Asp<->Glu, Lys«->Arg, Asn^GIn, and Phe«->Trp«->Tyr.

[0090] In constructing variants of the anti-SEMA4D binding molecule, e.g., an antibody or antigen-binding fragment thereof, polypeptides of interest, modifications are made such that variants continue to possess the desired properties, e.g., being capable of specifically binding to a SEMA4D, e.g., human, murine, or both human and murine SEMA4D, e.g., expressed on the surface of or secreted by a cell and having SEMA4D blocking activity, as described herein. In certain aspects, mutations made in the DNA encoding the variant polypeptide maintain the reading frame and do not create complementary regions that could produce secondary mRNA structure. See EP Patent Application Publication No. 75,444. [0091] Methods for measuring anti-SEMA4D binding molecule, e.g., an antibody or antigenbinding fragment, variant, or derivative thereof, binding specificity include, but are not limited to, standard competitive binding assays, assays for monitoring immunoglobulin secretion by T cells or B cells, T cell proliferation assays, apoptosis assays, ELISA assays, and the like. See, for example, such assays disclosed in WO 93/14125; Shi et al., Immunity 13:633-642 (2000); Kumanogoh et al., J Immunol 169: 1175-1181 (2002); Watanabe et al., J Immunol 167:4321- 4328 (2001); Wang et al., Blood 97:3498-3504 (2001); and Giraudon et al., J Immunol 172(2): 1246-1255 (2004), all of which are herein incorporated by reference.

[0092] When discussed herein whether any particular polypeptide, including the constant regions, CDRs, VH domains, or VL domains disclosed herein, is at least about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or even about 100% identical to another polypeptide, the % identity can be determined using methods and computer program s/software known in the art such as, but not limited to, the BESTFIT program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711). BESTFIT uses the local homology algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482-489, to find the best segment of homology between two sequences. When using BESTFIT or any other sequence alignment program to determine whether a particular sequence is, for example, 95% identical to a reference sequence according to the present disclosure, the parameters are set, of course, such that the percentage of identity is calculated over the full length of the reference polypeptide sequence and that gaps in homology of up to 5% of the total number of amino acids in the reference sequence are allowed.

[0093] For purposes of the present disclosure, percent sequence identity can be determined using the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62. The Smith-Waterman homology search algorithm is taught in Smith and Waterman (1981) Adv. Appl. Math. 2:482- 489. A variant can, for example, differ from a reference anti-SEMA4D antibody (e.g., MAb VX15/2503, 67, 76, or 2282) by as few as 1 to 15 amino acid residues, as few as 1 to 10 amino acid residues, such as 6-10, as few as 5, as few as 4, 3, 2, or even 1 amino acid residue. [0094] The constant region of an anti-SEMA4D antibody can be mutated to alter effector function in a number of ways. For example, see U.S. Pat. No. 6,737,056Bl and U.S. Patent Application Publication No. 2004/0132101A1, which disclose Fc mutations that optimize antibody binding to Fc receptors.

[0095] In certain anti-SEMA4D antibodies or fragments, variants or derivatives thereof useful in the methods provided herein, the Fc portion can be mutated to decrease effector function using techniques known in the art. For example, the deletion or inactivation (through point mutations or other means) of a constant region domain can reduce Fc receptor binding of the circulating modified antibody thereby increasing tumor localization. In other cases, constant region modifications consistent with the instant disclosure moderate complement binding and thus reduce the serum half-life. Yet other modifications of the constant region can be used to modify disulfide linkages or oligosaccharide moieties that allow for enhanced localization due to increased antigen specificity or antibody flexibility. The resulting physiological profile, bioavailability and other biochemical effects of the modifications, such as tumor localization, biodistribution and serum half-life, can easily be measured and quantified using well known immunological techniques without undue experimentation.

[0096] Anti-SEMA4D antibodies for use in the methods provided herein include derivatives that are modified, e.g., by the covalent attachment of any type of molecule to the antibody such that covalent attachment does not prevent the antibody from specifically binding to its cognate epitope. For example, but not by way of limitation, the antibody derivatives include antibodies that have been modified, e.g., by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, formylation, etc. Additionally, the derivative can contain one or more non- classical amino acids.

[0097] A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a side chain with a similar charge. Families of amino acid residues having side chains with similar charges have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), betabranched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Alternatively, mutations can be introduced randomly along all or part of the coding sequence, such as by saturation mutagenesis, and the resultant mutants can be screened for biological activity to identify mutants that retain activity (e.g., the ability to bind an anti-SEMA4D polypeptide, to block SEMA4D interaction with its receptor, or to inhibit, delay, or reduce metastases in a subject, e.g., a cancer patient).

[0098] For example, it is possible to introduce mutations only in framework regions or only in CDR regions of an antibody molecule. Introduced mutations can be silent or neutral missense mutations, i.e., have no, or little, effect on an antibody's ability to bind antigen. These types of mutations can be useful to optimize codon usage or improve a hybridoma's antibody production. Alternatively, non-neutral missense mutations can alter an antibody's ability to bind antigen. One of skill in the art would be able to design and test mutant molecules with desired properties such as no alteration in antigen binding activity or alteration in binding activity (e.g., improvements in antigen binding activity or change in antibody specificity). Following mutagenesis, the encoded protein can routinely be expressed and the functional and/or biological activity of the encoded protein, (e.g., ability to immunospecifically bind at least one epitope of a SEMA4D polypeptide) can be determined using techniques described herein or by routinely modifying techniques known in the art.

[0099] In certain embodiments, the anti-SEMA4D antibodies for use in the methods provided herein comprise at least one optimized complementarity-determining region (CDR). By "optimized CDR" is intended that the CDR has been modified and optimized to improve binding affinity and/or anti-SEMA4D activity that is imparted to an anti-SEMA4D antibody comprising the optimized CDR. "Anti-SEMA4D activity" or "SEMA4D blocking activity" can include activity which modulates one or more of the following activities associated with SEMA4D: B cell activation, aggregation and survival; CD40-induced proliferation and antibody production; antibody response to T cell dependent antigens; T cell or other immune cell proliferation; dendritic cell maturation; demyelination and axonal degeneration; apoptosis of pluripotent neural precursors and/or oligodendrocytes; induction of endothelial cell migration; inhibition of spontaneous monocyte migration; binding to cell surface plexin Bl or other receptor, or any other activity association with soluble SEMA4D or SEMA4D that is expressed on the surface of SEMA4D+ cells. In a particular embodiment, anti-SEMA4D activity includes the ability to inhibit, delay, or reduce the rate of cognitive decline in certain subjects having an MMSE score in the range of 22-26.

[00100] Examples of optimized antibodies based on murine anti-SEMA4D MAb BD16 were described in U.S. Publ. No. 2008/0219971 Al, International Patent Application WO 93/14125 and Herold et al., Int. Immunol. 7(1): 1-8 (1995), each of which are herein incorporated by reference in their entirety. The modifications can involve replacement of amino acid residues within the CDR such that an anti-SEMA4D antibody retains specificity for the SEMA4D antigen and has improved binding affinity and/or improved anti-SEMA4D activity.

Treatment Using Therapeutic Anti-SEMA4D Antibodies

[00101] Certain methods of the disclosure are directed to the use of anti-SEMA4D antibodies, including antigen-binding fragments, variants, and derivatives thereof, for the treatment of cognitive impairment indicated by an MMSE score in the range of 22-26 or by an equivalent score obtained via another standard cognitive assessment to inhibit, delay, or reduce further cognitive decline associated with AD. Such methods of the disclosure for treating, inhibiting, delaying, or reducing cognitive decline in a subject comprise (a) determining the cognitive impairment status of the subject; and (b) selecting the subject for treatment if the subject has a Mini Mental State Exam (MMSE) score in the range of 22-26 and/or an equivalent score from another standardized cognitive assessment test. In some embodiments, the subject has an elevated plasma level of Glial Fibrillary Acidic Protein (GFAP), an elevated ratio of A 42/AP4O in the cerebral spinal fluid (CSF), and/or the presence of amyloid plaque in the brain as evidence by positron emission tomography, for example.

Pharmaceutical Compositions and Administration Methods

[00102] Methods of preparing and administering anti-SEMA4D antibodies, or antigen-binding fragments, variants, or derivatives thereof alone or in combination with at least one other therapeutic agent for the treatment of cognitive decline to a subject in need thereof are well known to or are readily determined by those skilled in the art. The route of administration of the anti-SEMA4D antibody, or antigen-binding fragment, variant, or derivative thereof in combination can be, for example, oral, parenteral, by inhalation or topical at the same or different times for each therapeutic agent. The term parenteral as used herein includes, e.g., intravenous, intraarterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration. While all these forms of administration are clearly contemplated as being within the scope of the disclosure, an example of a form for administration would be a solution for injection, in particular for intravenous or intraarterial injection or drip. A suitable pharmaceutical composition for injection can comprise a buffer (e.g. acetate, phosphate or citrate buffer), a surfactant (e.g. polysorbate), optionally a stabilizer agent (e.g. human albumin), etc. However, in other methods compatible with the teachings herein, anti-SEMA4D antibodies, or antigen-binding fragments, variants, or derivatives thereof in combination with at least one other immune modulating therapy can be delivered directly to the site of the adverse cellular population thereby increasing the exposure of the diseased tissue to the therapeutic agent.

[00103] The amount of anti-SEMA4D antibody or binding fragment, variant, or derivative thereof, to be administered is readily determined by one of ordinary skill in the art without undue experimentation given the disclosure of the present disclosure. Factors influencing the mode of administration and the respective amount of anti-SEMA4D antibody, antigen-binding fragment, variant or derivative thereof to be administered include, but are not limited to, the severity of the cognitive decline, and the age, height, weight, health, and physical condition of the individual undergoing therapy. Similarly, the amount of anti-SEMA4D antibody, or fragment, variant, or derivative thereof to be administered will be dependent upon the mode of administration and the duration of treatment with this agent.

Examples

[00104] The examples presented herein represent certain embodiments of the present disclosure. However, it is to be understood that these examples are for illustration purposes only and do not intend, nor should any be construed, to be wholly definitive as to conditions and scope of this disclosure. The examples were carried out using standard techniques, which are known and routine to those of skill in the art, except where otherwise described in detail.

[00105] Example 1. Pepinemab Treatment for MCI. SIGNAL-AD is a clinical trial for people with MCI or mild dementia due to Alzheimer’s Disease (NCT04381468). The SIGNAL-AD study is a randomized, double-blinded, placebo-controlled Phase lb/2 study designed to evaluate the safety, tolerability and effects on cognition and brain metabolism of the SEMA4D inhibitor, pepinemab (an anti-SEMA4D antibody). Patients were randomized 1 : 1 to receive pepinemab (at 40 mg/kg or placebo), administered as an intravenous infusion (IV) every 4 weeks for 48 weeks (12 infusions). The study includes a safety and efficacy evaluation four weeks after the last dose of study drug. Outcome measures include safety, an evaluation of brain metabolism and a battery of biomarkers and standard cognitive assessments specific to

AD.

[00106] Patients were selected for participation in the study depending on amyloid-positive status and their score obtained in the CDR-GS assay or MMSE score. Subjects were selected for participation if they had a CDR-GS score of 0.5 (MCI) or 1.0 or 0 (normal, control subjects) and an MMSE score of 17-26. Pre-specified subgroups included a subgroup of participants with baseline CDR-GS score of 0.5 or 1, and a subgroup of patients with MMSE range of 22- 26 orl7-21. Fourteen subjects with a CDR-GS score of 0.5 and ten subjects with a CDR-GS score of 1 received 40 mg/kg pepinemab; 11 subjects with a CDR-GS score of 0.5 and 13 subjects with a CDR-GS score of 1.0 received placebo. These included thirteen subjects with an MMSE score of MMSE 22-26 and eleven subjects with an MMSE score of 17-21 who received 40 mg/kg pepinemab. Thirteen subjects with an MMSE score of 22-26 and thirteen subjects with an MMSE score of 17-21 received placebo. Subjects with non- Alzheimer’s disease- associated dementia, e.g. Lewy body dementia, frontotemporal dementia, were excluded from the study, as were subjects with psychiatric conditions that could cause cognitive impairment, schizophrenia or a history of concussions.

[00107] Key study outcomes included safety, tolerability, clinical outcome assessments including CDR-SB, iADRS, and ADAS-Cogl3, as well as changes in biomarkers like FDG-PET, plasma GFAP, plasma pTau 217, and other soluble biomarkers, e.g., Ap42/A[340 ratio.

[00108] Results: FDG-PET scans of the enrolled subjects show that patients with CDR-GS of

O.5 show an increased FDG-PET standardized uptake value ratio (FDG-PET SUVR) in key early Alzheimer’s disease brain regions of interest (ROI) compared to placebo controls and subjects who scored 1.0 on the CDR-GS at baseline. See Figures 1A-C.

[00109] Figures 1A-C display point estimates and 95% confidence intervals for the difference between treatment with pepinemab and placebo estimated from a fitted Mixed Model Repeated Measures (MMRM) model.

SUVR: Standardized uptake value ratios ROI: Region of interest

[00110] The effect of pepinemab treatment for these subj ects on the plasma level of GFAP, which is released into the blood by reactive astrocytes, is shown in Figures 2A and 2B.

[00111] The results show that pepinemab treatment reduces plasma GFAP in subjects having a baseline CDR-GS score of 0.5, but not in the total population (ALL) which includes both subjects with a baseline CDR-GS score of 0.5 and 1.0. -2.0

[00112] Example 2. Clinical Outcome Assessments. Clinical outcome assessments of the subjects enrolled above show that patients with baseline MMSE scores of 22-26 who are treated with pepinemab show improved numerical scores in CDR-SB, iADRS, and ADAS- Cogl3 over 48 weeks of treatment, compared to placebo controls and subjects whose MMSE score at baseline was 17-21. The difference amounted to 99%, 76% and 70% slowing of cognitive decline by pepinemab treatment on clinical outcome scales CDR-SB, iADRS, and ADAS-Cogl3, respectively, in the MMSE 22-26 subgroup. This compares favorably to reported % slowing in CDR-SB for FDA-approved anti-Amyloid Beta drugs of 29% slowing of cognitive decline during 18-months treatment duration reported for donanemab, and 27% reported for lecanemab. See Figure 3.

[00113] The graphs in Figure 3 display LS mean estimates (SE) for the difference between treatment with pepinemab and placebo estimated from a fitted MMRM model. Sample sizes at each time point are provided at the top of the plot. % slowing at 48 weeks is calculated as: ((LS Mean Change in Pepinemab - LS Mean Change in Placebo) / LS Mean Change in Placebo) * 100.

Claims

Claims:

1. Use of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) for treating a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), wherein the subject has a level of cognitive impairment indicated by a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

2. The use of claim 1, wherein said antibody or antigen-binding fragment thereof inhibits SEMA4D interaction with its receptor.

3. The use of claim 2, wherein the receptor is Plexin-Bl, Plexin-B2, CD72, or any combination thereof.

4. The use of claims 1-3, wherein the antibody or fragment thereof inhibits SEMA4D- mediated signal transduction.

5. The use of any one of claims 1-4, wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of

(i) an antibody or antigen binding fragment thereof comprising a variable heavy chain (VH) region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 1, 2, and 3, respectively, and a variable light chain (VL) region comprising VL CDRs 1-3 comprising SEQ ID NOS: 4, 5, and 6, respectively;

(ii) the antibody of (i), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 7 and SEQ ID NO: 8 (human), or SEQ ID NO: 9 and SEQ ID NO: 10 (mouse);

(iii) an antibody or antigen binding fragment thereof comprising a VH region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 11, 12, and 13, respectively; and a VL region comprising VL CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 14, 15, and 16, respectively; and

(iv) the antibody of (ii), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 17 and SEQ ID NO: 18.

6. The use of claim 5, wherein the antibody is pepinemab.

7. The use of any one of claims 1-6, wherein the cognitive test score is obtained by administering to the subject a standardized cognitive test selected from the Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating-Global Scale (CDR-GS).

8. The use of claim 7, wherein the standardized cognitive test is the MMSE.

9. The use of any one of claims 1-8, wherein administration of the isolated antibody or antigen-binding fragment thereof to the subject results in enhanced therapeutic efficacy relative to administration of the isolated antibody or antigen-binding fragment thereof to a subject with a cognitive test score of or equivalent to an MMSE score in the range of 17-21.

10. A method of selecting a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD) for treatment with an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D), said method comprising (a) determining the cognitive impairment status of the subject by administering a standardized cognitive test to the subject; and (b) selecting the subject for treatment if the subject has a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

11. A method of treating cognitive decline in a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), said method comprising (a) determining the cognitive impairment status of the subject by administering a standardized cognitive test to the subject; and (b) administering a therapeutically effective amount of an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) to the subject if the subject has a cognitive test score of or equivalent to a Mini Mental State Exam (MMSE) score in the range of 22-26.

12. A method of slowing cognitive decline in a subject having, suspected of having, or at risk of having Alzheimer’s disease (AD), said method comprising (a) determining the cognitive impairment status of the subject by administering at least one standardized cognitive test, preferably the Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) or Clinical Dementia Rating - Global Score (CDR-GS), to the subject; and (b) administering to the subject an isolated antibody or antigen-binding fragment thereof that specifically binds to semaphorin-4D (SEMA4D) if the subject has a Mini-Mental State Exam (MMSE) score in the range of 22-26, a MoCA score or 20-25 or 19-25 and/or a CDR-GS score of 0.5.

13. The method of any one of claims 10-12, wherein said antibody or antigen-binding fragment thereof inhibits SEMA4D interaction with its receptor.

14. The method of claim 13, wherein the receptor is Plexin-Bl, Plexin-B2, CD72, or any combination thereof.

15. The method of claim 14, wherein the antibody or fragment thereof inhibits SEMA4D- mediated signal transduction.

16. The method of any one of claims 10-15, wherein said antibody or antigen-binding fragment thereof is selected from the group consisting of

(i) an antibody or antigen binding fragment thereof comprising a variable heavy chain (VH) region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 1, 2, and 3, respectively, and a variable light chain (VL) region comprising VL CDRs 1-3 comprising SEQ ID NOS: 4, 5, and 6, respectively;

(ii) the antibody of (i), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 7 and SEQ ID NO: 8 (human), or SEQ ID NO: 9 and SEQ ID NO: 10 (mouse);

(iii) an antibody or antigen binding fragment thereof comprising a VH region having VH CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 11 , 12, and 13, respectively; and a VL region comprising VL CDRs 1-3 comprising amino acid sequences SEQ ID NOS: 14, 15, and 16, respectively; and

(iv) the antibody of (ii), or antigen binding fragment thereof, wherein the VH and VL chains comprise, respectively, SEQ ID NO: 17 and SEQ ID NO: 18.

17. The method of claim 16, wherein the antibody is pepinemab.

18. The method of any one of claims 10-17, wherein the standardized cognitive test is selected from the Mini Mental State Exam (MMSE), Montreal Cognitive Assessment (MoCA) and Clinical Dementia Rating-Global Scale (CDR-GS).

19. The method of claim 18, wherein the standardized cognitive test is the MMSE.

20. The method of any one of claims 10-19, wherein administration of the isolated antibody or antigen-binding fragment thereof results in enhanced therapeutic efficacy relative to administration of the isolated antibody or antigen-binding fragment thereof to a subject with a cognitive test score of or equivalent to an MMSE score in the range of 17-21.

21. The method of claim 20, wherein the standardized cognitive assessment test is the Montral Cognitive Assessment (MoCA).

22. The method of any one of claims 10-21, wherein administration of the isolated antibody or antigen-binding fragment thereof results in enhanced therapeutic efficacy relative to administration of the isolated antibody or antigen-binding fragment thereof to a subject with a MoCA test score of <19.

23. The method of claim 21 , wherein the standardized cognitive assessment test is the Clinical Dementia Rating-Global Scale (CDR-GS).

24. The method of claim 21, wherein the CDR-GS test score of the subject is 0.5.

25. The method of any one of claims 10-24, wherein the subject is suspected of having AD.