How to use anti-TREM2 antibodies

Abstract

The present disclosure is generally directed to the use of anti-TREM2 antibodies in preventing, reducing the risk of, or treating disease in individuals in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 980,929, filed February 24, 2020, which is incorporated herein by reference in its entirety.

[0002] Field of the Disclosure The present disclosure relates to therapeutic uses of anti-TREM2 antibodies.

[0003] Submitting a sequence listing as an ASCII text file The contents of the following submission in an ASCII text file are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 735022003440SEQLIST.TXT, Recording Date: February 23, 2021, Size: 108KB). [Background technology]

[0004] Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) whose pathogenesis is related to inflammatory and neurodegenerative processes. The pathological hallmark of MS is the formation of demyelinated lesions in white and gray matter (Lassmann, Bruck et al. 2007). Oligodendrocyte (OL) loss during demyelination is followed by remyelination, which is primarily sustained by oligodendrocyte progenitor cells (OPCs), which differentiate into mature OLs. In MS, the failure of OL production leads to an imbalance between demyelination and remyelination. The lack of remyelination in MS ultimately leads to axonal damage, which manifests clinically as neurological disability (Dulamea (2017) Adv Exp Med Biol, 958:91-127).

[0005] Resident microglial cells and infiltrating monocytes / macrophages are thought to play dual roles in demyelinating lesions, depending on the phase of lesion formation. On the one hand, they may contribute to myelin damage and lesion expansion; on the other hand, they may promote remyelination of such lesions by supporting the generation of OLs to clear myelin debris, reduce inflammation, and secrete regenerative factors (Kotter, Li et al. 2006; Lampron, Larochelle et al. 2015; Franklin and French-Constant 2017; Voet, Prinz et al. 2019). TREM2 is a key regulator of microglial function in the CNS (Cantoni, Bollman et al. 2015; Poliani, Wang et al. 2015; Kiialainen et al. 2005; Schmid et al. 2002). Mutations in TREM2 are associated with neurodegenerative diseases such as Nasu-Hakola disease (NHD), a rare genetic disorder characterized by loss of myelin and axons in the brain (Klunemann, Ridha et al. 2005), Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis (Guerreiro, Wojtas et al. 2012, Jonsson, Stefansson et al. 2012, Rayaprolu, Mullen et al. 2013, Cady, Koval et al. 2014).

[0006] Current treatments for demyelinating diseases such as MS target the inflammatory disease component, thereby reducing attack frequency. However, no treatments are currently available to regenerate myelin and halt disease progression. Thus, there is a need in the art for treatments that promote remyelination in MS and other demyelinating diseases.

[0007] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0008] The present disclosure is generally directed to methods of treating an individual having a demyelinating disease, comprising administering to the individual an antibody that binds to the TREM2 protein, wherein the antibody is an agonist.

[0009] In one aspect, provided herein are methods for treating or preventing a central nervous system (CNS) demyelinating disease, comprising administering to an individual in need thereof a therapeutically effective amount of an agonist antibody that binds to the TREM2 protein. In some embodiments, the antibody promotes remyelination in one or more demyelinating lesions in the individual's CNS.

[0010] In another aspect, provided herein is a method for promoting remyelination of one or more demyelinating lesions in an individual having a central nervous system (CNS) demyelinating disease, the method comprising administering to the individual a therapeutically effective amount of an agonist antibody that binds to TREM2 protein.

[0011] In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a mammalian or human protein. In some embodiments, the TREM2 protein is a wild-type protein, a naturally occurring variant, or a disease variant.

[0012] In some embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TREM2 activities selected from: (a) TREM2 binding to DAP12; (b) DAP12 phosphorylation; (c) activation of Syk kinase; (d) recruitment of Syk to the DAP12 / TREM2 complex; or (e) increased activity of one or more TREM2-dependent genes (optionally, wherein the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor).

[0013] In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities that are induced in the presence of myelin. In some embodiments, the one or more TREM2 activities that are induced in the presence of myelin include increased activity of one or more TREM2-dependent genes, optionally wherein the one or more TREM2-dependent genes include a nuclear factor of activated T cells (NFAT) transcription factor.

[0014] In some embodiments that may be combined with any of the preceding embodiments, the antibody promotes recruitment of oligodendrocyte progenitor cells (OPCs) to one or more demyelinating lesions in the CNS of an individual. In some embodiments, the OPCs are PDGFRα positive.

[0015] In some embodiments that may be combined with any of the preceding embodiments, the antibody promotes an increase in mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS of an individual. In some embodiments, the antibody promotes differentiation of OPCs into mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS of an individual. In some embodiments, the mature OLs are OLIG2 and / or CNPase positive.

[0016] In some embodiments that may be combined with any of the preceding embodiments, the antibody promotes increased levels of phosphorylated neurofilaments in one or more demyelinating lesions in the CNS of the individual. In some embodiments, the phosphorylated neurofilaments are SMI-31 positive.

[0017] In some embodiments that may be combined with any of the preceding embodiments, the antibody promotes clearance of myelin debris in one or more demyelinating lesions in an individual.

[0018] In some embodiments that may be combined with any of the preceding embodiments, the antibody is a murine antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody binds to one or more amino acids within amino acid residues 124-153 of SEQ ID NO:1, or within amino acid residues on a TREM2 protein corresponding to amino acid residues 124-153 of SEQ ID NO:1; within amino acid residues 129-153 of SEQ ID NO:1, or within amino acid residues on a TREM2 protein corresponding to amino acid residues 129-153 of SEQ ID NO:1; within amino acid residues 140-149 of SEQ ID NO:1, or within amino acid residues on a TREM2 protein corresponding to amino acid residues 140-149 of SEQ ID NO:1; within amino acid residues 149-157 of SEQ ID NO:1, or within amino acid residues on a TREM2 protein corresponding to amino acid residues 149-157 of SEQ ID NO:1; or within amino acid residues 153-162 of SEQ ID NO:1, or within amino acid residues on a TREM2 protein corresponding to amino acid residues 153-162 of SEQ ID NO:1. In some embodiments, the antibody binds to one or more amino acid residues selected from D140, L141, W142, F143, P144, E151, D152, H154, E156, or H157 of SEQ ID NO:1, or one or more amino acid residues on a mammalian TREM2 protein corresponding to amino acid residues selected from D140, L141, W142, F143, P144, E151, D152, H154, E156, or H157 of SEQ ID NO:1.

[0019] In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30. In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0020] In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein HVR-H1 comprises the amino acid sequence YAFSSWDMN (SEQ ID NO:36), HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO:37), HVR-H3 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO:38), HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO:39), HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO:40), and HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO:32). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:28, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:29. In some embodiments, the antibody comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; or (b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

[0021] In some embodiments that may be combined with any of the preceding embodiments, the antibody is a fragment, and the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In some embodiments, the antibody is of the IgG class, IgM class, or IgA class. In some embodiments, the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, the antibody has a human IgG1 isotype and contains amino acid substitutions at residue positions P331S and E430G in the Fc region, where residue numbering is according to EU numbering.

[0022] In some embodiments that may be combined with any of the preceding embodiments, the individual is a human. In some embodiments, the individual comprises at least one copy of a functional TREM2 gene. In some embodiments, the individual is heterozygous for a mutation in the TREM2 gene. In some embodiments, the individual is homozygous for a mutation in the TREM2 gene.

[0023] In some embodiments that may be combined with any of the preceding embodiments, the individual has or is at risk for a disease feature selected from myelin damage, one or more demyelinating lesions in the CNS, inflammation in the CNS, one or more plaques in the CNS, loss of myelin sheath, axonal injury, decreased OPCs, decreased OLs, decreased myelin debris clearance, axonal varicosity, axonal spheroids, gliosis, autofluorescent lipid-laden macrophages, axonal destruction, or any combination thereof. In some embodiments, the individual has or is at risk for axonal damage and / or one or more demyelinating lesions in the CNS. In some embodiments, the axonal damage and / or one or more demyelinating lesions in the CNS are present in the white matter, gray matter, or corpus callosum of the CNS.

[0024] In some embodiments that may be combined with any of the preceding embodiments, the individual has or is at risk of having a symptom selected from altered sensation, cramping, numbness, muscle weakness, clonus, muscle spasms, difficulty moving, difficulty with coordination, difficulty with balance, difficulty speaking, difficulty swallowing, difficulty with vision, fatigue, acute pain, chronic pain, bladder problems, bowel problems, cognitive problems, depression, unstable mood, Uhthoff phenomenon, Lhermitte's sign, or any combination thereof.

[0025] In some embodiments that may be combined with any of the preceding embodiments, the demyelinating disease or disorder is multiple sclerosis, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, or adrenomyeloneuropathy. In some embodiments, the demyelinating disease or disorder is multiple sclerosis.

[0026] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 52; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 53; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 54; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 55;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 56; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 57. In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

[0027] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 60; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 61; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 62; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 63;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 64; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 65. In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 60; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 61; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 63; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 64; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 65.

[0028] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 68; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 69; and / or the light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 70; and / or the light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 71;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 72; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 73. In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 69; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 71; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 72; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 73.

[0029] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 159; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 160; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 161; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 156;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 157; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 158. In some embodiments that may be combined with any of the preceding embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 159; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 160; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 161; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 156; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 157; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0030] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 169; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 170; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 171; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 166;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 167; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 168. In some embodiments that may be combined with any of the preceding embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0031] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 175; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 176; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 177; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 172;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 173; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 174. In some embodiments that may be combined with any of the preceding embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0032] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 181; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 182; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 183; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 178;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 179; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 180. In some embodiments that may be combined with any of the preceding embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 181; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 182; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 183; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 178; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 179; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 180. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0033] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 187; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 188; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 189; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 184;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 185; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 186. In some embodiments that may be combined with any of the preceding embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 187; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 188; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 189; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 184; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 185; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 186. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0034] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or different from the heavy chain variable domain amino acid sequence of antibody 42E8.H1, or to the amino acid sequence of SEQ ID NO:58, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 42E8.H1 or to the amino acid sequence of SEQ ID NO:59. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 42E8.H1 or to the amino acid sequence of SEQ ID NO: 58, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 42E8.H1.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 42E8.H1 or to the amino acid sequence of SEQ ID NO: 59, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 42E8.H1. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 42E8.H1 or to the amino acid sequence of SEQ ID NO: 58, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 42E8.H1 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 42E8.H1 or the amino acid sequence of SEQ ID NO: 58. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 42E8.H1 or SEQ ID NO: 58, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 42E8.H1, (b) the HVR-H2 amino acid sequence of antibody 42E8.H1, and (c) the HVR-H3 amino acid sequence of antibody 42E8.H1. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 42E8.H1 or to the amino acid sequence of SEQ ID NO: 59, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 42E8.H1 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 42E8.H1 or the amino acid sequence of SEQ ID NO: 59. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 42E8.H1 or SEQ ID NO: 59, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 42E8.H1, (b) the HVR-L2 amino acid sequence of antibody 42E8.H1, and (c) the HVR-L3 amino acid sequence of antibody 42E8.H1. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 59.

[0035] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or different from the heavy chain variable domain amino acid sequence of antibody RS9.F6, or to the amino acid sequence of SEQ ID NO: 66, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody RS9.F6 or to the amino acid sequence of SEQ ID NO:67. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody RS9.F6 or to the amino acid sequence of SEQ ID NO: 66, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody RS9.F6.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody RS9.F6 or to the amino acid sequence of SEQ ID NO: 67, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody RS9.F6. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody RS9.F6 or to the amino acid sequence of SEQ ID NO: 66, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody RS9.F6 or the amino acid sequence of SEQ ID NO: 66. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody RS9.F6 or the amino acid sequence of SEQ ID NO: 66. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody RS9.F6 or SEQ ID NO: 66, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody RS9.F6, (b) the HVR-H2 amino acid sequence of antibody RS9.F6, and (c) the HVR-H3 amino acid sequence of antibody RS9.F6. In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain (VL) sequence that has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody RS9.F6 or to the amino acid sequence of SEQ ID NO: 67, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although anti-TREM2 antibodies comprising that sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody RS9.F6 or the amino acid sequence of SEQ ID NO: 67. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody RS9.F6 or the amino acid sequence of SEQ ID NO: 67. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody RS9.F6 or SEQ ID NO: 67, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody RS9.F6, (b) the HVR-L2 amino acid sequence of antibody RS9.F6, and (c) the HVR-L3 amino acid sequence of antibody RS9.F6. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 66 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 67.

[0036] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 74; and / or the light chain variable domain comprises an amino acid sequence at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the amino acid sequence of SEQ ID NO: 74, and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 74. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 74. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions.Optionally, the anti-TREM2 antibody comprises the VH sequence of SEQ ID NO: 74, including post-translational modifications of that sequence. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 75, and contain substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 75. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the amino acid sequence of SEQ ID NO: 75. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of SEQ ID NO: 75, including post-translational modifications of that sequence. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 74 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 75.

[0037] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, at least 142%, at least 143%, at least 144%, at least 145%, at least 146%, at least 147%, at least 148%, at least 149, at least 150%, at least 151%, at least 152%, at least 15 and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 6E7 or the amino acid sequence of SEQ ID NO: 148. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 6E7 or to the amino acid sequence of SEQ ID NO: 149, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 6E7.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 6E7 or to the amino acid sequence of SEQ ID NO: 148, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 6E7. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 6E7 or to the amino acid sequence of SEQ ID NO: 149, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 6E7 or the amino acid sequence of SEQ ID NO: 149. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 6E7 or the amino acid sequence of SEQ ID NO: 149. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 6E7 or SEQ ID NO: 149, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 6E7, (b) the HVR-H2 amino acid sequence of antibody 6E7, and (c) the HVR-H3 amino acid sequence of antibody 6E7. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 6E7 or to the amino acid sequence of SEQ ID NO: 148, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to a reference sequence), although anti-TREM2 antibodies comprising that sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 6E7 or the amino acid sequence of SEQ ID NO: 148. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 6E7 or the amino acid sequence of SEQ ID NO: 148. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 6E7 or SEQ ID NO: 148, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 6E7, (b) the HVR-L2 amino acid sequence of antibody 6E7, and (c) the HVR-L3 amino acid sequence of antibody 6E7. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 149 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 148. In some embodiments, an anti-TREM2 antibody of the disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph.In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the same TREM2 epitope as the antibody of any of the embodiments described in this paragraph.

[0038] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or identical to the heavy chain variable domain amino acid sequence of antibody 5E3, or to the amino acid sequence of SEQ ID NO: 151, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 5E3 or to the amino acid sequence of SEQ ID NO: 150. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 5E3 or to the amino acid sequence of SEQ ID NO: 151, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 5E3.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 5E3 or to the amino acid sequence of SEQ ID NO: 150, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 5E3. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 5E3 or to the amino acid sequence of SEQ ID NO: 151, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 5E3 or the amino acid sequence of SEQ ID NO: 151. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 5E3 or the amino acid sequence of SEQ ID NO: 151. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 5E3 or SEQ ID NO: 151, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 5E3, (b) the HVR-H2 amino acid sequence of antibody 5E3, and (c) the HVR-H3 amino acid sequence of antibody 5E3. In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain (VL) sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 5E3 or to the amino acid sequence of SEQ ID NO: 150, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although anti-TREM2 antibodies comprising that sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 5E3 or the amino acid sequence of SEQ ID NO: 150. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 5E3 or the amino acid sequence of SEQ ID NO: 150. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 5E3 or SEQ ID NO: 150, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 5E3, (b) the HVR-L2 amino acid sequence of antibody 5E3, and (c) the HVR-L3 amino acid sequence of antibody 5E3. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 150. In some embodiments, an anti-TREM2 antibody of the disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph.In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the same TREM2 epitope as the antibody of any of the embodiments described in this paragraph.

[0039] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the amino acid sequence of the heavy chain variable domain of antibody 24G6, or to the amino acid sequence of SEQ ID NO: 153. and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 24G6 or to the amino acid sequence of SEQ ID NO: 152. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 24G6 or to the amino acid sequence of SEQ ID NO: 153, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 24G6.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 24G6 or to the amino acid sequence of SEQ ID NO: 152, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 24G6. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 24G6 or to the amino acid sequence of SEQ ID NO: 153, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 24G6 or the amino acid sequence of SEQ ID NO: 153. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 24G6 or the amino acid sequence of SEQ ID NO: 153. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 24G6 or SEQ ID NO: 153, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 24G6, (b) the HVR-H2 amino acid sequence of antibody 24G6, and (c) the HVR-H3 amino acid sequence of antibody 24G6. In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain (VL) sequence that has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 24G6 or to the amino acid sequence of SEQ ID NO: 152, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to a reference sequence), although anti-TREM2 antibodies comprising that sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 24G6 or the amino acid sequence of SEQ ID NO: 152. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 24G6 or the amino acid sequence of SEQ ID NO: 152. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 24G6 or SEQ ID NO: 152, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 24G6, (b) the HVR-L2 amino acid sequence of antibody 24G6, and (c) the HVR-L3 amino acid sequence of antibody 24G6. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 153 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 152.In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0040] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or identical to the heavy chain variable domain amino acid sequence of antibody 25F12, or to the amino acid sequence of SEQ ID NO: 155, such as at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 25F12 or to the amino acid sequence of SEQ ID NO: 154. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 25F12 or to the amino acid sequence of SEQ ID NO: 155, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 25F12.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 25F12 or to the amino acid sequence of SEQ ID NO: 154, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 25F12. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 25F12 or to the amino acid sequence of SEQ ID NO: 155, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 25F12 or the amino acid sequence of SEQ ID NO: 155. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 25F12 or the amino acid sequence of SEQ ID NO: 155. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 25F12 or SEQ ID NO: 155, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 25F12, (b) the HVR-H2 amino acid sequence of antibody 25F12, and (c) the HVR-H3 amino acid sequence of antibody 25F12. In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain (VL) sequence that has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 25F12 or to the amino acid sequence of SEQ ID NO: 154, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although anti-TREM2 antibodies comprising that sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 25F12 or the amino acid sequence of SEQ ID NO: 154. In certain embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 25F12 or the amino acid sequence of SEQ ID NO: 154. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 25F12 or SEQ ID NO: 154, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody 25F12, (b) the HVR-L2 amino acid sequence of antibody 25F12, and (c) the HVR-L3 amino acid sequence of antibody 25F12. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 155 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 154.In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0041] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 165; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 165; The amino acid sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of 14C12 or to the amino acid sequence of SEQ ID NO:164. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 165, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 13E7 14C12.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 164, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody 13E7 14C12. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 165, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or the amino acid sequence of SEQ ID NO: 165. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 13E7 14C12 or the amino acid sequence of SEQ ID NO: 165. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 13E7 14C12 or SEQ ID NO: 165, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody 13E7 14C12, (b) the HVR-H2 amino acid sequence of antibody 13E7 14C12, and (c) the HVR-H3 amino acid sequence of antibody 13E7 14C12. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 13E7 14C12 or to the amino acid sequence of SEQ ID NO: 164, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 13E7 14C12 or the amino acid sequence of SEQ ID NO: 164. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 13E7 14C12 or the amino acid sequence of SEQ ID NO: 164. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 13E7 14C12 or SEQ ID NO: 164, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 13E7 14C12, (b) the HVR-L2 amino acid sequence of antibody 13E7 14C12, and (c) the HVR-L3 amino acid sequence of antibody 13E7 14C12. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:165 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:164.In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0042] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or different from the heavy chain variable domain amino acid sequence of antibody 13E7 (SST202443), or to the amino acid sequence of SEQ ID NO: 163, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 13E7 (SST202443) or to the amino acid sequence of SEQ ID NO: 162. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody 13E7 (SST202443) or to the amino acid sequence of SEQ ID NO: 163, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody 13E7 (SST202443).In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody 13E7 (SST202443) or to the amino acid sequence of SEQ ID NO: 162, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequence of antibody 13E7 (SST202443). In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody 13E7 (SST202443) or to the amino acid sequence of SEQ ID NO: 163, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody 13E7 (SST202443) or the amino acid sequence of SEQ ID NO: 163. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the antibody 13E7 (SST202443) heavy chain variable domain amino acid sequence or the amino acid sequence of SEQ ID NO: 163. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions.Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody 13E7 (SST202443) or SEQ ID NO: 163, including post-translational modifications of that sequence. In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody 13E7 (SST202443), (b) the HVR-H2 amino acid sequence of antibody 13E7 (SST202443), and (c) the HVR-H3 amino acid sequence of antibody 13E7 (SST202443). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody 13E7 (SST202443) or to the amino acid sequence of SEQ ID NO: 162, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 13E7 (SST202443) or the amino acid sequence of SEQ ID NO: 162. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody 13E7 (SST202443) or the amino acid sequence of SEQ ID NO: 162. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody 13E7 (SST202443) or SEQ ID NO: 162, including post-translational modifications of that sequence.In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody 13E7 (SST202443), (b) the HVR-L2 amino acid sequence of antibody 13E7 (SST202443), and (c) the HVR-L3 amino acid sequence of antibody 13E7 (SST202443). In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 163 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 162. In some embodiments, an anti-TREM2 antibody of the disclosure competes for binding to TREM2 with the antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the disclosure binds to the same TREM2 epitope as the antibody of any of the embodiments described in this paragraph.

[0043] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 34; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 35; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 41; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 41;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 33; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 32;

[0044] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 36; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 37; and / or said light chain variable domain comprises one or more of: (a) an HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 38; and / or said light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 39;(b) an HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 40; and (c) an HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 32;

[0045] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or different from the heavy chain variable domain amino acid sequence of antibody AL2p-47, or to the amino acid sequence of SEQ ID NO: 28, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO:29. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 28, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-47.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 29, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-47. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 28, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 28. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-47 or SEQ ID NO: 28, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody AL2p-47; (b) the HVR-H2 amino acid sequence of antibody AL2p-47; and (c) the HVR-H3 amino acid sequence of antibody AL2p-47. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 29, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 29. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 29. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-47 or SEQ ID NO: 29, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody AL2p-47, (b) the HVR-L2 amino acid sequence of antibody AL2p-47, and (c) the HVR-L3 amino acid sequence of antibody AL2p-47. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0046] In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain has a sequence similar to or at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% similar to the heavy chain variable domain amino acid sequence of antibody AL2p-58, or to the amino acid sequence of SEQ ID NO:27. and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO:30. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 27, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-58.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 30, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-58. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 27, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 27. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 27. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-58 or SEQ ID NO: 27, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody AL2p-58, (b) the HVR-H2 amino acid sequence of antibody AL2p-58, and (c) the HVR-H3 amino acid sequence of antibody AL2p-58. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 30, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 30. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-58 or SEQ ID NO: 30, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody AL2p-58, (b) the HVR-L2 amino acid sequence of antibody AL2p-58, and (c) the HVR-L3 amino acid sequence of antibody AL2p-58. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.

[0047] It should be understood that one, some, or all of the features of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described in the following detailed description.

[0048] The patent or application file contains at least one drawing executed in color. Copies of this patent publication or published patent application with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. [Brief explanation of the drawings]

[0049] [Figure 1A] Figure 1 shows the results of an experiment analyzing myelin debris clearance in the brains of Trem2+ / +, Trem2- / -, and Trem2+ / - mice with cuprizone (CPZ)-induced central nervous system (CNS) demyelination. Representative immunohistochemical images of the corpus callosum of Trem2+ / +, Trem2- / -, and Trem2+ / - mice with CPZ-induced CNS demyelination are shown. Anti-degraded myelin basic protein (dMBP) antibody was used to determine the amount of myelin debris accumulation; anti-Iba1 antibody was used to image Iba1+ microglia; and 4',6-diamidino-2-phenylindole (DAPI) was used to image DNA. [Figure 1B] Figure 1 shows the results of an experiment analyzing myelin debris clearance in the brains of Trem2+ / +, Trem2- / -, and Trem2+ / - mice with cuprizone (CPZ)-induced central nervous system (CNS) demyelination. Quantification of the experiment shown in Figure 1A is shown. Bars indicate the percentage of dMBP+ staining, measured as the number of dMBP-positive pixels per mm2. Data shown are means ± standard deviations (sd), with p<0.05 considered statistically significant. Asterisks indicate statistical significance ("*" = p<0.05; "**" = p<0.01; "***" = p<0.001; "****" = p<0.0001). [Figure 1C]Figure 1 shows the results of an experiment analyzing myelin debris clearance in the brains of Trem2+ / +, Trem2- / -, and Trem2+ / - mice with cuprizone (CPZ)-induced central nervous system (CNS) demyelination. Quantification of the experiment shown in Figure 1A is shown. Bars indicate the density of Iba1+ cells, measured as the number of Iba1+ cells per mm2. Data shown are means ± standard deviations (sd), with p<0.05 considered statistically significant. Asterisks indicate statistical significance ('*' = p<0.05; '**' = p<0.01; '***' = p<0.001; '****' = p<0.0001). [Figure 2] Figure 2 shows the results of immunoprecipitation experiments assessing the effect of anti-TREM2 antibody 7E5 on TREM2 signaling in vitro. Immunoblots of DAP12 phosphorylation in TREM2 immunodeposits from Trem2+ / + and Trem2- / - bone marrow-derived macrophages (BMDMs) crosslinked or stimulated in vitro with soluble anti-TREM2 antibody 7E5 or an isotype control antibody. DAP12 phosphorylation was analyzed using an anti-phosphotyrosine antibody. Actin immunoblots were used as a loading / input control. In Figure 2, "x crosslinked" indicates that anti-TREM2 antibody 7E5 or an isotype control antibody was crosslinked with the secondary antibody. "Soluble" indicates that crosslinking with the secondary antibody was not performed. [Figure 3A] Figure 1 shows the results of an in vitro TREM2 activity assay using BWZ cells expressing mouse TREM2 and DAP12 and transduced with a luciferase reporter gene under the control of an NFAT promoter. BWZ cells were treated with the indicated concentrations of anti-TREM2 antibody 7E5 or an isotype control antibody. The y-axis shows the fold luminescence induced by anti-TREM2 antibody 7E5 relative to the isotype control antibody (fold over control). Data shown are mean ± standard deviation (sd), with P<0.05 considered statistically significant. Asterisks indicate statistical significance (* = p<0.05; ** = p<0.01; *** = p<0.001; **** = p<0.0001). [Figure 3B] Figure 1 shows the results of an in vitro TREM2 activity assay using BWZ cells expressing mouse TREM2 and DAP12 and transduced with a luciferase reporter gene under the control of an NFAT promoter. BWZ cells were seeded with the indicated concentrations of myelin and subsequently treated with anti-TREM2 antibody 7E5 or an isotype control antibody. The y-axis shows the fold luminescence induced by anti-TREM2 antibody 7E5 relative to the isotype control antibody (fold over control). Data shown are mean ± standard deviation (sd), with P<0.05 considered statistically significant. Asterisks indicate statistical significance (* = p<0.05; ** = p<0.01; *** = p<0.001; **** = p<0.0001). [Figure 4A] Figure 1 shows the results of immunoprecipitation experiments analyzing the effect of anti-TREM2 antibody 7E5 on TREM2 signaling in vivo. Immunoblot of DAP12 phosphorylation in TREM2 immunodeposits from thioglycollate-induced macrophages obtained from C57BL / 6 mice treated with anti-TREM2 antibody 7E5 or an isotype control antibody. DAP12 phosphorylation was analyzed using an anti-phosphotyrosine antibody. Actin immunoblots were used as loading / input controls. [Figure 4B] Figure 4 shows the results of immunoprecipitation experiments analyzing the effect of anti-TREM2 antibody 7E5 on TREM2 signaling in vivo. Quantification of the experiment shown in Figure 4A is shown. Bars indicate normalized phosphotyrosine signal (i.e., phosphorylated DAP12). Data shown are mean ± standard deviation (sd), with P<0.05 considered statistically significant. Asterisks indicate statistical significance ("*" = p<0.05; "**" = p<0.01; "***" = p<0.001; "****" = p<0.0001). [Figure 5A]

[0039] Figure 1 shows the results of an in vivo experiment assessing the effect of anti-TREM2 antibody 7E5 on myelin debris clearance in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Figure 2 shows a diagram of the dosing regimen for anti-TREM2 antibody 7E5 or an isotype control antibody in Trem2+ / - mice. WKS = week; ON = active CPZ feeding; OFF = post-CPZ feeding; D = day; +3D = 3 days after CPZ withdrawal; +7D = 7 days after CPZ withdrawal; +14D = 14 days after CPZ withdrawal. Asterisks indicate the day brain samples were collected for analysis. "INJ" = injection of anti-TREM2 antibody 7E5 or an isotype control antibody. [Figure 5B] Figure 5 shows the results of an in vivo experiment evaluating the effect of the anti-TREM2 antibody 7E5 on myelin debris clearance in the brains of Trem2+ / − mice with CPZ-induced CNS demyelination. Representative immunohistochemistry images of the brains of Trem2+ / − mice with CPZ-induced CNS demyelination treated with the anti-TREM2 antibody 7E5 or an isotype control antibody as shown in the diagram in Figure 5A are shown. Myelin debris accumulation was determined using an anti-dMBP antibody; DNA was imaged using DAPI. WK4 = 4 weeks after CPZ feeding; WK4+3D = 3 days after CPZ withdrawal; WK4+7D = 7 days after CPZ withdrawal; WK4+14D = 14 days after CPZ withdrawal. [Figure 5C] Figures 5A-5B show results from an in vivo experiment evaluating the effect of the anti-TREM2 antibody 7E5 on myelin debris clearance in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Quantification of the experiment shown in Figures 5A-5B is shown. Bars represent the percent of dMBP+ staining at the indicated time points, measured as the number of dMBP-positive pixels per mm2. Data shown are mean ± standard deviation (sd), with P<0.05 considered statistically significant. Asterisks indicate statistical significance ("*" = p<0.05; "**" = p<0.01; "***" = p<0.001; "****" = p<0.0001). WK4 = 4 weeks after CPZ feeding; WK4+3D = 3 days after CPZ withdrawal; WK4+7D = 7 days after CPZ withdrawal; WK4+14D = 14 days after CPZ withdrawal. [Figure 6A] Figure 6 shows the results of an in vivo experiment evaluating the effect of the anti-TREM2 antibody 7E5 on the recruitment of oligodendrocyte precursor cells (OPCs) to demyelinating lesions in the brains of Trem2+ / − mice with CPZ-induced CNS demyelination. Figure 5A shows representative immunohistochemistry images of PDGFRα in the brains of Trem2+ / − mice administered the anti-TREM2 antibody 7E5 or an isotype control antibody as shown in the diagram. Figure 6A shows images from brain samples taken 3 days (WK4+3D) and 7 days (WK4+7D) after CPZ withdrawal. DNA was imaged using DAPI. [Figure 6B] Figure 6 shows the results of an in vivo experiment evaluating the effect of the anti-TREM2 antibody 7E5 on the recruitment of oligodendrocyte precursor cells (OPCs) to demyelinated lesions in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Quantification of the experiment shown in Figure 6A is shown. Bars represent the density of PDGFRα+ cells at the indicated time points, measured as the number of PDGFRα-positive cells per mm2. Data shown are mean ± standard deviation (sd), with p<0.05 considered statistically significant. Asterisks indicate statistical significance ("*" = p<0.05; "**" = p<0.01; "***" = p<0.001; "****" = p<0.0001). [Figure 7A] Figure 7A shows the results of an in vivo experiment evaluating the effect of the anti-TREM2 antibody 7E5 on OPC differentiation into mature oligodendrocytes (OLs) in the brains of Trem2+ / − mice with CPZ-induced CNS demyelination. Figure 7A shows representative immunohistochemical images of OLIG2 and CNPase in the brains of Trem2+ / − mice administered the anti-TREM2 antibody 7E5 or an isotype control antibody as shown in Figure 5A. The images shown in Figure 7A are from brain samples taken 3 days after CPZ withdrawal (WK4+3D). DNA was imaged using DAPI. [Figure 7B]Figure 7 shows the results of an in vivo experiment assessing the effect of the anti-TREM2 antibody 7E5 on OPC differentiation into mature oligodendrocytes (OLs) in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Quantification of the experiment shown in Figure 7A is shown 3 days (WK4+3D) and 7 days (WK4+7D) after CPZ withdrawal. Bars represent the density of OLIG2+ cells, measured as the number of OLIG2-positive cells per mm2. Data shown are mean ± standard deviation (sd), with p<0.05 considered statistically significant. Asterisks indicate statistical significance ("*" = p<0.05; "**" = p<0.01; "***" = p<0.001; "****" = p<0.0001). [Figure 7C] Figure 7 shows the results of an in vivo experiment assessing the effect of the anti-TREM2 antibody 7E5 on OPC differentiation into mature oligodendrocytes (OLs) in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Quantification of the experiment shown in Figure 7A is shown 3 days (WK4+3D) and 7 days (WK4+7D) after CPZ withdrawal. Bars represent the percent CNPase+ staining, measured as the number of CNPase-positive pixels per mm2. Data shown are mean ± standard deviation (sd), with P<0.05 considered statistically significant. Asterisks indicate statistical significance ('*' = p<0.05; '**' = p<0.01; '***' = p<0.001; '****' = p<0.0001). [Figure 8A] Figure 8 shows the results of an in vivo experiment assessing the effect of the anti-TREM2 antibody 7E5 on axonal health in the brains of Trem2+ / − mice with CPZ-induced CNS demyelination. Figure 8A shows representative immunohistochemistry images of SMI-31 in the brains of Trem2+ / − mice administered the anti-TREM2 antibody 7E5 or an isotype control antibody as shown in the diagram in Figure 5A. The images shown in Figure 8A are from brain samples taken 7 days after CPZ withdrawal (WK4+7D). [Figure 8B]Figure 8 shows the results of an in vivo experiment assessing the effect of the anti-TREM2 antibody 7E5 on axonal health in the brains of Trem2+ / - mice with CPZ-induced CNS demyelination. Quantification of the experiment shown in Figure 8A is shown at 3 days (WK4+3D) and 7 days (WK4+7D) after CPZ withdrawal. Bars represent the percent SMI31+ staining at the indicated time points, measured as the number of SMI31-positive pixels per mm2. Data shown are mean ± standard deviation (sd), with p<0.05 considered statistically significant. Asterisks indicate statistical significance ('*' = p<0.05; '**' = p<0.01; '***' = p<0.001; '****' = p<0.0001). DETAILED DESCRIPTION OF THE INVENTION

[0050] Provided herein are methods for treating disorders and diseases associated with demyelination by administering an agonist of TREM2, including, but not limited to, multiple sclerosis, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, and adrenomyeloneuropathy. Agonists of TREM2 include anti-TREM2 antibodies that induce one or more TREM2 activities, enhance one or more TREM2 activities induced in the presence of myelin, promote the recruitment of oligodendrocyte progenitor cells (OPCs) to one or more demyelinating lesions in the CNS, promote the increase in mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS, promote the differentiation of OPCs into mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS, promote the increase in levels of phosphorylated neurofilaments in one or more demyelinating lesions in the CNS, or promote the clearance of myelin debris in one or more demyelinating lesions in an individual.

[0051] definition As used herein, the term "preventing" includes providing prophylaxis for the occurrence or recurrence of a particular disease, disorder, or condition, including delaying the onset of a particular disease, disorder, or condition, in individuals who may be susceptible to, predisposed to, or at risk of developing such disease, disorder, or condition, but who have not yet been diagnosed with the disease, disorder, or condition.

[0052] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms, prior to the treatment methods described herein. "At risk" indicates that an individual has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition, as known in the art. Individuals who have one or more of these risk factors have a higher probability of developing a particular disease, disorder, or condition than individuals who do not have one or more of these risk factors.

[0053] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual's clinical pathology. Desirable therapeutic effects include reducing the rate of progression, ameliorating or alleviating morbidity, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully "treated," for example, if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0054] An "effective amount" refers to at least an amount that is effective, at a dosage and for a period of time necessary to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. The effective amount herein can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the treatment to induce a desired response in the individual. An effective amount is also one in which the therapeutic beneficial effects outweigh any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desired results include eliminating or reducing the risk, reducing the severity, or delaying the onset of disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes seen during the course of disease development. For therapeutic use, beneficial or desired results include clinical results, such as reducing one or more symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other drugs required to treat the disease, enhancing the effect of another drug, for example, delaying disease progression, and / or prolonging survival. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment.As understood in clinical situations, the effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.Therefore, "effective amount" can be determined in light of the administration of one or more therapeutic agents, and a single agent can be considered to be given in an effective amount when it can or does achieve the desired result in conjunction with one or more other agents.

[0055] An "individual" for purposes of treating, preventing, or reducing risk refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual is a human.

[0056] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Administering in conjunction also encompasses administration as a co-formulation or as separate compositions, including at different dosing frequencies or intervals, and using the same or different routes of administration.

[0057] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0058] The basic four-chain antibody unit is a heterotetrameric glycoprotein consisting of two identical light (L) chains and two identical heavy (H) chains. H and V L pairing together to form a single antigen-binding site. For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0059] Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of their heavy chain constant domains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known; see, e.g., Abbas et al., Cellular and Molecular Immunology, 4 th It is generally described in Saunders Co., ed. (WB Saunders Co., 2000).

[0060] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains at one end a variable domain (V) followed by a number of constant domains. H Each light chain has a variable domain (V L ) at its other end, with the light-chain constant domain aligned with the first heavy-chain constant domain and the light-chain variable domain aligned with the heavy-chain variable domain. Particular amino acid residues are believed to form an interface between the light-chain variable domain and the heavy-chain variable domain.

[0061] An "isolated" antibody, such as an isolated anti-TREM2 antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free from association with substantially all other contaminating components from the production environment. Contaminating components from the production environment, such as those arising from recombinantly engineered cells, are typically materials that would interfere with research, diagnostic, or therapeutic uses for the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide will be purified (1) to greater than 95% by weight, and in some embodiments, greater than 99% by weight, of the antibody, as determined, for example, by the Lowry method; (2) to at least 15 residues from the N-terminus, or sufficient to obtain internal amino acid sequence by use of a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver staining.

[0062] The "variable region" or "variable domain" of an antibody, such as the anti-TREM2 antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (compared to other antibodies of the same class) and contain the antigen-binding sites.

[0063] The term "variable" refers to the fact that certain segments of variable domains differ extensively in sequence among antibodies, such as the anti-TREM2 antibodies of the present disclosure. Variable domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the span of the variable domains. Instead, variability is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more conserved portions of variable domains are called framework regions (FRs). Naturally occurring heavy and light-chain variable domains each contain four FR regions connected by three HVRs that primarily adopt a beta-sheet configuration and form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0064] As used herein, the term "monoclonal antibody" refers to an antibody, such as a monoclonal anti-TREM2 antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they may be synthesized by hybridoma culture, substantially uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as obtained from a substantially homogeneous antibody population and should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies to be used in accordance with the present invention can be produced using, for example, hybridoma techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, for example, U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al. al.,J.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Nat'l Acad. Sci. USA 101(34):12467-472(2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132(2004)), yeast display technology (e.g., WO2009 / 036379A2; WO2010105256; WO2012009568, and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013)), as well as techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and These antibodies can be produced by a variety of techniques, including immunohistochemistry (see Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0065] The terms "full length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to an antibody, such as an anti-TREM2 antibody of the present disclosure, in a substantially intact form, as opposed to an antibody fragment. Specifically, a complete antibody includes an antibody having a heavy chain and a light chain, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0066] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen-binding and / or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (see Example 2 of U.S. Pat. No. 5,641,870; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.

[0067] Papain digestion of antibodies, such as the anti-TREM2 antibodies of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments, and a residual "Fc" fragment (a name reflecting its ability to crystallize readily). The Fab fragment contains the variable region domains of the heavy chains (V H ) and the first constant domain of one heavy chain (C H Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment that roughly corresponds to two disulfide-linked Fab fragments that are capable of binding and cross-linking antigen. The Fab' fragment contains a C(ab')2 fragment containing one or more cysteines from the antibody hinge region. HF(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine ​​residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments can be produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0068] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of an antibody are determined by the sequences in the Fc region that are recognized by Fc receptors (FcRs) found on certain types of cells.

[0069] An "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one heavy-chain and one light-chain variable region domain in tight, non-covalent association. The folding of these two domains leaves six hypervariable loops (three loops from each H and L chain) that contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, a single variable domain (or half of an Fv containing only three HVRs specific for an antigen) can still recognize and bind to antigen, albeit with lower affinity than the entire binding site.

[0070] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains linked in a single polypeptide chain. Preferably, the sFv polypeptide contains a VH domain that enables the sFv to form the desired structure for antigen binding. H Domain and V LThe sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0071] A "functional fragment" of an antibody, such as an anti-TREM2 antibody of the present disclosure, includes a portion of the intact antibody that generally includes the antigen-binding or variable region of the intact antibody or the Fc region of the antibody that retains or modifies FcR binding ability.

[0072] The term "diabody" refers to a V diabody in which inter-chain, rather than intra-chain, pairing of variable domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domain and V L Diabodies refer to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10 residues) between the domains. Diabodies are described in more detail, for example, in EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0073] As used herein, a "chimeric antibody" refers to an antibody, such as a chimeric anti-TREM2 antibody of the present disclosure, in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, so long as the desired biological activity is exhibited (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies include antibodies in which the variable regions of the antibody are derived from a mouse antibody and the constant regions are derived from a human antibody. As used herein, a "humanized antibody" is a subset of a "chimeric antibody."

[0074] "Humanized" forms of non-human (e.g., murine) antibodies, such as humanized forms of the anti-TREM2 antibodies of the present disclosure, are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences and all or substantially all of the FR regions are those of human immunoglobulin sequences. However, the FR region may contain one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than six in the H chain and no more than three in the L chain. Humanized antibodies will optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0075] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody, such as the anti-TREM2 antibody of the present disclosure, generated using any of the techniques for generating human antibodies disclosed herein or otherwise known in the art. This definition of human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomouse, that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006), regarding human antibodies generated by human B cell hybridoma technology. Alternatively, human antibodies can be prepared using yeast libraries and methods as disclosed, for example, in WO2009 / 036379A2; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013).

[0076] The term "hypervariable region" or "HVR," as used herein, refers to a region of an antibody variable domain, such as an anti-TREM2 antibody of the present disclosure, that is hypervariable in sequence and / or forms structurally defined loops. Generally, antibodies contain six HVRs: three in the VH (H1, H2, and H3) and three in the VL (L1, L2, and L3). In natural antibodies, H3 and L3 represent the most diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0077] Several HVR delineations are in use and are encompassed herein. In some embodiments, HVRs may be Kabat complementarity-determining regions (CDRs), which are based on sequence variability and are the most commonly used (Kabat et al., supra). In some embodiments, HVRs may be Chothia CDRs. Chothia instead refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In some embodiments, HVRs may be AbM HVRs. AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used by Oxford Molecular's AbM antibody modeling software. In some embodiments, HVRs may be "contact" HVRs. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are shown below. [Table 1]

[0078] HVRs may also include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) of the VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) of the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0079] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0080] The phrases "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used in the heavy or light chain variable domains of the antibody compilations in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues for a given antibody may be determined by aligning the regions of homology of the antibody's sequence with the "standard" Kabat-numbered sequence.

[0081] The Kabat numbering system is commonly used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The terms "EU numbering system," "EU numbering," or "EU index" are commonly used when referring to residues in the immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). "Kabat's EU index" refers to the residue numbering of the human IgG1 EU antibody. References to residue numbers in the variable domain of an antibody refer to residue numbering according to the Kabat numbering system. References to residue numbers in the constant region of an antibody refer to residue numbering according to the EU numbering system (see, e.g., U.S. Patent Application Publication No. 2010-280227).

[0082] As used herein, an "acceptor human framework" is a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When pre-existing amino acid changes are present in the VH, preferably, these changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0083] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as defined in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). For VL, the subgroup may be, for example, subgroup kappa I, kappa II, kappa III, or kappa IV, as defined in Kabat et al., supra. Additionally, for VH, the subgroup may be, for example, subgroup I, subgroup II, or subgroup III, as defined in Kabat et al., supra.

[0084] For example, an "amino acid modification" at a particular position of an anti-TREM2 antibody of the present disclosure refers to a substitution or deletion of the particular residue, or an insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue refers to an insertion within one to two residues thereof. The insertion may be at the N-terminus or C-terminus of the particular residue. A preferred amino acid modification herein is a substitution.

[0085] An "affinity matured" antibody, such as the affinity matured anti-TREM2 antibody of the present disclosure, is an antibody with one or more modifications in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody lacking those modification(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies can be produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described, for example, by Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0086] As used herein, the term "specifically binds" refers to a measurable and reproducible binding interaction between a target and an antibody, such as between an anti-TREM2 antibody and TREM2, that determines the presence of the target within a heterogeneous population of molecules, such as biological molecules. For example, an antibody, such as the anti-TREM2 antibody of the present disclosure, that specifically binds to a target or epitope of a target is an antibody that preferentially binds to this target or epitope, e.g., with higher affinity or antibody avidity than it binds to other, unrelated targets or epitopes. It is also understood that an antibody that specifically binds to a first target may or may not specifically bind to a second target. Thus, "specific binding" does not necessarily require (although it can include) exclusive binding. An antibody that specifically binds to a target has at least about 10 3 M -1 Or 10 4 M-1 , depending on the time, about 10 5 M -1 Or 10 6 M -1 , in other cases, about 10 6 M -1 Or 10 7 M -1 , about 10 8 M -1 ~10 9 M -1 , or 10 10 M -1 ~10 11 M -1 The binding constant may be greater than or equal to 100 kJ / min. Various immunoassay formats can be used to select antibodies specifically immunoreactive with a particular protein. For example, solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein. For a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, or Vashist and Luong (2018) Handbook of Immunoassay Technologies, Approaches, Performances, and Applications, Academic Press.

[0087] As used herein, an antibody "inhibits the interaction" between two proteins when the antibody disrupts, reduces, or completely eliminates the interaction between the two proteins by binding to one of the two proteins.

[0088] An "agonist" antibody is an antibody that, upon binding to a target, induces (eg, increases) one or more activities or functions of the target.

[0089] An "antagonist" or "blocking" antibody is an antibody that reduces or eliminates (e.g., decreases) antigen binding to one or more binding partners after the antibody binds to the antigen and / or reduces or eliminates (e.g., decreases) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, an antagonist or blocking antibody substantially or completely inhibits antigen binding to one or more binding partners and / or one or more activities or functions of the antigen.

[0090] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.

[0091] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226 or Pro230 to its carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population having all K447 residues removed, an antibody population having no K447 residues removed, and an antibody population having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0092] A "native-sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native-sequence human Fc regions include native-sequence human IgG1 Fc regions (non-A allotypes and A allotypes), native-sequence human IgG2 Fc regions, native-sequence human IgG3 Fc regions, and native-sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0093] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to the native-sequence Fc region, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions in the native-sequence Fc region. The variant Fc region herein will preferably be at least about 80% homologous to the native-sequence Fc region, most preferably at least about 90% homologous thereto, and more preferably at least about 95% homologous thereto.

[0094] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced ​​forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibiting receptors"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. (See, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0095] In vivo FcR binding and serum half-life of human FcR high-affinity binding polypeptides can be assayed, for example, in transgenic mice or transgenic human cell lines expressing human FcR, or in primates to which polypeptides having variant Fc regions are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcR. See also, e.g., Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0096] As used herein, "percent amino acid sequence identity" and "homology" with respect to peptide, polypeptide, or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to those in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for alignment comparisons, including any algorithms known in the art necessary to achieve maximal alignment over the full length of the sequences being compared.

[0097] For example, an "isolated" nucleic acid molecule encoding an antibody, such as the anti-TREM2 antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule that is normally associated with the environment in which it is produced. Preferably, an isolated nucleic acid is free from association with substantially all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are distinguished from nucleic acids that naturally occur in a cell.

[0098] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of the host cell upon introduction into the host cell, and thereby be replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably, as the plasmid is the most commonly used form of vector.

[0099] "Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide can also contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can also be interrupted by non-nucleotide components. A polynucleotide can also contain modification(s) that are performed after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps," substitution of one or more of the naturally occurring nucleotides with analogs; and internucleotide modifications, such as those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing pendant moieties such as proteins (e.g., nucleases, toxins, antibodies, signal peptides, ply-L-lysine, etc.), those containing intercalators (e.g., acridine, psoralens, etc.), those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylators, those with modified linkages (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present on the sugars may be replaced with, for example, phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to prepare further linkages to additional nucleotides, or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methylribose, 2'-O-allylribose, 2'-fluororibose, or 2'-azidoribose; carbocyclic sugar analogs; α-anomeric sugars; epimeric sugars such as arabinose, xylose, or lyxose; pyranose sugars; furanose sugars; sedoheptulose; acyclic analogs; and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C), optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl. Not all linkages in a polynucleotide need be identical. The foregoing applies to all polynucleotides referred to herein, including RNA and DNA.

[0100] A "host cell" includes, for example, an individual cell or cell culture that may contain a vector(s) or other foreign nucleic acid that incorporates a polynucleotide insert(s). In some embodiments, the vector or other foreign nucleic acid is incorporated into the genome of the host cell. A host cell includes the progeny of a single host cell, and the progeny may not necessarily be completely identical (morphologically or in terms of genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. A host cell includes cells that have been transfected in vivo with a polynucleotide(s) of the invention.

[0101] As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, a physiologically acceptable carrier is a pH-buffered aqueous solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0102] The term "about" as used herein refers to a normal range of error for the respective value, which is readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter itself.

[0103] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, reference to an "antibody" is a reference to one antibody to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, and so forth.

[0104] It is understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0105] overview The present disclosure relates to methods of treating disorders and diseases associated with demyelination by administering agonists of TREM2. Such diseases or disorders include, but are not limited to, multiple sclerosis, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, and adrenomyeloneuropathy. TREM2 agonists include anti-TREM2 antibodies that induce one or more TREM2 activities and / or enhance one or more activities induced by binding of one or more ligands to TREM2. For example, an agonist anti-TREM2 antibody can decrease soluble TREM2, induce spleen tyrosine kinase (Syk) phosphorylation, induce TREM2 binding to DAP12, induce DAP12 phosphorylation, increase proliferation, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells (microglia), or increase the activity and / or expression of TREM2-dependent genes.

[0106] Demyelinating diseases such as multiple sclerosis are characterized by persistent demyelination and myelin debris accumulation in the brain, ultimately leading to axonal damage that manifests clinically as neurological disability (Dulamea 2017).Possible explanations for the failure of remyelination in demyelinating diseases include a failure of oligodendrocyte precursor cell (OPC) activation or recruitment to sites of demyelination and / or abnormalities in OPC differentiation into myelinating mature oligodendrocytes (OLs) (Franklin and Ffrench-Constant 2017).

[0107] Accordingly, certain aspects of the present disclosure are based, at least in part, on the discovery that, using an in vivo mouse toxin-induced model of demyelination in the CNS, an agonistic anti-TREM2 antibody (see, e.g., Example 2) significantly enhanced myelin debris clearance in vivo (see, e.g., Example 3); promoted the recruitment of oligodendrocyte progenitor cells (OPCs) to demyelinated lesions in vivo (see, e.g., Example 4); promoted the differentiation of OPCs into mature oligodendrocytes in vivo (see, e.g., Example 4); and promoted axonal health in the corpus callosum in vivo (see, e.g., Example 5).

[0108] Methods of the present disclosure The present disclosure provides methods for treating, preventing, or reducing the risk of a central nervous system (CNS) demyelinating disease, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody that binds to a TREM2 protein, wherein the antibody is an agonist. In some embodiments, the antibody promotes remyelination in one or more demyelinating lesions in the individual's CNS.

[0109] Also provided herein is a method for promoting remyelination of one or more demyelinating lesions in an individual with a central nervous system (CNS) demyelinating disease, comprising administering to the individual a therapeutically effective amount of an antibody that binds to the TREM2 protein, wherein the antibody is an agonist.

[0110] Demyelinating diseases "Demyelination" or "demyelinating" disease, as used herein, refers to any disease, disorder, or condition characterized by the presence of one or more demyelinating lesions. Typically, demyelinating lesions, also known as plaques, are characterized by damage to or loss of the myelin sheath of neurons in the white and / or gray matter of the central nervous system. In some cases, demyelinating lesions exhibit a T cell- and macrophage-mediated inflammatory response. In some embodiments, demyelinating lesions can be diagnosed, measured, and / or classified according to methods known in the art, for example, using the four demyelinating lesion patterns described in Lucchinetti et al., (2000), Am Neurological Assoc, 47:707-17, and Popescu et al., (2013), Continuum (Minneap Minn), 19(4 Multiple Sclerosis):901-21. Demyelinating diseases include, but are not limited to, multiple sclerosis, such as optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenoleukodystrophy, adrenomyeloneuropathy, mucopolysaccharidoses (Hurler's syndrome), sphingolipid storage diseases, Krabbe disease and other leukodystrophies, Leber's hereditary optic atrophy, phenylketonuria, Tay-Sachs disease, Niemann-Pick disease, Gaucher disease, acute hemorrhagic leukoencephalitis, osmotic demyelinating syndrome, and Marchiafava-Bignami disease. In some embodiments, the demyelinating disease is multiple sclerosis.

[0111] Without wishing to be bound by theory, it is believed that agonizing TREM2 ameliorates the symptoms of demyelinating diseases, such as multiple sclerosis. In certain embodiments, TREM2 antibodies as described herein may activate or increase signaling by TREM2 to compensate for or otherwise restore reduced TREM2 function or copy number.

[0112] In some embodiments, an individual receiving an anti-TREM2 antibody according to the methods provided herein has or is at risk for a disease feature selected from myelin damage, one or more demyelinating lesions in the CNS, inflammation in the CNS, one or more plaques in the CNS, loss of myelin sheath, axonal injury, decreased OPCs, decreased OLs, decreased myelin debris clearance, axonal varicosity, axonal spheroids, gliosis, autofluorescent lipid-laden macrophages, axonal destruction, or any combination thereof. In some embodiments, the individual has or is at risk for axonal damage and / or one or more demyelinating lesions in the CNS. In some embodiments, the axonal damage and / or one or more demyelinating lesions in the CNS are in the white matter, gray matter, or corpus callosum of the CNS. In some embodiments, the individual has or is at risk of having a symptom selected from altered sensation, cramping, numbness, muscle weakness, clonus, muscle spasms, difficulty moving, difficulty with coordination, difficulty with balance, difficulty speaking, difficulty swallowing, difficulty with vision, fatigue, acute pain, chronic pain, bladder problems, bowel problems, cognitive problems, depression, unstable mood, Uhthoff phenomenon, Lhermitte's sign, or any combination thereof.

[0113] Multiple sclerosis Multiple sclerosis (MS) can also be called disseminated sclerosis or disseminated encephalomyelitis. MS is an inflammatory disease in which the fatty myelin sheath surrounding the axons in the brain and spinal cord is damaged, resulting in demyelination and scarring and a wide range of signs and symptoms. MS affects the ability of nerve cells in the brain and spinal cord to communicate effectively with each other. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are contained within an insulating substance called myelin. In MS, the body's immune system attacks and damages the myelin. When myelin is lost, axons can no longer conduct signals effectively. MS onset usually occurs in young adults and is more common in women.

[0114] Symptoms of MS include, but are not limited to, changes in sensation such as decreased sensitivity or tingling; pins and needles or numbness such as hypoesthesia and dysesthesia; muscle weakness; clonus; muscle spasms; difficulty moving; coordination and balance disorders such as ataxia; difficulty speaking such as dysarthria or swallowing such as dysphagia; visual disturbances such as nystagmus, optic neuritis including flashing lights and diplopia; fatigue, acute or chronic pain; and bladder and bowel disorders; cognitive impairment of varying degrees; emotional symptoms of depression or anxious mood; Uhthoff phenomenon, which is a worsening of existing symptoms due to exposure to temperatures higher than normal ambient temperature; and Lhermitte sign, which is an electrical sensation down the back when bending the neck.

[0115] In some embodiments, administration of an anti-TREM2 antibody of the present disclosure can prevent, reduce the risk of, and / or treat multiple sclerosis. In some embodiments, administration of an anti-TREM2 antibody can induce one or more TREM2 activities (e.g., DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more pro-inflammatory mediators) in an individual with multiple sclerosis. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure results in improvement or alleviation of one or more symptoms of multiple sclerosis, including decreased or tingling sensitivity; pins and needles or numbness, such as hypoesthesia and dysesthesia; muscle weakness; clonus; muscle spasms; difficulty moving; coordination and balance disorders, such as ataxia; difficulty speaking, such as dysarthria, or swallowing, such as dysphagia; visual disturbances, such as nystagmus, optic neuritis, including flashing lights and diplopia; fatigue, acute or chronic pain; and bladder and bowel disorders; cognitive impairment of varying degrees; emotional symptoms of depression or anxious mood; Uhthoff phenomenon, which is a worsening of existing symptoms due to exposure to temperatures higher than normal ambient temperatures; and Lhermitte's sign, which is an electrical sensation down the back when bending the neck.

[0116] TREM2 protein The present disclosure provides a method of treating, preventing, or reducing the risk of a demyelinating disease in an individual, comprising administering to the individual an antibody that binds to the TREM2 protein, wherein the antibody is an agonist.

[0117] Triggering receptor expressed on myeloid cells 2 (TREM2) is variously referred to as TREM-2, TREM2a, TREM2b, TREM2c, triggering receptor expressed on myeloid cells-2a, and triggering receptor expressed on monocytes 2. TREM2 is a 230-amino acid membrane protein. TREM2 is an immunoglobulin-like receptor expressed primarily on myeloid cells, including, but not limited to, macrophages, dendritic cells, monocytes, dermal Langerhans cells, Kupffer cells, osteoclasts, and microglia. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 phosphorylates and signals through DAP12 (an ITAM domain adaptor protein). In some embodiments, TREM2 signaling leads to downstream activation of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signaling is important for activating TREM2 activity, for example, in the context of infection responses. TLRs, such as those expressed on macrophages and dendritic cells, also play a key role in pathological inflammatory responses.

[0118] TREM2 proteins of the present disclosure include, but are not limited to, the human TREM2 protein (Uniprot accession number Q9NZC2, SEQ ID NO: 1), and non-human mammalian TREM2 proteins, such as the mouse TREM2 protein (Uniprot accession number Q99NH8, SEQ ID NO: 2), the rat TREM2 protein (Uniprot accession number D3ZZ89, SEQ ID NO: 3), the rhesus monkey TREM2 protein (Uniprot accession number F6QVF2, SEQ ID NO: 4), the cynomolgus monkey TREM2 protein (NCBI accession number XP_015304909.1, SEQ ID NO: 5), the horse TREM2 protein (Uniprot accession number F7D6L0, SEQ ID NO: 6), the pig TREM2 protein (Uniprot accession number H2EZZ3, SEQ ID NO: 7), and the dog TREM2 protein (Uniprot accession number E2RP46, SEQ ID NO: 8). As used herein, "TREM2 protein" refers to both wild-type and naturally occurring variant sequences. In some embodiments, the agonist anti-TREM2 antibodies of the present disclosure bind to a wild-type TREM2 protein, a naturally occurring variant of a TREM2 protein, or a disease variant of a TREM2 protein.

[0119] In some embodiments, an example of a human TREM2 amino acid sequence is shown below as SEQ ID NO: 1: [ka]

[0120] In some embodiments, human TREM2 is a preprotein that includes a signal peptide. In some embodiments, human TREM2 is a mature protein. In some embodiments, the mature TREM2 protein does not include a signal peptide. In some embodiments, the mature TREM2 protein is expressed on a cell. In some embodiments, TREM2 contains a signal peptide located at amino acid residues 1-18 of human TREM2 (SEQ ID NO: 1), an extracellular immunoglobulin-like variable (IgV) domain located at amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1), an additional extracellular sequence located at amino acid residues 113-174 of human TREM2 (SEQ ID NO: 1), a transmembrane domain located at amino acid residues 175-195 of human TREM2 (SEQ ID NO: 1), and an intracellular domain located at amino acid residues 196-230 of human TREM2 (SEQ ID NO: 1). The TREM2 cleavage site has been identified as occurring C-terminal to histidine 157 (see WO2018 / 015573), and cleavage at that site results in shedding of the relevant portion of the TREM2 extracellular domain, which can be detected as an increase in soluble TREM2 (sTREM2) corresponding to that portion of TREM2.

[0121] The transmembrane domain of human TREM2 contains a lysine at amino acid residue 186 that can interact with an aspartate in DAP12, a key adaptor protein that transduces signaling from TREM2, TREM1, and other related IgV family members.

[0122] TREM2 mutations In certain embodiments, the demyelinating disease is associated with a TREM2 protein that has reduced function when compared to a TREM2 protein determined to have "wild-type" function or function determined to be within the normal range. In certain embodiments, the demyelinating disease is characterized by a mutation in the TREM2 gene in the affected individual. In certain embodiments, the mutation results in reduced function of TREM2 in the affected individual. The mutation may be of any type, including, for example, a missense mutation, an indel, or a mutation that produces a truncated protein product. In some embodiments, the individual comprises at least one copy of a functional TREM2 gene. In some embodiments, the individual is heterozygous for the mutation in the TREM2 gene. In some embodiments, the individual is homozygous for the mutation in the TREM2 gene.

[0123] Anti-TREM2 antibody Certain aspects of the present disclosure relate to antibodies (e.g., monoclonal antibodies) that bind to agonistic TREM2 protein. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein, which is expressed on cells. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein expressed on one or more human cells selected from human dendritic cells, human macrophages, human monocytes, human osteoclasts, human dermal Langerhans cells, human Kupffer cells, human microglia, and any combination thereof. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein expressed on one or more human microglia.

[0124] Anti-TREM2 antibodies that induce and / or enhance ligand-induced activity In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that induce one or more TREM2 activities, ie, the antibodies induce one or more activities of TREM2 after binding to a TREM2 protein expressed on a cell.

[0125] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the TREM2 protein without competing with, inhibiting, or otherwise blocking one or more TREM2 ligands from binding to the TREM2 protein. Examples of TREM2 ligands include, but are not limited to, TREM2 ligands expressed by E. coli cells, apoptotic cells, nucleic acids, anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2, anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidated APOE3, lipidated APOE4, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptide. Thus, in certain embodiments, the one or more TREM2 ligands include E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine (PS), sulfatides, phosphatidylcholine, sphingomyelin (SM), phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptides.

[0126] The anti-TREM2 antibodies used in the methods of the present disclosure are agonistic antibodies. In some embodiments, antibodies of the present disclosure that bind to the TREM2 protein may include agonistic antibodies that bind to TREM2 with their epitope specificity and activate one or more TREM2 activities. In some embodiments, such antibodies may stimulate TREM2 to transduce signals by binding to a ligand-binding site on TREM2 and mimicking the action of one or more TREM2 ligands, or by binding to one or more domains that are not the ligand-binding site. In some embodiments, the antibodies do not compete with or otherwise block ligand binding to TREM2. In some embodiments, the antibodies act additively or synergistically with one or more TREM2 ligands to activate and / or enhance more than one TREM2 activity, as described below.

[0127] Agonist anti-TREM2 antibodies of the present disclosure may exhibit the ability to bind to TREM2 without blocking the simultaneous binding of one or more TREM2 ligands. Anti-TREM2 antibodies of the present disclosure may further exhibit additive and / or synergistic functional interactions with one or more TREM2 ligands. Thus, in some embodiments, the maximal activity of TREM2 when bound to an anti-TREM2 antibody of the present disclosure in combination with one or more TREM2 ligands of the present disclosure may be higher (e.g., enhanced) than the maximal activity of TREM2 when exposed to a saturating concentration of the ligand alone or to a saturating concentration of the antibody alone. Additionally, the activity of TREM2 at a given concentration of TREM2 ligand may be higher (e.g., enhanced) in the presence of the antibody.

[0128] Thus, in some embodiments, the anti-TREM2 antibodies of the present disclosure have an additive effect with one or more TREM2 ligands, enhancing one or more TREM2 activities when bound to a TREM2 protein. In some embodiments, the anti-TREM2 antibodies of the present disclosure synergize with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies of the present disclosure increase the potency of one or more TREM2 ligands to induce one or more TREM2 activities compared to the potency of the one or more TREM2 ligands to induce one or more TREM2 activities in the absence of the antibody. In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities in the absence of cell surface clustering of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities by inducing or maintaining cell surface clustering of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure are clustered by one or more Fc-gamma receptors expressed on one or more immune cells, including, but not limited to, B cells and microglial cells. In some embodiments, enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein is measured in primary cells, including, but not limited to, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells, or in cell lines.

[0129] In certain embodiments, anti-TREM2 antibodies of the present disclosure that enhance one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein induce at least a 2-fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, at least a 10-fold, at least a 11-fold, at least a 12-fold, at least a 13-fold, at least a 14-fold, at least a 15-fold, at least a 16-fold, at least a 17-fold, at least a 18-fold, at least a 19-fold, at least a 20-fold or greater increase in one or more TREM2 activities when compared to the level of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in the absence of the anti-TREM2 antibody.

[0130] In some embodiments, agonist anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities induced in the presence of myelin. In some embodiments, the one or more TREM2 activities induced in the presence of myelin include increased activity of one or more TREM2-dependent genes. In some embodiments, the one or more TREM2-dependent genes include the nuclear factor of activated T cells (NFAT) transcription factor. In some embodiments, the ability of an anti-TREM2 antibody to activate a mouse or human TREM2-dependent gene is assessed using a luciferase reporter gene under the control of the NFAT (nuclear factor of activated T cells) promoter, for example, as described below.

[0131] In some embodiments, TREM2 activities that may be induced and / or enhanced by an anti-TREM2 antibody of the present disclosure and / or one or more TREM2 ligands of the present disclosure include, but are not limited to, TREM2 binding to DAP12; DAP12 phosphorylation; activation of Syk kinase; modulation of one or more pro-inflammatory mediators selected from IFN-β, IL-1α, IL-1β, TNF-α, YM-1, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, Rorc, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, CSF-1, MHC-II, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally). the modulation occurs in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells; recruitment of Syk, ZAP70, or both to the DAP12 / TREM2 complex; increased activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; CD83, CD86 These include modulating the expression of one or more stimulatory molecules selected from MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells may comprise bone marrow-derived dendritic cells); increasing memory, and reducing cognitive impairment. In some embodiments, the anti-TREM2 antibodies of the present disclosure increase memory and / or reduce cognitive impairment when administered to an individual.

[0132] In some embodiments, the agonist anti-TREM2 antibodies of the present disclosure induce one or more TREM2 activities selected from TREM2 binding to DAP12, DAP12 phosphorylation, activation of Syk kinase, recruitment of Syk to the DAP12 / TREM2 complex, increased activity of one or more TREM2-dependent genes, or any combination thereof. In some embodiments, the one or more TREM2-dependent genes include the nuclear factor of activated T cells (NFAT) transcription factor.

[0133] Syk phosphorylation In some embodiments, the anti-TREM2 antibodies of the present disclosure may induce spleen tyrosine kinase (Syk) phosphorylation after binding to TREM2 protein expressed in cells.

[0134] Spleen tyrosine kinase (Syk) is an intracellular signaling molecule that functions downstream of TREM2 by phosphorylating several substrates, thereby promoting the formation of signaling complexes that lead to cell activation and inflammatory processes.

[0135] In some embodiments, the ability of agonistic TREM2 antibodies to induce Syk activation is determined by culturing mouse macrophages and measuring the phosphorylation state of Syk protein in cell extracts. In some embodiments, bone marrow-derived macrophages (BMDMs) from wild-type (WT) mice, TREM2 knockout (KO) mice, and mice lacking expression of a functional Fc receptor common gamma chain gene (FcgR KO; REF: Takai T 1994. Cell 76(3):519-29) are starved in 1% serum RPMI for 4 hours, then removed from the tissue culture dish with PBS-EDTA, washed with PBS, and counted. In some embodiments, cells are coated on ice with full-length TREM2 antibodies or control antibodies for 15 minutes. In some embodiments, after washing with cold PBS, cells are incubated at 37°C in the presence of goat anti-human IgG for the indicated periods. In some embodiments, after stimulation, cells are lysed with lysis buffer (1% v / v NP-40%, 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1.5 mM MgCl, 10% glycerol, and protease and phosphatase inhibitors), followed by centrifugation at 16,000 g for 10 minutes at 4°C to remove insoluble material. In some embodiments, the lysate is then immunoprecipitated with an anti-Syk antibody (N-19 for BMDM or 4D10 for human DC, Santa Cruz Biotechnology). In some embodiments, the deposited proteins are fractionated by SDS-PAGE, transferred to a PVDF membrane, and probed with an anti-phosphotyrosine antibody (4G10, Millipore). In some embodiments, immunoblots are reprobed with anti-Syk antibody (for BMDM, Abcam) or anti-Syk (for human DC, Novus Biological) to confirm proper immunodeposition of all substrates. In some embodiments, visualization is performed with an enhanced chemiluminescence (ECL) system (GE healthcare) as described (e.g., Peng et al., (2010) Sci Signal., 3(122):ra38).

[0136] DAP12 binding and phosphorylation In some embodiments, the anti-TREM2 antibodies of the present disclosure may induce TREM2 binding to DAP12. In other embodiments, the anti-TREM2 antibodies of the present disclosure may induce DAP12 phosphorylation after binding to TREM2 protein expressed on cells. In other embodiments, TREM2-mediated DAP12 phosphorylation is induced by one or more SRC family tyrosine kinases. Examples of Src family tyrosine kinases include, but are not limited to, Src, Syk, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, and Frk.

[0137] DAP12 is variously referred to as TYRO protein tyrosine kinase binding protein, TYROBP, KARAP, and PLOSL. DAP12 is a transmembrane signaling protein containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. In certain embodiments, anti-TREM2 antibodies can induce DAP12 phosphorylation at the ITAM motif. Any method known in the art for determining protein phosphorylation, such as DAP12 phosphorylation, may be used.

[0138] In some embodiments, DAP12 is phosphorylated by an SRC family kinase, resulting in the recruitment and activation of Syk kinase, ZAP70 kinase, or both, to the DAP12 / TREM2 complex.

[0139] In some embodiments, the ability of TREM2 antibodies to induce DAP12 activation is determined by culturing mouse macrophages and measuring the phosphorylation state of DAP12 protein in cell extracts. In some embodiments, mouse wild-type (WT) bone marrow-derived macrophages (BMDMs) and TREM2 knockout (KO) BMDMs are starved in 1% serum RPMI for 4 hours before stimulation with the antibody. In some embodiments, 15×10 6Cells are incubated with full-length TREM2 antibody or control antibody for 15 minutes on ice. In some embodiments, cells are washed and incubated in the presence of goat anti-human IgG at 37°C for the indicated time periods. In some embodiments, after stimulation, cells are lysed with lysis buffer (1% v / v n-dodecyl-β-D-maltoside, 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1.5 mM MgCl2, 10% glycerol, and protease and phosphatase inhibitors) followed by centrifugation at 16,000g for 10 minutes at 4°C to remove insoluble material. In some embodiments, cell lysates are immunoprecipitated with a secondary TREM2 antibody (R&D Systems). In some embodiments, deposited proteins are fractionated by SDS-PAGE, transferred to a PVDF membrane, and probed with an anti-phosphotyrosine Ab (4G10, Millipore). In some embodiments, the membranes are stripped and reprobed with anti-DAP12 antibody (Cells Signaling, D7G1X). In some embodiments, each cell lysate used for TREM2 immunoprecipitation contains equal amounts of protein as indicated by a control antibody (anti-Actin, Santa Cruz).

[0140] Proliferation, survival and function of TREM2-expressing cells In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the proliferation, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells (microglia) after binding to TREM2 protein expressed in the cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure do not inhibit the growth (e.g., proliferation and / or survival) of one or more innate immune cells.

[0141] In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the proliferation, survival, and / or function of microglial cells (microglia) after binding to the TREM2 protein expressed in the cells. Microglial cells are a type of glial cell that are resident macrophages in the brain and spinal cord, and therefore act as the first and primary form of active immune defense in the central nervous system (CNS). Microglial cells comprise 20% of the total glial cell population in the brain. Microglial cells constantly remove plaques, damaged neurons, and infectious agents from the CNS. The brain and spinal cord are considered "immune-privileged" organs, separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from reaching vulnerable neural tissue. When infectious agents are introduced directly into the brain or cross the blood-brain barrier, microglial cells must respond quickly to reduce inflammation and destroy them before they can damage sensitive neural tissue. Unable to utilize antibodies from the rest of the body (few antibodies are small enough to cross the blood-brain barrier), microglia must be able to recognize foreign particles, engulf them, and act as antigen-presenting cells to activate T cells. Because this process must occur rapidly to prevent potentially fatal damage, microglial cells are extremely sensitive to even minor pathological changes in the CNS. They achieve this sensitivity in part by possessing unique potassium channels that respond to even small changes in extracellular potassium.

[0142] As used herein, macrophages of the present disclosure include, but are not limited to, M1 macrophages, activated M1 macrophages, and M2 macrophages. As used herein, microglial cells of the present disclosure include, but are not limited to, M1 microglial cells, activated M1 microglial cells, and M2 microglial cells.

[0143] In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the expression of CD83 and / or CD86 on dendritic cells, monocytes, and / or macrophages.

[0144] As used herein, proliferation rate, survival, and / or function of macrophages, dendritic cells, monocytes, and / or microglia can include increased expression when the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a subject treated with an anti-TREM2 antibody of the disclosure is greater than the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a corresponding subject not treated with an anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibodies of the disclosure decrease the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a subject, e.g., by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 10 ... The increase may be 0%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%.In other embodiments, the anti-TREM2 antibodies of the disclosure increase the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a subject, e.g., by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, or more, compared to the proliferation rate, survival, and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia in a corresponding subject not treated with the anti-TREM2 antibody. The increase may be at least 2.1 fold, at least 2.15 fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, at least 2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5 fold, at least 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least 4.0 fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, at least 6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold, at least 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5 fold, or at least 10 fold.

[0145] In some embodiments, to assess the ability of anti-TREM2 antibodies to induce or enhance cell survival in vitro, macrophages lacking the gamma chain subunits of the FcgRI, FcgRIII, and FceRI receptors (Fcgr1KO mice; REF: Takai T, Li M, Sylvestre D, Clynes R, Ravetch J. (1994). Cell, 76:519-529) are cultured in the presence of plate-bound anti-TREM2 antibodies to determine cell viability when the cells are cultured under suboptimal growth conditions. In some embodiments, murine bone marrow progenitor cells from FcgR1 KO mice (Taconic, Model 584) are obtained by flushing tibial and femoral bone marrow cells with cold PBS. In some embodiments, after one wash with PBS, red blood cells are lysed using ACK lysis buffer (Lonza), washed twice with PBS, and 0.5 × 10 6Macrophages were generated by suspending 2.5 × 10 cells / ml in complete RPMI medium (10% FCS, Pen / Strep, Gln, neAA) with the indicated amount of M-CSF (Peprotech). In some embodiments, to analyze cell viability of bone marrow-derived macrophages, cells were prepared as above and 2.5 × 10 4 Cells are plated in 96-well plates at 200 μl / well with a suboptimal amount of M-CSF (10 ng / ml) in non-tissue culture treated plates for 2 days. In some embodiments, cells are then quantified using a ToxGlo™ kit (Promega), and luminescence is determined as a measure of cell viability. In some embodiments, all experiments are performed in the presence or absence of anti-TREM2 antibodies or isotype control antibodies.

[0146] TREM2-dependent gene expression In some embodiments, the anti-TREM2 antibodies of the present disclosure may increase the activity and / or expression of TREM2-dependent genes, such as one or more transcription factors of the nuclear factor of activated T cells (NFAT) family of transcription factors.

[0147] In some embodiments, the ability of soluble full-length anti-TREM2 antibodies to activate mouse or human TREM2-dependent genes is assessed using a luciferase reporter gene under the control of the NFAT (nuclear factor of activated T cells) promoter. In some embodiments, the mouse thymic lymphoma T lymphocyte-derived cell line BW5147.G.1.4 (ATCC® TIB48™) is infected with mouse TREM2 and DAP12 and with Cignal Lenti NFAT-luciferase virus (Qiagen). Alternatively, in some embodiments, the BW5147.G.1.4 cell line is infected with human TREM2 / DAP12 fusion protein and with Cignal Lenti NFAT-luciferase virus (Qiagen). In some embodiments, PMA (0.05 μg / ml) and ionomycin (0.25 μM) are added together as a positive control for signal transduction. In some embodiments, cells are incubated with soluble anti-TREM2 and isotype control antibodies for 6 hours, and luciferase activity is measured by adding OneGlo reagent (Promega) to each well and incubating for 3 minutes at room temperature on a plate shaker. In some embodiments, luciferase signals are measured using a BioTek plate reader. In some embodiments, cells exhibit sustained TREM2-dependent signaling, either due to the presence of endogenous ligands that result in TREM2 signaling, or due to spontaneous receptor aggregation.

[0148] In some embodiments, the enhancement of one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein is measured, for example, using an in vitro cell assay. In some embodiments, the increase in one or more TREM2 activities can be measured by any suitable in vitro cell-based assay or suitable in vivo model described herein or known in the art, for example, by using a luciferase-based reporter assay to measure TREM2-dependent gene expression, by using Western blot analysis to measure the increase in TREM2-induced phosphorylation of downstream signaling partners such as Syk, or by using flow cytometry such as fluorescence-activated cell sorting (FACS) to measure changes in cell surface levels of markers of TREM2 activation. To measure the interaction (e.g., binding) between TREM2 and one or more TREM2 ligands, any in vitro cell-based assay or suitable in vivo model described herein or known in the art can be used.

[0149] In some embodiments, increases in one or more TREM2 activities are measured by in vitro cell-based assays. To assess the ability of anti-TREM2 antibodies to enhance cell survival in vitro, macrophages lacking the gamma chain subunits of the FcgRI, FcgRIII, and FceRI receptors (Fcgr1KO mice, REF: Takai T, Li M, Sylvestre D, Clynes R, Ravetch J. (1994). Cell, 76:519-529) are cultured in the presence of plate-bound anti-TREM2 antibodies, and cell viability is determined when the cells are cultured under suboptimal growth conditions. In some embodiments, mouse bone marrow progenitor cells from FcgR1 KO mice (Taconic, Model 584) are obtained by flushing tibial and femoral bone marrow cells with cold PBS. In some embodiments, after one wash with PBS, red blood cells are lysed using ACK lysis buffer (Lonza), washed twice with PBS, and 0.5 × 106 Macrophages were generated by suspending 2.5 × 10 cells / ml in complete RPMI medium (10% FCS, Pen / Strep, Gln, neAA) with the indicated amount of M-CSF (Peprotech). In some embodiments, to analyze cell viability of bone marrow-derived macrophages, cells were prepared as above and 2.5 × 10 4 Cells are plated in 96-well plates at 200 μl / well with a suboptimal amount of M-CSF (10 ng / ml) in non-tissue culture treated plates for 2 days. In some embodiments, cells are then quantified using a ToxGlo™ kit (Promega), and luminescence is determined as a measure of cell viability. In some embodiments, all experiments are performed in the presence or absence of anti-TREM2 antibodies or isotype control antibodies.

[0150] In some embodiments, increases in one or more TREM2 activities are measured by in vivo cell-based assays. In some embodiments, to evaluate the ability of an anti-TREM2 antibody to increase immune cell numbers in vivo, C57B16 mice are intraperitoneally (IP) injected with an anti-TREM2 antibody or a mouse IgG1 isotype control antibody, and the number of immune cells in the brain is quantified by FACS. In some embodiments, 3 to 4 mice per group are administered an IP injection of 40 mg / kg of an anti-TREM2 antibody or an isotype control antibody mIgG1 (clone MOPC-21, Bioxcell). In some embodiments, after 48 hours, whole brains are harvested, rinsed with PBS, incubated in PBS containing 1 mg / ml collagenase at 37°C, and processed through a cell strainer to obtain a single-cell suspension. In some embodiments, the cells are then incubated with anti-CD45-PerCp-Cy7, anti-CD11b-PerCP-Cy5.5, anti-Gr1-FITC antibodies and a cell viability dye (Life Technologies, Cat# L34957) on ice for 30 minutes, and then washed twice with cold FACS buffer. In some embodiments, the 4% PFA-fixed samples are then analyzed by FACS. In some embodiments, data were acquired on a BD FACSCanto™ II cytometer (Becton Dickinson) and analyzed with FlowJo software.

[0151] In some embodiments, the TREM2 ligand is administered to its EC 50 An anti-TREM2 antibody of the present disclosure enhances one or more TREM2 activities induced by binding of a TREM2 ligand to a TREM2 protein if, when used at a concentration in the range of about 0.5 nM to about 50 nM, or greater than 50 nM, it induces an increase in ligand-induced TREM2-dependent gene transcription in the range of about 1.5-fold to about 6-fold, or greater than 6-fold, compared to the level of TREM2-dependent gene transcription induced by binding of the TREM2 ligand to the TREM2 protein in the absence of the anti-TREM2 antibody. In some embodiments, a TREM2 ligand is administered at its EC 50When used at concentrations in the range of about 0.5 nM to about 50 nM, or when used at concentrations greater than 50 nM, the increase in ligand-induced TREM2-dependent gene transcription is at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, at least 20-fold or more compared to the level of TREM2-dependent gene transcription induced by binding of the TREM2 ligand to the TREM2 protein in the absence of the anti-TREM2 antibody.

[0152] In some embodiments, the anti-TREM2 antibody is used at a concentration of at least 0.5 nM, at least 0.6 nM, at least 0.7 nM, at least 0.8 nM, at least 0.9 nM, at least 1 nM, at least 2 nM, at least 3 nM, at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, at least 30 nM, at least 35 nM, at least 40 nM, at least 45 nM, at least 46 nM, at least 47 nM, at least 48 nM, at least 49 nM, or at least 50 nM. In some embodiments, the TREM2 ligand is phosphatidylserine (PS). In some embodiments, the TREM2 ligand is sphingomyelin (SM). In some embodiments, an increase in one or more TREM2 activities may be measured by any suitable in vitro cell-based assay or suitable in vivo model described herein or known in the art. In some embodiments, a luciferase-based reporter assay is used to measure the fold increase in ligand-induced TREM2-dependent gene expression in the presence and absence of an antibody, for example, as described in WO2017 / 062672 and WO2019 / 028292.

[0153] As used herein, an anti-TREM2 antibody of the present disclosure does not compete with, inhibit, or otherwise block the interaction (e.g., binding) between one or more TREM2 ligands and TREM2 if it reduces ligand binding to TREM2 by less than 20% at saturating antibody concentrations using any in vitro or cell-based culture assay described herein or known in the art. In some embodiments, an anti-TREM2 antibody of the present disclosure inhibits the interaction (e.g., binding) of one or more TREM2 ligands with TREM2 by less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% at saturating antibody concentrations using any in vitro or cell-based culture assay described herein or known in the art.

[0154] Anti-TREM2 antibodies that reduce soluble TREM2 In some embodiments, agonist anti-TREM2 antibodies reduce soluble TREM2 (sTREM2). In some embodiments, agonist anti-TREM2 antibodies reduce the levels of sTREM2 that are "shed" from the cell surface of cells into extracellular samples (e.g., shedding). In some embodiments, such antibodies bind to a region of TREM2 that blocks cleavage of TREM2. In such embodiments, the antibody binds to a region that includes His157, the cleavage site of TREM2.

[0155] The degree of inhibition of TREM2 cleavage by an anti-TREM2 antibody negatively correlates with the amount of soluble TREM2 (sTREM2) in the presence of the anti-TREM2 antibody compared to the amount of sTREM2 in the absence of the anti-TREM2 antibody. For example, an anti-TREM2 antibody can be determined to inhibit TREM2 cleavage if the amount of sTREM2 in the presence of the anti-TREM2 antibody is 0-90%, preferably 0-80%, more preferably 0-70%, even more preferably 0-60%, even more preferably 0-50%, and even more preferably 0-20% of the amount of sTREM2 in the absence of the anti-TREM2 antibody, as assayed, for example, by ELISA-based quantification of sTREM2.

[0156] In some embodiments, an anti-TREM2 antibody reduces the level of sTREM2 when the amount of sTREM2 in a treated sample is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more when compared to a control value. In some embodiments, the control value is the amount of sTREM2 in an untreated sample (e.g., supernatant from TREM2-expressing cells that have not been treated with an anti-TREM2 antibody, or a sample from a subject that has not been treated with an anti-TREM2 antibody) or a sample that has been treated with a suitable non-TREM2-binding antibody.

[0157] In some embodiments, sTREM2 shedding is measured using a sample comprising a fluid, e.g., blood, plasma, serum, urine, or cerebrospinal fluid. In some embodiments, the sample comprises cerebrospinal fluid. In some embodiments, the sample comprises supernatant from a cell culture (e.g., supernatant from primary cells or cell lines that endogenously express TREM2, e.g., human macrophages, or primary cells or cell lines that have been engineered to express TREM2).

[0158] In some embodiments, the level of sTREM2 in a sample is measured using an immunoassay. Immunoassays are known in the art and include, but are not limited to, enzyme immunoassays (EIAs), such as enzyme-amplified immunoassays (EMIAs), enzyme-linked immunosorbent assays (ELISAs), microparticle enzyme immunoassays (MEAs), immunohistochemistry (IHC), immunocytochemistry, capillary electrophoresis immunoassays (CEIAs), radioimmunoassays (RIAs), immunofluorescence, chemiluminescence immunoassays (CLs), and electrochemiluminescence immunoassays (ECLs). In some embodiments, the level of sTREM2 is measured using an ELISA assay.

[0159] In some embodiments, an ELISA assay can be used to quantify sTREM2 levels in cell culture supernatants. In some embodiments, an ELISA for human sTREM2 is performed using a Meso Scale Discovery SECTOR Imager 2400. In some embodiments, streptavidin-coated 96-well plates are blocked overnight at 4°C in 0.5% bovine serum albumin (BSA) and 0.05% Tween 20 (blocking buffer) in PBS (pH 7.4). In some embodiments, plates are shaken for 1 hour at room temperature with a biotinylated polyclonal goat anti-human TREM2 capture antibody (0.25 mg / ml; R&D Systems) diluted in blocking buffer. In some embodiments, the plate is then washed four times with 0.05% Tween 20 in PBS (wash buffer) and incubated for 2 hours at room temperature with samples diluted 1:4 in 0.25% BSA and 0.05% Tween 20 in PBS (pH 7.4) supplemented with protease inhibitors (Sigma) (assay buffer). In some embodiments, recombinant human TREM2 protein (Holzel Diagnostica) is serially diluted two-fold in assay buffer and used for a standard curve (concentration range, 4000-62.5 pg / ml). In some embodiments, the plate is washed three times for 5 minutes with wash buffer and then incubated for 1 hour at room temperature with mouse monoclonal anti-TREM2 antibody (1 mg / ml; Santa Cruz Biotechnology; B-3) diluted in blocking buffer. In some embodiments, after three additional washing steps, the plate is incubated with SULFO-TAG-labeled anti-mouse secondary antibody (1:1000; Meso Scale Discovery) and incubated in the dark for 1 hour. In some embodiments, the plate is washed three times with wash buffer, followed by two washing steps in PBS, and developed by adding Meso Scale Discovery Read buffer.In some embodiments, light emission at 620 nm after electrochemical stimulation is measured using a Meso Scale Discovery SECTOR Imager 2400 reader. In some embodiments, conditioned medium from biological replicates is analyzed in duplicate to quantify secreted TREM2 levels. In some embodiments, a sTREM2 standard curve is generated by a five-parameter logistic fit using MasterPlex ReaderFit software (MiraiBio Group, Hitachi Solutions America). In some embodiments, sTREM2 levels are then normalized to immature TREM2 levels as quantified from Western blots.

[0160] In some embodiments, sTREM2 may be an inactive variant of the cellular TREM2 receptor. In some embodiments, sTREM2 may be present peripherally, e.g., in the subject's plasma or brain, and may sequester an anti-TREM2 antibody. Such a sequestered antibody would not be able to bind to and activate, for example, a cellular TREM2 receptor present on a cell. Thus, in certain embodiments, the anti-TREM2 antibodies of the present disclosure, e.g., the agonistic anti-TREM2 antibodies of the present disclosure, do not bind to soluble TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure, e.g., the agonistic anti-TREM2 antibodies of the present disclosure, do not bind to soluble TREM2 in vivo. In some embodiments, an agonist anti-TREM2 antibody of the present disclosure that does not bind soluble TREM2 may bind to an epitope on TREM2 that may include, for example, a portion of the extracellular domain of cellular TREM2 that is not included in sTREM2, e.g., one or more amino acid residues within amino acid residues 161-175; may be at or near the transmembrane portion of TREM2; or may include the transmembrane portion of TREM2.

[0161] Anti-TREM2 antibodies promote myelin clearance The pathological hallmark of demyelinating diseases is the formation of demyelinating lesions in the CNS. For example, in multiple sclerosis, demyelinating lesions can be found in both white and gray matter (Lassmann, Bruck et al. 2007). It is known that removal and clearance of myelin debris by phagocytes is important for eliminating inhibitory signals that can interfere with remyelination in tissues (Kotter, Li et al. 2006; Lampron, Larochelle et al. 2015; Franklin and Ffrench-Constant 2017).

[0162] Thus, in some embodiments, an anti-TREM2 antibody of the present disclosure (e.g., an agonist anti-TREM2 antibody) increases or promotes the clearance of myelin debris in one or more demyelinating lesions in an individual (e.g., in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the present disclosure reduces the amount of myelin debris in one or more demyelinating lesions in an individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In some embodiments, an anti-TREM2 antibody of the present disclosure reduces the amount of myelin debris in one or more demyelinating lesions in an individual compared to the amount of myelin debris in one or more demyelinating lesions in the same individual before administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure reduces the amount of myelin debris in one or more demyelinating lesions in an individual compared to the amount of myelin debris in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals reduces the amount of myelin debris in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the amount of myelin debris in one or more demyelinating lesions in the same plurality of individuals prior to administration of the anti-TREM2 antibody.

[0163] In some embodiments, an anti-TREM2 antibody of the disclosure increases the rate of myelin debris clearance in one or more demyelinating lesions by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of myelin debris clearance in one or more demyelinating lesions in an individual compared to the rate of myelin debris clearance in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of myelin debris clearance in one or more demyelinating lesions in an individual compared to the rate of myelin debris clearance in a corresponding individual who has not been administered the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the rate of myelin debris clearance in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the rate of myelin debris clearance in one or more demyelinating lesions in the same plurality of individuals before administration of the anti-TREM2 antibody.

[0164] Demyelinating lesions and / or myelination status can be measured in an individual using any method in the art, such as magnetization transfer ratio (MTR), restricted proton fraction (f), myelin water fraction, and diffusion tensor imaging (DTI), positron emission tomography (PET), and magnetic resonance imaging (MRI) (see, e.g., Mallik et al., (2014) J Neurology, Neurosurgery, and Psychiatry, 85(12):1396-1404).

[0165] Anti-TREM2 antibodies promote oligodendrocytes Typically, oligodendrocyte (OL) loss during demyelination is followed by remyelination, which is primarily sustained by oligodendrocyte progenitor cells (OPCs), multipotent adult progenitor cells widely distributed in the CNS. In multiple sclerosis, impaired generation of OLs from OPCs leads to an imbalance between demyelination and remyelination, which is the primary cause of persistent demyelination and myelin debris accumulation in the brain, ultimately resulting in axonal damage that manifests clinically as neurological disability (Dulamea 2017). Without wishing to be bound by theory, it is thought that the failure of axonal remyelination in demyelinating diseases such as MS may be due to impaired OPC activation, inadequate recruitment of OPCs to demyelinated sites, and / or abnormalities in OPC differentiation into myelinating mature OLs (Franklin and Ffrench-Constant 2017).

[0166] Thus, in some embodiments, an anti-TREM2 antibody of the present disclosure (e.g., an agonist anti-TREM2 antibody) increases or promotes the recruitment of OPCs to one or more demyelinating lesions in an individual (e.g., in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the disclosure increases the number of OPCs in one or more demyelinating lesions in an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the number of OPCs in one or more demyelinating lesions in an individual compared to the number of OPCs in the one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody, hi some embodiments, an anti-TREM2 antibody of the present disclosure increases the number of OPCs in one or more demyelinating lesions in an individual compared to the number of OPCs in the one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the number of OPCs in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the number of OPCs in one or more demyelinating lesions in the same plurality of individuals before administration of the anti-TREM2 antibody. In some embodiments, the OPCs are PDGFRa positive.

[0167] In other embodiments, an anti-TREM2 antibody of the present disclosure (e.g., an agonist anti-TREM2 antibody) increases or promotes the differentiation of OPCs into mature OLs in one or more demyelinating lesions in an individual (e.g., in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the disclosure increases the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in an individual compared to the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in an individual compared to the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the rate of differentiation of OPCs into mature OLs in one or more demyelinating lesions in the same plurality of individuals before administration of the anti-TREM2 antibody.

[0168] In some embodiments, an anti-TREM2 antibody of the present disclosure (eg, an agonist anti-TREM2 antibody) promotes an increase in mature OLs in one or more demyelinating lesions in an individual (eg, in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the disclosure increases the number of mature OLs in one or more demyelinating lesions in an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the number of mature OLs in one or more demyelinating lesions in an individual compared to the number of mature OLs in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the number of mature OLs in one or more demyelinating lesions in an individual compared to the number of mature OLs in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the number of mature OLs in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the individuals in the plurality compared to the number of mature OLs in one or more demyelinating lesions in the same individuals before administration of the anti-TREM2 antibody.

[0169] In some embodiments, mature OLs are OLIG2 and / or CNPase positive. Methods for quantifying mature OLs have been described (see, e.g., Lucchinetti et al. (1999) Brain 122(12):2279-2295).

[0170] Anti-TREM2 antibodies promote remyelination and axonal health Demyelination in demyelinating diseases such as multiple sclerosis ultimately leads to axonal damage that manifests clinically as neurological disability (Dulamea 2017).

[0171] Thus, in some embodiments, an anti-TREM2 antibody of the present disclosure (e.g., an agonist anti-TREM2 antibody) increases or promotes remyelination in one or more demyelinating lesions in an individual (e.g., in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the disclosure increases remyelination in one or more demyelinating lesions in an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases remyelination in one or more demyelinating lesions in an individual compared to remyelination in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases remyelination in one or more demyelinating lesions in an individual compared to remyelination in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases remyelination in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to remyelination in one or more demyelinating lesions in the same plurality of individuals prior to administration of the anti-TREM2 antibody.

[0172] In some embodiments, an anti-TREM2 antibody of the disclosure increases the rate of remyelination in one or more demyelinating lesions by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least 2.0-fold, at least 2.1-fold, at least 2.15-fold, at least 2.2-fold, at least 2.25-fold, at least 2.3-fold, at least 2.35-fold, at least 2.4-fold, at least 2.45-fold, at least 2.5-fold, at least 2.55-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, at least 5.5-fold, at least 6.0-fold, at least 6.5-fold, at least 7.0-fold, at least 7.5-fold, at least 8.0-fold, at least 8.5-fold, at least 9.0-fold, at least 9.5-fold, or at least 10-fold. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of remyelination in one or more demyelinating lesions in an individual compared to the rate of remyelination in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the rate of remyelination in one or more demyelinating lesions in an individual compared to the rate of remyelination in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody. In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the rate of remyelination in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the rate of remyelination in one or more demyelinating lesions in the same plurality of individuals before administration of the anti-TREM2 antibody.

[0173] In some embodiments, an anti-TREM2 antibody of the present disclosure (e.g., an agonist anti-TREM2 antibody) increases or promotes axonal health in one or more demyelinating lesions in an individual (e.g., in the CNS of an individual). For example, in some embodiments, an anti-TREM2 antibody of the present disclosure increases the level of phosphorylated neurofilaments in one or more demyelinating lesions in an individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the level of phosphorylated neurofilaments in one or more demyelinating lesions in an individual compared to the level of phosphorylated neurofilaments in one or more demyelinating lesions in the same individual prior to administration of the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the level of phosphorylated neurofilaments in one or more demyelinating lesions in an individual compared to the level of phosphorylated neurofilaments in one or more demyelinating lesions in a corresponding individual who has not been administered the anti-TREM2 antibody.In some embodiments, administration of an anti-TREM2 antibody of the present disclosure to a plurality of individuals increases the level of phosphorylated neurofilaments in one or more demyelinating lesions in at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or 100% of the plurality of individuals compared to the level of phosphorylated neurofilaments in one or more demyelinating lesions in the same plurality of individuals prior to administration of the anti-TREM2 antibody. In some embodiments, the phosphorylated neurofilaments are SMI31 positive.

[0174] The level of remyelination, rate of remyelination, and / or axonal health in one or more demyelinating lesions can be measured in an individual using any method known in the art, such as magnetization transfer ratio (MTR), restricted proton fraction f, myelin water fraction, and diffusion tensor imaging (DTI), positron emission tomography (PET), visual evoked potentials (VEPs), and magnetic resonance imaging (MRI) (see, e.g., Malik et al., (2014) J Neurology, Neurosurgery, and Psychiatry, 85(12):1396-1404; and Bove et al., (2017) Neurotherapeutics, 14:894-904).

[0175] In some embodiments, axonal health can be measured using biomarkers of axonal health and / or neurodegeneration. For example, biomarkers of axonal health and / or neurodegeneration (e.g., SIM31, SMI35, NF-L, NF-H, NF-M, alpha-Internexin, tau, the amino acid n-acetylaspartic acid, pNF-H, and other markers known in the art) can be detected in cerebrospinal fluid samples and / or blood samples from individuals using methods known in the art, such as ELISA, Western blot, mass spectrometry, and dot blot (see, e.g., Gresle et al., (2011) Multiple Sclerosis International, 315406).

[0176] Antibodies that affect TREM2 clustering In vivo, anti-TREM2 antibodies of the present disclosure can activate receptors by multiple potential mechanisms. In some embodiments, agonistic anti-TREM2 antibodies of the present disclosure have the ability to activate TREM2 in solution, with appropriate epitope specificity, without the need for clustering with a secondary antibody bound on a plate or via Fcg receptors. In some embodiments, anti-TREM2 antibodies of the present disclosure have a human antibody isotype, such as IgG2, which, due to their unique structure, has the inherent ability to cluster receptors or hold receptors in a clustered configuration, thereby activating receptors such as TREM2 without binding to Fc receptors (e.g., White et al., (2015) Cancer Cell 27, 138-148).

[0177] In certain embodiments, agonist anti-TREM2 antibodies may induce or maintain clustering on the cell surface to activate TREM2 and transmit signals. In certain embodiments, agonist anti-TREM2 antibodies with appropriate epitope specificity can induce or maintain clustering of TREM2 on the cell surface and / or activate TREM2. In some embodiments, the agonist anti-TREM2 antibody binds to one or more amino acids within amino acid residues 124-153 of SEQ ID NO:1, or within the amino acid residues on the TREM2 protein corresponding to amino acid residues 124-153 of SEQ ID NO:1; amino acid residues 129-153 of SEQ ID NO:1, or within the amino acid residues on the TREM2 protein corresponding to amino acid residues 129-153 of SEQ ID NO:1; amino acid residues 140-149 of SEQ ID NO:1, or within the amino acid residues on the TREM2 protein corresponding to amino acid residues 140-149 of SEQ ID NO:1; amino acid residues 149-157 of SEQ ID NO:1, or within the amino acid residues on the TREM2 protein corresponding to amino acid residues 149-157 of SEQ ID NO:1; or within amino acid residues 153-162 of SEQ ID NO:1, or within the amino acid residues on the TREM2 protein corresponding to amino acid residues 153-162 of SEQ ID NO:1. In some embodiments, an agonist anti-TREM2 antibody binds to one or more amino acid residues selected from the group consisting of D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian TREM2 protein corresponding to amino acid residues selected from the group consisting of D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO: 1. In some embodiments, the anti-TREM2 antibodies of the present disclosure cluster receptors (e.g., TREM2) by binding to Fcg receptors on adjacent cells.Binding of the constant IgG Fc portion of an antibody to an Fcg receptor results in aggregation of the antibody, which then aggregates the receptors that bind via their variable regions (Chu et al. (2008) Mol Immunol 45:3926-3933; and Wilson et al., (2011) Cancer Cell 19, 101-113). Any suitable assay known to those skilled in the art (such as those described in WO2017 / 062672 and WO2019 / 028292) can be used to determine antibody clustering.

[0178] Other mechanisms can also be used to cluster receptors (e.g., TREM2). For example, in some embodiments, antibody fragments (e.g., Fab fragments) that cross-link together can be used to cluster receptors (e.g., TREM2) in a manner similar to antibodies with Fc regions that bind to Fcg receptors, as described above. In some embodiments, cross-linked antibody fragments (e.g., Fab fragments) can function as agonist antibodies if they induce receptor clustering at the cell surface and bind to the appropriate epitope on the target (e.g., TREM2).

[0179] Antibodies that rely on binding to FcgR receptors to activate their target receptors can lose their agonistic activity if engineered to eliminate FcgR binding (see, e.g., Wilson et al., (2011) Cancer Cell 19, 101-113; Armour at al., (2003) Immunology 40 (2003) 585-593; and White et al., (2015) Cancer Cell 27, 138-148). Thus, it is believed that anti-TREM2 antibodies of the present disclosure with appropriate epitope specificity can activate TREM2 when the antibody has an Fc domain.

[0180] Exemplary antibody Fc isotypes and modifications are provided below in Table A. In some embodiments, the antibody has an Fc isotype listed in Table A below. [Table 2-1] [Table 2-2]

[0181] In some embodiments, the antibody is of the IgG class, IgM class, or IgA class, hi some embodiments, the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

[0182] In addition to the isotypes listed in Table A, and without wishing to be bound by theory, it is believed that antibodies with human IgG1 or IgG3 isotypes and variants thereof that bind to human activating Fcg receptors I, IIA, IIC, IIIA, and IIIB, and / or mouse Fcg receptors I, III, and IV (e.g., Strohl (2009) Current Opinion in Biotechnology 2009, 20:685-691) may act as agonist antibodies in vivo, but may also be associated with ADCC-related effects. However, such Fcg receptors appear to be less available for antibody binding in vivo compared to the inhibitory Fcg receptor FcgRIIB (see, e.g., White, et al., (2013) Cancer Immunol. Immunother. 62, 941-948; and Li et al., (2011) Science 333(6045):1030-1034).

[0183] In certain embodiments, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments, the antibody induces one or more TREM2 activities, DAP12 activities, or both, independent of binding to an Fc receptor. In certain embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγRIIB), which minimizes or eliminates ADCC. In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., compared to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are V234A (Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A (Cole et al. (1999) Transplantation, 68:563-571), H268Q, V309L, A330S, P331S (U.S. Patent Application Publication No. 2007 / 0148167; Armour et al. (1999) Eur J Immunol 29:2613-2624; Armour et al. (2000) The Haematology Journal 1(Suppl. 1):27; Armour et al. (2000) The Haematology Journal 1 (Suppl. 1):27), C232S, and / or C233S (White et al. (2015) Cancer Cell 27, 138-148), S267E, L328F (Chu et al., (2008) Mol Immunol, 45:3926-3933), M252Y, S254T, and / or T256E, where amino acid positions are according to EU numbering rules.

[0184] In some embodiments, the antibody has an IgG2 isotype with a heavy chain constant domain containing a C127S amino acid substitution, where the amino acid position is according to the EU numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0185] In some embodiments, the antibody has an IgG2 isotype with a kappa light chain constant domain containing the C214S amino acid substitution, where the amino acid positions are according to the EU numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0186] In certain embodiments, the antibody has an IgG1 isotype. In some embodiments, the antibody contains a mouse IgG1 constant region. In some embodiments, the antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγRIIB). In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., compared to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from the group consisting of N297A (Bolt S et al. (1993) Eur J Immunol 23:403-411), D265A (Shields et al. (2001) RJBiol. Chem. 276, 6591-6604), L234A, L235A (Hutchins et al. (1995) Proc Natl Acad Sci USA, 92:11980-11984; Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A (Alegre et al. (1994) Transplantation 57:1537-1543.31; Xu et al. al. (2000) Cell Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchern et al., (2007) Blood, 109:1185-1192), P331S (Sazinsky et al., (2008) Proc Natl Acad Sci USA 2008, 105:20167-20172), S267E, L328F, A330L, M252Y, S254T, and / or T256E, where amino acid positions are according to EU numbering rules.

[0187] In some embodiments, the antibody comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region (White et al., (2015) Cancer Cell 27, 138-148). In certain embodiments, the IgG2 isotype CH1 and hinge region comprises the amino acid sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP (SEQ ID NO: 42). In some embodiments, the antibody Fc region contains an S267E amino acid substitution, an L328F amino acid substitution, or both, and / or an N297A or N297Q amino acid substitution, where amino acid positions are according to EU numbering rules.

[0188] In certain embodiments, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγRIIB). In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., compared to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from L235A, G237A, S228P, L236E (Reddy et al., (2000) J Immunol, 164:1925-1933), S267E, E318A, L328F, M252Y, S254T, and / or T256E, where the amino acid positions are according to the EU numbering convention.

[0189] In certain embodiments, the antibody has a hybrid IgG2 / 4 isotype. In some embodiments, the antibody comprises an amino acid sequence containing amino acids 118 to 260, EU numbering, of human IgG2 and amino acids 261 to 447, EU numbering, of human IgG4 (WO1997 / 11971; WO2007 / 106585).

[0190] In certain embodiments, the antibody contains a murine IgG4 constant region (Bartholomaeus, et al. (2014). J. Immunol. 192, 2091-2098).

[0191] In some embodiments, the Fc region further contains one or more additional amino acid substitutions selected from A330L, L234F, L235E, and / or P331S according to EU numbering; and any combination thereof.

[0192] In certain embodiments, the antibody contains one or more amino acid substitutions in the Fc region at residue positions selected from C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof (residue numbering according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S (residue position numbering according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G and P331S (residue position numbering according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G and K322A (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S, and P331S (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, A330S, and P331S (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and A330S (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and P331S (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions S267E and L328F (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions C127S (residue positions are numbered according to EU numbering). In some embodiments, the Fc region contains amino acid substitutions at positions E345R, E430G, and S440Y (residue positions are numbered according to EU numbering).

[0193] In some embodiments, the antibody has a human IgG1 isotype and comprises amino acid substitutions in the Fc region at residue positions P331S and E430G (residue numbering according to EU numbering). An Fc region comprising amino acid substitutions at residue positions P331S and E430G is sometimes referred to as "PSEG."

[0194] Further IgG mutations In some embodiments, one or more of the IgG1 variants described herein may be combined with the A330L mutation (Lazar et al., (2006) Proc Natl Acad Sci USA, 103:4005-4010), or one or more of the L234F, L235E, and / or P331S mutations (Sazinsky et al., (2008) Proc Natl Acad Sci USA, 105:20167-20172) to eliminate complement activation (amino acid positions according to EU numbering convention). In some embodiments, the IgG variants described herein may be combined with one or more mutations to increase the antibody half-life in human serum (e.g., M252Y, S254T, T256E mutations according to the EU numbering convention) (Dall'Acqua et al., (2006) J Biol Chem, 281:23514-23524; and Strohl et al., (2009) Current Opinion in Biotechnology, 20:685-691).

[0195] In some embodiments, the IgG4 variants of the present disclosure may be combined with one or more mutations described in the EU numbering convention, such as the S228P mutation (Angal et al., (1993) Mol Immunol, 30:105-108, and / or Peters et al., (2012) J Biol Chem. 13;287(29):24525-33), to enhance antibody stability.

[0196] Exemplary Anti-TREM2 Antibodies In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to TREM2 with high affinity, are agonists, and induce one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies enhance one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein compared to one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein in the absence of the isolated antibody. In some embodiments, the anti-TREM2 antibodies enhance one or more TREM2 activities without competing with or otherwise blocking the binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody is a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. Exemplary descriptions of such antibodies are found throughout this disclosure. In some embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen.

[0197] In some embodiments, anti-TREM2 antibodies of the present disclosure bind to human TREM2 or homologs thereof, including, but not limited to, mammalian (e.g., non-human mammalian) TREM2 protein, mouse TREM2 protein (Uniprot Accession No. Q99NH8), rat TREM2 protein (Uniprot Accession No. D3ZZ89), rhesus monkey TREM2 protein (Uniprot Accession No. F6QVF2), cynomolgus monkey TREM2 protein (NCBI Accession No. XP_015304909.1), horse TREM2 protein (Uniprot Accession No. F7D6L0), porcine TREM2 protein (Uniprot Accession No. H2EZZ3), and canine TREM2 protein (Uniprot Accession No. E2RP46). In some embodiments, anti-TREM2 antibodies of the present disclosure specifically bind to human TREM2. In some embodiments, anti-TREM2 antibodies of the present disclosure specifically bind to cynomolgus monkey TREM2. In some embodiments, an anti-TREM2 antibody of the present disclosure specifically binds to both human TREM2 and cynomolgus monkey TREM2. In some embodiments, an anti-TREM2 antibody of the present disclosure induces at least one TREM2 activity of the present disclosure.

[0198] Anti-TREM2 antibody binding region In some embodiments, an anti-TREM2 antibody of the present disclosure binds to amino acid residues 124-153 of SEQ ID NO:1, or one or more amino acids within the amino acid residues on a TREM2 protein corresponding to amino acid residues 124-153 of SEQ ID NO:1; amino acid residues 129-153 of SEQ ID NO:1, or one or more amino acids within the amino acid residues on a TREM2 protein corresponding to amino acid residues 129-153 of SEQ ID NO:1; amino acid residues 140-149 of SEQ ID NO:1, or one or more amino acids within the amino acid residues on a TREM2 protein corresponding to amino acid residues 140-149 of SEQ ID NO:1; amino acid residues 149-157 of SEQ ID NO:1, or one or more amino acids within the amino acid residues on a TREM2 protein corresponding to amino acid residues 149-157 of SEQ ID NO:1; or amino acid residues 153-162 of SEQ ID NO:1, or one or more amino acids within the amino acid residues on a TREM2 protein corresponding to amino acid residues 153-162 of SEQ ID NO:1. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more of amino acid residues D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO:1, or to one or more amino acid residues on a mammalian TREM2 protein corresponding to amino acid residues selected from the group consisting of D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO:1.

[0199] Anti-TREM2 antibody light and heavy chain variable regions In some embodiments, the anti-TREM2 antibody used in the methods of the disclosure is described in WO2018 / 195506, WO2019 / 028292, WO2018 / 015573, or WO2019 / 055841, each of which is incorporated herein by reference. In some embodiments, the anti-TREM2 antibody used in the methods of the disclosure induces or enhances one or more of the following TREM2 activities: TREM2 binding to DAP12; DAP12 phosphorylation; Syk kinase activation; IFN-β, IL-1α, IL-1β, TNF-α, YM-1, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, Rorc, IL-20 family members, modulation of one or more pro-inflammatory mediators selected from IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, CSF-1, MHC-II, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, wherein the modulation is in the activation of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglia); glial cells); recruitment of Syk, ZAP70, or both to the DAP12 / TREM2 complex; increased activity of one or more TREM2-dependent genes (optionally, wherein the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; modulation of expression of one or more stimulatory molecules selected from CD83, CD86, MHC class II, CD40, and any combination thereof (optionally, wherein CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells include bone marrow-derived dendritic cells); increased memory; and alleviation of cognitive impairment.In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance memory and / or reduce cognitive impairment when administered to an individual.

[0200] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 34; (b) SEQ ID NO: 35; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 31; and / or a light chain variable domain comprising one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 41; and / or a light chain variable domain comprising one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95% identity to SEQ ID NO: 41; , at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 32;

[0201] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 36; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 36; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO:37; and and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 39; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO:40; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO:40;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 32;

[0202] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YAFSSWDMN (SEQ ID NO: 36), HVR-H2 comprising the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), HVR-H3 comprising the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), HVR-L2 comprising the amino acid sequence KVSNRVS (SEQ ID NO: 40), and HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 32). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), HVR-H2 comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), HVR-L2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 33), and HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one, two, three, or four framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4, wherein VH FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 9-11, VH FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 12 and 13, VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and VH FR4 comprises the sequence of SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three, or four framework regions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein VL FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 17-20, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, and VL FR3 comprises a sequence selected from the group consisting of SEQ ID NOs:23 and 24, and VL FR4 comprises a sequence selected from the group consisting of SEQ ID NOs:25 and 26.

[0203] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-47, or to the amino acid sequence of SEQ ID NO:28. and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO:29. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 28, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-47.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 29, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-47. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 28, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 28. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 28. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the antibody AL2p-47 or SEQ ID NO: 28 VH sequence, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody AL2p-47; (b) the HVR-H2 amino acid sequence of antibody AL2p-47; and (c) the HVR-H3 amino acid sequence of antibody AL2p-47. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO: 29, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 29. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 29. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-47 or SEQ ID NO: 29, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody AL2p-47, (b) the HVR-L2 amino acid sequence of antibody AL2p-47, and (c) the HVR-L3 amino acid sequence of antibody AL2p-47. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 29.

[0204] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-58, or to the amino acid sequence of SEQ ID NO:27. and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO:30. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the heavy chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 27, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-58.In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 30, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-58. In some embodiments, an anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 27, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although the anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 27. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 27. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-58 or SEQ ID NO: 27, including post-translational modifications of that sequence.In certain embodiments, the VH comprises one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of antibody AL2p-58, (b) the HVR-H2 amino acid sequence of antibody AL2p-58, and (c) the HVR-H3 amino acid sequence of antibody AL2p-58. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO: 30, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared to the reference sequence), although an anti-TREM2 antibody comprising that sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 30. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-58 or the amino acid sequence of SEQ ID NO: 30. In certain embodiments, the substitutions, insertions, or deletions occur in regions outside the HVRs (i.e., in the FR regions). In some embodiments, the substitutions, insertions, or deletions occur in the FR regions. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-58 or SEQ ID NO: 30, including post-translational modifications of that sequence. In certain embodiments, the VL comprises one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of antibody AL2p-58, (b) the HVR-L2 amino acid sequence of antibody AL2p-58, and (c) the HVR-L3 amino acid sequence of antibody AL2p-58. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 30.

[0205] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or a heavy chain comprising the amino acid sequence of SEQ ID NO: 44 and a light chain comprising the amino acid sequence of SEQ ID NO: 47.

[0206] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; or a heavy chain comprising the amino acid sequence of SEQ ID NO: 46 and a light chain comprising the amino acid sequence of SEQ ID NO: 48.

[0207] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 52; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 52; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 53; and (d) HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 54. and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 55; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 56; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 56;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 57. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 52; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 53; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 54; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 55; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 56; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 57.

[0208] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 60; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 60; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 61; and and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 63; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 64; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 64;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 65. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 60; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 61; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 62; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 63; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 64; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 65.

[0209] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 68; (b) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 68; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 70; and and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 71; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 72; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 72;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 73. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 68; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 69; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 70; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 71; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 72; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 73.

[0210] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 159; (b) SEQ ID NO: 160; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 161; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 156; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 157; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 157;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 158. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 159; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 160; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 161; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 156; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 157; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0211] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 169; (b) SEQ ID NO: 170; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 171; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 166; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 167; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 167;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 168. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 169; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 170; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 171; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 166; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 167; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 168. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0212] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 175; (b) SEQ ID NO: 176; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 177; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 1%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 172; and / or the light chain variable domain comprises one or more of: (a) an HVR-H3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, %, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 173; (b) HVR-L2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 173;and (c) one or more of HVR-L3 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 174. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 175; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 177; and the light chain variable domain comprises (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 172; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 173; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 174. In some embodiments, an anti-TREM2 antibody of the present disclosure competes for binding to TREM2 with an antibody of any of the embodiments described in this paragraph. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to the same TREM2 epitope as an antibody of any of the embodiments described in this paragraph.

[0213] In some embodiments, an anti-TREM2 antibody of the disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity to SEQ ID NO: 181; (b) SEQ ID NO: 182; and (c) HVR-H2 comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%,...

Claims

1. A pharmaceutical for promoting remyelination of one or more demyelinating lesions in the central nervous system (CNS) of an individual with a CNS demyelinating disease, comprising a therapeutically effective amount of an agonist antibody that binds to a TREM2 protein.

2. The pharmaceutical of claim 1 , wherein the TREM2 protein is a mammalian or human protein.

3. The method of claim 2 , wherein the TREM2 protein is a wild-type protein, a naturally occurring variant, or a disease variant.

4. The antibody a. TREM2 binding to DAP12; b. DAP12 phosphorylation; c. Activation of Syk kinase; d. Recruitment of Syk to the DAP12 / TREM2 complex; and e. Increased activity of one or more TREM2-dependent genes, optionally wherein said one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor. The pharmaceutical agent according to any one of claims 1 to 3, which induces one or more TREM2 activities selected from the group consisting of:

5. The pharmaceutical agent of any one of claims 1 to 4, wherein the antibody enhances one or more TREM2 activities induced in the presence of myelin.

6. The pharmaceutical of claim 5, wherein the one or more TREM2 activities induced in the presence of myelin include increased activity of one or more TREM2-dependent genes, and optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor.

7. The medicament of any one of claims 1 to 6, wherein the antibody promotes the recruitment of oligodendrocyte progenitor cells (OPCs) to one or more demyelinating lesions in the CNS of the individual.

8. The pharmaceutical composition according to claim 7, wherein the OPC is PDGFRα-positive.

9. The medicament of any one of claims 1 to 8, wherein the antibody promotes an increase in mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS of the individual.

10. The medicament of any one of claims 1 to 9, wherein the antibody promotes differentiation of OPCs into mature oligodendrocytes (OLs) in one or more demyelinating lesions in the CNS of the individual.

11. The pharmaceutical agent according to claim 9 or 10, wherein the mature OL is OLIG2 and / or CNPase positive.

12. The method of any one of claims 1 to 11, wherein the antibody promotes an increase in the level of phosphorylated neurofilaments in one or more demyelinating lesions in the CNS of the individual.

13. The pharmaceutical according to claim 12, wherein the phosphorylated neurofilament is SMI-31 positive.

14. The method of any one of claims 1 to 13, wherein the antibody promotes clearance of myelin debris in one or more demyelinating lesions in the individual.

15. The pharmaceutical according to any one of claims 1 to 14, wherein the antibody is a mouse antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody.

16. The pharmaceutical according to any one of claims 1 to 15, wherein the antibody is a monoclonal antibody.

17. The pharmaceutical of any one of claims 1 to 16, wherein the antibody binds to one or more amino acids within amino acid residues 124 to 153 of SEQ ID NO: 1, or within amino acid residues on the TREM2 protein corresponding to amino acid residues 124 to 153 of SEQ ID NO: 1; within amino acid residues 129 to 153 of SEQ ID NO: 1, or within amino acid residues on the TREM2 protein corresponding to amino acid residues 129 to 153 of SEQ ID NO: 1; within amino acid residues 140 to 149 of SEQ ID NO: 1, or within amino acid residues 140 to 149 of SEQ ID NO: 1; within amino acid residues 149 to 157 of SEQ ID NO: 1, or within amino acid residues 149 to 157 of SEQ ID NO: 1; or within amino acid residues 153 to 162 of SEQ ID NO: 1, or within amino acid residues on the TREM2 protein corresponding to amino acid residues 153 to 162 of SEQ ID NO:

1.

18. The pharmaceutical of any one of claims 1 to 16, wherein the antibody binds to one or more amino acid residues selected from the group consisting of D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian TREM2 protein corresponding to the amino acid residues selected from the group consisting of D140, L141, W142, F143, P144, E151, D152, H154, E156, and H157 of SEQ ID NO:

1.

19. The antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 34), the HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 35), and the HVR-H3 comprises the amino acid sequence The pharmaceutical composition of any one of claims 1 to 18, wherein the HVR-L1 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 31), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 41), the HVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 33), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

20. The pharmaceutical according to any one of claims 1 to 19, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

30.

21. The antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3, and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1 comprises the amino acid sequence YAFSSDWMN (SEQ ID NO: 36), the HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 37), and the HVR-H3 comprises the amino acid sequence The pharmaceutical composition of any one of claims 1 to 18, wherein the HVR-L1 comprises the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 38), the HVR-L1 comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 39), the HVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 40), and the HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 32).

22. The pharmaceutical according to any one of claims 1 to 18 or 21, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 28 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

29.

23. The pharmaceutical according to any one of claims 1 to 22, wherein the antibody is a fragment, and the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

24. The pharmaceutical according to any one of claims 1 to 22, wherein the antibody is of the IgG class, the IgM class, or the IgA class.

25. The pharmaceutical of claim 24, wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

26. 25. The medicament of claim 24, wherein the antibody has a human IgG1 isotype and comprises amino acid substitutions at residue positions P331S and E430G in the Fc region, the numbering of the residues being according to EU numbering.

27. The antibody a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 43 and a light chain comprising the amino acid sequence of SEQ ID NO: 47; or b. A heavy chain comprising the amino acid sequence of SEQ ID NO: 44, and a light chain comprising the amino acid sequence of SEQ ID NO:

47. The pharmaceutical composition according to any one of claims 1 to 20, comprising:

28. The antibody a. a heavy chain comprising the amino acid sequence of SEQ ID NO: 45 and a light chain comprising the amino acid sequence of SEQ ID NO: 48; or b. A heavy chain comprising the amino acid sequence of SEQ ID NO: 46, and a light chain comprising the amino acid sequence of SEQ ID NO:

48. The pharmaceutical composition according to any one of claims 1 to 18 or 21 to 22, comprising:

29. The pharmaceutical composition according to any one of claims 1 to 28, wherein the individual is a human.

30. The method of any one of claims 1 to 29, wherein the individual comprises at least one copy of a functional TREM2 gene.

31. The method of claim 30, wherein the individual is heterozygous for a mutation in the TREM2 gene.

32. The method of claim 30, wherein the individual is homozygous for a mutation in the TREM2 gene.

33. The pharmaceutical composition of any one of claims 1 to 32, wherein the individual has or is at risk of having a disease feature selected from the group consisting of myelin damage, one or more demyelinating lesions in the CNS, inflammation in the CNS, one or more plaques in the CNS, loss of myelin sheath, axonal injury, decreased OPCs, decreased OLs, decreased myelin debris clearance, axonal varicosity, axonal spheroids, gliosis, macrophages with autofluorescent lipids, axonal destruction, and any combination thereof.

34. The method of claim 33, wherein the individual has or is at risk of having axonal damage and / or one or more demyelinating lesions in the CNS.

35. The pharmaceutical of claim 34, wherein the axonal damage and / or the one or more demyelinating lesions in the CNS are present in the white matter, gray matter, or corpus callosum of the CNS.

36. 36. The medicament of any one of claims 1 to 35, wherein the individual has or is at risk of having a symptom selected from the group consisting of altered sensation, cramping, numbness, muscle weakness, clonus, muscle spasms, difficulty moving, difficulty coordinating, difficulty with balance, difficulty speaking, difficulty swallowing, vision problems, fatigue, acute pain, chronic pain, bladder problems, bowel problems, cognitive problems, depression, mood lability, Uhthoff phenomenon, Lhermitte's sign, and any combination thereof.

37. The medicament according to any one of claims 1 to 36, wherein the demyelinating disease is selected from the group consisting of multiple sclerosis, adrenoleukodystrophy, Krabbe disease, optic neuritis, neuromyelitis optica (Devic's disease), transverse myelitis, acute disseminated encephalomyelitis, adrenomyeloneuropathy, mucopolysaccharidosis (Hurler syndrome), sphingolipid storage disease, leukodystrophy, Leber's hereditary optic atrophy, phenylketonuria, Tay-Sachs disease, Niemann-Pick disease, Gaucher disease, acute hemorrhagic leukoencephalitis, osmotic demyelinating syndrome, and Marchiafaver-Bignami disease.

Images