Anti-TREM2 antibodies and methods of use thereof

Abstract

To provide anti-TREM2 antibodies, and to provide therapeutic uses of such antibodies.SOLUTION: The present invention provides methods and compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, and the like, that specifically bind a TREM2 protein, e.g., a mammalian TREM2 and / or human TREM2. The methods provided herein provides an isolated antibody that binds to a TREM2 protein, for use in preventing, reducing the risk of, or treating an individual having dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, or multiple sclerosis.SELECTED DRAWING: Figure 16

Description

[Technical Field]

[0001] Related cross-applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 035,336, filed August 8, 2014, U.S. Provisional Patent Application No. 62 / 135,110, filed March 18, 2015, and U.S. Provisional Patent Application No. 62 / 135,122, filed March 18, 2015, each of which is incorporated by reference herein in its entirety.

[0002] Submission of 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: 735022000440SEQLISTING.TXT, Date Recorded: August 7, 2015, Size: 240 KB).

[0003] The present invention relates to anti-TREM2 and anti-DAP12 antibodies and therapeutic uses of such antibodies. [Background technology]

[0004] Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoglobulin-like receptor expressed primarily on myeloid cells, such as macrophages, dendritic cells, monocytes, dermal Langerhans cells, Kupffer cells, osteoclasts, and microglia. It is required for the regulation (e.g., suppression) of Toll-like receptor (TLR) signaling, regulation of inflammatory cytokines, and normal osteoclast development. TREM2 was discovered as a member of the TERM transmembrane glycoprotein family, a single immunoglobulin variable (IgV) domain receptor family. Human and mouse TREM2-encoding genes are located on human chromosome 6p21.1 and mouse chromosome 17C3, respectively. The TREM cluster includes genes encoding TREM1, TREM2, TREM4, and TREM5, as well as TREM-like genes in both humans and mice. Furthermore, TERM3 and plasmacytoid dendritic cell (pDC) TREMs have been identified in mice. The TREM-like genes, human TREML1 and TREML2 and mouse TREML1 and TREML2, encode TLT-1 and TLT-2, respectively. Two of the best-characterized of these receptors, TREM1 and TREM2, show some sequence homology with other members of the Ig-SF, such as activating NK cell receptors (20% identity with NKp44), and act through association with the DAP12-mediated pathway for signal transduction.

[0005] TREM2 was originally cloned as a cDNA encoding a TREM1 homolog (Bouchon, A et al., J Exp Med, 2001. 194(8): pp. 1111-22). This receptor is a glycoprotein of approximately 40 kDa, which is reduced to 26 kDa after N-deglycosylation. The TREM2 gene encodes a 230 amino acid protein containing an extracellular domain, a transmembrane domain, and a short cytoplasmic tail. The extracellular domain, encoded by exon 2, consists of a single V-type Ig-SF domain containing three potential N-glycosylation sites. The putative transmembrane domain contains a charged lysine residue. The cytoplasmic tail of TREM2 lacks signaling motifs, and it is thought to signal via the signaling adaptor molecule DAP12 / TRYROBP.

[0006] The signaling adaptor molecule DAP12 is expressed as a homodimer on the surface of various cells involved in the innate immune response, including microglia, macrophages, granulocytes, NK cells, and dendritic cells (DCs). DAP12 is a member of the type I transmembrane adaptor protein family, based on its homology to the human T cell receptor (TCR)-associated CD3 chain and Fc receptor (FcR) gamma chain (Turnbull, IR and Colonna, M, Nat Rev Immunol, 2007. 7(2): pp. 155-61). These proteins share many structural and functional features, including one or more ITAM motifs in their cytoplasmic domains, charged and acidic residues in the transmembrane region (important for interaction with partner chains), and the ability to recruit Src homology domain 2 (SH2)-containing proteins after tyrosine phosphorylation. The ITAM motifs mediate signal propagation through activation of ZAP70 or Syk tyrosine kinases. Both kinases phosphorylate several substrates, thereby promoting the formation of signaling complexes that lead to cell activation. Interestingly, some B and T cells also express DAP12 under inflammatory conditions. In humans, CD4 + CD28 - T cells, αβTCR+ CD4 + T cells and CD8 + A subset of T cells has been described in patients suffering from chronic inflammatory diseases in association with autoimmune T cells (Schleinitz, N. et al., PLoS ONE, 4 (2009), p. e6264). Considering the significant level of DAP12 expression in mouse peritoneal macrophages, this protein is thought to be expressed in other macrophage-related cells such as osteoclasts in the bone marrow, Kupffer cells in the liver, alveolar macrophages in the lungs, Langerhans cells in the skin, and microglial cells in the brain (Takaki, R et al., Immunol Rev, 2006. 214: p. 118-29).

[0007] TREM2 has been identified as expressed on the surface of human monocyte-derived dendritic cells and as an mRNA transcript in the murine macrophage cell line RAW264 (Bouchon, A et al., J Exp Med, 2001. 194(8): pp. 1111-22). Human TREM2 was the first DAP12-associated receptor described on the surface of DCs. Studies have demonstrated that TREM2 cell surface expression is reduced in DAP12-deficient bone marrow-derived dendritic cells (BMDCs) and DAP12-deficient macrophages compared to wild-type cells (Ito, H and Hamerman, JA, Eur J Immunol. 42(1): p. 176-85; Hamerman, JA et al., J Immunol, 2006. 177(4): p. 2051-5, and Hamerman, JA et al., Nat Immunol, 2005. 6(6): p. 579-86), indicating that formation of the TREM2 / DAP12 complex is required for maximal TREM2 surface expression.

[0008] Recent studies have also demonstrated cell surface expression of TREM2 on macrophages infiltrating tissues from the circulation and on macrophages activated by IL-4 or IL-13 (Turnbull, IR et al., J Immunol, 2006. 177(6): pp. 3520-4). However, TREM2 expression was not necessarily found on other cell populations, such as tissue-resident macrophages, circulating monocytes, or corresponding progenitor cells in the bone marrow, suggesting that TREM2 expression is not centrally induced but is induced locally during tissue infiltration or by cytokine-mediated activation. Furthermore, IFN-γ and LPS have been observed to reduce or otherwise eliminate TREM2 expression. Furthermore, it has recently been reported that TREM2 is highly expressed in microglia and infiltrating macrophages in the central nervous system in experimental autoimmune encephalomyelitis or Alzheimer's disease (Piccio, L et al., Eur J Immunol, 2007. 37(5): p. 1290-301, and Wang Y, Cell. 2015 Mar 12; 160(6):1061-71).

[0009] TREM2 has been shown to signal through DAP12, which downstream leads to activation of the Syk / Zap70 tyrosine kinase family, PI3K, and other intracellular signals. In myeloid cells, TLR signaling is important for activation in response to infection and plays a key role in pathological inflammatory responses by macrophages and dendritic cells (Hamerman, JA et al., (2006) J Immunol 177: 2051-2055; Ito, H et al., Eur J Immunol 42: 176-185; Neumann, H et al., (2007) J Neuroimmunol 184: 92-99; Takahashi, K et al., (2005) J Exp Med 201: 647-657; and Takahashi, K et al., (2007) PLoS Med 4: e124). Deficiency of either TREM2 or DAP12 is thought to result in increased proinflammatory signaling. The effects of TREM2 deficiency in vitro have been demonstrated in the context of stimulation with representative TLR ligands, such as LPS, CpG DNA, and zymosan. TREM2-deficient dendritic cells exhibit increased release of IL-12p70, TNF, IL-6, and IL-10 in the presence, but not in the absence, of stimulation.

[0010] Several recent studies have explored the intracellular signaling events induced by activation of the TREM2 / DAP12 pathway. For example, TREM2 is thought to activate signaling pathways involved in cell survival (e.g., protein kinase B-Akt), cell activation and differentiation (e.g., Syk, ERK1 / 2, PLC-γ, etc.), and actin cytoskeleton regulation (e.g., Syk, Vav, etc.) (Peng, Q et al., Sci Signal. 3(122): p. ra38, and Whittaker, GC et al., J Biol Chem. 285(5): p. 2976-85). After TREM2 ligation, the ITAM tyrosine of DAP12 is phosphorylated by SRC family kinases, leading to the recruitment and activation of Syk kinase and / or ZAP70 kinase. In mice, Syk may be the predominant kinase involved, whereas in humans, both Syk and ZAP70 appear to efficiently couple such ITAM-containing subunits, linking them via tandem SH2 domains.

[0011] Studies on TREM2 signaling have revealed that, like TREM1, TREM2-mediated signaling through DAP12 also leads to increased intracellular calcium ion levels and ERK1 / 2 phosphorylation (Bouchon, A et al., J Exp Med, 2001. 194(8): pp. 1111-22, and Sharif, O and Knapp, S, Immunobiology, 2008. 213(9-10): pp. 701-13). Importantly, TREM2 receptor ligation does not induce the degradation of IkB-α and subsequent nuclear translocation of NF-kB, indicating a possible difference between TREM2 and TREM1 signaling (Bouchon, A et al., J Exp Med, 2001. 194(8): pp. 1111-22). Receptor cross-linking of TREM2 in immature dendritic cells induces up-regulation of molecules involved in T cell costimulation, such as CD86, CD40, and MHC class II, as well as up-regulation of the chemokine receptor CCR7 (Bouchon, A et al., J Exp Med, 2001. 194(8): pp. 1111-22). TREM2 is also expressed in microglia, where receptor cross-linking leads to increased ERK1 / 2 phosphorylation and CCR7, but not CD86 or MHC class II expression, suggesting possible cell-type-specific differences in TREM2 signaling. Furthermore, overexpression of TREM2 in bone marrow cells resulted in increased phagocytosis of degenerating myelin (Takahashi, K et al., PLoS Med, 2007. 4(4): p. e124, and Neumann, H and Takahashi, K, J Neuroimmunol, 2007. 184(1-2): p. 92-9).

[0012] It has also been shown that bone marrow-derived macrophages (BMDMs) silenced for TREM2 using shRNAi display increased TNF secretion in response to the TLR2 / 6 ligand zymosan and the TLR9 ligand CpG compared with control BMDM cells treated with nonspecific shRNAi, indicating that TREM2 negatively regulates cytokine synthesis in macrophages (Ito, H and Hamerman, JA, Eur J Immunol. 42(1): pp. 176-85; Hamerman, JA et al., J Immunol, 2006. 177(4): pp. 2051-5; and Hamerman, JA et al., Nat Immunol, 2005. 6(6): pp. 579-86). These results were confirmed using BMDM cells from TREM2 knockout mice, demonstrating that TREM2 expression is significantly increased in BMDMs. - / - Furthermore, we have demonstrated that TNF and IL-6 levels in BMDM cells were higher than those in wild-type BMDM cells (Turnbull, IR, et al., J Immunol, 2006. 177(6): pp. 3520-4, and Turnbull, IR and Colonna, M, Nat Rev Immunol, 2007. 7(2): pp. 155-61). Furthermore, overexpression of TREM2 in microglia has been shown to result in decreased TNF and inducible nitric oxide (iNOS) mRNA levels after culturing these cells with apoptotic neurons, whereas TREM2 knockdown resulted in a modest increase in TNF and iNOS mRNA levels. This suggests that TREM2 is a negative regulator of cytokine synthesis, in contrast to TREM1, which is a positive regulator of cytokine synthesis. This effect of TREM2 on inflammation may be independent of macrophage type, as it occurs in both microglial and BMDM cells.

[0013] It has been shown that activation of microglia can induce inflammation in resident myeloid cells in the central nervous system (CNS) (Neumann, H et al., (2007) J Neuroimmunol 184: 92-99; Takahashi, K et al., (2005) J Exp Med 201: 647-657; Takahashi, K et al., (2007) PLoS Med 4: e124; and Hsieh, CL et al., (2009) J Neurochem 109: 1144-1156). Furthermore, microglial activation has also been implicated in frontotemporal dementia (FTD), Alzheimer's disease, Parkinson's disease, stroke / ischemic brain injury, and multiple sclerosis. Reduced TREM2 activation resulted in increased specific activation and inflammatory markers, such as NOS2 gene transcription, in myeloid cells, whereas increased TREM2 activation resulted in decreased NOS2 transcription. Dying neurons are thought to express endogenous ligands for TREM2. HSP60 has been implicated as a ligand for TREM2 on neuroblastoma cells (Stefani, L et al., (2009) Neurochem 110: 284-294). TREM2 overexpression also leads to increased phagocytosis of dying neurons by microglia, as well as increased phagocytosis by other myeloid cells.

[0014] In humans, complete absence of TREM2 has been shown to cause Nasu-Hakola disease, a rare neurodegenerative disorder associated with late-onset dementia, demyelination, and brain atrophy (Paloneva, J et al., (2002) Am J Hum Genet 71: 656-662, and Paloneva, J et al., (2003) J Exp Med 198: 669-675). Nasu-Hakola disease may also be caused by DAP12 deficiency.

[0015] TREM2 gene expression has also been shown to be increased in APP23 transgenic mice, an Alzheimer's disease model in which mice express a mutant form of the amyloid precursor protein associated with familial Alzheimer's disease (Melchior, B et al., ASN Neuro 2: e00037). Amyloid 1-42 uptake has also been shown to be increased in the BV-2 microglial cell line, which overexpresses TREM2.

[0016] TREM2 has further been shown to be upregulated in the EAE mouse model of multiple sclerosis (Neumann, H et al., (2007) J Neuroimmunol 184: 92-99; Takahashi, K et al., (2005) J Exp Med 201: 647-657; and Takahashi, K et al., (2007) PLoS Med 4: e124). Transduction of bone marrow-derived myeloid progenitor cells (BM-DCs) with TREM2 in vitro results in increased phagocytosis of degenerated myelin. In response to LPS, these cells show increased IL-10 and decreased IL-1β. Intravenous transplantation of TREM2-overexpressing bone marrow cells can suppress EAE in vivo.

[0017] Furthermore, exome sequencing of individuals with frontotemporal dementia (FTD) symptoms has identified homozygous mutations in TREM2 (Guerreiro, RJ et al., JAMA Neurol 70: 78-84, and Guerreiro, RJ et al., Arch Neurol: 1-7). Some of these mutations result in truncation and possible loss of function of TREM2. These same TREM2 mutations can also cause Nasu-Hakola disease in some individuals. Imaging studies in certain individuals with TREM2 homozygous mutations have also shown evidence of demyelination.

[0018] Heterozygous mutations in TREM2, the same mutations that cause Nasu-Hakola disease and FTD, also increase the risk of Alzheimer's disease (Guerreiro, R et al., N Engl J Med 368: 117-127; Jonsson, T et al., N Engl J Med 368: 107-116; and Neumann, H et al., N Engl J Med 368: 182-184). Although these TREM2 mutations are rarer than known risk variants for Alzheimer's disease (e.g., APOE4), the impact of carrying these mutations is similarly severe: an approximately threefold increase in the risk of developing Alzheimer's disease. Furthermore, even individuals without Alzheimer's disease who carry heterozygous TREM2 mutations exhibit poorer cognition compared to individuals with two normal TREM2 alleles. Furthermore, it has been shown that the most common TREM2 mutation (at most 1 in 200 individuals), the TREM2 R47H variant (an arginine to histidine amino acid substitution at position 47 of TREM2), is located within the immunoglobulin domain of TREM2, thereby altering ligand binding (Wang Y, Cell. 2015 Mar 12;160(6):1061-71).

[0019] Furthermore, an integrative network-based approach to rank-ordered organization of molecular networks of gene expression associated with late-onset progressive developmental Alzheimer's disease (LOAD) identified TYROBP / DAP12 as a signaling molecule for TREM2 as a key regulator of the immune / microglial gene module associated with LOAD. TYROBP was found to be the highest-scoring causal regulator of the immune / microglial module when ranked based on the number and magnitude of loss of control of other genes regulated by TREM2 and their differential expression in LOAD brains. TYROBP was significantly upregulated in LOAD brains, and there was a progression of TYROBP expression changes throughout mild cognitive impairment (MCI), which often precedes LOAD (Zhang et al., (2013) Cell 153, 707-720). Targeting such causal networks in a manner that restores normality may provide a therapeutic approach.

[0020] Thus, there is a need for antibodies that specifically bind to TREM2 and / or its signaling adapter molecule DAP12 / TRYROBP on the cell surface and modulate (e.g., activate or inhibit) one or more TREM2 and / or DAP12 activities to treat one or more diseases, disorders, and conditions associated with reduced TREM2 and / or DAP12 activity, as well as conditions associated with unwanted TREM2 and / or DAP12 activity.

[0021] Furthermore, the tumor microenvironment consists of a heterogeneous immune infiltrate, including T lymphocytes, macrophages, and cells of the myeloid / granulocytic lineage. Therapeutic approaches that modulate specific subsets of immune cells are changing the standard of care. "Checkpoint blocking" antibodies that target immune regulatory molecules expressed on T cells (e.g., CTLA-4 and PD-1) have demonstrated clinical activity against a variety of tumor types (Naidoo et al., (2014) British Journal of Cancer 111, 2214-2219).

[0022] Cancer immunotherapy targeting tumor-associated macrophages (e.g., M2-type macrophages) is an area of ​​significant research. The presence of M2 macrophages in tumors is associated with poor prognosis. Thus, there is a need for antibodies that specifically bind to TREM2 and / or DAP12 and modulate (e.g., activate or inhibit) TREM2 and / or DAP12 activity in one or more tumor-associated immune cells, such as macrophages, dendritic cells, myeloid / granulocytic cells, T cells, and monocytes.

[0023] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0024] The present invention generally relates to methods and compositions comprising antibodies, e.g., monoclonal antibodies, chimeric antibodies, bispecific antibodies, humanized antibodies, antibody fragments, etc., that specifically bind to a TREM2 protein, such as mammalian TREM2, human TREM2, mammalian DAP12, or human DAP12, including wild-type proteins and naturally occurring variants thereof, and / or its signaling adaptor molecule, DAP12. The antibodies of the present disclosure may include agonist, inactive, and / or antagonist antibodies. The methods provided herein find use in preventing, reducing the risk of, or treating individuals with dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, or multiple sclerosis; inducing or promoting innate immune cell survival in individuals in need thereof; and / or reducing innate immune cell survival in individuals in need thereof.

[0025] Certain aspects of the present disclosure relate to different classes of anti-TREM2 antibodies. In some embodiments, the anti-TREM2 antibodies are agonistic antibodies that bind to TREM2 and activate, induce, promote, stimulate, or otherwise increase one or more TREM2 activities, survival of one or more innate immune cells, and / or expression of IL-6. In some embodiments, the agonistic anti-TREM2 antibodies of the present disclosure compete with a TREM2 ligand for binding to TREM2 expressed on the cell surface. In some embodiments, the agonistic anti-TREM2 antibodies of the present disclosure do not compete with a TREM2 ligand for binding to TREM2 expressed on the cell surface. In some embodiments, the anti-TREM2 antibodies are inactive or antagonistic antibodies that bind to TREM2 and decrease, inhibit, or otherwise reduce one or more TREM2 activities and / or survival of one or more innate immune cells. In some embodiments, the inactive or antagonistic anti-TREM2 antibodies of the present disclosure block or otherwise inhibit ligand binding to TREM2 expressed on the cell surface.

[0026] Another aspect of the present disclosure relates to an isolated agonist antibody that binds to a TREM2 protein, a DAP12 protein, or both, wherein the antibody induces one or more TREM2 activities, DAP12 activities, or both.

[0027] In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are mammalian or human proteins. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are wild-type proteins. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are naturally occurring variants. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are expressed on human dendritic cells, human macrophages, human monocytes, human osteoclasts, human dermal Langerhans cells, human Kupffer cells, and / or human microglia. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody induces or maintains TREM2 clustering, DAP12 clustering, or both, on the cell surface. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities include TREM2 binding to DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the one or more DAP12 activities include DAP12 binding to TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both include DAP12 phosphorylation, TREM2 phosphorylation, or both. In certain embodiments that may be combined with any of the preceding embodiments, DAP12 phosphorylation, TREM2 phosphorylation, or both are induced by one or more SRC family tyrosine kinases. In certain embodiments that may be combined with any of the preceding embodiments, the one or more SRC family tyrosine kinases include Syk kinase. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both include PI3K activation. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both include increased expression of one or more anti-inflammatory cytokines.In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise increased expression of one or more anti-inflammatory mediators (e.g., cytokines) selected from the group consisting of IL-12p70, IL-6, and IL-10. In certain embodiments that may be combined with any of the preceding embodiments, the increased expression occurs in one or more cells selected from the group consisting of macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise reduced expression of one or more pro-inflammatory cytokines. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both comprise reduced expression of one or more pro-inflammatory mediators selected from the group consisting of IFN-α4, IFN-b, IL-6, IL-12p70, IL-1β, TNF, TNF-α, IL-10, IL-8, CRP, a TGF-β member of the chemokine protein family, an IL-20 family member, IL-33, LIF, IFN-γ, OSM, CNTF, TGF-β, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both comprise reduced expression of TNF-α, IL-6, or both. In certain embodiments that may be combined with any of the preceding embodiments, the reduced expression of one or more pro-inflammatory mediators occurs in one or more cells selected from the group consisting of macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise extracellular signal-regulated kinase (ERK) phosphorylation. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise increased expression of CC chemokine receptor 7 (CCR7).In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include inducing chemotaxis of microglial cells toward CCL19- and CCL21-expressing cells. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include enhancing, normalizing, or both, the ability of bone marrow-derived dendritic cells to induce antigen-specific T cell proliferation. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include inducing osteoclast production, increasing the rate of osteoclast formation, or both. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include increasing survival of macrophages, microglial cells, or both. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include increasing the function of macrophages, microglial cells, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells. In certain embodiments that may be combined with any of the preceding embodiments, the macrophages are M1 macrophages and / or microglia, M2 macrophages and / or microglia, or both. In certain embodiments that may be combined with any of the preceding embodiments, the M1 macrophages and / or microglia are activated M1 macrophages and / or microglia. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include inducing one or more clearances selected from the group consisting of apoptotic neuron clearance, neural tissue debris clearance, non-neural tissue debris clearance, bacterial or other foreign body clearance, pathogenic protein clearance, pathogenic peptide clearance, and pathogenic nucleic acid clearance.In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both include induction of phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, or pathogenic nucleic acids. In certain embodiments that may be combined with any of the preceding embodiments, the pathogenic protein is amyloid beta or a fragment thereof, tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, The pathogenic nucleic acid is selected from the group consisting of lysozyme, beta2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, and proline-arginine (PR) repeat peptide. In certain embodiments that may be combined with any of the preceding embodiments, the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat-expanded RNA. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activity, DAP12 activity, or both includes normalization of disrupted TREM2 / DAP12-dependent gene expression. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include recruitment of Syk, ZAP70, or both, to the DAP12 / TREM2 complex. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include Syk phosphorylation.In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise increased expression of CD83 and / or CD86 on dendritic cells, macrophages, and / or monocytes. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both comprise reduced secretion of one or more pro-inflammatory cytokines. In certain embodiments that may be combined with any of the preceding embodiments, the one or more pro-inflammatory cytokines are selected from the group consisting of TNF-α, IL-10, IL-6, MCP-1, IFN-α4, IFN-β, IL-1β, IL-8, CRP, TGF-beta members of the chemokine protein family, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise reducing the expression of one or more inflammatory receptors. In certain embodiments that may be combined with any of the preceding embodiments, the one or more inflammatory receptors comprise CD86. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise increasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia under conditions of reduced levels of M-CSF. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise decreasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia in the presence of normal levels of M-CSF. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprise increasing the activity of one or more TREM2-dependent genes. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2-dependent genes include one or more nuclear factor of activated T cells (NFAT) transcription factors.In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, IgM class, or IgA class. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TREM2 activities, DAP12 activities, or both, independently of binding to an Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region comprising one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG1 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG1 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions.In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region. In certain embodiments that may be combined with any of the preceding embodiments, the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397). In certain embodiments that may be combined with any of the preceding embodiments, the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and / or a N297A or N297Q amino acid substitution, and the numbering of residues on the IgG1 is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a murine IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG4 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications.In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, where the residues are numbered according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has a hybrid IgG2 / 4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, where the residues are numbered according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a murine IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12, and the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0028] Another aspect of the disclosure relates to an isolated inactive antibody that binds to the TREM2 protein.Another aspect of the disclosure relates to an isolated antagonist antibody that binds to the TREM2 protein.

[0029] In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are mammalian or human proteins. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are wild-type proteins. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein, the DAP12 protein, or both, are naturally occurring variants. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits one or more TREM2 activities, DAP12 activities, or both. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, comprises reducing the activity of one or more TREM2-dependent genes. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2-dependent genes comprise one or more nuclear factor of activated T cells (NFAT) transcription factors. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both, include reducing survival of macrophages, microglial cells, M1 macrophages, M1 microglial cells, M2 macrophages, M2 microglial cells, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or dendritic cells. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits the interaction between TREM2 and one or more TREM2 ligands, inhibits TREM2 signaling, or both. In certain embodiments that may be combined with any of the preceding embodiments, the antibody cannot bind to Fcγ receptors (FcγRs). In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG1 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG1 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications.In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a mouse IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG4 constant region comprises an Fc region.In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment.

[0030] In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody competes for binding of TREM2 to one or more TREM2 ligands. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 ligands are selected from the group consisting of E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged lipids, phosphatidylserine, sulfatide, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptides. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a bispecific antibody that recognizes a first antigen and a second antigen.In certain embodiments that may be combined with any of the preceding embodiments, the first antigen is human TREM2 or a naturally occurring variant thereof, and the second antigen is amyloid beta or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin a pathogenic protein selected from the group consisting of insulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, and proline-arginine (PR) repeat peptide; a blood-brain barrier targeting protein selected from the group consisting of transferrin receptor, insulin receptor, insulin-like growth factor receptor, LRP-1, and LRP1; or a ligand and / or protein expressed on immune cells.In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12, and the antibody is selected from the group consisting of amyloid beta or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin ... In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a monoclonal antibody.

[0031] In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to a linear epitope on TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the linear epitope on TREM2 is located within the extracellular domain of TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the linear epitope on TREM2 is located within the extracellular immunoglobulin-like variable (IgV) domain of TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to a TREM2 protein, the isolated antibody binding to: i. amino acid residues 29-112 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 29-112 of SEQ ID NO:1; ii. amino acid residues 29-41 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 29-41 of SEQ ID NO:1; iii. amino acid residues 40-44 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 40-44 of SEQ ID NO:1; iv. amino acid residues 47-69 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 47-69 of SEQ ID NO:1; v. amino acid residues 67-76 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 67-76 of SEQ ID NO:1. vi. amino acid residues 76 to 86 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 76 to 86 of SEQ ID NO: 1; vii. amino acid residues 91 to 100 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 91 to 100 of SEQ ID NO: 1; viii. amino acid residues 99 to 115 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 99 to 115 of SEQ ID NO: 1; ix. amino acid residues 104 to 112 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 104 to 112 of SEQ ID NO: 1; and x. amino acid residues 114 to 118 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 114 to 118 of SEQ ID NO: 1.In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to amino acid residues 43-50 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on the TREM2 protein that correspond to amino acid residues 43-50 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to amino acid residues 49-57 of SEQ ID NO: 1, or one or more amino acids within the amino acid residues on the TREM2 protein that correspond to amino acid residues 49-57 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to an epitope that includes one or more amino acids within amino acid residues 43-50 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to an epitope that includes one or more amino acids within amino acid residues 43-50 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to an epitope comprising one or more amino acid residues selected from the group consisting of: i. amino acid residues Arg47 or Asp87 of SEQ ID NO: 1; ii. amino acid residues 40-44 of SEQ ID NO: 1; iii. amino acid residues 67-76 of SEQ ID NO: 1; and iv. amino acid residues 114-118 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody binds to one or more amino acids within amino acid residues 22-40 of SEQ ID NO: 2, or amino acid residues on the DAP12 protein corresponding to amino acid residues 22-40 of SEQ ID NO: 2. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a bispecific antibody that binds to one or more amino acids selected from the group consisting of: i. one or more amino acid residues in SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to the amino acid residues in SEQ ID NO: 1; and ii. one or more amino acid residues in SEQ ID NO: 2, or amino acid residues on the DAP12 protein corresponding to the amino acid residues in SEQ ID NO: 2.

[0032] In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab52, and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab52. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 398. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 399. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H3 comprises the amino acid sequence of SEQ ID NO: 400. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L1 comprises the amino acid sequence of SEQ ID NO: 401. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 402. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 403.In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 398; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 399; and / or (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 400. and / or the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 401; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 402; and / or (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 403. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab21, and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab21. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 404. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 405. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H3 comprises the amino acid sequence of SEQ ID NO: 406. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L1 comprises the amino acid sequence of SEQ ID NO: 407. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 408.In certain embodiments that may be combined with any of the preceding embodiments, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 409. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 404; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 405; and / or (c) the amino acid sequence of SEQ ID NO: 406, or an amino acid sequence with at least about 95% identity to the amino acid sequence of SEQ ID NO: 406. and / or the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 407; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 408; and / or (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409, or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 409.

[0033] Another aspect of the present disclosure relates to an isolated anti-human TREM2 antibody, the isolated antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab52; and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab52. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 398. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 399. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H3 comprises the amino acid sequence of SEQ ID NO: 400. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L1 comprises the amino acid sequence of SEQ ID NO: 401. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 402. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 403. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and / or the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403.

[0034] Another aspect of the present disclosure relates to an isolated anti-human TREM2 antibody, the isolated antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 398; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 399; and / or (c) an amino acid sequence of SEQ ID NO: 400, or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 400. and / or the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 401; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 402; and / or (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 403.

[0035] Another aspect of the present disclosure relates to an isolated anti-human TREM2 antibody, the isolated antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab21; and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab21. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 404. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 405. In certain embodiments that may be combined with any of the preceding embodiments, HVR-H3 comprises the amino acid sequence of SEQ ID NO: 406. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L1 comprises the amino acid sequence of SEQ ID NO: 407. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 408. In certain embodiments that may be combined with any of the preceding embodiments, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 409. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and / or the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409.

[0036] Another aspect of the present disclosure relates to an isolated anti-human TREM2 antibody, the isolated antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 404; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 405; and / or (c) the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 406. and / or the light chain variable domain comprises (a) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 407; (b) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 408; and / or (c) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 409.

[0037] Another aspect of the disclosure relates to an isolated anti-human TREM2 antibody that binds to essentially the same TREM2 epitope as antibody Ab52.Another aspect of the disclosure relates to an isolated anti-human TREM2 antibody that binds to essentially the same TREM2 epitope as antibody Ab21.

[0038] In certain embodiments that may be combined with any of the preceding embodiments, the antibody is an agonist antibody, and the antibody induces one or more TREM2 activities, DAP12 activities, or both. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody induces or maintains TREM2 clustering, DAP12 clustering, or both on the cell surface. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities, DAP12 activities, or both are determined by TREM2 binding to DAP12; DAP12 binding to TREM2; TREM2 phosphorylation; DAP12 phosphorylation; PI3K activation; increased expression of one or more anti-inflammatory mediators (e.g., cytokines) selected from the group consisting of IL-12p70, IL-6, and IL-10; IFN-α4, IFN-b, a reduction in the expression of one or more proinflammatory mediators selected from the group consisting of IL-6, IL-12p70, IL-1β, TNF, TNF-α, IL-10, IL-8, CRP, TGF-beta members of the chemokine protein family, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP; a reduction in the expression of one or more proinflammatory mediators selected from the group consisting of TNF-α, IL-6, or increasing expression of CC chemokine receptor 7 (CCR7); inducing microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; increasing, normalizing, or both, the ability of bone marrow-derived dendritic cells to induce antigen-specific T cell proliferation; inducing osteoclast production, increasing the rate of osteoclast formation, or both; increasing the survival and / or function of one or more of dendritic cells, macrophages, microglial cells, M1 macrophages and / or microglial cells, activated M1 macrophages and / or microglial cells, M2 macrophages and / or microglial cells, monocytes, osteoclasts, dermal Langerhans cells, and Kupffer cells; apoptotic neuron clearance, neural tissue debris clearance, non-neural tissue debris clearance, bacterial or other foreign body clearance, pathogenic protein clearance, pathogenic peptide clearance,and pathogenic nucleic acid clearance; induction of phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, or pathogenic nucleic acids; normalization of disrupted TREM2 / DAP12-dependent gene expression; recruitment of Syk, ZAP70, or both to the TREM2 / DAP12 complex; Syk phosphorylation; increased expression of CD83 and / or CD86 on dendritic cells, macrophages, monocytes, and / or microglia; and induction of clearance of one or more of TNF-α, IL-10, IL-6, MCP-1, IFN-α4, IFN-β, IL-1β, IL-8, CRP, TGF-β members of the chemokine protein family. the antibody is selected from the group consisting of: reducing the secretion of one or more inflammatory cytokines selected from the group consisting of BAR, IL-20 family members, IL-33, LIF, IFN-γ, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL-18, and CRP; reducing the expression of one or more inflammatory receptors; increasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia under conditions of reduced levels of M-CSF; decreasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia in the presence of normal levels of M-CSF; increasing the activity of one or more TREM2-dependent genes; and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, IgM class, or IgA class. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody exhibits one or more of TREM2 activity, DAP12 activity, or a combination thereof, independent of binding to an Fc receptor.or both. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG1 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG1 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T,and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region. In certain embodiments that may be combined with any of the preceding embodiments, the IgG2 isotype CH1 and hinge region comprises the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397). In certain embodiments that may be combined with any of the preceding embodiments, the antibody Fc region comprises an S267E amino acid substitution, an L328F amino acid substitution, or both, and / or an N297A or N297Q amino acid substitution, wherein the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a mouse IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG4 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof;Residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has a hybrid IgG2 / 4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a mouse IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12, wherein the antibody fragment is crosslinked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an inactive antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antagonist antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits one or more TREM2 activities. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: reducing the activity of one or more TREM2-dependent genes; reducing the activity of one or more nuclear factor of activated T cells (NFAT) transcription factors; reducing the survival of macrophages, microglial cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or dendritic cells; and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits the interaction between TREM2 and one or more TREM2 ligands; inhibits TREM2 signaling;In certain embodiments that may be combined with any of the preceding embodiments, the antibody is unable to bind to an Fcγ receptor (FcγR). In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG1 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG1 constant region. In certain embodiments that may be combined with any of the embodiments, the human IgG1 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a mouse IgG1 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype.In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG4 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG4 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more modifications. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region comprises one or more amino acid substitutions. In certain embodiments that may be combined with any of the preceding embodiments, the one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody.In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a monoclonal antibody.

[0039] Another aspect of the present disclosure relates to an isolated antibody that binds to the TREM2 protein, wherein the isolated antibody promotes survival of one or more innate immune cells. Another aspect of the present disclosure relates to an isolated antibody that binds to the TREM2 protein, wherein the isolated antibody increases IL-6 expression. Another aspect of the present disclosure relates to an isolated antibody that binds to the TREM2 protein, wherein the isolated antibody promotes survival of one or more innate immune cells or increases IL-6 expression. Another aspect of the present disclosure relates to an isolated antibody that binds to the TREM2 protein, wherein the isolated antibody promotes survival of one or more innate immune cells and increases IL-6 expression. In certain embodiments, the one or more innate immune cells are selected from the group consisting of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and any combination thereof. In certain embodiments, the one or more innate immune cells are macrophages. In certain embodiments, the one or more innate immune cells are microglial cells. In certain embodiments, the one or more innate immune cells are M1 microglial cells. In certain embodiments, the one or more innate immune cells are activated M1 microglial cells. In certain embodiments, the one or more innate immune cells are M2 microglial cells. In certain embodiments, the one or more innate immune cells are dendritic cells (DCs). In certain embodiments, the one or more innate immune cells are M1 macrophages. In certain embodiments, the one or more innate immune cells are activated M1 macrophages. In certain embodiments, the one or more innate immune cells are M2 macrophages. In certain embodiments, the one or more innate immune cells are monocytes. In certain embodiments, the one or more innate immune cells are osteoclasts. In certain embodiments, the one or more innate immune cells are dermal Langerhans cells. In certain embodiments, the one or more innate immune cells are Kupffer cells.

[0040] Another aspect of the present disclosure relates to an isolated antibody that binds to a TREM2 protein, the isolated antibody binding to: i. amino acid residues 29-112 of SEQ ID NO:1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 29-112 of SEQ ID NO:1; ii. amino acid residues 29-41 of SEQ ID NO:1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 29-41 of SEQ ID NO:1; iii. amino acid residues 40-44 of SEQ ID NO:1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 40-44 of SEQ ID NO:1; iv. SEQ ID NO:1 or amino acid residues on the TREM2 protein corresponding to amino acid residues 43 to 50 of SEQ ID NO: 1; v. amino acid residues 49 to 57 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 49 to 57 of SEQ ID NO: 1; vi. amino acid residues 47 to 69 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 47 to 69 of SEQ ID NO: 1; vii. amino acid residues 67 to 76 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 67 to 76 of SEQ ID NO: 1 amino acid residues; viii. amino acid residues 76 to 86 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 76 to 86 of SEQ ID NO: 1; ix. amino acid residues 91 to 100 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 91 to 100 of SEQ ID NO: 1; x. amino acid residues 99 to 115 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 99 to 115 of SEQ ID NO: 1; xi. amino acid residues 104 to 112 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 99 to 115 of SEQ ID NO: 1 xii. amino acid residues 114 to 118 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 114 to 118 of SEQ ID NO: 1; xiii. amino acid residues 130 to 171 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 130 to 171 of SEQ ID NO: 1; xiv. amino acid residues 139 to 146 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 139 to 146 of SEQ ID NO: 1; xv.xvi. amino acid residues 130-144 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 130-144 of SEQ ID NO: 1; and xvii. amino acid residues 158-171 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 158-171 of SEQ ID NO: 1. In certain embodiments, the isolated antibody binds to one or more amino acids within amino acid residues 43-50 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 1. In certain embodiments, the isolated antibody binds to one or more amino acids within amino acid residues 49-57 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 1. In certain embodiments, the isolated antibody binds to one or more amino acids within amino acid residues 139-146 of SEQ ID NO:1, or amino acid residues 49-57 of SEQ ID NO:1. In certain embodiments, the isolated antibody binds to one or more amino acids within amino acid residues 140-153 of SEQ ID NO:1, or amino acid residues 140-153 of SEQ ID NO:1. In certain embodiments, the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 43-50 of SEQ ID NO:1. In certain embodiments, the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 49-57 of SEQ ID NO:1. In certain embodiments, the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 139-146 of SEQ ID NO:1. In certain embodiments, the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 140-153 of SEQ ID NO:1.

[0041] In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a mammalian or human protein. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a wild-type protein. In certain embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a naturally occurring variant. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is an agonist antibody, and the antibody induces one or more TREM2 activities. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody induces or maintains TREM2 clustering on the cell surface. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities include: i. TREM2 binding to DAP12; ii. DAP12 phosphorylation; iii. increasing survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells; iv. Syk phosphorylation; v. increasing expression of CD83 and / or CD86 on dendritic cells; vi. increasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia; vii. optionally, the one or more TREM2-dependent genes include one or more nuclear factor of activated T cells (NFAT) transcription factors; and viii.In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, IgM class, or IgA class. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TREM2 activities independently of binding to an Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, i. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype, wherein the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein residue numbering is according to EU or Kabat numbering; iii.the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; iv. the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, optionally the IgG2 isotype CH1 and hinge region are selected from the group consisting of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397), optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and / or a N297A or N297Q amino acid substitution, wherein residue numbering is according to EU or Kabat numbering; v. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; or vi.The isolated antibody has a hybrid IgG2 / 4 isotype, and optionally, the antibody comprises an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an inactive antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antagonist antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits one or more TREM2 activities. In certain embodiments that may be combined with any of the preceding embodiments, the inhibition of one or more TREM2 activities is selected from the group consisting of: decreasing the activity of one or more TREM2-dependent genes; decreasing the activity of one or more nuclear factor of activated T cells (NFAT) transcription factors; decreasing the survival of macrophages, microglial cells, M1 macrophages, M1 microglial cells, M2 macrophages, M2 microglial cells, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or dendritic cells; decreasing the expression of one or more mediators selected from the group consisting of IL-12p70, IL-6, and IL-10; and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits the interaction between TREM2 and one or more TREM2 ligands, inhibits TREM2 signaling, or both. In certain embodiments that may be combined with any of the preceding embodiments, the antibody cannot bind to Fcγ receptors (FcγRs). In certain embodiments that may be combined with any of the preceding embodiments, i.The isolated antibody has a human or murine IgG1 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. optionally, the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; or iii.The isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2 and naturally occurring variants of human TREM2, and the antibody fragment is crosslinked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment, and the antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody competes for binding of TREM2 to one or more TREM2 ligands. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 ligands are selected from E.In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is selected from the group consisting of a coli cell, an apoptotic cell, a nucleic acid, an anionic lipid, a zwitterionic lipid, a negatively charged lipid, a phosphatidylserine, a sulfatide, a phosphatidylcholine, a sphingomyelin, a membrane phospholipid, a lipidated protein, a proteolipid, a lipidated peptide, and a lipidated amyloid beta peptide. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that may be combined with any of the preceding embodiments, the first antigen is human TREM2 or a naturally occurring variant thereof, and the second antigen is amyloid beta or a fragment thereof, tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation products, dipeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, or ribonucleotides. a pathogenic protein selected from the group consisting of a glycine-arginine (GR) repeat peptide, a proline-alanine (PA) repeat peptide, and a proline-arginine (PR) repeat peptide; or a blood-brain barrier targeting protein selected from the group consisting of transferrin receptor, insulin receptor, insulin-like growth factor receptor, LRP-1, and LRP1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2 and natural variants of human TREM2; the antibody is selected from the group consisting of amyloid beta or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transaminase, ribosomal protein ... In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a monoclonal antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is a bispecific antibody that binds to TREM2 and DAP12.

[0042] In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-24, 398, and 404; HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-49, 399, and 405; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50-119, 400, and 406; and / or the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120-137, 401, and 407; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 138-152, 402, and 408; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 153-236, 403, and 409.

[0043] Another aspect of the present disclosure relates to an isolated anti-human TREM2 antibody, the isolated antibody comprising a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3-24, 398, and 404; HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-49, 399, and 405; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50-119, 400, and 406; and / or the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120-137, 401, and 407; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 138-152, 402, and 408; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 153-236, 403, and 409. Other aspects of the present disclosure include Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, Ab87, Ab88, Ab89, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab90, Ab910, Ab911, Ab912, Ab913, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab90, Ab910, Ab911, Ab91 The present invention relates to an isolated anti-human TREM2 antibody that binds to essentially the same TREM2 epitope as a monoclonal antibody selected from the group consisting of Ab0, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87.Other aspects of the disclosure include the following antibodies for binding to TREM2: Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab 47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87.

[0044] In certain embodiments that may be combined with any of the preceding embodiments, the antibody is an agonist antibody, and the antibody induces one or more TREM2 activities. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody induces or maintains TREM2 clustering on the cell surface. In certain embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities include: TREM2 binding to DAP12; DAP12 phosphorylation; increasing survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells; increased expression of IL-6; Syk phosphorylation; increased expression of CD83 and / or CD86 on dendritic cells; increasing phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia; and, optionally, increasing the activity of one or more TREM2-dependent genes, wherein the one or more TREM2-dependent genes include one or more nuclear factor of activated T cells (NFAT) transcription factors;and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, the IgM class, or the IgA class. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In certain embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In certain embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TREM2 activities independently of binding to an Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fcγ receptor IIB (FcγRIIB). In certain embodiments that may be combined with any of the preceding embodiments, i. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions of an Fc region at residue positions selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype, wherein the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein residue numbering is according to EU or Kabat numbering;iii. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering; iv. the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, optionally the IgG2 isotype CH1 and hinge region are selected from the group consisting of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT v. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering;Alternatively, vi. the isolated antibody has a hybrid IgG2 / 4 isotype, optionally comprising an amino acid sequence comprising amino acids 118-260 of human IgG2 and amino acids 261-447 of human IgG4, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2 and naturally occurring variants of human TREM2, wherein the antibody fragment is crosslinked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, human DAP12, and naturally occurring variants of human DAP12. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment, wherein the antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an inactive antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antagonist antibody. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits one or more TREM2 activities. In certain embodiments that may be combined with any of the preceding embodiments, inhibiting one or more TREM2 activities includes reducing the activity of one or more TREM2-dependent genes; reducing the activity of one or more nuclear factor of activated T cells (NFAT) transcription factors; reducing the survival of macrophages, microglial cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or dendritic cells; reducing the expression of one or more mediators selected from the group consisting of IL-12p70, IL-6, and IL-10;and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody inhibits the interaction between TREM2 and one or more TREM2 ligands, inhibits TREM2 signaling, or both. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is unable to bind to Fcγ receptors (FcγRs). In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the residue numbering is: optionally, the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering;or iii. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2 and naturally occurring variants of human TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is an antibody fragment, and the antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, where the residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is a monoclonal antibody;

[0045] In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody specifically binds to both human TREM2 and mouse TREM2. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human TREM2 and mouse TREM2 that ranges from less than about 5.75 nM to less than about 0.09 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human TREM2-Fc fusion protein in the range of less than about 1.51 nM to less than about 0.35 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human monomeric TREM2 protein in the range of less than about 5.75 nM to less than about 1.15 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for mouse TREM2-Fc fusion protein in the range of less than about 0.23 nM to less than about 0.09 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human TREM2 and mouse TREM2 that ranges from less than about 6.70 nM to less than about 0.23 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human TREM2-Fc fusion protein in the range of less than about 0.71 nM to less than about 0.23 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for human monomeric TREM2 protein in the range of less than about 6.70 nM to less than about 0.66 nM. D In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody has a dissociation constant (K) for mouse TREM2-Fc fusion protein in the range of less than about 4.90 nM to less than about 0.35 nM. D )

[0046] Another aspect of the present disclosure relates to an isolated nucleic acid encoding the antibody of any one of the preceding embodiments. Another aspect of the present disclosure relates to a vector comprising the nucleic acid of any one of the preceding embodiments. Another aspect of the present disclosure relates to a host cell comprising the vector of any one of the preceding embodiments. Another aspect of the present disclosure relates to an isolated host cell comprising the vector of any one of the preceding embodiments. Another aspect of the present disclosure relates to a method of producing an antibody, comprising culturing a cell of any one of the preceding embodiments so that the antibody is produced. In certain embodiments, the method further comprises recovering the antibody produced from the cell. Another aspect of the present disclosure relates to an isolated antibody produced by any of the preceding methods of producing an antibody. Another aspect of the present disclosure relates to a pharmaceutical composition comprising the antibody of any one of the preceding embodiments and a pharmaceutically acceptable carrier.

[0047] Another aspect of the present disclosure relates to a method of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, and multiple sclerosis, comprising administering to the individual a therapeutically effective amount of the isolated agonist antibody of any one of the preceding embodiments. Another aspect of the present disclosure relates to the isolated agonist antibody of any one of the preceding embodiments for use in preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, and multiple sclerosis. Another aspect of the present disclosure relates to the use of the isolated agonist antibody of any one of the preceding embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, and multiple sclerosis. In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant of TREM2, wherein the variant comprises one or more substitutions selected from the group consisting of: i. a glutamic acid terminating codon substitution in a nucleic acid sequence encoding amino acid residue Glu14 of SEQ ID NO:1; ii. a glutamine terminating codon substitution in a nucleic acid sequence encoding amino acid residue Gln33 of SEQ ID NO:1; iii. a tryptophan terminating codon substitution in a nucleic acid sequence encoding amino acid residue Trp44 of SEQ ID NO:1; iv. an arginine to histidine amino acid substitution at the amino acid corresponding to amino acid residue Arg47 of SEQ ID NO:1; v. a tryptophan terminating codon substitution in a nucleic acid sequence encoding amino acid residue Trp78 of SEQ ID NO:1; vi. a valine to glycine amino acid substitution at the amino acid corresponding to amino acid residue Val126 of SEQ ID NO:1; vii. an aspartic acid to glycine amino acid substitution at the amino acid corresponding to amino acid residue Asp134 of SEQ ID NO:1; and viii. a lysine to asparagine amino acid substitution at the amino acid corresponding to amino acid residue Lys186 of SEQ ID NO:1.In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant in TREM2, wherein the variant comprises a guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G313 of the nucleic acid sequence encoding SEQ ID NO: 1; a guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G267 of the nucleic acid sequence encoding SEQ ID NO: 1; or both. In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant in DAP12, wherein the variant comprises one or more variants selected from the group consisting of: i. a methionine to threonine substitution at the amino acid corresponding to amino acid residue Met1 of SEQ ID NO: 2; ii. a glycine to arginine amino acid substitution at the amino acid corresponding to amino acid residue Gly49 of SEQ ID NO: 2; iii. a deletion within exons 1-4 of the nucleic acid sequence encoding SEQ ID NO: 2; iv. an insertion of 14 amino acid residues in exon 3 of the nucleic acid sequence encoding SEQ ID NO: 2; and v. a guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G141 of the nucleic acid sequence encoding SEQ ID NO: 2.

[0048] Another aspect of the present disclosure relates to a method of inducing or promoting survival of innate immune cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the isolated agonist antibody of any one of the preceding embodiments. Another aspect of the present disclosure relates to the isolated agonist antibody of any one of the preceding embodiments for use in inducing or promoting survival of innate immune cells in an individual in need thereof. Another aspect of the present disclosure relates to the use of the isolated agonist antibody of any one of the preceding embodiments in the manufacture of a medicament for inducing or promoting survival of innate immune cells in an individual in need thereof. Another aspect of the present disclosure relates to a method of inducing or promoting wound healing in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to the isolated agonist antibody that binds to TREM2 protein for use in inducing or promoting wound healing in an individual in need thereof. Another aspect of the present disclosure relates to the use of the isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for inducing or promoting wound healing in an individual in need thereof.

[0049] Another aspect of the present disclosure relates to a method of reducing innate immune cell survival in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the isolated antagonist antibody of any one of the preceding embodiments. Another aspect of the present disclosure relates to the isolated antagonist antibody of any one of the preceding embodiments for use in reducing innate immune cell survival in an individual in need thereof. Another aspect of the present disclosure relates to the use of the isolated antagonist antibody of any one of the preceding embodiments in the manufacture of a medicament for reducing innate immune cell survival in an individual in need thereof.

[0050] Another aspect of the present disclosure is a method for treating dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, comprising administering to an individual a therapeutically effective amount of the isolated antibody of any one of the preceding embodiments. The present invention relates to a method of preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of: encephalomyelitis, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, and cancer. Other aspects of the present disclosure include the use of a variety of therapeutic agents, including but not limited to, dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal cerebrovascular disease, and the like. and / or any one of the preceding embodiments, for use in preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of nuclear ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, and cancer.Other aspects of the present disclosure include the use of a variety of therapeutic agents, including but not limited to, dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglia and the use of the isolated antibody of any one of the preceding embodiments in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, and cancer.

[0051] In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is (a) an agonist antibody; (b) an inactive antibody; or (c) an antagonist antibody. In certain embodiments that may be combined with any of the preceding embodiments, (a) the antibody is of the IgG class, the IgM class, or the IgA class, and / or (b) the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In certain embodiments that may be combined with any of the preceding embodiments, the antibody is (a) V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof; (b) N297A, D265A, L2 34A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof; (c) L235A, G237A, S228P, L236E, S267E, E318 A, L328F, M252Y, S254T, T256E, and any combination thereof; (d) N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, (e) P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof; (f) V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof;or (f) the Fc region comprises one or more amino acid substitutions at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein residue numbering is according to EU or Kabat numbering. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody (a) binds to one or more amino acids within amino acid residues 43-50 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO:1, or (b) binds to one or more amino acids within amino acid residues 49-57 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO:1. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody (a) binds essentially the same TREM2 epitope as antibody Ab52; (b) comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab52; and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab52;(c) a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 398, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 399, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 400; and / or the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 401, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 402, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403 (d) comprises HVR-L3 comprising the sequence or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 403, (d) binds essentially the same TREM2 epitope as antibody Ab21; (e) comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, HVR-H2, and / or HVR-H3 of monoclonal antibody Ab21; and / or the light chain variable domain comprises HVR-L1, HVR-L2, and / or HVR-L3 of monoclonal antibody Ab21; or (f) comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 404, and HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 405;and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 406; and / or the light chain variable domain comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 407, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408 or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 408; and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409 or an amino acid sequence at least about 95% identical to the amino acid sequence of SEQ ID NO: 409. In certain embodiments that may be combined with any of the preceding embodiments, the isolated antibody is the isolated antibody of any one of the preceding embodiments. In certain embodiments that may be combined with any of the preceding embodiments, the isolated agonist antibody is the isolated agonist antibody of any one of the preceding embodiments. In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant in TREM2, the variant comprising: i. a glutamic acid terminating codon substitution in a nucleic acid sequence encoding amino acid residue Glu14 of SEQ ID NO:1; ii. a glutamine terminating codon substitution in a nucleic acid sequence encoding amino acid residue Gln33 of SEQ ID NO:1; iii. a tryptophan terminating codon substitution in a nucleic acid sequence encoding amino acid residue Trp44 of SEQ ID NO:1; iv. an arginine to histidine amino acid substitution at the amino acid corresponding to amino acid residue Arg47 of SEQ ID NO:1; v. a tryptophan terminating codon substitution in a nucleic acid sequence encoding amino acid residue Trp78 of SEQ ID NO:1; vi. a valine to glycine amino acid substitution at the amino acid corresponding to amino acid residue Val126 of SEQ ID NO:1; vii. an aspartic acid to glycine amino acid substitution at the amino acid corresponding to amino acid residue Asp134 of SEQ ID NO:1;and viii. a lysine to asparagine amino acid substitution at the amino acid corresponding to amino acid residue Lys186 of SEQ ID NO: 1. In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant of TREM2, wherein the variant comprises a guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G313 of the nucleic acid sequence encoding SEQ ID NO: 1; a guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G267 of the nucleic acid sequence encoding SEQ ID NO: 1; or both. In certain embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant in DAP12, wherein the variant comprises one or more variants selected from the group consisting of: i. a methionine to threonine substitution at an amino acid corresponding to amino acid residue Met1 in SEQ ID NO:2; ii. a glycine to arginine amino acid substitution at an amino acid corresponding to amino acid residue Gly49 in SEQ ID NO:2; iii. a deletion within exons 1-4 of the nucleic acid sequence encoding SEQ ID NO:2; iv. an insertion of 14 amino acid residues in exon 3 of the nucleic acid sequence encoding SEQ ID NO:2; and v. a guanine nucleotide deletion at a nucleotide corresponding to nucleotide residue G141 of the nucleic acid sequence encoding SEQ ID NO:2;

[0052] In certain embodiments that may be combined with any of the preceding embodiments, the cancer is selected from the group consisting of bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, and thyroid cancer. In certain embodiments that may be combined with any of the preceding embodiments, the method further comprises administering to the individual at least one antibody that specifically binds to an inhibitory checkpoint molecule and / or another standard or investigational anti-cancer therapy. In certain embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with an isolated antibody. In certain embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory checkpoint molecule is selected from the group consisting of an anti-PD-L1 antibody, an anti-CTLA4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, and an anti-HVEM antibody, an anti-B- and T-lymphocyte attenuator (BTLA) antibody, an anti-killer inhibitory receptor (KIR) antibody, an anti-GAL9 antibody, an anti-TIM3 antibody, an anti-A2AR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the standard or investigational anticancer therapy is one or more therapies selected from the group consisting of radiation therapy, cytotoxic chemotherapy, targeted therapy, imatinib (Gleevec®), trastuzumab (Herceptin®), adoptive cell transfer (ACT), chimeric antigen receptor T cell transfer (CAR-T), vaccine therapy, and cytokine therapy. In certain embodiments that may be combined with any of the preceding embodiments, the method further comprises administering to the individual at least one antibody that specifically binds to an inhibitory cytokine. In certain embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with an isolated antibody.In certain embodiments that may be combined with any of the preceding embodiments, the at least one antibody that specifically binds to an inhibitory cytokine is selected from the group consisting of an anti-CCL2 antibody, an anti-CSF-1 antibody, an anti-IL-2 antibody, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the method further comprises administering to the individual at least one agonist antibody that specifically binds to a stimulatory checkpoint protein. In certain embodiments that may be combined with any of the preceding embodiments, the at least one agonist antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with an isolated antibody. In certain embodiments that may be combined with any of the preceding embodiments, the at least one agonist antibody that specifically binds to a stimulatory checkpoint protein is selected from the group consisting of an agonist anti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOS antibody, an agonist anti-CD28 antibody, an agonist anti-CD137 / 4-1BB antibody, an agonist anti-CD27 antibody, an agonist anti-glucocorticoid-inducible TNFR-related protein GITR antibody, and any combination thereof. In certain embodiments that may be combined with any of the preceding embodiments, the method further includes administering at least one stimulatory cytokine to the individual. In certain embodiments that may be combined with any of the preceding embodiments, the at least one stimulatory cytokine is administered in combination with the isolated antibody. In certain embodiments that may be combined with any of the preceding embodiments, the at least one stimulatory cytokine is selected from the group consisting of TNF-α, IL-10, IL-6, IL-8, CRP, a TGF-beta member of the chemokine protein family, an IL-20 family member, IL-33, LIF, OSM, CNTF, TGF-beta, IL-11, IL-12, IL-17, IL-8, CRP, IFN-α, IFN-β, IL-2, IL-18, GM-CSF, G-CSF, and any combination thereof. [Brief explanation of the drawings]

[0053] [Figure 1A]1 shows an amino acid sequence alignment between the human TREM2 protein (SEQ ID NO: 426) and the human NCTR2 protein (SEQ ID NO: 427), demonstrating the homology between the two proteins. The consensus sequence is SEQ ID NO: 446. [Figure 1B] Figure 1 shows a structure-based sequence alignment between several TREM proteins and other members of the IgV family: TREM1_human (SEQ ID NO: 429), TREM2_human (SEQ ID NO: 430), TREM1_mouse (SEQ ID NO: 431), TREM2_mouse (SEQ ID NO: 432), TREM3_mouse (SEQ ID NO: 433), NKp44 (SEQ ID NO: 434), aTCR_human (SEQ ID NO: 435), bTCR_human (SEQ ID NO: 436), gTCR_human (SEQ ID NO: 437), dTCR_human (SEQ ID NO: 438), Vd_human (SEQ ID NO: 439), hIGG1_mouse (SEQ ID NO: 440), lIGG1_mouse (SEQ ID NO: 441), CD8_human (SEQ ID NO: 442), and CTLA4_human (SEQ ID NO: 443). The numbering of amino acid residues is consistent with the mature sequence of the human TREM1 protein. Secondary structure elements of TREM1 are depicted as arrows for β-strands and cylinders for α-helices. Amino acid residues involved in homodimer and heterodimer formation are shown on a black background. Cysteine ​​residues that form disulfide bonds and are conserved for the V-type Ig fold are shown in bold and marked with an asterisk. Gaps are indicated with a "-". M-1 residues that disrupt the antibody-like dimerization mode are marked with a black triangle (e.g., Radaev et al., (2003) Structure. 11(12):1527-1535). [Figure 2A] 1 shows an amino acid sequence alignment between the human TREM1 protein (SEQ ID NO: 428) and the human TREM2 protein (SEQ ID NO: 426), showing the homology between the two proteins. The consensus sequence is SEQ ID NO: 447. [Figure 2B] The amino acid sequences of the heavy chain variable regions of antibodies Ab21 and Ab52 are shown. The CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 2C] The amino acid sequences of the light chain variable regions of antibodies Ab21 and Ab52 are shown. The CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 3A] 1 shows FACS histograms demonstrating binding of TREM2 antibodies Ab21, Ab52, Ab16, Ab20, Ab66, and Ab68 to a mouse cell line (BWZ T2) expressing recombinant mouse TREM2. [Figure 3B] Antibodies Ab21 and Ab52 bind to wild-type (Trem+ / +) and TREM2-deficient (TREM2- / -) bone marrow-derived mouse macrophages (BMMac). Shaded histograms represent the TREM2 antibody-negative population. Black outlined histograms represent the TREM2 antibody-positive population. [Figure 4A] Figure 1 shows FACS histograms demonstrating binding of TREM2 antibodies Ab21, Ab52, Ab43, and Ab60 to a human cell line (293) expressing recombinant human TREM2-DAP12 fusion protein. Shaded histograms represent the TREM2 antibody-negative population. Black outlined histograms represent the TREM2 antibody-positive population. [Figure 4B] Antibodies Ab21, Ab52, Ab43, and Ab60 binding to primary human dendritic cells (hDCs) are shown. The shaded histogram represents the negative control of secondary antibody alone. The black outlined histogram represents the TREM2 antibody-positive population. [Figure 5A] Figure 1 shows FACS dot plots demonstrating the expression of cell surface markers CD83 and CD86 on human dendritic cells (DCs) after incubation with plate-bound TREM2 antibodies Ab21 or Ab52. Antibody Ab88 represents a negative isotype control. Plots were gated on CD11c+ HLA-DR+ LIN- DCs. The percentage of cells within the CD83+CD86+ gate is displayed on each plot. [Figure 5B]Figure 1 shows FACS histograms demonstrating the expression of the cell surface marker CD86 on human dendritic cells (DCs) after incubation with cross-linked TREM2 antibodies Ab21 or Ab52. The antibodies were cross-linked with an anti-human secondary antibody. Antibody Ab88 represents a negative isotype control. [Figure 6A] Syk phosphorylation as measured by Western blot in wild-type and TREM2-deficient (TREM2- / -) mouse (left and center panels) and human (right panel) macrophages after incubation with TREM2 antibodies Ab21 and Ab52. Antibodies Ab89 and Ab92 are non-agonist negative controls. [Figure 6B] Figure 1 shows Syk phosphorylation as measured by Western blot in primary human dendritic cells after incubation with TREM2 antibodies Ab21 and Ab52. [Figure 7A] Figure 1 shows DAP12 phosphorylation as measured by Western blot in mouse macrophages after incubation with the TREM2 antibody Ab52. [Figure 7B] Figure 1 shows DAP12 phosphorylation as measured by Western blot in wild-type and TREM2-deficient (TREM2- / -) mouse macrophages after incubation with the TREM2 antibody Ab21. [Figure 8] Figure 1 shows competitive binding between TREM2 antibodies and E. coli bacteria expressing putative TREM2 ligands to mouse and human cell lines expressing TREM2. Bacterial binding is expressed as a percentage of the control. Mean of two independent experiments; black bars: not different from isotype control; red bars: significantly different from isotype control (ANOVA). [Figure 9A] Protein levels of the inflammatory cytokines TNFα, IL-6, IL-10, and MCP-1 secreted in response to stimulation of WT and TREM2 KO macrophages with the inflammatory mediators LPS or zymosan are shown. [Figure 9B]Protein levels of the inflammatory cytokines IL-6 and TNFα secreted in response to stimulation of WT, TREM2 heterozygous (Het), and TREM2 KO macrophages with the cytokines IL-4 or IFNg are shown. [Figure 10A] FACS data demonstrating the expression of cell surface markers CD86 and CD206 on WT, TREM2 heterozygous (Het), and TREM2 KO macrophages after stimulation with cytokines IL-4 or IFNg are shown. [Figure 10B] Expression of the cell surface marker CD86 on WT and TREM2 KO macrophages after stimulation with the inflammatory mediators LPS or zymosan is shown. [Figure 11A] The numbers of viable WT, TREM2 heterozygous (TREM2+ / -), and TREM2 KO (TREM2- / -) macrophages are shown after culture in the growth factor M-CSF for the indicated days. [Figure 11B] FACS plots demonstrating staining of WT, TREM2 heterozygous (TREM2+ / -), and TREM2 KO (TREM2- / -) macrophages after culture in M-CSF for 6 days (+M-CSF) or in M-CSF for 4 days followed by 36 hours without M-CSF (-M-CSF) are shown. The percentage of live macrophages within the CD11b+DAPI- gate is indicated above each plot. [Figure 11C] Luminescence levels detected by luciferase viability assay are shown after culturing WT and TREM2 KO dendritic cells, M1 macrophages, and M2 macrophages in the growth factors GM-CSF, M-CSF, or M-CSF+IL-4, respectively. [Figure 11D] The frequencies of viable WT, TREM2 heterozygous (Het), and TREM2 KO macrophages (CD11b+) are shown after culture in the inflammatory mediators IFNg, LPS, or zymosan. [Figure 12]Figure 1 shows phagocytosis of apoptotic cells and E. coli by wild-type (WT) and TREM2 KO (TREM2- / -) bone marrow-derived macrophages (BMmacs) cultured without M-CSF. [Figure 13] 1 shows the epitope map of the TREM2 antibody Ab52. [Figure 14] Figure 1 shows Syk phosphorylation as measured by Western blot in wild-type and TREM2-deficient (TREM2- / -) mouse macrophages after incubation with TREM2 antibodies MAB17291 (RD) or 78.18, demonstrating that antibody 78.18 does not induce Syk phosphorylation or TREM2 signaling. [Figure 15A] 1 shows a Fortebio analysis demonstrating simultaneous binding of antibody MAB17291 and antibody Ab21 to TREM2-Fc. [Figure 15B] Figure 1 shows a Fortebio analysis demonstrating simultaneous binding of antibody MAB17291 and antibody Ab52 to TREM2-Fc. [Figure 16] Figure 1 shows increased viability of wild-type (WT) and TREM2 knockout (KO) mouse bone marrow-derived macrophages cultured in the presence of plate-bound cross-linking Fab of TREM2 antibodies Ab21 or Ab52 and M-CSF. Antibody Ab88 represents a negative isotype control. [Figure 17A] 1 shows a luminescent viability assay of mouse bone marrow-derived macrophages cultured in the presence of soluble, non-crosslinking TREM2 antibody Ab21 or Ab52 Fab and M-CSF. Antibody Ab99 represents a negative isotype control. [Figure 17B] Figure 1 shows a luminescent viability assay of mouse bone marrow-derived macrophages cultured in the presence of soluble full-length TREM2 antibodies Ab21 or Ab52 and M-CSF. Antibody Ab91 represents a negative isotype control. The dotted line "NT" indicates the mean viability obtained with untreated macrophages (no antibody added). The dotted line "No M-CSF" indicates the mean viability obtained when macrophages are cultured in the absence of M-CSF. [Figure 18A]Figure 1 shows induction of TREM2-dependent gene expression by plate-bound full-length anti-TREM2 antibodies Ab21 and Ab52 in a cell-based assay using a luciferase reporter gene. [Figure 18B] Figure 1 shows induction of TREM2-dependent gene expression by plate-bound phosphatidylserine (PS). [Figure 18C] 1 shows activation of the TREM2-dependent gene IL-6 in mouse macrophages by the plate-bound Fab anti-TREM2 antibodies Ab21 and Ab52. [Figure 18D] Figures 18C and 18D show activation of the TREM2-dependent gene MCP-1 in mouse macrophages by the plate-bound Fabs of anti-TREM2 antibodies Ab21 and Ab52. Data in Figures 18C and 18D are shown as mean ± SD, with n = 3 mice per group. In Figures 18C and 18D, "No Ab" indicates a negative control without antibody treatment, "21" indicates treatment with the Fab of Ab21, "52" indicates treatment with the Fab of Ab52, and "ctr" indicates treatment with the Fab of a control antibody. [Figure 19] Figure 1 shows inhibition of TREM2-dependent gene expression by soluble, full-length anti-TREM2 antibodies Ab21 and Ab52 in a cell-based assay using a luciferase reporter gene. [Figure 20A-1] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-2] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-3] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-4]The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-5] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-6] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-7] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-8] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20A-9] The amino acid sequence of the heavy chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-1] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-2] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-3] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-4]The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-5] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-6] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-7] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-8] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 20B-9] The amino acid sequence of the light chain variable region of the TREM2 antibody is shown. CDR sequences are underlined in each sequence. The sequence regions between each underlined CDR sequence correspond to framework regions. [Figure 21A] 1 shows FACS histograms demonstrating binding of TREM2 antibodies Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65 to a mouse cell line (BWZ T2) expressing recombinant mouse TREM2. [Figure 21B] Antibodies Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65 bind to WT (Trem+ / +) and TREM2-deficient (TREM2- / -) bone marrow-derived mouse macrophages (BMMac). Antibody Ab88 represents a negative isotype control. Shaded histograms represent the TREM2 antibody-negative population. Black outlined histograms represent the TREM2 antibody-positive population. [Figure 22A]Figure 1 shows FACS histograms demonstrating binding of TREM2 antibodies Ab1, Ab9, Ab14, Ab22, Ab43, Ab45, Ab60, and Ab65 to a human cell line (293) expressing recombinant human TREM2-DAP12 fusion protein. Shaded histograms represent the TREM2 antibody-negative population. Black outlined histograms represent the TREM2 antibody-positive population. [Figure 22B] Antibodies Ab1, Ab9, Ab14, Ab22, Ab43, Ab45, Ab60, and Ab65 binding to primary human dendritic cells (hDCs) are shown. Antibody Ab88 represents a negative isotype control. Shaded histograms represent negative controls of secondary antibody alone. Black outlined histograms represent TREM2 antibody-positive populations. [Figure 23A] Figure 1 shows FACS dot plots demonstrating the expression of cell surface markers CD83 and CD86 on human dendritic cells (DCs) after incubation with plate-bound TREM2 antibodies Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65. Antibody Ab88 represents a negative isotype control. Plots were gated on CD11c+ HLA-DR+ LIN- DCs. The percentage of cells within the CD83+CD86+ gate is displayed on each plot. [Figure 23B] Figure 1 shows FACS histograms demonstrating the expression of the cell surface marker CD86 on human dendritic cells (DCs) after incubation with cross-linking TREM2 antibodies Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65. The antibodies were cross-linked with an anti-human secondary antibody. Antibody Ab88 represents a negative isotype control. [Figure 24A] Figure 1 shows Syk phosphorylation as measured by Western blot in wild-type and TREM2-deficient (TREM2- / -) mouse macrophages after incubation with TREM2 antibodies Ab1, Ab9, or Ab45. Antibodies Ab89 and Ab92 are negative isotype controls. [Figure 24B]Figure 1 shows Syk phosphorylation as measured by Western blot in human macrophages after incubation with TREM2 antibodies Ab1, Ab9, Ab14, Ab20, Ab22, Ab45, and Ab65. Antibodies Ab16 and Ab77 are non-agonist negative controls. [Figure 24C] Shown is Syk phosphorylation as measured by Western blot in primary human dendritic cells after incubation with TREM2 antibodies Ab1, Ab5, Ab9, Ab22, Ab45, or Ab65. [Figure 25] Figure 1 shows competitive binding between TREM2 antibodies Ab1, Ab9, Ab14, Ab22, Ab45, Ab65, Ab66, and Ab68 and E. coli bacteria expressing putative TREM2 ligands to mouse and human cell lines expressing TREM2. Bacterial binding is expressed as a percentage of control. Mean of two independent experiments; black bars: not different from isotype control; red bars: significantly different from isotype control (ANOVA). [Figure 26A] Figure 1 shows DAP12 phosphorylation as measured by Western blot in mouse macrophages after incubation with TREM2 antibodies Ab45 or Ab65. [Figure 26B] DAP12 phosphorylation as measured by Western blot in wild-type and TREM2-deficient (TREM2- / -) mouse macrophages after incubation with TREM2 antibodies Ab1, Ab9, Ab22, or Ab45 is shown. [Figure 27A] 1 shows epitope maps of TREM2 antibodies Ab1 and Ab9. [Figure 27B] 1 shows the epitope maps of the TREM2 antibodies Ab45 and Ab65. [Figure 28] Figure 1 shows Fortebio analysis demonstrating simultaneous binding of antibody MAB17291 and antibodies Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65 to TREM2-Fc. Control antibodies Ab63 and Ab87 did not simultaneously bind to TREM2-Fc. [Figure 29]Figure 1 shows increased viability of wild-type (WT) and TREM2 knockout (KO) mouse bone marrow-derived macrophages cultured in the presence of plate-bound cross-linking Fab of TREM2 antibodies Ab22, Ab45, or Ab65 and M-CSF. Antibody Ab88 represents a negative isotype control. [Figure 30A] 1 shows a luminescent viability assay of mouse bone marrow-derived macrophages cultured in the presence of a soluble, non-crosslinked TREM2 antibody Fab and M-CSF. Antibody Ab99 represents a negative isotype control. [Figure 30B] Figure 1 shows a luminescent viability assay of mouse bone marrow-derived macrophages cultured in the presence of a soluble full-length TREM2 antibody and M-CSF. Antibody Ab91 represents a negative isotype control. The dotted line "NT" indicates the mean viability obtained with untreated macrophages (no antibody added). The dotted line "No M-CSF" indicates the mean viability obtained when macrophages are cultured in the absence of M-CSF. [Figure 31A] Figure 1 shows induction of TREM2-dependent gene expression by plate-bound full-length anti-TREM2 antibodies in a cell-based assay using a luciferase reporter gene. [Figure 31B] Figure 1 shows induction of TREM2-dependent gene expression by plate-bound full-length anti-TREM2 antibodies in a cell-based assay using a luciferase reporter gene. [Figure 31C] Figure 1 shows induction of TREM2-dependent gene expression by plate-bound phosphatidylserine (PS). [Figure 32] Figure 1 shows the inhibition of TREM2-dependent gene expression by a soluble, full-length anti-TREM2 antibody in a cell-based assay using a luciferase reporter gene. [Figure 33] Figure 1 shows the competitive interaction between TREM2 antibodies Ab22 and Ab45 and phosphatidylserine (PS) or sphingomyelin (SM) in mouse and human cell lines expressing TREM2. [Figure 34A]1 shows activation of the TREM2-dependent gene IL-6 in mouse macrophages by plate-bound Fab anti-TREM2 antibodies Ab22 and Ab65. [Figure 34B] Figures 34A and 34B show activation of the TREM2-dependent gene MCP-1 in mouse macrophages by the plate-bound Fabs of anti-TREM2 antibodies Ab22 and Ab65. Data in Figures 34A and 34B are shown as mean ± SD, with n = 3 mice per group. In Figures 34A and 34B, "No Ab" indicates a negative control without antibody treatment, "22" indicates treatment with the Fab of Ab22, "65" indicates treatment with the Fab of Ab65, and "ctr" indicates treatment with the Fab of a control antibody. DETAILED DESCRIPTION OF THE INVENTION

[0054] General Technology Conventional methodologies by those skilled in the art, such as Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JM Miller and MP Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JE Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, The techniques and procedures described or referenced herein are generally well understood and commonly used, using widely accepted methodologies such as those described in The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).

[0055] definition As used herein, the term "preventing" includes providing prophylaxis against the occurrence or recurrence of a particular disease, disorder, or condition in an individual who may be susceptible to, predisposed to, or at risk of developing a particular disease, disorder, or condition, but who has not yet been diagnosed with the disease, disorder, or condition.

[0056] 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" refers to an individual having 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.

[0057] 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, improving or alleviating the pathological state, 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.

[0058] An "effective amount" refers to an amount that is at least effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations.

[0059] A "therapeutically effective amount" is at least the minimum concentration required to produce a measurable improvement in a particular disease, disorder, or condition. The therapeutically effective amount herein may vary according to factors such as the patient's condition, age, sex, and weight, and the ability of the anti-TREM2 and / or anti-DAP12 antibody to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the anti-TREM2 and / or anti-DAP12 antibody are outweighed by the therapeutically beneficial effects.

[0060] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Co-administration 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.

[0061] An "individual" for purposes of treatment, prevention, or risk reduction 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. Preferably, the individual is a human.

[0062] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" is used broadly herein to specifically cover 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.

[0063] 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 Ltogether 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.

[0064] 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 the constant domain (CH) of their heavy chains, immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, with heavy chains called 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 ed. (WB Saunders Co., 2000).

[0065] "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 heavy-chain variable 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.

[0066] An "isolated" antibody, such as an isolated anti-TREM2 and / or anti-DAP12 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 all other contaminating components from the production environment. Contaminating components from the production environment, such as those arising from recombinantly transfected 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, 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. Isolated antibodies include antibodies in situ within recombinant T cells. Ordinarily, however, isolated polypeptide or antibody will be prepared by at least one purification step, since at least one component of the antibody's natural environment will not be present.

[0067] The "variable region" or "variable domain" of an antibody, such as an anti-TREM2 and / or anti-DAP12 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.

[0068] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence between antibodies, such as the anti-TREM2 and / or anti-DAP12 antibodies of the present disclosure. V domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not evenly 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 highly conserved portions of the 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 conformation 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 directly involved in binding of the antibody to an antigen, but exhibit various effector functions, such as antibody-dependent cellular toxicity.

[0069] As used herein, the term "monoclonal antibody" refers to an antibody, such as an anti-TREM2 and / or anti-DAP12 monoclonal 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 natural 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 are synthesized by a hybridoma culture, 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 methods (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 methods (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., 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)), 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., WO1998 / 24893; WO1996 / 34096; WO1996 / 33735; WO1991 / 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 may be produced by a variety of techniques, including immunoprecipitation (see Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0070] The terms "full length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to an antibody, such as an anti-TREM2 and / or anti-DAP12 antibody of the present disclosure, in substantially intact form, as opposed to an antibody fragment. Specifically, a complete antibody includes an antibody having heavy and light chains, 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.

[0071] 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.

[0072] Papain digestion of antibodies, such as the anti-TREM2 and / or anti-DAP12 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 domain of the heavy chain (V H ) and the first constant region of one heavy chain (C H 1). 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 with different antigen-binding activities and is still capable of cross-linking antigen. The Fab' fragment contains 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 were originally produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0073] The Fc fragment contains the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of the antibody are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain types of cells.

[0074] 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) still has the ability to recognize and bind antigen, albeit with lower affinity than the entire binding site.

[0075] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is a VFv fragment linked to a single polypeptide chain. H and V L Preferably, the sFv polypeptide is an antibody fragment containing a V domain that enables the sFv to form the desired structure for antigen binding. H Domain and V LIt further comprises a polypeptide linker between the domains. 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).

[0076] A "functional fragment" of an antibody, such as an anti-TREM2 and / or anti-DAP12 antibody of the present disclosure, includes a portion of the intact antibody, generally comprising the antigen-binding or variable region of the intact antibody or the F region of the antibody that retains or modifies FcR binding ability. Examples of antibody fragments include, but are not limited to, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0077] The term "diabody" refers to a V domain in which intrachain, but not interchain, pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. H Domain and V L Refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with a short linker (approximately 5-10 residues) between the domains. Bispecific diabodies are small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with a short linker (approximately 5-10 residues) between the domains. H and V L Diabodies are heterodimers of two "crossover" sFv fragments in which the domains are present on different polypeptide chains. Diabodies are described in more detail in, for example, EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0078] As used herein, "chimeric antibody" refers to antibodies (immunoglobulins), such as the chimeric anti-TREM2 and / or anti-DAP12 antibodies 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 of interest herein include PRIMATIZED® antibodies, in which the antigen-binding region of the antibody is derived from, for example, an antibody produced by immunizing macaque monkeys with an antigen of interest. As used herein, "humanized antibody" is used as a subset of "chimeric antibody."

[0079] "Humanized" forms of non-human (e.g., murine) antibodies, such as humanized forms of the anti-TREM2 and / or anti-DAP12 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 (donor antibody) such as a mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some cases, 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 improve antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and usually 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, or immunogenicity. 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 optionally will 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.

[0080] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody, such as the anti-TREM2 and / or anti-DAP12 antibodies of the present disclosure, that is produced by a human and / or that has been generated using any of the techniques for producing human antibodies as disclosed herein. This definition of human antibody specifically excludes humanized antibodies that contain non-human antigen-binding residues. Human antibodies can be produced using a variety of 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). Additionally, the 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 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). Also see, 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.

[0081] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to regions of an antibody variable domain, such as an anti-TREM2 and / or anti-DAP12 antibody of the disclosure, that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs;H Three of these (H1, H2, H3) and V L HVRs comprise three HVRs (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). Indeed, natural camelid antibodies consist only of heavy chains that 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).

[0082] Numerous HVR diagrams are in use and are encompassed herein. Kabat complementarity-determining regions (CDRs), HVRs, are based on sequence variability and are the most commonly used (Kabat et al., supra). Chothia, instead, refers to the location of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). AbM HVRs represent a compromise between Kabat CDRs and Chothia structural loops and are used in Oxford Molecular's AbM antibody modeling software. "Contact" HVRs are based on analysis of available complex crystal structures. Residues from each of these HVRs are represented below.

[0083] TIFF0007730936000001.tif44170

[0084] The HVR may include an "extended HVR" as follows: L 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3), and VH 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3). The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0085] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0086] The phrases "Kabat-like variable domain residue numbering" or "Kabat-like amino acid position numbering," and variations thereof, refer to the numbering system used for the heavy chain variable domain or light chain variable domain of the antibody compilation of 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, a FR or HVR 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 antibody's sequence at the region of homology with the "standard" Kabat-numbered sequence.

[0087] The Kabat numbering system is generally 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 "EU numbering system" or "EU index" is generally 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 Publication No. 2010-280227).

[0088] As used herein, an "acceptor human framework" refers to a V-framework derived from a human immunoglobulin framework or a human consensus framework. L or V H The 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. If the pre-existing amino acid changes are V H When present, preferably these changes occur at three, two, or only one of positions 71H, 73H, and 78H, e.g., the amino acid residues at these positions may be 71A, 73T, and / or 78A. L The acceptor human framework has the sequence V LIt is identical to a human immunoglobulin framework sequence or a human consensus framework sequence.

[0089] The "human consensus framework" is based on human immunoglobulin V L or V H In selecting framework sequences, the framework represents the most commonly occurring amino acid residues. L or V H The selection of sequences is from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup such as those described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). V L For example, the subgroup may be subgroup kappa I, kappa II, kappa III, or kappa IV as in Kabat et al., supra. H In this case, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra.

[0090] For example, an "amino acid modification" at a particular position of an anti-TREM2 and / or anti-DAP12 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 N-terminal or C-terminal to the particular residue. A preferred amino acid modification herein is a substitution.

[0091] An "affinity matured" antibody, such as an affinity matured anti-TREM2 and / or anti-DAP12 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 its 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 are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe V H Domain and V L Affinity maturation by domain shuffling is described. Random mutagenesis of HVR and / or framework residues is 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).

[0092] As used herein, the terms "specifically recognize" or "specifically bind" refer to a measurable and reproducible interaction, such as attraction or binding, between a target and an antibody, e.g., between an anti-TREM2 antibody and TREM2, or between an anti-DAP12 antibody and DAP12, that determines the presence of a target in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody, such as the anti-TREM2 and / or anti-DAP12 antibodies of the present disclosure, that specifically or preferentially binds to a target or epitope is an antibody that binds to this target or epitope with higher affinity, avidity, more readily, and / or for a longer duration than it binds to other targets or other epitopes of targets. For example, it is understood by reading this definition that an antibody (or moiety) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, "specific binding" or "preferential 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 -1The binding constant may be greater than or equal to 100 kJ / min. A variety of 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. See, e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0093] As used herein, an "interaction" between a TREM2 protein or a DAP12 protein and a second protein includes, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, bonds, covalent bonds, and ionic bonds. 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. An antibody or fragment thereof of the present disclosure "inhibits the interaction" between two proteins when the antibody or fragment thereof binds to one of the two proteins.

[0094] An "agonist" or "activating" antibody is an antibody, such as an agonist anti-TREM2 antibody or an agonist anti-DAP12 antibody of the present disclosure, that induces (e.g., increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0095] An "antagonist" or "blocking" antibody is an antibody, such as an antagonist anti-TREM2 antibody or antagonist anti-DAP12 antibody of the present disclosure, that reduces or eliminates (e.g., reduces) antigen binding to one or more ligands after the antibody binds to the antigen and / or reduces or eliminates (e.g., reduces) one or more activities or functions of the antigen after the antibody binds to the antigen.

[0096] 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.

[0097] 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, intact antibody compositions may include antibody populations in which all K447 residues have been removed, antibody populations in which the K447 residue has not been removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present invention include human IgG1, IgG2, IgG3, and IgG4.

[0098] 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.

[0099] 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 or the Fc region of a parent polypeptide, 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 or the Fc region of a parent polypeptide. The variant Fc region herein will preferably have at least about 80% homology with the native-sequence Fc region and / or the Fc region of the parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto.

[0100] "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 (an "activating receptor") and FcγRIIB (an "inhibiting receptor"), 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, including those to be identified in the future, are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0101] In vivo binding to FcRn and serum half-life of human FcRn high-affinity binding polypeptides can be assayed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which polypeptides having variant Fc regions are administered. WO2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcRs. See also, for example, Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0102] 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 amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity; any conservative substitutions are not considered as part of the sequence identity. Alignment to determine percent amino acid sequence identity can be accomplished by a variety of means 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 measuring alignment, including any algorithms known in the art, needed to achieve maximum alignment over the entire length of the sequences being compared.

[0103] An "isolated" nucleic acid molecule encoding an antibody, such as an anti-TREM2 and / or anti-DAP12 antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule normally associated with the environment in which it is produced. Preferably, an isolated nucleic acid is free from association with all components associated with the production environment. Isolated nucleic acid molecules encoding the polypeptides and antibodies herein are in a form other than in the form or setting in which they are found in nature. Thus, isolated nucleic acid molecules are distinguished from nucleic acids encoding the polypeptides and antibodies herein that are naturally present in a cell.

[0104] 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 are 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 of utility in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" are sometimes used interchangeably, as the plasmid is the most commonly used form of vector.

[0105] "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 be interrupted by non-nucleotide components. A polynucleotide can also contain modification(s) 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 an analog, 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 or phosphate groups, protected with standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or conjugated to solid or semi-solid supports. The 5'- and 3'-terminal OH groups may be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls may also be derivatized to standard protecting groups.Polynucleotides may also contain ribose or deoxyribose sugars in analog forms 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 with 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 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.

[0106] A "host cell" includes an individual cell or cell culture that can be or has been the recipient of a vector(s) for incorporation of a polynucleotide insert. 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 transfected in vivo with a polynucleotide(s) of the invention.

[0107] As used herein, "carrier" refers to a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, physiologically acceptable carriers are pH-buffered aqueous solutions. 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 dextrin; 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™.

[0108] As used herein, the term "about" 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.

[0109] 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.

[0110] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0111] overview The present disclosure relates to anti-TREM2 and / or anti-DAP12 antibodies having one or more agonist or antagonist activities; methods for making and using such antibodies; pharmaceutical compositions containing such antibodies; nucleic acids encoding such antibodies; and host cells containing nucleic acids encoding such antibodies.

[0112] In some embodiments, without wishing to be bound by theory, it is believed that the agonistic activity of the anti-TREM2 and / or anti-DAP12 antibodies of the present disclosure is at least partially due to the ability of the antibodies to induce or maintain TREM2 receptor clustering on the cell surface. In some embodiments, it is believed that TREM2 and / or anti-DAP12 antibodies can induce or maintain TREM2 receptor clustering in vivo by not only specifically binding to TREM2 but also binding to Fc receptors on neighboring cells, which in turn leads to antibody aggregation that aggregates TREM2. Advantageously, certain immunoglobulin isotypes, including but not limited to IgG2 and IgM, have the inherent ability to induce or maintain clustering of target antigens (e.g., TREM2) without binding to Fc receptors on neighboring cells. In some embodiments, agonist TREM2 activity can be measured or tested in vitro by any of several techniques disclosed herein (see, e.g., Examples 23-26, 34-37, 41-44, 52-55, and 67-68), including, but not limited to, plate-binding full-length anti-TREM2 antibodies to increase the density of antibodies exposed to TREM2 and cross-linking anti-TREM2 antibodies.

[0113] Accordingly, certain embodiments of the present disclosure are capable of binding with high affinity to both human TREM2 and mouse TREM2 (see, e.g., Examples 1 and 40); competing with TREM2 ligands for binding to the ligand-binding site on human and mouse TREM2 (see, e.g., Examples 26 and 43); and CD83. + CD86 +The present invention is based on the identification of anti-TREM2 and / or anti-DAP12 antibodies that exhibit one or more agonistic TREM2 activities, including, but not limited to, induction of dendritic cells (see, e.g., Examples 23 and 41), induction of the TREM2 downstream signaling molecule Syk in macrophages and dendritic cells (see, e.g., Examples 24 and 42), induction of the TREM2 signaling adaptor molecule DAP12 in macrophages (see, e.g., Examples 25 and 44), induction of cell survival in innate immune cells such as macrophages (see, e.g., Examples 34 and 52), and activation of TREM2-dependent gene expression (see, e.g., Examples 36, 38, 54, 56, and 68).

[0114] Further aspects of the present disclosure are based, at least in part, on the surprising discovery that TREM2 and / or anti-DAP12 antibodies of the present disclosure can also induce antagonist activity when the antibodies are produced or otherwise formatted such that they are unable to induce or maintain TREM2 receptor clustering. In some embodiments, the TREM2 and / or anti-DAP12 antibodies of the present disclosure exhibit one or more antagonist TREM2 activities, including, but not limited to, inhibition of cell survival of innate immune cells (see, e.g., Examples 35 and 53) and inhibition of TREM2-dependent gene expression (see, e.g., Examples 37, 55, and 67).

[0115] TREM2 protein In one aspect, the invention provides antibodies that bind to a TREM2 protein of the disclosure and modulate one or more TREM2 activities after binding to a TREM2 protein expressed in a cell.

[0116] TREM2 proteins of the present disclosure include, but are not limited to, mammalian TREM2 proteins, human TREM2 protein (Uniprot Accession No. Q9NZC2), mouse TREM2 protein (Uniprot Accession No. Q99NH8), rat TREM2 protein (Uniprot Accession No. D3ZZ89), rhesus monkey TREM2 protein (Uniprot Accession No. F6QVF2), bovine TREM2 protein (Uniprot Accession No. Q05B59), equine TREM2 protein (Uniprot Accession No. F7D6L0), porcine TREM2 protein (Uniprot Accession No. H2EZZ3), and canine TREM2 protein (Uniprot Accession No. E2RP46). As used herein, "TREM2 protein" refers to both wild-type and naturally occurring variant sequences.

[0117] Triggering receptor expressed on myeloid cells 2 (TREM2) is variously referred to as TREM-2, Trem2a, Trem2b, Trem2c, and triggering receptor expressed on monocytes 2. TREM2 is a 230-amino acid membrane protein. TREM2 is an immunoglobulin-like receptor primarily expressed on myeloid cells, including, but not limited to, macrophages, dendritic cells, osteoclasts, microglia, monocytes, dermal Langerhans cells, and Kupffer cells. 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] In some embodiments, an example of a human TREM2 amino acid sequence is shown below as SEQ ID NO: 1:

[0119] TIFF0007730936000002.tif55170

[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).

[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] Homologs of human TREM2 include, but are not limited to, natural killer (NK) cell receptor NK-p44 (NCTR2), polymeric immunoglobulin receptor (pIgR), CD300E, CD300A, CD300C, and TREML1 / TLT1. In some embodiments, NCTR2 shares similarity with TREM2 within the IgV domain.

[0123] DAP12 protein In one aspect, the invention provides antibodies that bind to a DAP12 protein of the disclosure and modulate one or more DAP12 activities after binding to DAP12 expressed in a cell.

[0124] DAP12 proteins of the present disclosure include, but are not limited to, mammalian DAP12 proteins, human DAP12 protein (Uniprot accession number O43914), mouse DAP12 protein (Uniprot accession number O54885), rat DAP12 protein (Uniprot accession number Q6X9T7), rhesus monkey DAP12 protein (Uniprot accession number Q8WNQ8), bovine DAP12 protein (Uniprot accession number Q95J80), and porcine DAP12 protein (Uniprot accession number Q9TU45). As used herein, "DAP12 protein" refers to both wild-type and naturally occurring variant sequences.

[0125] DNAX-activating protein 12 (DAP12) is variously referred to as killer-activating receptor-associated protein, KAR-associated protein (KARAP), PLOSL, PLO-SL, TYRO protein, and tyrosine kinase-binding protein. DAP12 is a 113-amino acid membrane protein. In some embodiments, DAP12 functions as a transmembrane signaling polypeptide containing an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. It may associate with membrane glycoproteins of the killer cell inhibitory receptor (KIR) family and act as an activating signaling element. In other embodiments, DAP12 protein binds to zeta chain (TCR)-associated protein kinase 70 kDa (ZAP-70) and spleen tyrosine kinase (SYK), and is involved in signal transduction, bone formation, brain myelination, and inflammation.

[0126] Mutations in the gene encoding DAP12 are associated with lipomembranous polycystic osseous dysplasia with sclerosing leukoencephalopathy (PLOSL), also known as Nasu-Hakola disease. Without wishing to be bound by theory, the DAP12 receptor is thought to be TREM2, which also causes PLOSL. Multiple alternative transcript variants encoding different isoforms of DAP12 have been identified. DAP12 noncovalently associates with activating receptors of the CD300 family. Cross-linking of the CD300-TYROBP / DAP12 complex results in cell activation, such as integrin-mediated neutrophil activation. DAP12 is a homodimeric disulfide-linked protein. In some embodiments, DAP12 interacts with SIRPB1, TREM1, CLECSF5, SIGLEC14, CD300LB, CD300E, and CD300D by homology and via the ITAM domain, and with SYK via the SH2 domain. In another embodiment, DAP12 activates SYK, which mediates integrin-mediated activation of neutrophils and macrophages. In another embodiment, DAP12 interacts with KLRC2 and KIR2DS3.

[0127] In some embodiments, an exemplary human DAP12 amino acid sequence is shown below as SEQ ID NO:2.

[0128] TIFF0007730936000003.tif27170

[0129] In some embodiments, human DAP12 is a preprotein including a signal peptide. In some embodiments, human DAP12 is a mature protein. In some embodiments, the mature DAP12 protein does not include a signal peptide. In some embodiments, the mature DAP12 protein is expressed on a cell. DAP12 is a single-pass type I membrane protein. It contains an extracellular domain located at amino acid residues 22-40 of human DAP12 (SEQ ID NO: 2); a transmembrane domain located at amino acid residues 41-61 of human DAP12 (SEQ ID NO: 2); and an intracellular domain located at amino acid residues 62-113 of human DAP12 (SEQ ID NO: 2). An immunoreceptor tyrosine-based activation motif (ITAM) domain is located at amino acid residues 80-118 of human DAP12 (SEQ ID NO: 2).

[0130] In some embodiments, an aspartic acid residue in DAP12 interacts with the transmembrane domain of human TREM2, which contains a lysine at amino acid residue 186, transducing signaling from TREM2, TREM1, and other related IgV family member proteins.

[0131] Anti-TREM2 and anti-DAP12 antibodies Certain aspects of the present disclosure relate to antibodies that specifically bind to TREM2 and / or DAP12. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein and / or DAP12 protein. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein and / or DAP12 protein, where the mature TREM2 protein and / or DAP12 protein is expressed on a cell. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein and / or DAP12 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 are agonistic antibodies. In some embodiments, the antibodies of the present disclosure are inactive antibodies. In some embodiments, the antibodies of the present disclosure are antagonistic antibodies.

[0132] Agonist antibodies The anti-TREM2 and / or anti-DAP12 antibodies of the present disclosure generally bind to one or more TREM2 and / or DAP12 proteins expressed on cells. One class of antibodies is agonist antibodies. For example, it is believed that TREM2 receptors require clustering on the cell surface to transmit signals. Therefore, agonist antibodies may have unique characteristics that stimulate the TREM2 receptor, for example. For example, they may have appropriate epitope specificity compatible with receptor activation and the ability to induce or maintain receptor clustering on the cell surface.

[0133] In vivo, antibodies can cluster receptors by several potential mechanisms. Due to their unique structure, some human antibody isotypes, such as IgG2, have 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).

[0134] Other antibodies cluster receptors (e.g., TREM2) by binding to Fcg receptors on adjacent cells. Binding of the constant IgG Fc portion of antibodies to Fcg receptors results in aggregation of the antibodies, which in turn aggregate the receptors to which they bind via their variable regions (Chu et al. (2008) Mol Immunol , 45:3926-3933; and Wilson et al., (2011) Cancer Cell 19, 101-113). Because binding to FcgRIIB is not associated with adverse immune effects, binding to the inhibitory Fcg receptor FcgR (FcgRIIB), which does not induce cytokine secretion, oxidative burst, increased phagocytosis, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), is often the preferred means of clustering antibodies in vivo.

[0135] Other mechanisms may also be used to cluster receptors (e.g., TREM2). For example, antibody fragments (e.g., Fab fragments) that are cross-linked together may 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. Without wishing to be bound by theory, it is believed that cross-linked antibody fragments (e.g., Fab fragments) induce receptor clustering on the cell surface and may function as agonist antibodies when bound to the appropriate epitope on the target (e.g., TREM2).

[0136] Thus, in some embodiments, antibodies that bind to TREM2 and / or DAP12 proteins may include agonist antibodies that bind to TREM2 and / or DAP12 with epitope specificity and activate one or more TREM2 and / or DAP12 activities. Without wishing to be bound by theory, such antibodies may bind to a ligand-binding site on a target antigen (e.g., TREM2 and / or DAP12) and mimic the action of the natural ligand, or may stimulate the target antigen to transduce a signal by binding to one or more domains that are not the ligand-binding site. Such antibodies will not interfere with ligand binding and may act additively or synergistically with the natural ligand.

[0137] In some embodiments, the antibodies of the present disclosure are agonistic antibodies that induce one or more TREM2 activities, one or more DAP12 activities, or one or more TREM2 activities and one or more DAP12 activities, hi some embodiments, the antibodies induce one or more activities of TREM2 and / or DAP12 after binding to TREM2 and / or DAP12 protein expressed in a cell. In certain embodiments, the one or more TREM2 activities, the one or more DAP12 activities, or both, are determined by TREM2 binding to DAP12; DAP12 binding to TREM2; DAP12 phosphorylation; TREM2 phosphorylation; PI3K activation; increased expression of one or more anti-inflammatory cytokines; increased expression of one or more anti-inflammatory mediators (e.g., cytokines) selected from IL-12p70, IL-6, and IL-10; reduced expression of one or more pro-inflammatory cytokines; IFN-α4, IFN-b, IL-6, IL-12p70, IL-1β, TNG, TNF-α, IL-10, IL-8, CRP, a TGF-beta member of the chemokine protein family, an IL-20 family member, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17 reducing the expression of one or more pro-inflammatory mediators selected from the group consisting of IL-18, mCP-1, and CRP; reducing the expression of TNF-α; reducing the expression of IL-6; extracellular signal-regulated kinase (ERK) phosphorylation; increasing the expression of CC chemokine receptor 7 (CCR7); inducing chemotaxis of microglial cells toward CCL19- and CCL21-expressing cells; enhancing, normalizing, or both, the ability of bone marrow-derived dendritic cells to induce antigen-specific T cell proliferation; inducing osteoclast production, increasing the rate of osteoclast formation, or both; increasing the survival and / or function of one or more of macrophages, microglial cells, M1 macrophages and / or microglial cells, activated M1 macrophages and / or microglial cells, M2 macrophages and / or microglial cells, monocytes, osteoclasts, dermal Langerhans cells, and Kupffer cells;Induction of clearance of one or more selected from apoptotic neuron clearance, neural tissue debris clearance, non-neural tissue debris clearance, bacteria or other foreign body clearance, pathogenic protein clearance, pathogenic peptide clearance, and pathogenic nucleic acid clearance; induction of phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign body, pathogenic protein, pathogenic protein, pathogenic peptide, or pathogenic nucleic acid (e.g., antisense GGCCCC (G2C4) repeat expansion RNA); normalization of disrupted TREM2 / DAP12-dependent gene expression; recruitment of Syk, ZAP70, or both to the TREM2 / DAP12 complex; Syk phosphorylation; increased expression of CD83 and / or CD86 on dendritic cells, macrophages, monocytes, and / or microglia; reduction in secretion of one or more inflammatory cytokines; TNF the reduction in secretion of one or more inflammatory cytokines selected from IL-α, IL-10, IL-6, MCP-1, FN-α4, IFN-β, IL-1β, IL-8, CRP, TGF-beta members of the chemokine protein family, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, and IL-18; the reduction in expression of one or more inflammatory receptors; the increase in phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia under conditions of reduced levels of M-CSF; the decrease in phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia in the presence of normal levels of M-CSF; the increase in activity of one or more TREM2-dependent genes (e.g., transcription factors of the nuclear factor of activated T cells (NFAT) family of transcription factors);

[0138] Antibodies that rely on binding to FcgR receptors to activate target receptors can lose their agonistic activity if genetically 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). As such, antibodies of the present disclosure with appropriate epitope specificity are believed to be agonistic antibodies and capable of activating target antigens with minimal adverse effects when the antibodies possess an Fc domain derived from a human IgG2 isotype (CH1 and hinge region) or another type of Fc domain capable of preferentially binding to the inhibitory FcgRIIB receptor, or a variant thereof.

[0139] Exemplary agonist antibody Fc isotypes and modifications are provided below in Table 2. In some embodiments, the agonist antibody has an Fc isotype set forth in Table 2 below.

[0140] TIFF0007730936000004.tif230170

[0141] In addition to the isotypes listed in Table 2, and without wishing to be bound by theory, it is believed that antibodies with human IgG1 or IgG3 isotypes and their variants 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) can also act as agonist antibodies in vivo but may be associated with adverse effects related to ADCC. However, such 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) IScience 333(6045):1030-1034).

[0142] In some embodiments, the agonist antibody is of the IgG class, the IgM class, or the IgA class. In some embodiments, the agonist antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

[0143] In certain embodiments, the agonist antibody has an IgG2 isotype. In some embodiments, the agonist antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments, the agonist antibody induces one or more TREM2 activities, DAP12 activities, or both, independent of binding to an Fc receptor. In some embodiments, the agonist antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fcγ 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 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 (US2007 / 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 or Kabat numbering conventions.

[0144] In some embodiments, the agonist antibody has an IgG2 isotype with a heavy chain constant domain containing a C127S amino acid substitution, where the amino acid positions are according to the EU or Kabat numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0145] In some embodiments, the agonist antibody has an IgG2 isotype with a kappa light chain constant domain containing a C214S amino acid substitution, where the amino acid positions are according to the EU or Kabat numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0146] In certain embodiments, the agonist antibody has an IgG1 isotype. In some embodiments, the agonist antibody contains a mouse IgG1 constant region. In some embodiments, the agonist antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region comprises an Fc region. In some embodiments, the agonist antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fcγ 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) RJ Biol. 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., (2000) Cell Immunol, 200:16-26), and / or G237A (Alegre et al. (1994) Transplantation 57:1537-1543. 31; Xu et al., (2000) Cell Immunol, 200:16-26). 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 numbered according to EU or Kabat numbering conventions.

[0147] 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 contains the amino acid sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397). 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 or Kabat numbering conventions.

[0148] In certain embodiments, the agonist antibody has an IgG4 isotype. In some embodiments, the agonist antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region comprises an Fc region. In some embodiments, the agonist antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is inhibitory Fcγ 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 EU or Kabat numbering conventions.

[0149] In certain embodiments, the agonist antibody has a hybrid IgG2 / 4 isotype. In some embodiments, the agonist antibody comprises an amino acid sequence containing amino acids 118 to 260 according to the Kabat numbering convention of human IgG2 and amino acids 261 to 447 according to the EU or Kabat numbering of human IgG4 (WO1997 / 11971; WO2007 / 106585).

[0150] In certain embodiments, the antibody contains a murine IgG4 constant region (Bartholomaeus, et al. (2014). J. Immunol. 192, 2091-2098).

[0151] In some embodiments, the Fc region further contains one or more additional amino acid substitutions selected from the group consisting of A330L, L234F, L235E, and / or P331S, where the amino acid positions are according to the EU or Kabat numbering convention.

[0152] inert antibody Another class of antibodies of the present disclosure includes inactive antibodies. As used herein, an "inactive" antibody refers to an antibody that specifically binds to a target antigen but does not modulate (e.g., reduce / inhibit or activate / induce) antigen function. For example, in the case of TREM2, an inactive antibody does not modulate ligand binding and / or TREM2 activity. Without wishing to be bound by theory, it is believed that an antibody that does not have the ability to cluster TREM2 on the cell surface may be an inactive antibody, even if it has an epitope specificity compatible with receptor activation.

[0153] In some embodiments, antibodies that bind to TREM2 and / or DAP12 proteins can include antibodies that bind TREM2 and / or DAP12 but, due to their epitope specificity, do not modulate protein function. Such functionally inactive antibodies can be used as cargo to deliver toxins, as described for the CD33 antibody gemtuzumab ozogamicin (sold as Mylotarg), which has been conjugated to a cytotoxic agent of the calicheamicin class and used to target and kill acute myeloid leukemia tumors. (Naito et al., (2000), Leukemia, 14, 1436-1443; Ricart (2011) Clin Cancer Res 17; 6417-6436; Hamann et al., (2002) Journal: Bioconjugate Chemistry, 13, 47-58; and Beitz et al., (2001) Clin Cancer Res 7; 1490-6.) Thus, in some embodiments, the antibodies of the present disclosure are inactive antibodies that bind to TREM2 and / or DAP12 but are unable to induce one or more TREM2 activities (e.g., a TREM2 activity described herein) and / or DAP12 activities (e.g., a DAP12 activity described herein).

[0154] Fc isotypes and modifications of exemplary inactivating antibodies are provided below in Table 3. In some embodiments, the inactivating antibody has an Fc isotype set forth in Table 3 below.

[0155] Antagonist antibodies A third class of antibodies of the present disclosure includes antagonist antibodies. In some embodiments, antibodies that bind to TREM2 and / or DAP12 proteins may include antagonist antibodies that bind to TREM2 and / or DAP12 and inhibit one or more TREM2 and / or DAP12 activities by either preventing the interaction between TREM2 and / or DAP12 and its ligand(s) or by preventing the transmission of a signal from the extracellular domain of TREM2 and / or DAP12 to the cytoplasm in the presence of a ligand. In some embodiments, antagonist antibodies of the present disclosure may have the epitope specificity of the agonist antibodies of the present disclosure but have an Fc domain that is incapable of binding to Fcg receptors, thereby, for example, incapable of clustering DAP12 and / or TREM2 receptors.

[0156] In some embodiments, an antibody of the present disclosure is an antagonist antibody. In some embodiments, the antagonist antibody inhibits one or more TREM2 and / or DAP12 activities. In some embodiments, the antagonist antibody reduces the activity of one or more TREM2-dependent genes. In some embodiments, the one or more TREM2-dependent genes include, but are not limited to, one or more nuclear factor of activated T cells (NFAT) transcription factors. In some embodiments, the antagonist antibody reduces the survival of macrophages, microglial cells, M1 macrophages, M1 microglial cells, M2 macrophages, M2 microglial cells, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or dendritic cells. In some embodiments, the antagonist antibody inhibits the interaction between TREM2 and / or DAP12 and one or more TREM2 and / or DAP12 ligands. In some embodiments, the antagonist antibody inhibits TREM2 and / or DAP12 signaling. In some embodiments, the antagonist antibody inhibits the interaction between TREM2 and / or DAP12 and one or more TREM2 and / or DAP12 ligands, inhibiting TREM2 and / or DAP12 signaling.

[0157] In some embodiments, antibody cross-linking is required for agonist antibody function. Antibody cross-linking can occur via binding to a secondary antibody in vitro or via binding to an Fc receptor in vivo. For example, an antagonist antibody can be converted to an agonist antibody via biotin / streptavidin cross-linking or secondary antibody binding in vitro (see, e.g., Gravestein et al., (1996) J. Exp. Med. 184:675-685; Gravestein et al., (1994) International Immunol. 7:551-557). Agonist antibodies may exert their activity by mimicking the biological activity of receptor ligands or enhancing receptor aggregation, thereby activating receptor signaling. In some embodiments, the absence of antibody cross-linking is required for antagonist activity. Antagonist antibodies may exert their activity by blocking receptor-ligand interactions.

[0158] Exemplary antagonist antibody Fc isotypes and modifications are provided below in Table 3. In some embodiments, the antagonist antibody has an Fc isotype set forth in Table 3 below.

[0159] Inactive and antagonist antibody Fc isotypes In some embodiments, the inactive and / or antagonist anti-TREM antibodies of the present disclosure comprise one or more of the Fc isotypes and modifications listed in Table 3.

[0160] TIFF0007730936000005.tif177170

[0161] 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 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, N297Q (Bolt S et al. (1993) Eur J Immunol 23:403-411), D265A, L234A, L235A (McEarchern et al., (2007) Blood, 109:1185-1192), C226S, C229S (McEarchern et al., (2007) Blood, 109:1185-1192), P238S (Davis et al., (2007) J Rheumatol, 34:2204-2210), E233P, L234V (McEarchern et al., (2007) Blood, 109:1185-1192), P238A, A327Q, A327G, P329A (Shields RL. et al., (2001) J Biol Chem. 276(9):6591-604), K322A, L234F, L235E (Hezareh, et al., (2001) J Virol 75, 12161-12168; Oganesyan et al., (2008). Acta Crystallographica 64, 700-704), P331S (Oganesyan et al., (2008) Acta Crystallographica 64, 700-704), T394D (Wilkinson et al. (2013) MAbs 5(3): 406-417), A330L, M252Y, S254T, and / or T256E, where the amino acid positions are according to the EU or Kabat numbering convention. In certain embodiments, the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to the EU or Kabat numbering convention.

[0162] In some embodiments, the antibody has an IgG1 isotype with a heavy chain constant region containing a C220S amino acid substitution according to the EU or Kabat numbering convention.

[0163] 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 the EU or Kabat numbering convention.

[0164] 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 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 V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, and / or T256E, wherein the amino acid positions are according to the EU or Kabat numbering convention.

[0165] 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 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 E233P, F234V, L235A, G237A, E318A (Hutchins et al. (1995) Proc Natl Acad Sci USA, 92:11980-11984), S228P, L236E, S241P, L248E (Reddy et al., (2000) J Immunol,164:1925-1933; Angal et al., (1993) Mol Immunol. 30(1):105-8; US 8614299 B2), T394D, M252Y, S254T, T256E, N297A, and / or N297Q, wherein the amino acid positions are according to EU or Kabat numbering conventions.

[0166] In some embodiments, the Fc region further contains one or more additional amino acid substitutions selected from M252Y, S254T, and / or T256E, where the amino acid positions are according to the EU or Kabat numbering convention.

[0167] 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, where amino acid positions are according to EU or Kabat numbering conventions. 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, 256E mutations according to the EU or Kabat 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).

[0168] In some embodiments, the IgG4 variants of the present disclosure may be combined with the S228P mutation according to the EU or Kabat numbering convention (Angal et al., (1993) Mol Immunol, 30:105-108) and / or one or more of the mutations described in Peters et al., (2012) J Biol Chem. 13;287(29):24525-33 to enhance antibody stability.

[0169] Anti-TREM2 antibody Certain aspects of the present disclosure relate to anti-TREM2 antibodies.

[0170] In certain embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that induce one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that promote the survival of one or more innate immune cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure promote the survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells. In some embodiments, promoting the survival of one or more innate immune cells includes prolonging cell survival or otherwise delaying cell death. Thus, in some embodiments, the anti-TREM2 antibodies of the present disclosure prolong cell survival of one or more innate immune cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure delay cell death of one or more innate immune cells. In some embodiments, promoting cell survival and / or prolonging cell survival is determined by measuring cell survival of one or more innate immune cells in the presence of an anti-TREM2 antibody, compared to cell survival of the corresponding one or more innate immune cells in the absence of the anti-TREM2 antibody. In some embodiments, delaying cell death is determined by measuring cell death of one or more innate immune cells in the presence of an anti-TREM2 antibody, compared to cell death of the corresponding one or more innate immune cells in the absence of the anti-TREM2 antibody. Any suitable method for measuring cell survival or cell death known in the art and disclosed herein may be used (e.g., see Examples 30, 34, 35, 38, 52, 53, and 56). In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that increase IL-6 expression. In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonistic antibodies that promote survival of one or more innate immune cells and increase IL-6 expression. Any suitable method known in the art and disclosed herein for measuring IL-6 expression in cells may be used (see, e.g., Examples 28, 38, and 68).

[0171] In certain embodiments, the anti-TREM2 antibodies of the present disclosure are inactive or antagonistic antibodies that inhibit one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies of the present disclosure are inactive or antagonistic antibodies that reduce the survival of one or more innate immune cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce the survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells. In some embodiments, reducing cell survival is determined by measuring the cell survival of one or more innate immune cells in the presence of an antagonist anti-TREM2 antibody compared to the cell survival of the corresponding one or more innate immune cells in the absence of the antagonist anti-TREM2 antibody. Any suitable method for measuring cell viability or cell death known in the art and disclosed herein may be used (see, eg, Examples 30, 34, 35, 38, 52, 53, and 56).

[0172] In some embodiments, the isolated anti-TREM2 antibodies of the present disclosure compete for binding of TREM2 with one or more TREM2 ligands. In some embodiments, the antibody is a human antibody, 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.

[0173] In certain embodiments, the TREM2 protein is expressed on the cell surface. In some embodiments, the anti-TREM2 antibodies of the present disclosure modulate (e.g., induce or inhibit) one or more TREM2 activities. TREM2 activity modulated (e.g., induced or inhibited) by anti-TREM2 antibodies includes DAP12 phosphorylation; TREM2 phosphorylation; recruitment of Syk, ZAP70, or both, to the DAP12 / TREM2 complex; PI3K activation; increased expression of anti-inflammatory mediators (e.g., cytokines); decreased expression of pro-inflammatory mediators; ERK phosphorylation; increased expression of CCR7, induction of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; enhanced, normalized, or both, the ability of bone marrow-derived dendritic cells to induce antigen-specific T cell proliferation; induction of osteoclast production, increased rate of osteoclast formation, or both; and increased expression of microglial cells and / or macrophages (e.g., M1 macrophages and / or microglial cells, activated M1 macrophages and / or microglial cells, and / or M2 macrophages and / or microglial cells), dendritic cells, monocytes, osteoclasts, and / or dendritic cells. increased expression of CD83 and / or CD86 on dendritic cells, monocytes, macrophages, and / or microglia; reduced secretion of one or more inflammatory cytokines (e.g., TNF-α, IL-10, IL-6, and / or MCP-1); reduced expression of one or more inflammatory receptors (e.g., CD86); increased phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia under conditions of reduced levels of M-CSF; reduced phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia in the presence of normal levels of M-CSF; and / or increased activity of one or more TREM2-dependent genes (e.g., transcription factors of the nuclear factor of activated T cells (NFAT) family of transcription factors).The anti-TREM2 antibodies of the disclosure are useful in treating dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multisystemic dementia, and other conditions. The anti-TREM2 antibodies of the present disclosure can be used to prevent, reduce the risk of, or treat conditions such as atrophy of the retina, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related diseases, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone mineral density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, and cancer. The anti-TREM2 antibodies of the present disclosure may also be used to promote advanced wound healing. In some embodiments, the anti-TREM2 antibodies of the present disclosure are monoclonal antibodies.The anti-TREM2 antibodies of the disclosure can be used to inhibit one or more TREM2 activities (e.g., TREM2 autophosphorylation; DAP12 phosphorylation; Syk phosphorylation; recruitment of Syk, ZAP70, or both to the TREM2 / DAP12 complex; PI3K activation; increased cytokine expression; reduced expression of pro-inflammatory mediators; ERK phosphorylation; increased expression of CCR7, induction of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; maturation of bone marrow-derived dendritic cells; enhanced or normalized ability of bone marrow-derived dendritic cells to induce antigen-specific T-cell proliferation; increased ability of dendritic cells, monocytes, microglia, and / or macrophages to induce T-cell proliferation; induction of osteoclast production, increased rate of osteoclast formation, or both; or induction of osteoclastogenesis in dendritic cells, macrophages, or other cells expressing CCR7. the induction of phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells; the reduction of secretion of one or more inflammatory cytokines; the reduction of expression of one or more inflammatory receptors; the increase of phagocytosis by macrophages, dendritic cells, monocytes, and / or microglial cells in the presence of reduced levels of M-CSF; the reduction of phagocytosis by macrophages, dendritic cells, monocytes, and / or microglial cells in the presence of normal levels of M-CSF; the normalization of disrupted TREM2 / DAP12-dependent gene expression; the increase of activity of one or more TREM2-dependent genes.For example, anti-TREM2 antibodies can be assayed in vitro for tyrosine phosphorylation of TREM2, DAP12, Syk, and / or ERK by assaying for recruitment of Syk and / or ZAP70 to DAP12, by assaying for PI3K activation, by assaying for induction of cytokine (e.g., IL-12p70, IL-6, and IL-10) or CCR7 expression, or by assaying for reduced expression of pro-inflammatory mediators (e.g., IL1-β and TNF) using TLR stimulation (e.g., LPS, CpG DNA, or zymosan).Useful assays include Western blot (e.g., for tyrosine-phosphorylated DAP12 or threonine / serine-phosphorylated PI3K kinase substrates), ELISA (e.g., for secreted interleukin or cytokine secretion), FACS (e.g., for anti-TREM2, which binds to TREM2), immunocytochemistry (e.g., for tyrosine-phosphorylated DAP12 or threonine / serine-phosphorylated PI3K kinase substrates), reporter gene assays (e.g., for TLR activation, increased survival and / or function of dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and / or microglia, apoptotic neurons, damaged synapses, amyloid beta or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, Hanchuck protein, and the like). Insulin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation products, dipeptide repeat (DPR) peptides, glycine-alanine ( The assays may include assays for increased phagocytosis of neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or tumor cells, increased cytoskeletal reorganization, and decreased microglial pro-inflammatory responses, or other assays known in the art.

[0174] In some embodiments, an anti-TREM2 antibody of the present disclosure modulates (i.e., increases or decreases) the expression and / or secretion of one or more inflammatory cytokines (e.g., TNF-α, IL-10, IL-6, MCP-1, IFN-α4, IFN-β, IL-1β, IL-8, CRP, TGF-beta members of the chemokine protein family, IL-20 family members, IL-33, LIF, IFN-gamba, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, and IL-18). In some embodiments, an anti-TREM2 antibody of the present disclosure increases the expression and / or secretion of one or more inflammatory cytokines. In some embodiments, an anti-TREM2 antibody of the present disclosure decreases the expression and / or secretion of one or more inflammatory cytokines. In some embodiments, an anti-TREM2 antibody of the present disclosure modulates (i.e., increases or decreases) the expression and / or secretion of one or more inflammatory receptors (e.g., CD86). In some embodiments, the anti-TREM2 antibodies of the present disclosure increase the expression and / or secretion of one or more inflammatory receptors. In some embodiments, the anti-TREM2 antibodies of the present disclosure decrease the expression and / or secretion of one or more inflammatory receptors.

[0175] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to human TREM2 or homologs thereof, including, but not limited to, mammalian TREM2 proteins, mouse TREM2 protein (Uniprot Accession No. Q99NH8), rat TREM2 protein (Uniprot Accession No. D3ZZ89), rhesus monkey TREM2 protein (Uniprot Accession No. F6QVF2), bovine TREM2 protein (Uniprot Accession No. Q05B59), equine TREM2 protein (Uniprot Accession No. F7D6L0), porcine TREM2 protein (Uniprot Accession No. H2EZZ3), and canine TREM2 protein (Uniprot Accession No. E2RP46). In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to human TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to mouse TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to both human TREM2 and mouse TREM2, hi some embodiments, the anti-TREM2 antibodies of the present disclosure modulate (e.g., induce or inhibit) at least one TREM2 activity.In some embodiments, the at least one TREM2 activity is DAP12 phosphorylation, TREM2 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators (e.g., cytokines), reduced expression of one or more pro-inflammatory mediators, increased survival and / or function of microglial cells, dendritic cells, macrophages, monocytes, osteoclasts, dermal Langerhans cells, and / or Kupffer cells; increased expression of TNF-α, SYK phosphorylation; CD83 on dendritic cells, macrophages, monocytes, and / or macrophages. and / or increased expression of CD86; reduced secretion of one or more inflammatory cytokines; reduced expression of one or more inflammatory receptors; increased phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia under conditions of reduced levels of M-CSF; reduced phagocytosis by macrophages, dendritic cells, monocytes, and / or microglia in the presence of normal levels of M-CSF; and / or increased activity of one or more TREM2-dependent genes (e.g., transcription factors of the nuclear factor of activated T cells (NFAT) family of transcription factors).

[0176] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the TREM2 protein and / or naturally occurring variants of the present disclosure. In certain preferred embodiments, the anti-TREM2 antibodies bind to human TREM2.

[0177] In some embodiments, the anti-TREM2 antibodies of the present disclosure are agonist or antagonist antibodies that bind to a TREM2 protein of the present disclosure expressed on the surface of a cell and modulate (e.g., induce or inhibit) at least one TREM2 activity of the present disclosure after binding to the surface-expressed TREM2 protein. In some embodiments, the anti-TREM2 antibodies of the present disclosure are inactive antibodies.

[0178] In certain embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 29-112 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 29-41 of human TREM2 (SEQ ID NO: 1), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 29-41 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 47-69 of human TREM2 (SEQ ID NO: 1), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 47-69 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 76-86 of human TREM2 (SEQ ID NO: 1), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 76-86 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 91-100 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 91-100 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 99-115 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 99-115 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 104-112 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 104-112 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 114-118 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 114-118 of SEQ ID NO: 1.In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 130-171 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 130-171 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-153 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-153 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 130-144 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 130-144 of SEQ ID NO: 1. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 158-171 of human TREM2 (SEQ ID NO: 1) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 158-171 of SEQ ID NO: 1.

[0179] In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 43-50 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 49-57 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 1. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 140-153 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 140-153 of SEQ ID NO: 1.

[0180] The TREM2 proteins of the present disclosure comprise a complementarity determining region 1 (CDR1) located at amino acid residues corresponding to amino acid residues 40-44 of human TREM2 (SEQ ID NO: 1); a complementarity determining region 2 (CDR2) located at amino acid residues corresponding to amino acid residues 67-76 of human TREM2 (SEQ ID NO: 1); and a complementarity determining region 3 (CDR3) located at amino acid residues corresponding to amino acid residues 114-118 of human TREM2 (SEQ ID NO: 1). Thus, in some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more amino acids within amino acid residues 40-44 of human TREM2 (SEQ ID NO: 1) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 40-44 of SEQ ID NO: 1. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more amino acids within amino acid residues 67-76 of human TREM2 (SEQ ID NO: 1) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 67-76 of SEQ ID NO: 1. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 114-118 of human TREM2 (SEQ ID NO:1) or within amino acid residues on the TREM2 protein corresponding to amino acid residues 114-118 of SEQ ID NO:1.

[0181] In other embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope comprising amino acid residues Arg47 or Asp87 of human TERM2 (SEQ ID NO: 1). In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope comprising amino acid residues 40-44 of human TERM2 (SEQ ID NO: 1). In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope comprising amino acid residues 67-76 of human TERM2 (SEQ ID NO: 1). In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope comprising amino acid residues 114-118 of human TERM2 (SEQ ID NO: 1).

[0182] In some embodiments, an anti-TREM2 antibody of the present disclosure competitively inhibits the binding of at least one antibody selected from any of the antibodies listed in Table 1 and / or Table 8. In some embodiments, the anti-TREM2 antibodies of the disclosure are selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, The antibody competitively inhibits the binding of at least one antibody selected from Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. In some embodiments, an anti-TREM2 antibody of the present disclosure competitively inhibits the binding of at least one of the following anti-TREM2 antibodies: Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope on human TREM2 that is the same as or shares a common TREM2 epitope bound by at least one antibody selected from any of the antibodies listed in Table 1 and / or Table 8.In some embodiments, the anti-TREM2 antibodies of the disclosure are selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, The antibody binds to an epitope on human TREM2 that is the same as or shares a common region with an epitope on TREM2 bound by at least one antibody selected from Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope of human TREM2 that is the same as or shares a common TREM2 epitope bound by at least one of the following anti-TREM2 antibodies: Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to essentially the same TREM2 epitope bound by at least one antibody selected from any of the antibodies listed in Table 1 and / or Table 8.In some embodiments, the anti-TREM2 antibodies of the disclosure are selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47 , Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to essentially the same TREM2 epitope bound by at least one of the following anti-TREM2 antibodies: Ab1, Ab9, Ab14, Ab22, Ab45, and Ab65. Detailed exemplary methods for mapping antibody-binding epitopes are provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ).

[0183] In an exemplary competitive assay, immobilized TREM2 or cells expressing TREM2 (e.g., human or non-human primate) on the cell surface are incubated in a solution containing a labeled primary antibody that binds to TREM2 and an unlabeled secondary antibody being tested for its ability to compete with the primary antibody for binding to TREM2. The secondary antibody may be present in hybridoma supernatant. As a control, immobilized TREM2 or cells expressing TREM2 are incubated in a solution containing the labeled primary antibody but no unlabeled secondary antibody. After incubation under conditions that allow binding of the primary antibody to TREM2, excess unbound antibody is removed and the amount of label associated with immobilized TREM2 or cells expressing TREM2 is measured. If the amount of label associated with immobilized TREM2 or cells expressing TREM2 is substantially reduced in the test sample compared to the control sample, then this indicates that the secondary antibody competes with the primary antibody for binding to TREM2. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0184] In some embodiments, the anti-TREM2 antibody of the disclosure is (a) any one of the antibodies listed in Table 1 and / or Table 8, or selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42 , Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. , HVR-H2, and HVR-H3; and / or (b) a heavy chain variable region comprising at least one, two, or three HVRs selected from Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84,It comprises a light chain variable region comprising at least one, two, or three HVRs selected from HVR-L1, HVR-L2, and HVR-L3 of any one of antibodies selected from Ab85, Ab86, and Ab87. In some embodiments, HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 are as shown in Table 1 and / or Table 8, or Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, Ab87, Ab88, Ab89, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab10, Ab10, Ab11, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab 9, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65 , Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87.

[0185] In some embodiments, the anti-TREM2 antibody of the disclosure is (i) any of the antibodies listed in Table 1 and / or Table 8, or selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44 an HVR-H1 comprising the amino acid sequence of any of the HVR-H1 sequences derived from an antibody selected from Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87;(ii) any of the compounds listed in Table 1 and / or Table 8, or any of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, Ab87, Ab88, Ab89, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab10, Ab105, Ab106, Ab107, Ab108, Ab109, Ab110, Ab111, Ab112, Ab113, Ab114, Ab115, Ab116, Ab117, Ab118, Ab119, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25 an HVR-H2 comprising the amino acid sequence of any of the HVR-H2 sequences derived from an antibody selected from Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87; (iii) any of the compounds listed in Table 1 and / or Table 8, or any of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, an HVR-H3 comprising the amino acid sequence of any of the HVR-H3 sequences derived from an antibody selected from Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87;(iv) any of the compounds listed in Table 1 and / or Table 8, or any of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, HVR-L1 comprising any amino acid sequence of the HVR-L1 sequences derived from an antibody selected from Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. (v) a compound selected from the group consisting of: a ... an HVR-L2 comprising the amino acid sequence of any of the HVR-L2 sequences derived from an antibody selected from Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87;and (vi) any of the antibodies listed in Table 1 and / or Table 8, or any of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab 23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab5 and HVR-L3 comprising the amino acid sequence of any of the HVR-L3 sequences derived from an antibody selected from Ab80, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87;

[0186] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises: (a) HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 to 24, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 3 to 24; (b) HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25 to 49, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 25 to 49; and (c) HVR-L comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 to 119, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 50 to 119. and / or the light chain variable domain comprises one or more of: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 to 137, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 120 to 137; (b) HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 138 to 152, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 138 to 152; and (c) HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 153 to 236, or an amino acid sequence having at least about 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 138 to 152.

[0187] In some embodiments, the anti-TREM2 antibodies of the disclosure are selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, Ab87, Ab88, Ab89, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab10, Ab100, Ab101, Ab102, Ab103, Ab104, Ab105, Ab106, Ab107, Ab108, Ab109, Ab110, Ab111, Ab112, Ab113, Ab114, Ab115, Ab116, Ab117, Ab118, Ab119 2, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. chain variable regions, and / or those described in Table 1 and / or Table 8, or which include Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, Ab87, Ab88, Ab89, Ab90, Ab91, Ab92, Ab93, Ab94, Ab95, Ab96, Ab97, Ab98, Ab99, Ab10, Ab102, Ab103, Ab104, Ab105, Ab106, Ab107, Ab108, Ab109, Ab110, Ab111, Ab112, Ab113, Ab114, Ab115, Ab116, Ab117, Ab118, Ab119, Ab20, Ab21 The antibody comprises any one of the light chain variable regions of antibodies selected from Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87.

[0188] Any of the antibodies of the present disclosure may be produced by a cell line. In some embodiments, the cell line may be a yeast cell line. In other embodiments, the cell line may be a mammalian cell line. In certain embodiments, the cell line may be a hybridoma cell line. Any cell line known in the art that is suitable for antibody production may be used to produce the antibodies of the present disclosure. Exemplary cell lines for antibody production are described throughout this disclosure.

[0189] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, The anti-TREM2 monoclonal antibody is selected from Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody.

[0190] In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab1. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab1. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab1. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab1. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab1. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 3, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 25 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 25, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 50 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 50, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 120. (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 138; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 153.

[0191] In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab9. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab9. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab9. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab9. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab9. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 9, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 33, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 58, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 124. and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 161.

[0192] In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody Ab14. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab14. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of the monoclonal antibody Ab14. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody Ab14. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody Ab14. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 13, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 36, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 63, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 122. and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 166 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 166.

[0193] In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab22. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab22. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab22. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab22. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab22. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 11, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 34, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence having at least about 95% homology to the amino acid sequence of SEQ ID NO: 60, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 123. and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 173.

[0194] In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab45. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab45. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab45. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab45. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab45. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 7, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 29, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 87, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 120. (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 138; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 196 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 196.

[0195] In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab65. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab65. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab65. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab65. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab65. In certain embodiments, the anti-TREM2 antibody is an agonistic antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody. In some embodiments, the anti-TREM2 antibody of the present disclosure is an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 9, (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 34, (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 101, or (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 124. and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 215 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 215.

[0196] In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more amino acids within amino acid residues 43-50 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 1. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more amino acids within amino acid residues 49-57 of human TREM2 (SEQ ID NO: 1), or within amino acid residues on the TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 1. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope comprising one or more amino acid residues within amino acid residues 43-50 of human TERM2 (SEQ ID NO: 1). In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope comprising one or more amino acid residues within amino acid residues 49-57 of human TERM2 (SEQ ID NO: 1). In some embodiments, an anti-TREM2 antibody of the present disclosure competitively inhibits the binding of at least one of the following anti-TREM2 antibodies: Ab21 and Ab52. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope of human TREM2 that is the same as or shares a common TREM2 epitope bound by at least one of the following anti-TREM2 antibodies: Ab21 and Ab52. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises (a) a heavy chain variable region comprising at least one, two, or three HVRs selected from HVR-H1, HVR-H2, and HVR-H3 of any one of antibodies Ab21 and Ab52; and / or (b) a light chain variable region comprising at least one, two, or three HVRs selected from HVR-L1, HVR-L2, and HVR-L3 of any one of antibodies Ab21 and Ab52. In some embodiments, HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprise Kabat CDR, Chothia CDR, or contact CDR sequences as set forth in Table 1 and / or Table 8. In some embodiments, an anti-TREM2 antibody of the disclosure comprises the heavy chain variable region of any one of antibodies Ab21 and Ab52; and / or the light chain variable region of any one of antibodies Ab21 and Ab52.In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonal antibody Ab52 or Ab21. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to essentially the same TREM2 epitope as Ab52 or Ab21. In certain embodiments, the anti-TREM2 antibody is an agonist antibody. In other embodiments, the anti-TREM2 antibody is an antagonist antibody.

[0197] In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 of monoclonal antibody Ab52 or Ab21. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab52 or Ab21. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domains HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domains HVR-L1, HVR-L2, and HVR-L3 of monoclonal antibody Ab52 or Ab21. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise: (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 398; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 399; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 400; (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 400; and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 403.In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise (i) an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 404; (ii) an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 405; (iii) an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406 or an amino acid sequence having at least about 95% identity to the amino acid sequence of SEQ ID NO: 406; (iv) an HVR-H4 comprising the amino acid sequence of SEQ ID NO: 407 or an amino acid sequence having at least about 95% identity to the amino acid se...

Claims

1. 1. An isolated antibody that binds to a TREM2 protein and is a TREM2 antagonist, the isolated antibody binds to an epitope of human TREM2 that is the same TREM2 epitope as a reference anti-TREM2 antibody; the reference anti-TREM2 antibody comprises a heavy chain variable region and a light chain variable region; (a) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 9, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 58, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 124, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 144, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 161; (b) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 166; (c) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 7, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 29, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 87, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 120, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 138, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 196; (d) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403; (e) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409; or (f) the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 173; Isolated antibodies.

2. The isolated antibody of claim 1 , wherein the isolated antibody inhibits one or more TREM2 activities.

3. 3. The isolated antibody of claim 2, wherein the isolated antibody inhibits one or more TREM2 activities when the isolated antibody is not cross-linked or bound to a plate.

4. 4. The isolated antibody of claim 2 or 3, wherein the one or more TREM2 activities inhibited by the isolated antibody include (a) macrophage survival, and / or (b) expression of one or more TREM2-dependent genes.

5. 5. The isolated antibody of claim 4, wherein the isolated antibody inhibits expression of one or more TREM2-dependent genes when the isolated antibody is not cross-linked or bound to a plate.

6. 6. The isolated antibody of claim 4 or 5, wherein the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor.

7. Inhibition of one or more TREM2-dependent gene expression is assessed by a luciferase-based reporter assay to measure expression of TREM2-dependent genes in BW5147.G.1.4 cells expressing mouse TREM2 and DAP12, using a luciferase reporter gene under the control of the nuclear factor of activated T cells (NFAT) transcription factor promoter; 7. The isolated antibody of any one of claims 4 to 6, wherein a decrease in expression of a luciferase reporter gene in the presence of the isolated antibody compared to the level of expression of the luciferase reporter gene in the absence of the isolated antibody indicates inhibition of TREM2-dependent gene expression.

8. 8. The isolated antibody of any one of claims 4 to 7, wherein the isolated antibody inhibits macrophage survival when the isolated antibody is not cross-linked or plate-bound.

9. 9. The isolated antibody of any one of claims 1 to 8, wherein the isolated antibody competes with one or more TREM2 ligands for binding to TREM2.

10. 10. The isolated antibody of claim 9, wherein the one or more TREM2 ligands are selected from the group consisting of a TREM2 ligand expressed in E. coli cells, phosphatidylserine, and sphingomyelin.

11. the isolated antibody amino acid residues 43-50 of SEQ ID NO:1, or amino acid residues in a TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO:1; amino acid residues 49-57 of SEQ ID NO:1, or amino acid residues in a TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO:1; Amino acid residues 139-146 of SEQ ID NO:1, or amino acid residues in a TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO:1; or Amino acid residues 140-153 of SEQ ID NO: 1, or amino acid residues in TREM Protein 2 corresponding to amino acid residues 140-153 of SEQ ID NO: 1 and binding to one or more amino acids within the amino acid residues selected from the group consisting of: An isolated antibody according to any one of claims 1 to 10.

12. the isolated antibody i. has a dissociation constant (Kn) for human TREM2-Fc fusion protein in the range of 0.23 nM to 1.51 nM; and / or ii. has a dissociation constant (Kn) for human monomeric TREM2 protein in the range of 0.66 nM to 6.70 nM; An isolated antibody described in any one of claims 1 to 11.

13. 13. The isolated antibody of any one of claims 1 to 12, which specifically binds to both human TREM2 and mouse TREM2.

14. the isolated antibody comprises a heavy chain variable region and a light chain variable region; (a) the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:9, HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and HVR-H3 comprising the amino acid sequence of SEQ ID NO:58, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO:124, HVR-L2 comprising the amino acid sequence of SEQ ID NO:144, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:161; (b) the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 166; (c) the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:7, HVR-H2 comprising the amino acid sequence of SEQ ID NO:29, and HVR-H3 comprising the amino acid sequence of SEQ ID NO:87, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO:120, HVR-L2 comprising the amino acid sequence of SEQ ID NO:138, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:196; or (d) the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403; 14. An isolated antibody according to any one of claims 1 to 13.

15. the isolated antibody comprises a heavy chain variable region and a light chain variable region; (a) the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:258, or the amino acid sequence of SEQ ID NO:258 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:259, or the amino acid sequence of SEQ ID NO:259 with one or more conservative amino acid substitutions; (b) the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:268, or the amino acid sequence of SEQ ID NO:268 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:269, or the amino acid sequence of SEQ ID NO:269 with one or more conservative amino acid substitutions; (c) the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO: 322, or the amino acid sequence of SEQ ID NO: 322 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO: 323, or the amino acid sequence of SEQ ID NO: 323 with one or more conservative amino acid substitutions; or (d) the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO: 412, or the amino acid sequence of SEQ ID NO: 412 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO: 413, or the amino acid sequence of SEQ ID NO: 413 with one or more conservative amino acid substitutions.

15. An isolated antibody according to any one of claims 1 to 14. (a) the heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:9, HVR-H2 comprising the amino acid sequence of SEQ ID NO:33, and HVR-H3 comprising the amino acid sequence of SEQ ID NO:58, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO:124, HVR-L2 comprising the amino acid sequence of SEQ ID NO:144, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:161; (b) the heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 13, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 36, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 63, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 122, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 166; (c) the heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO:7, HVR-H2 comprising the amino acid sequence of SEQ ID NO:29, and HVR-H3 comprising the amino acid sequence of SEQ ID NO:87, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO:120, HVR-L2 comprising the amino acid sequence of SEQ ID NO:138, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:196; or (d) the heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 398, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 399, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 400, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 401, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 402, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 403; 16. An isolated antibody according to any one of claims 1 to 15.

17. (a) the heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:258, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:259; (b) the heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:268, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:269; (c) the heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO: 322, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO: 323; or (d) the heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO: 412, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:

413.

17. An isolated antibody according to any one of claims 1 to 16.

18. the isolated antibody comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 409; An isolated antibody according to any one of claims 1 to 7 and 9 to 13.

19. the isolated antibody comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:410, or the amino acid sequence of SEQ ID NO:410 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:411, or the amino acid sequence of SEQ ID NO:411 with one or more conservative amino acid substitutions; An isolated antibody according to any one of claims 1 to 7, 9 to 13, and 18.

20. The heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 404, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 405, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 406, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 407, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 408, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:

409.

20. An isolated antibody according to any one of claims 1 to 7, 9 to 13, and 18 to 19.

21. The heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:410, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:

411. The isolated antibody of any one of claims 1 to 7, 9 to 13, and 18 to 20.

22. the isolated antibody comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region of the isolated antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and the light chain variable region of the isolated antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-L3 comprising the amino acid sequence of SEQ ID NO: 173; An isolated antibody according to any one of claims 1 to 3 and 9 to 13.

23. the isolated antibody comprises a heavy chain variable region and a light chain variable region; the heavy chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:262, or the amino acid sequence of SEQ ID NO:262 with one or more conservative amino acid substitutions, and the light chain variable region of the isolated antibody comprises the amino acid sequence of SEQ ID NO:279, or the amino acid sequence of SEQ ID NO:279 with one or more conservative amino acid substitutions; The isolated antibody of any one of claims 1 to 3, 9 to 13, and 22.

24. The heavy chain variable region of the reference anti-TREM2 antibody comprises HVR-H1 comprising the amino acid sequence of SEQ ID NO: 11, HVR-H2 comprising the amino acid sequence of SEQ ID NO: 34, and HVR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and the light chain variable region of the reference anti-TREM2 antibody comprises HVR-L1 comprising the amino acid sequence of SEQ ID NO: 123, HVR-L2 comprising the amino acid sequence of SEQ ID NO: 141, and HVR-L3 comprising the amino acid sequence of SEQ ID NO:

173. An isolated antibody according to any one of claims 1 to 3, 9 to 13, and 22 to 23.

25. The heavy chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:262, and the light chain variable region of the reference anti-TREM2 antibody comprises the amino acid sequence of SEQ ID NO:

279. An isolated antibody according to any one of claims 1 to 3, 9 to 13, and 22 to 24.

26. 26. The isolated antibody of any one of claims 1 to 25, wherein the isolated antibody is of the IgG class, the IgM class, or the IgA class.

27. 27. The isolated antibody of claim 26, wherein the isolated antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

28. 28. The isolated antibody of any one of claims 1 to 27, wherein the isolated antibody is incapable of binding to an Fcγ receptor (FcγR).

29. 29. The isolated antibody of any one of claims 1 to 28, wherein the isolated antibody is unable to induce or maintain clustering of TREM2.

30. i. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C220S, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU numbering; ii. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in an Fc region at residue positions selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C220S, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein residue numbering is according to EU numbering, and the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU numbering; iii. The isolated antibody has a human or mouse IgG1 isotype and is selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C220S, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and the Fc region comprises one or more amino acid substitutions at residue positions selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, wherein residue numbering is according to EU numbering; iv. the isolated antibody has a human or mouse IgG1 isotype and is selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C220S, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof. wherein the Fc region comprises one or more amino acid substitutions at a position selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof, wherein residue numbering is according to EU numbering; v. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of V234A, G237A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering; vi. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering; or vii. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU numbering, and the Fc region further comprises a S228P amino acid substitution according to EU numbering.

30. The isolated antibody of any one of claims 27 to 29.

31. The isolated antibody of claim 30, wherein the Fc region further comprises one or more additional amino acid substitutions at positions selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU numbering.

32. The isolated antibody is an antibody fragment, and the antibody fragment is Fab, Fab', Fab'-SH, F(ab') ２ 32. The isolated antibody of any one of claims 1 to 31, which is an Fv or scFv fragment.

33. 33. The isolated antibody of any one of claims 1 to 32, wherein the isolated antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody.

34. 34. The isolated antibody of any one of claims 1 to 33, which is a monoclonal antibody.

35. The isolated antibody of any one of claims 1 to 34, wherein the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of wild-type human TREM2 and naturally occurring variants of human TREM2, and the antibody fragment is cross-linked to a secondary antibody fragment that binds to one or more human proteins selected from the group consisting of wild-type human TREM2, naturally occurring variants of human TREM2, wild-type human DAP12, and naturally occurring variants of human DAP12.

36. the isolated antibody is a bispecific antibody that recognizes a first antigen and a second antigen; the first antigen is wild-type human TREM2 or a naturally occurring variant thereof; The second antigen is (a) DAP12; (b) amyloid beta or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, or S-IB. a pathogenic protein selected from the group consisting of M protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, and proline-arginine (PR) repeat peptide; or (c) a blood-brain barrier targeting protein selected from the group consisting of transferrin receptor, insulin receptor, insulin-like growth factor receptor, LRP-1, and LRP1.

35. An isolated antibody according to any one of claims 1 to 34.

37. A kit comprising the isolated antibody of any one of claims 1 to 34, the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of wild-type human TREM2 and naturally occurring variants of human TREM2; The kit may comprise amyloid beta or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin G, in combination with one or more antibodies that specifically bind to a pathogenic protein selected from the group consisting of globulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation product, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, and proline-arginine (PR) repeat peptide, and any combination thereof; kit.

38. An isolated nucleic acid encoding the isolated antibody of any one of claims 1 to 36.

39. A vector comprising the nucleic acid of claim 38.

40. 40. An isolated host cell comprising the vector of claim 39.

41. A pharmaceutical composition comprising the isolated antibody of any one of claims 1 to 36 and a pharmaceutically acceptable carrier.

42. 37. A medicament for use in a method of reducing expression of one or more TREM2-dependent genes in an individual in need thereof, comprising the isolated antibody of any one of claims 1 to 36.

43. 38. A medicament for use in a method for reducing innate immune cell survival in an individual in need thereof, comprising the isolated antibody of any one of claims 1 to 36 or the kit of claim 37.

44. 38. A medicament for use in a method for preventing, reducing the risk of, or treating a disease, disorder, or injury, comprising the isolated antibody of any one of claims 1 to 36 or the kit of claim 37.

45. 45. The pharmaceutical of claim 44, wherein the disease, disorder, or injury is cancer.

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