Anti-TREM2 antibodies and methods of use thereof

Abstract

This disclosure generally concerns compositions comprising antibodies that specifically bind to the TREM2 protein, such as mammalian TREM2 or human TREM2, such as monoclonal, chimeric, or humanized antibodies or antibody fragments, and the use of such compositions in preventing, reducing, or treating the risk thereof in an individual in need. [Selection Diagram] Figure 9B

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 238,044, filed October 6, 2015, and U.S. Provisional Patent Application No. 62 / 369,666, filed August 1, 2016, each of which is incorporated by reference herein in its entirety.

[0002] Submitting a sequence listing as an ASCII text file The contents of the following submission, in an ASCII text file, are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 735022000940SEQLISTING.TXT, Recorded: October 6, 2016, Size: 651 KB).

[0003] Field of the Disclosure The present disclosure relates to anti-TREM2 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 of Toll-like receptor (TLR) signaling, inflammatory cytokine regulation, and normal osteoclast development. TREM2 was discovered as a member of the TREM transmembrane glycoprotein family, a single immunoglobulin variable (IgV) domain receptor family. The genes encoding human and mouse TREMs 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. Additionally, TERM3 and plasmacytoid dendritic cell (pDC) TREMs have been identified in mice. The TREM-like genes, TREML1 and TREML2 in humans and Treml1 and Treml2 in mice, encode the TLT-1 and TLT-2 proteins, respectively. TREM1 and TREM2, the two best-characterized members of this receptor family, share approximately 20% sequence identity and some homology with other members of the Ig-SF, such as the activating NK cell receptor (NKp44), and act through cooperation with the DAP12-mediated pathway for signaling.

[0005] TREM2 was originally cloned as a cDNA encoding a TREM1 homolog (Bouchon, A et al., J Exp Med, 2001, 194(8):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) γ 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 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 motif mediates signal propagation through activation of the 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 with 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): p. 1111-22). Human TREM2 was the first DAP12-related 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). This indicates that maximal TREM2 surface expression requires the formation of a TREM2 / DAP12 complex.

[0008] Recent studies have also demonstrated cell surface expression of TREM2 on macrophages infiltrating tissues from the circulation, as well as on macrophages activated by IL-4 or IL-13 (Turnbull, IR et al., J Immunol, 2006, 177(6):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 induced locally during tissue infiltration or by cytokine-mediated activation, rather than centrally. Furthermore, IFN-γ and LPS have been observed to decrease TREM2 expression. Furthermore, it has recently been reported that TREM2 is highly expressed in microglia and infiltrating macrophages in the central nervous system during experimental autoimmune encephalomyelitis or Alzheimer's disease (Picchio, 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 activates the Syk / Zap70 tyrosine kinase family, PI3K, and other intracellular signals. In myeloid cells, TLR signaling is important for activation, such as in response to infection, but also plays a key role in pathological inflammatory responses, such as in 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 shown in the context of stimulation with typical TLR ligands, such as LPS, CpG DNA, and zymosan. TREM-2-deficient dendritic cells exhibit increased release of IL-12p70, TNF, IL-6, and IL-10 in the presence of stimulation, but not in the absence of stimulation.

[0010] Several recent studies have explored 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 associate with such ITAM-containing subunits, linking them via tandem SH2 domains.

[0011] Studies of TREM2 signaling have shown 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):1111-22, and Sharif, O and Knapp, S, Immunobiology, 2008, 213(9-10):701-13). Importantly, TREM2 receptor ligation fails to 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):1111-22). Receptor cross-linking of TREM2 in immature dendritic cells induces upregulation of molecules involved in T cell costimulation, such as CD86, CD40, and MHC class II, as well as upregulation of the chemokine receptor CCR7 (Bouchon, A et al., J Exp Med, 2001. 194(8): p. 1111-22). TREM2 is also expressed on 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. Additionally, overexpression of TREM2 signaling in microglia, myeloid precursors, CHO, or EK293 cells leads to increased phagocytosis of apoptotic neurons, neural and non-neuronal tissue debris, disease-causing proteins, bacteria, and other foreign invaders in the nervous system, which is achieved in an ERK-dependent manner by polarization and reorganization of F-actin (Takahashi, K et al., PLoS Med, 2007.4(4):p.e124; Neumann, H and Takahashi, K, J Neuroimmunol, 2007.184(1-2):p.92-9; and Kleinberg et al., Sci Transl Med. 2014 Jul 2;6(243):243ra86). However, in some physiological situations, such as pneumococcal pneumonia, TREM2 appears to reduce phagocytosis.Accordingly, TREM2-deficient alveolar macrophages exhibit enhanced clearance of bacteria from the lungs and enhanced bacterial phagocytosis in vivo (Sharif et al., PLoS Pathog. 2014 Jun 12;10(6):e1004167).

[0012] Bone marrow-derived macrophages (BMDMs) silenced for TREM2 using shRNAi display have also been shown to exhibit increased secretion of TNF in response to the TLR2 / 6 ligand zymosan and the TLR9 ligand CpG compared to 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): 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). These results have been confirmed using BMDM cells from TREM2 knockout mice, where TNF and IL-6 levels were also significantly increased in response to LPS. - / -Furthermore, the expression of TREM2 in BMDM cells was significantly higher than that in wild-type BMDM cells (Turnbull, IR, et al., J Immunol, 2006, 177(6):3520-4; and Turnbull, IR and Colonna, M, Nat Rev Immunol, 2007, 7(2):155-61). Additionally, overexpression of TREM2 in microglia has been shown to result in decreased TNF and inducible nitric oxide (iNOS) mRNA levels after co-culture 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 appears to be independent of macrophage type, as it occurs in both microglial and BMDM cells.

[0013] It has also been shown that microglial activation can cause inflammation in resident myeloid cells of 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 been implicated in frontotemporal dementia (FTD), Alzheimer's disease, Parkinson's disease, stroke / ischemic brain injury, and multiple sclerosis. Decreased TREM2 activation leads to increased specific activation and inflammatory markers, such as NOS2 gene transcription, in myeloid cells, whereas increased TREM2 activation leads to 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. TREM2 has also been implicated in myeloid cell migration, as TREM2-deficient myeloid cells fail to assemble in the brain of a rodent model for Alzheimer's disease (Malm, TM et al., Neurotherapeutics. 2014 Nov 18).

[0014] In humans, complete absence of TREM2 has been shown to cause Nasu-Hakola disease, a rare neurodegenerative disorder characterized by 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 can also be caused by DAP12 deficiency. Furthermore, exome sequencing of individuals presenting with frontotemporal dementia (FTD) has identified homozygous mutations in TREM2 (Guerreiro, RJ et al., (2013) JAMA Neurol 70:78-84; Guerreiro, RJ et al., (2012) Arch Neurol:1-7). More recently, heterozygous mutations in TREM2 have been found to increase the risk of Alzheimer's disease by up to threefold (Guerreiro, R et al., (2013) N Engl J Med 368:117-127; Jonsson, T et al., (2013) N Engl J Med 368:107-116; and Neumann, H et al., (2013) N Engl J Med 368:182-184). Individuals without Alzheimer's disease who harbor heterozygous TREM2 mutations also exhibit poorer cognition compared with individuals with two normal TREM2 alleles. These carriers also exhibit a doubling of the rate of brain volume shrinkage (Rajagopalan et al., (2013) N Engl J Med 369;16). Some of these mutations result in truncation and possibly loss of function of TREM2. While others involve amino acid changes, including Q33X, R47H, T66M, and S116C (Borroni B, et al. Neurobiol Aging. 2014 Apr;35(4):934.e7-10). Imaging analysis of certain individuals with homozygous TREM2 mutations has also shown evidence of demyelination. Furthermore, the most common TREM2 mutation, the TREM2 R47H variant (an arginine to histidine amino acid substitution at position 47 of TREM2), is located within the immunoglobulin domain of TREM2 and has been shown to reduce ligand binding.Other TREM2 mutations have been shown to reduce cell surface expression of TREM2, indicating that this loss of function contributes to an increased risk of AD (Wang Y, Cell. 2015;160(6):1061-71).

[0015] In addition, an integrative network-based approach to rank-ordered organization of molecular networks of gene expression associated with late-onset Alzheimer's disease (LOAD) identified TYROBP / DAP12, a signaling molecule for TREM2, as a key regulator of the immune / microglial gene module associated with LOAD. When rank-ordered based on the number of other genes regulated by TREM2, the magnitude of their deregulation, and their differential expression in LOAD brains, TYROBP was found to be the highest-scoring causal regulator of the immune / microglial module. 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, and Ma et al., Mol Neurobiol. 2014 Jul 23). Targeting such causal networks to restore normality may be one way to treat the disease.

[0016] TREM2 is highly expressed on microglia and infiltrating macrophages in the central nervous system during pathological conditions, including Alzheimer's disease (Picchio, L et al., (2007) Eur J Immunol, 37(5):p.1290-301; and Wang et al., (2015) Cell.;160(6):1061-71). TREM2 gene expression has also been shown to be increased in APP23 transgenic mice, an Alzheimer's disease model that expresses a mutant form of 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.

[0017] 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 beads or neuronal fragments. In response to LPS, these cells show increased IL-10 and decreased IL-1β. Intravenous transplantation of TREM2-overexpressing myeloid cells can suppress EAE in vivo. Conversely, TREM2 deficiency has been shown to exacerbate multiple sclerosis in the Cuprizon model of the disease (Cantoni et al., Acta Neuropathol (2015) 129(3):429-47; Luigi Poliani et al., (2015) J Clin Invest. 125(5):2161-2170). TREM2 deficiency has also been shown to exacerbate Alzheimer's disease in rodent models (Wang et al., (2015) Cell.; 160(6):1061-71), although data showing a beneficial effect of TREM2 deficiency on Alzheimer's disease in rodent models have also been reported (Jay et al., (2015) J Exp Med 212:287-295). TREM2 has also been shown to be required for microglial survival in the brain (Otero et al., (2009) Nat Immunol.;10:734-43). Collectively, TREM2 variants have been identified as genetic risk factors for frontotemporal dementia, Parkinson's disease, and amyotrophic lateral sclerosis (Borroni B, et al. Neurobiol Aging. 2014 Apr;35(4):934.e7-10; Rayaprolu S, et al., Mol Neurodegener. 2013 Jun 21;8:19; and Cady J, et al., JAMA Neurol. 2014 Apr;71(4):449-53).This common genetic linkage suggests a more general role for TREM2 in regulating neurodegenerative disease pathology.

[0018] Although TREM2 antibodies have been described, their only reported effect is on cultured cells, limiting their therapeutic utility in part because they block the interaction between TREM2 and its natural ligand and act as antagonists in solution. Such antibodies in solution would mimic the pathogenic loss-of-function phenotype of TREM2 mutations and therefore present safety and efficacy risks. Another problem with existing anti-TREM2 antibodies is that they require clustering by coating on plastic plates or with a secondary antibody to induce agonist activity. Therefore, there is a need for antibodies that specifically bind to TREM2 on the cell surface and safely and effectively modulate (e.g., activate) one or more TREM2 activities to treat one or more diseases, disorders, and conditions associated with decreased TREM2 activity.

[0019] Some diseases may require TREM2-blocking antibodies that do not activate TREM2 under all circumstances. For example, the tumor microenvironment is composed of a heterogeneous immune infiltrate, which includes T lymphocytes, macrophages, and myeloid / granulocytic cells. Therapeutic approaches that modulate specific subsets of immune cells are changing the standard of care. "Checkpoint blockade" antibodies that target immune modulator molecules expressed on T cells (such as CTLA-4 and PD-1) have demonstrated clinical activity across a variety of tumor types (Naidoo et al., (2014) British Journal of Cancer 111, 2214-2219).

[0020] 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.

[0021] Therefore, there is also a need for antibodies that specifically bind to TREM2 on the cell surface and modulate (e.g., inhibit and / or otherwise decrease) ligand binding and / or one or more TREM2 activities to prevent, reduce the risk of, or treat cancer.

[0022] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the Invention

[0023] The present disclosure is generally directed to compositions comprising antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind to a TREM2 protein, e.g., mammalian TREM2 (e.g., any non-human mammal) or human TREM2, and methods of using such compositions. The antibodies of the present disclosure may include agonist, antagonist, and / or inactive antibodies.The methods provided herein include treatment of dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy, disease), Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, age-related illnesses, stroke, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteoporosis Osteopathies, Paget's disease of bone, solid and hematological cancers, 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, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow derived tumors, tumors expressing TREM2 and / or TREM2 ligands, thyroid cancer, infectious diseases, CNS herpes, parasitic infections, Trypanosoma brucei infection, Pseudomonas The methods provided herein are useful in preventing, reducing the risk of, or treating individuals with: aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type 1, and Haemophilus influenzae. The methods provided herein are also useful in inducing or promoting the survival, maturation, function, migration, or proliferation of one or more immune cells in an individual in need thereof.The methods provided herein are further used to decrease the activity, function, or survival of regulatory T cells, tumor-buried immunosuppressive dendritic cells, tumor-buried immunosuppressive macrophages, neutrophils, natural killer (NK) cells, myeloid-derived suppressor cells, tumor-associated macrophages, neutrophils, NK cells, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells, or chronic myeloid leukemia (CML) cells in an individual in need thereof.

[0024] In some embodiments, tumor cells, such as acute myeloblastic leukemia (AML) cells, express TREM2. Accordingly, the anti-TREM2 antibodies of the present disclosure are also used to treat cancer. In some embodiments, anti-TREM2 antibodies and / or TREM2 antibody-drug conjugates, including antibodies that exhibit antibody-dependent cell-mediated cytotoxicity (ADCC), can be used to target and inhibit cancers, such as AML.

[0025] Certain aspects of the present disclosure are based, at least in part, on the identification of two distinct classes of isolated antibodies that specifically bind to and modulate TREM2 protein.

[0026] One class of antibodies relates to agonistic antibodies that induce one or more TREM2 activities, for example, in human primary immune cells and TREM2-expressing cell lines, and that, when combined with one or more TREM2 ligands, enhance one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein. Advantageously, such agonistic anti-TREM2 antibodies can enhance ligand-induced TREM2 activity without competing with our otherwise blocking binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, agonistic antibodies can activate and / or enhance one or more TREM2 activities regardless of whether the antibody is clustered or in solution. In some embodiments, agonistic antibodies can activate TREM2 in solution without the need for clustering by a secondary antibody, an Fc receptor, or binding to a plate. In some embodiments, agonistic antibodies can activate TREM2 regardless of whether mechanisms for clustering the antibody exist at the site of therapeutic effect in vivo. In some embodiments, agonistic antibodies may have improved safety and efficacy. In some embodiments, agonistic antibodies may ensure that TREM2-expressing immune cells can act primarily in the locations where they are needed for therapeutic efficacy and interact with their physiological targets. In some embodiments, agonistic antibodies do not block TREM2 activity, resulting in an increased disease risk similar to that observed with genetic mutations that reduce TREM2 activity.

[0027] A second class of antibodies relates to antagonist antibodies that specifically bind to and inhibit TREM2 and are unable to activate TREM2, regardless of whether the antibody is clustered or in solution. In some embodiments, antagonist antibodies have high safety and efficacy. In some embodiments, antagonist antibodies are unable to activate TREM2, regardless of their location or their ability to cluster.

[0028] Accordingly, certain aspects of the present disclosure relate to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, induces one or more TREM2 activities, and enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein compared to one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein in the absence of the isolated antibody. In some embodiments, the antibody enhances one or more TREM2 activities without blocking binding of the one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody does not compete with one or more TREM2 ligands for binding to the TREM2 protein. In some embodiments, the antibody enhances binding of one or more TREM2 ligands to the TREM2 protein.

[0029] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein and induces one or more TREM2 activities without blocking the binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody does not compete with one or more TREM2 ligands for binding to the TREM2 protein. In some embodiments, the antibody enhances the binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein compared to one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein in the absence of the isolated antibody.

[0030] In some embodiments that may be combined with any of the preceding embodiments, the antibody synergizes with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments that may be combined with any of the preceding embodiments, the antibody synergizes with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities in the absence of cell surface clustering of TREM2. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities by inducing or maintaining cell surface clustering of TREM2. In some embodiments that may be combined with any of the preceding embodiments, the antibody is clustered by Fc-gamma receptors expressed on one or more immune cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more immune cells are B cells or microglial cells. In some embodiments that may be combined with any of the preceding embodiments, the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein is measured in primary cells selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells, or in a cell line, and the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein is measured using an in vitro cell assay. In some embodiments that may be combined with any of the preceding embodiments, the antibody increases the level of soluble TREM2, increases the half-life of soluble TREM2, or both. In some embodiments that may be combined with any of the preceding embodiments, the level of soluble TREM2 is selected from the group consisting of serum levels of TREM2, cerebrospinal fluid (CSF) levels of TREM2, tissue levels of TREM2, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibodyIt does not bind to soluble TREM2. In some embodiments that may be combined with any of the preceding embodiments, the antibody does not bind to soluble TREM2 in vivo. In some embodiments that may be combined with any of the preceding embodiments, the soluble TREM2 corresponds to amino acid residues selected from the group consisting of amino acid residues 19-160 of SEQ ID NO:1, amino acid residues 19-159 of SEQ ID NO:1, amino acid residues 19-158 of SEQ ID NO:1, amino acid residues 19-157 of SEQ ID NO:1, amino acid residues 19-156 of SEQ ID NO:1, amino acid residues 19-155 of SEQ ID NO:1, and amino acid residues 19-154 of SEQ ID NO:1. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces the level of TREM2 in one or more cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces cell surface levels of TREM2, reduces intracellular levels of TREM2, reduces total levels of TREM2, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibody induces TREM2 degradation, TREM2 cleavage, TREM2 internalization, TREM2 shedding, downregulation of TREM2 expression, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the level of TREM2 in one or more cells is measured in a primary cell or cell line selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells, and the cellular level of TREM2 is measured using an in vitro cell assay. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is mammalian, e.g., a non-human mammalian protein, or a human protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a wild-type protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a naturally occurring variant. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is expressed in human dendritic cells, human macrophages, human monocytes, human osteoclasts,In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) TREM2 phosphorylation, (c) DAP12 phosphorylation, (d) activation of one or more tyrosine kinases (optionally, the one or more tyrosine kinases include Syk kinase, ZAP70 kinase, or both), (e) activation of phosphatidylinositol 3-kinase (PI3K), (f) activation of protein kinase B (Akt), (g) activation of phosphoinositide (PI3K), (h) activation of phosphoinositide (PI3K), (i) activation of phosphoinositide (PI3K), (j) activation of phosphoinositide (PI3K), (j) activation of phosphoinositide (PI3K), (k ... (g) recruitment of phospholipase C-gamma (PLC-gamma) to the cell plasma membrane, activation of PLC-gamma, or both; (h) recruitment of the TEC-family kinase dVav to the cell plasma membrane; (i) activation of nuclear factor-rB (NF-rB); (j) inhibition of MAPK signaling; (k) phosphorylation of linker for activating T cells (LAT), linker for activating B cells (LAB), or both; (l) activation of IL-2-inducible tyrosine kinase (Itk); (m) induction of IFN-β, IL-1α, and IL-1α. modulation of one or more pro-inflammatory mediators selected from the group consisting of: IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, modulation is indicative of a reduction in macrophage activity, M1 macrophages, activation of (n) modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation is(o) modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR); (p) phosphorylation of extracellular signal-regulated kinase (ERK); (q) modulation of one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells; ... (r) modulation of CC chemokine receptor 7 (CCR7) expression in one or more cells selected from the group consisting of phages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, and any combination thereof; (s) induction of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; (t) normalization of disrupted TREM2 / DAP12-dependent gene expression; (t) interfering with the DAP12 / TREM2 complex by Syk, ZAP70, or (u) increased activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); (v) increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof; (w) increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 macrophages, and M2 macrophages that stimulate or modulate T cell function. (x) increasing the ability of M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof (optionally, the T cells are one or more cells selected from the group consisting of CD8+ T cells, CD4+ T cells, regulatory T cells, and any combination thereof); (x) enhancing the ability of bone marrow-derived dendritic cells to stimulate or regulate the function of antigen-specific T cells, normalizing the ability of bone marrow-derived dendritic cells, or both (optionally, the antigen-specific T cells are CD8+ T cells, CD4+ T cells, regulatory T cells,and any combination thereof), (y) enhancing the ability of bone marrow-derived dendritic cells to induce antigen-specific T cell proliferation, normalizing the ability thereof, or both; (z) inducing osteoclast production, increasing the rate of osteoclast formation, or both; (aa) increasing the survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (bb) increasing the survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof. (cc) increasing the function of a combination; (cc) increasing phagocytosis by dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (dd) inducing one or more types of clearance selected from the group consisting of clearance of apoptotic neurons, clearance of neural tissue debris, clearance of non-neural tissue debris, clearance of bacteria or other foreign bodies, clearance of pathogens, clearance of tumor cells, or any combination thereof (optionally, the pathogen 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, and glycine-alanine (GA), glycine-proline (GP), glycine-arginine (G) (e) inducing phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogens, tumor cells, or any combination thereof (optionally, the pathogen 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, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, ketone ... (ff) modulation of expression of one or more stimulatory molecules selected from the group consisting of CD83, CD86 MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells); (gg) IFN-β;one or more selected from the group consisting of IL-1α, IL-1β, CD86, TNF-α, IL-6, IL-8, CRP, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (hh) modulation of secretion of pro-inflammatory mediators (optionally, the modulation occurs in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells); (hh) modulation of secretion of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation occurs in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells). ), (ii) modulation of expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2.CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, and VEGF, (jj) increased memory, and (kk) reduced cognitive impairment. In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) DAP12 phosphorylation, (c) activation of Syk kinase, (d) IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3,modulation of one or more pro-inflammatory mediators selected from the group consisting of IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, the modulation occurs in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells); (e) recruitment of Syk to the DAP12 / TREM2 complex; (f) increasing the activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); (g) increasing survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (h) modulating the expression of one or more stimulatory molecules selected from the group consisting of CD83, CD86 MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells); (i) increasing memory; and (j) reducing cognitive impairment. In some 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 some 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 some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In some embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments that may be combined with any of the preceding embodiments, the antibody isIn some embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In some embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments that may be combined with any of the preceding embodiments, (a) the isolated antibody has a human or mouse IgG1 isotype and has one or more amino acid substitutions in the Fc region, including N297A, D265A, D270A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L32 (b) the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, wherein optionally 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: 886), and optionally the antibody Fc region comprises (c) the isolated antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof (residue numbering is according to EU numbering); (d) the isolated antibody has a human or murine IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof (residue numbering is according to EU numbering); or (e) the isolated antibody has a hybrid IgG2 / 4 isotype, and optionally the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4 (residue numbering according to EU numbering). In some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG4 isotype. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a S228P amino acid substitution at residue position 228, a F234A amino acid substitution at residue position 234, and a L235A amino acid substitution at residue position 235 (residue positions numbered according to EU numbering).

[0031] In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to one or more amino acids within the amino acid residues selected from the group consisting of: (i) amino acid residues 19-174 of SEQ ID NO:1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 19-174 of SEQ ID NO:1; (ii) 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; (iii) amino acid residues 113-174 of SEQ ID NO:1; (iv) amino acid residues on the TREM2 protein corresponding to amino acid residues 113 to 174 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 35 to 49 of SEQ ID NO: 1, (v) amino acid residues 35 to 49 and 140 to 150 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 35 to 49 and 140 to 150 of SEQ ID NO: 1, (vi) amino acid residues 39 to 49 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 39 to 49 of SEQ ID NO: 1 (vii) amino acid residues 39 to 49 and 63 to 77 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 39 to 49 and 63 to 77 of SEQ ID NO: 1; (viii) amino acid residues 51 to 61 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 51 to 61 of SEQ ID NO: 1; (ix) amino acid residues 55 to 62 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 62 of SEQ ID NO: 1; (x) amino acid residues 55 to 62, 104 and 114 of SEQ ID NO: 1 (xi) amino acid residues on a TREM2 protein corresponding to amino acid residues 55 to 62, 104 to 109, and 160 to 166 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 55 to 62, 104 to 109, and 160 to 166 of SEQ ID NO: 1; (xii) amino acid residues 55 to 65 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 55 to 65 of SEQ ID NO: 1;(xiii) amino acid residues 55 to 65 and 124 to 134 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 65 and 124 to 134 of SEQ ID NO: 1; (xiv) amino acid residues 63 to 73 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 63 to 73 of SEQ ID NO: 1; (xv) amino acid residues 63 to 77 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 63 to 77 of SEQ ID NO: 1; (xvi) amino acid residues 104 to 106 of SEQ ID NO: 1 (xvii) amino acid residues 117 to 133 of SEQ ID NO: 1 or amino acid residues on a TREM2 protein corresponding to amino acid residues 117 to 133 of SEQ ID NO: 1; (xviii) amino acid residues 124 to 134 of SEQ ID NO: 1 or amino acid residues on a TREM2 protein corresponding to amino acid residues 124 to 134 of SEQ ID NO: 1; (xix) amino acid residues 137 to 146 of SEQ ID NO: 1 or amino acid residues 137 to 146 of SEQ ID NO: 1. (xx) amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 147 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 147 of SEQ ID NO: 1; (xxi) amino acid residues 139 to 149 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 149 of SEQ ID NO: 1; (xxii) amino acid residues 140 to 150 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 150 of SEQ ID NO: 1; xxiii) amino acid residues 140 to 146 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 146 of SEQ ID NO: 1; (xxiv) amino acid residues 140 to 143 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 143 of SEQ ID NO: 1; (xxv) amino acid residues 142 to 152 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 142 to 152 of SEQ ID NO: 1; (xxvi) amino acid residues 146 to 154 of SEQ ID NO: 1;or amino acid residues on a TREM2 protein corresponding to amino acid residues 146 to 154 of SEQ ID NO: 1; (xxvii) amino acid residues 148 to 158 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 148 to 158 of SEQ ID NO: 1; (xxviii) amino acid residues 149 to 157 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 149 to 157 of SEQ ID NO: 1; (xxix) amino acid residues 149 and 150 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 149 and 150 of SEQ ID NO: 1; (xxx) amino acid residues 151 to 155 of SEQ ID NO: 1, or amino acid residues 151 to 155 of SEQ ID NO: 1. (xxxi) amino acid residues 154 to 161 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 154 to 161 of SEQ ID NO: 1; (xxxii) amino acid residues 156 to 170 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 156 to 170 of SEQ ID NO: 1; (xxxiii) amino acid residues 160 to 166 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 160 to 166 of SEQ ID NO: 1; and (xxxiv) amino acid residues 162 to 165 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 162 to 165 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to one or more amino acid residues selected from the group consisting of K42, H43, W44, G45, H67, R77, T88, H114, E117, E151, D152, H154, and E156 of SEQ ID NO: 1, or one or more amino acid residues on a mammalian TREM2 protein that correspond to amino acid residues selected from the group consisting of K42, H43, W44, G45, H67, R77, T88, H114, E117, E151, D152, H154, and E156 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to one or more amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO: 1, or E151, D152,In some embodiments that may be combined with any of the preceding embodiments, the antibody competes for binding to TREM2 with one or more antibodies selected from the group consisting of: 3B10, 7B3, 8F8, 9F5, 9G1, 9G3, 11A8, 12F9, 7E9, 7F6, 8C3, 2C5, 3C5, 4C12, 7D9, 2F6, 3A7, 7E5, 11H5, 1B4, 6H2, 7B11, 18D8, 18E4, 29F6, 40D5, 43B9, 44A8, 44B4, and any combination thereof.

[0032] In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain, or the heavy chain variable domain, or both, is selected from the group consisting of 4D11, 7C5, 6G12, 8F11, 8E10, 7E5, 7F8, 8F8, 1H7, 2H8, 3A2, 3A7, 3B10, 4F11, 6H6, 7A9, 7B3, 8A1, 9F5, 9G1, 9G3, 10A9, 11A8, 12D9, 12F9, 10C1, 7E9, 7F6, 8C3, 2C5, It comprises at least one, two, three, four, five, or six HVRs selected from HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3 of an antibody selected from the group consisting of 3C5, 4C12, 7D9, 2F6, 11H5, B4, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2. In some embodiments that may be combined with any of the preceding embodiments, (a) HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, 581, 690-694, 734-738, and 826-828; (b) HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-33, 695-697, and 739-743; and (c) HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-47, 582, 583, 698-702, and 744-746. (d) HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 48-65, 584, 703-705, 747-754, and 829-835, (e) HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66-84, 585-587, 706-708, 755-762, 836-842, and 888, or (f) HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 85-102, 588, 589, 709, 710, and 763-770. In some embodiments that may be combined with any of the preceding embodiments, (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, and HVR-L3 comprises(b) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 39, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 53, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 71, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 90; (c) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 36, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 51, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 69, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 88; (d) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, and HVR-H1 comprises the amino acid sequence (e) HVR-H1 comprises the amino acid sequence of SEQ ID NO: 58, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 76, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 95; (f) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 60. wherein HVR-H2 comprises the amino acid sequence of SEQ ID NO: 78, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 97; (g) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 44, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 61, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 79, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 98; (h) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 21, and HVR-L2 comprises(i) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 22, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 46, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 63, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 45, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 62, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 80, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 99; wherein HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 65, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 84, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 102; or (j) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35 In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises: (a) HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, 581, 690 to 694, 734 to 738, and 826 to 828, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, 581, 690 to 694, 734 to 738, and 826 to 828; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 33, 695 to 697, and 739 to 743, or a sequence and (c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746, wherein the heavy chain variable domain comprises (a) SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754,and 829 to 835, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 708, 755 to 762, 836 to 842, and 888, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 708, 755 to 762, 836 to 842, and 888; and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 219-398, 602-634, 679-689, 724-730, 809-816, 821, 843, 844, 849, and 850, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 399-580, 635-678, 731-733, and 817-820, 822-825, and 845-847. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein: (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 333, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521; (b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 850, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521; (c) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522; (d) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 335, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 523; (e) the light chain variable domain comprises(f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 336, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 524; (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 337, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 525; (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 338, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526; (h) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 339, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526; (i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 340, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 527; (j) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 341, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 528; (k) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 342. (l) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 343 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 530; (m) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 843 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 845; (n) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 846; (o) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 847; (p) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 219 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 399; (q) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 230; and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 409, (r) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 252 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 419, (s) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 241 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429, (t) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 849 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429, (u) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 263 and the heavy chain (v) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 274 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 449; (w) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 285 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 459; (x) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 286 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 460; (y) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 287 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 460; (z) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 298 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429; (aa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 299 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 471; (bb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 310 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 461; (cc) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 679 and the heavy chain variable domain , comprising the amino acid sequence of SEQ ID NO: 481, (dd) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 311 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 491, (ee) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 322 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 511, (ff) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 344 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 531, (gg) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 355 and the heavy chain variable domain comprises(hh) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 365 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 541; (ii) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 376 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 551; (jj) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 387 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 561; (kk) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 398 and the heavy chain variable domain comprises (ll) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 724 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (mm) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 809 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (nn) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 725 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 732; (oo) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises (pp) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 817; (qq) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 727 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (rr) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 728 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (ss) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 810 and the heavy chain variable domain comprises (tt) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 811 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (uu) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 729 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (vv) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 812 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 819; (ww) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 729 and the heavy chain variable domain comprises(xx) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 730 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (yy) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 813 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (zz) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 814 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 822; (aaa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 815 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 824; or (bbb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 816 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 825. In some embodiments that may be combined with any of the preceding embodiments, the antibody is selected from the group consisting of 3B10, 7B3, 8F8, 9F5, 9G1, 9G3, 11A8, 12F9, 7E9, 7F6, 8C3, 2C5, 3C5, 4C12, 7D9, 2F6, 3A7, 7E5, 11H5, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2. and / or a heavy chain variable domain of an antibody selected from the group consisting of 3B10, 7B3, 8F8, 9F5, 9G1, 9G3, 11A8, 12F9, 7E9, 7F6, 8C3, 2C5, 3C5, 4C12, 7D9, 2F6, 3A7, 77E5, 11H5, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2. In some embodiments that may be combined with any of the preceding embodiments, the anti-TREM2 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3; and the heavy chain variable domain comprises HVR-H1, HVR-H2, and HVR-H3, wherein HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 85-102, 588, 589, 709, 710, and 763-770, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 85-102, 588, 589, 709, 710, and 763-770.

[0033] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, wherein the antibody binds to one or more amino acids within the amino acid residues selected from the group consisting of: (i) amino acid residues 19-174 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 19-174 of SEQ ID NO: 1; (ii) 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; (iii) amino acid residues 113-114 of SEQ ID NO: 1; (iv) amino acid residues 35 to 49 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 35 to 49 of SEQ ID NO: 1; (v) amino acid residues 35 to 49 and 140 to 150 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 35 to 49 and 140 to 150 of SEQ ID NO: 1; (vi) amino acid residues 39 to 49 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 39 to 49 of SEQ ID NO: 1. (vii) amino acid residues 39 to 49 and 63 to 77 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 39 to 49 and 63 to 77 of SEQ ID NO: 1; (viii) amino acid residues 51 to 61 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 51 to 61 of SEQ ID NO: 1; (ix) amino acid residues 55 to 62 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 62 of SEQ ID NO: 1; (x) amino acid residues 55 to 62 of SEQ ID NO: 1 , 104 to 109, and 148 to 158, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 62, 104 to 109, and 148 to 158 of SEQ ID NO: 1; (xi) amino acid residues 55 to 62, 104 to 109, and 160 to 166 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 62, 104 to 109, and 160 to 166 of SEQ ID NO: 1; (xii) amino acid residues 55 to 65 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 65 of SEQ ID NO: 1;(xiii) amino acid residues 55 to 65 and 124 to 134 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 55 to 65 and 124 to 134 of SEQ ID NO: 1; (xiv) amino acid residues 63 to 73 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 63 to 73 of SEQ ID NO: 1; (xv) amino acid residues 63 to 77 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 63 to 77 of SEQ ID NO: 1; (xvi) amino acid residues 104 to 106 of SEQ ID NO: 1 (xvii) amino acid residues 117 to 133 of SEQ ID NO: 1 or amino acid residues on a TREM2 protein corresponding to amino acid residues 117 to 133 of SEQ ID NO: 1; (xviii) amino acid residues 124 to 134 of SEQ ID NO: 1 or amino acid residues on a TREM2 protein corresponding to amino acid residues 124 to 134 of SEQ ID NO: 1; (xix) amino acid residues 137 to 146 of SEQ ID NO: 1 or amino acid residues 137 to 146 of SEQ ID NO: 1. (xx) amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 147 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 147 of SEQ ID NO: 1; (xxi) amino acid residues 139 to 149 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 139 to 149 of SEQ ID NO: 1; (xxii) amino acid residues 140 to 150 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 150 of SEQ ID NO: 1; xxiii) amino acid residues 140 to 146 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 146 of SEQ ID NO: 1; (xxiv) amino acid residues 140 to 143 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 140 to 143 of SEQ ID NO: 1; (xxv) amino acid residues 142 to 152 of SEQ ID NO: 1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 142 to 152 of SEQ ID NO: 1; (xxvi) amino acid residues 146 to 154 of SEQ ID NO: 1;or amino acid residues on a TREM2 protein corresponding to amino acid residues 146 to 154 of SEQ ID NO: 1; (xxvii) amino acid residues 148 to 158 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 148 to 158 of SEQ ID NO: 1; (xxviii) amino acid residues 149 to 157 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 149 to 157 of SEQ ID NO: 1; (xxix) amino acid residues 149 and 150 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 149 and 150 of SEQ ID NO: 1; (xxx) amino acid residues 151 to 155 of SEQ ID NO: 1, or amino acid residues 151 to 155 of SEQ ID NO: 1. (xxxi) amino acid residues 154 to 161 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 154 to 161 of SEQ ID NO: 1, (xxxii) amino acid residues 156 to 170 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 156 to 170 of SEQ ID NO: 1, (xxxiii) amino acid residues 160 to 166 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 160 to 166 of SEQ ID NO: 1, and (xxxiv) amino acid residues 162 to 165 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 162 to 165 of SEQ ID NO: 1. In some embodiments, the antibody induces one or more TREM2 activities and enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody further binds to 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.

[0034] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, wherein the antibody binds to one or more amino acid residues selected from the group consisting of K42, H43, W44, G45, H67, R77, T88, H114, E117, E151, D152, H154, and E156 of SEQ ID NO:1, or one or more amino acid residues on a mammalian TREM2 protein that correspond to the amino acid residues selected from the group consisting of K42, H43, W44, G45, H67, R77, T88, H114, E117, E151, D152, H154, and E156 of SEQ ID NO:1. In some embodiments, the antibody binds to one or more amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO: 1, or to one or more amino acid residues on a mammalian TREM2 protein that correspond to amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO: 1. Another aspect of the disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, wherein the antibody binds to one or more amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO: 1, or to one or more amino acid residues on a mammalian TREM2 protein that correspond to amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO: 1.

[0035] Another aspect of the disclosure is an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, and which is selected from the group consisting of: 1A7, 3A2, 3B10, 6G12, 6H6, 7A9, 7B3, 8A1, 8E10, 8F11, 8F8, 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, 4D7, 4D11, 6C11, 6G12, 7A3, 7C5, 7E9, 7F6, 7G1, 7H1, 8C3, 8F10, 12A1, 1E9, 2C5, 3C5, 4C12, 4F2, 5A2, 6B3, 7D1, 7D9, 11D8, 8A1 2, 10E7, 10B11, 10D2, 7D5, 2A7, 3G12, 6H9, 8G9, 9B4, 10A1, 11A8, 12F3, 2F8, 10E3, 1H7, 2F6, 2H8, 3A7, 7E5, 7F8, 11H5, 7C5, 4F11, 12D9, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, 44B4v2, and any combination thereof.

[0036] Another aspect of the present disclosure is an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain, or the heavy chain variable domain, or both, are selected from the group consisting of 1A7, 3A2, 3B10, 6G12, 6H6, 7A9, 7B3, 8A1, 8E10, 8F11, 8F8, 9F5, 9G1 , 9G3, 10A9, 10C1, 11A8, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, 4D7, 4D11, 6C11, 6G12, 7A3, 7C5, 7E9, 7 F6, 7G1, 7H1, 8C3, 8F10, 12A1, 1E9, 2C5, 3C5, 4C12, 4F2, 5A2, 6B3, 7D1, 7D9, 11D8, 8A12, 10E7, 10 B11, 10D2, 7D5, 2A7, 3G12, 6H9, 8G9, 9B4, 10A1, 11A8, 12F3, 2F8, 10E3, 1H7, 2F6, 2H8, 3A7, 7E5, 7 F8, 11H5, 7C5, 4F11, 12D9, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 2 The present invention relates to an antibody comprising at least one, two, three, four, five, or six HVRs selected from HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3 of an antibody selected from the group consisting of 9F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2. In some embodiments, (a) HVR-L1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, 581, 690 to 694, 734 to 738, and 826 to 828; (b) HVR-L2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 33, 695 to 697, and 739 to 743; and (c) HVR-L3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and (d) HVR-H1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835; (e) HVR-H2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 708, 755 to 762, 836 to 842, and 888;or (f) HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 85-102, 588, 589, 709, 710, and 763-770. In some embodiments, (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 9, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 24, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 34, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 48, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 66, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 85; wherein HVR-H1 comprises the amino acid sequence of SEQ ID NO: 48, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 66, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 85; (c) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 25, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, wherein HVR-H1 comprises the amino acid sequence of SEQ ID NO: 49, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 67, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: (d) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 12, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 37, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 50, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 68, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 87; (e) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: (f) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 38, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 52, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 70, and HVR-H3 comprises(g) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 39, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 53, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 71, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 90; (h) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 38; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 52, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 70, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 89; (i) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 13, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 27, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 38; HVR-H1 comprises the amino acid sequence of SEQ ID NO: 52, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 70, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 89; (j) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15 (k) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 36, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 51, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 91; (l) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 55, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 73, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 92; (m) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15 and HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28;HVR-L3 comprises the amino acid sequence of SEQ ID NO: 40, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 54, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 72, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 91; (n) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 581, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 582, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 56, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 74, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 93 (o) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 17, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 30, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 41, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 57, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 75, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 94; (p) HVR-H1 comprises the amino acid sequence of SEQ ID NO: 58, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 76, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 95; (q) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 18, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 31, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 42, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 59, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 77, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 96; (r) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 60 HVR-H2 comprises the amino acid sequence of SEQ ID NO: 78, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 97; (s) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 20, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 44, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 61, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 79, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 98; (t) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 21, and HVR-L2 comprises(u) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 15, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 33, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 40, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 54, and HVR-H2 comprises the amino acid sequence of SEQ ID NO: 99; , and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 91; (v) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 22, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 46, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 63, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 82, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 100; (w) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 23; (x) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 47, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 64, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 83, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 101; (x) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 65, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 84, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 102; (y) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 581, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 582, and HVR-H1 comprises the amino acid sequence of SEQ ID NO: 56. (z) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 10, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, and HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 49, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 586, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 86, or (aa) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 14, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 583, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 584, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 587, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 589. In some embodiments, the light chain variable domain comprises (a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, 581, 690 to 694, 734 to 738, and 826 to 828, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 to 23, 581, 690 to 694, 734 to 738, and 826 to 828; (b) an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 33, 695 to 697, and 739 to 743, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24 to 33,and (c) an HVR-L3 comprising an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746, wherein the heavy chain variable domain comprises (a) an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835. (b) an HVR-H1 comprising an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 708, 755 to 762, 836 to 842, and 888, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 708, 755 to 762, 836 to 842, and 888. and (c) HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770. In some embodiments, the anti-TREM2 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3; and the heavy chain variable domain comprises HVR-H1, HVR-H2, and HVR-H3, wherein HVR-H3 has an amino acid sequence selected from the group consisting of SEQ ID NOs: 85-102, 588, 589, 709, 710, and 763-770, or SEQ ID NOs: 85-102, 588, 589, 709, 710,and 763 to 770. In some embodiments, the antibody comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 219-398, 602-634, 679-689, 724-730, 809-816, 821, 843, 844, 849, and 850, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 399-580, 635-678, 731-733, 817-820, 822-825, and 845-847. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 333, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521; (b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 850, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521; (c) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522; (d) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 335, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 523; (e) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 336, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 524; (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 338 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526; (h) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 339 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526; (i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 340 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 527; (j) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 341 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 528; (k) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 342 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 529; (l) the light chain variable domain is(m) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 843 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 845; (n) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 846; (o) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 847; (p) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 2 (q) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 230 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 409; (r) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 252 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 419; (s) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 241 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429; (t) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 849. (u) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 263 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 439; (v) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 274 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 449; (w) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 285 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 459; (x) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 286. (y) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 287 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 461; (z) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 298 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429; (aa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 299 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 471; (bb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 310;and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 461, (cc) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 679 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 481, (dd) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 311 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 491, (ee) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 322 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 511, (ff) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 344, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 531, (gg) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 355 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 635, (hh) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 365 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 541, (ii) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 376 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 551, (jj) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 387, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 561, (kk) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 398 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 571, (ll) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 724 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731, (mm) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 809 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731, (nn) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 725, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 732, (oo) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731, (pp) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 817, (qq) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 727 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731, (rr) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 728,and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (ss) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 810 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 818; (tt) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 811 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (uu) the light chain variable domain is (vv) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 812 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 819; (ww) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 729 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 820; (xx) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 730 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (yy) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 732; (zz) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 814 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 822; (aaa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 815 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 824; or (bbb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 816 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 825.

[0037] Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, the antibody comprising a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 219-398, 602-634, 679-689, 724-730, 809-816, 821, 843, 844, 849, and 850, and / or a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 399-580, 635-678, 731-733, and 817-820, 822-825, and 845-847. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 843 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 845. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 843 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 846. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 843 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 847. In some embodiments, the antibody comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 844 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 847. In some embodiments, the antibody comprises a light chain variable domain and a heavy chain variable domain, wherein (a) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 333 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521, (b) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 850 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 521, (c) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522, (d) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522, (e) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522, (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522, (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 522, (h) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 334, (i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 334, and (j) the light chain variable domain (e) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 336 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 524; (f) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 337 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 525; (g) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 338 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526;(h) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 339, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 526; (i) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 340, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 527; (j) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 341, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 528; (k) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 342, and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 529; (l) (m) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 343 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 530; (n) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 846; (o) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 844 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 847; (p) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 848 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 849; (q) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 230 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 409; (r) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 252 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 419; (s) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 241 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429; (t) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 242; (u) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 263 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 439; (v) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 274 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 449; (w) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 285 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 459; (x) the light chain variable domain is(y) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 287 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 461; (z) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 298 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 429; (aa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 299 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 471; (bb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: (cc) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 679 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 481; (dd) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 311 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 491; (ee) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 322 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 511; (ff) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: (gg) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 355 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 635; (hh) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 365 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 541; (ii) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 376 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 551; (jj) the light chain variable domain is (kk) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 398 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 571; (ll) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 724 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (mm) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 809 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (nn) the light chain variable domain is(oo) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (pp) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 726 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 817; (qq) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 727 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731. (rr) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 728 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (ss) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 810 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 818; (tt) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 811 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 733; (uu) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 729 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: (vv) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 812 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 819; (ww) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 729 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 820; (xx) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 730 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 731; (yy) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 813. (zz) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 814 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 822; (aaa) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 815 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 824; or (bbb) the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 816 and the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 825.

[0038] Another aspect of the disclosure is an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, including any of the following: 1A7, 3A2, 3B10, 6G12, 6H6, 7A9, 7B3, 8A1, 8E10, 8F11, 8F8, 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, 4D7, 4D11, 6C11, 6G12, 7A3, 7C5, 7E9, 7F6, 7G1, 7H1, 8C3, 8F10, 12A1, 1E9, 2C5, 3C5, 4C12, 4F2, 5A2, 6B3, 7D1, 7 D9, 11D8, 8A12, 10E7, 10B11, 10D2, 7D5, 2A7, 3G12, 6H9, 8G9, 9B4, 10A1, 11A8, 12F3, 2F8, 10E3, 1H7, 2F6, 2H8, 3A7, 7E5, 7F8, 11H5, 7C5, 4F11, 12D9, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2 and / or the light chain variable domain of an antibody to be tested, such as 1A7, 3A2, 3B10, 6G12, 6H6, 7A9, 7B3, 8A1, 8E10, 8F11, 8F8, 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, 4D7, 4D11, 6C11, 6G12, 7A3, 7C5, 7E9, 7F6, 7G1, 7H1, 8C3, 8F10, 12A1, 1E9, 2C5, 3C5, 4C12, 4F2, 5A2, 6B3, 7D1, 7D9, 11D8, 8A12, 10E7, 10B11, The present invention relates to an antibody comprising a heavy chain variable domain of an antibody selected from the group consisting of: 10D2, 7D5, 2A7, 3G12, 6H9, 8G9, 9B4, 10A1, 11A8, 12F3, 2F8, 10E3, 1H7, 2F6, 2H8, 3A7, 7E5, 7F8, 11H5, 7C5, 4F11, 12D9, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2.

[0039] Another aspect of the disclosure is an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, including but not limited to: 1A7, 3A2, 3B10, 6G12, 6H6, 7A9, 7B3, 8A1, 8E10, 8F11, 8F8, 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, 4D7, 4D11, 6C11, 6G12, 7A3, 7C5, 7E9, 7F6, 7G1, 7H1, 8C3, 8F10, 12A1, 1E9, 2C5, 3C5, 4C12, 4F2, 5A2, 6B3, 7D1, 7D9, 11D8, 8A12, 10E7 , 10B11, 10D2, 7D5, 2A7, 3G12, 6H9, 8G9, 9B4, 10A1, 11A8, 12F3, 2F8, 10E3, 1H7, 2F6, 2H8, 3A7, 7E5, 7F8, 11H5, 7C5, 4F11, 12D9, 1B4v1, 1B4v2, 6H2, 7B11v1, 7B11v2, 18D8, 18E4v1, 18E4v2, 29F6v1, 29F6v2, 40D5v1, 40D5v2, 43B9, 44A8v1, 44A8v2, 44B4v1, and 44B4v2.

[0040] Another aspect of the present disclosure is an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, comprising a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain is selected from the group consisting of SEQ ID NOs: 9-23, 581, 690-694, 734-738, and 826-828, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-23, 581, 690-694, 734-738, and 826-828; (b) (c) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 34 to 47, 582, 583, 698 to 702, and 744 to 746. and the heavy chain variable domain comprises (a) an HVR-L3 comprising an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835, or an HVR-H1 comprising an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 48 to 65, 584, 703 to 705, 747 to 754, and 829 to 835; and (b) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 66 to 84, 585 to 587, 706 to 835, and (c) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710,and 763 to 770. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein, wherein the anti-TREM2 antibody comprises a light chain variable domain and a heavy chain variable domain, wherein the light chain variable domain comprises HVR-L1, HVR-L2, HVR-L3, and the heavy chain variable domain comprises HVR-H1, HVR-H2, and HVR-H3, and wherein HVR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770, or an amino acid sequence having at least about 90% homology to an amino acid sequence selected from the group consisting of SEQ ID NOs: 85 to 102, 588, 589, 709, 710, and 763 to 770.

[0041] In some embodiments that may be combined with any of the preceding embodiments, the antibody competes with one or more TREM2 ligands for binding to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TRME2 activities and enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TRME2 activities without blocking binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody induces one or more TRME2 activities without blocking binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities. In some embodiments that may be combined with any of the preceding embodiments, the antibody does not compete with one or more TREM2 ligands for binding to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein compared to one or more TREM2 activities induced by binding of the one or more TREM2 ligands to the TREM2 protein in the absence of the isolated antibody. In some embodiments that may be combined with any of the preceding embodiments, the antibody synergizes with the one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities in the absence of cell surface clustering of TREM2.In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities by inducing or maintaining cell surface clustering of TREM2. In some embodiments that may be combined with any of the preceding embodiments, the antibody is clustered by Fc-gamma receptors expressed on one or more immune cells. In some embodiments that may be combined with any of the preceding embodiments, the one or more immune cells are B cells or microglial cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody increases the level of soluble TREM2, increases the half-life of soluble TREM2, or both. In some embodiments that may be combined with any of the preceding embodiments, the level of soluble TREM2 is selected from the group consisting of serum levels of TREM2, cerebrospinal fluid (CSF) levels of TREM2, tissue levels of TREM2, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces the level of TREM2 in one or more cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces cell surface levels of TREM2, reduces intracellular levels of TREM2, reduces total levels of TREM2, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibody induces TREM2 degradation, TREM2 cleavage, TREM2 internalization, TREM2 shedding, downregulation of TREM2 expression, or any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the level of TREM2 in one or more cells is measured in primary cells or in a cell line selected from the group consisting of dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells, and the cellular level of TREM2 is measured using an in vitro cell assay. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a mammalian or human protein.In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a wild-type protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a naturally occurring variant. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is expressed on human dendritic cells, human macrophages, human monocytes, human osteoclasts, human dermal Langerhans cells, human Kupffer cells, human microglia, or any combination thereof.In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) TREM2 phosphorylation, (c) DAP12 phosphorylation, (d) activation of one or more tyrosine kinases (optionally, the one or more tyrosine kinases include Syk kinase, ZAP70 kinase, or both), (e) activation of phosphatidylinositol 3-kinase (PI3K), (f) activation of protein kinase B (Akt), (g) recruitment of phospholipase C-gamma (PLC-gamma) to the cell plasma membrane, activation of PLC-gamma, or both, (h) recruitment of the TEC-family kinase dVav to the cell plasma membrane, (i) activation of nuclear factor-rB (NF-rB), (j) inhibition of MAPK signaling, (k) activation of linker for activating T cells (LAT), activation of B cells, or both. (l) activation of IL-2-inducible tyrosine kinase (Itk); (m) activation of IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD 11c. Modulation of one or more pro-inflammatory mediators selected from the group consisting of GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, the modulation occurs in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells). (n) modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-α, IL-1Rα, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation is in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells). (o) modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR); (p) phosphorylation of extracellular signal-regulated kinase (ERK); (q) modulation of one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, and any combination thereof. (r) modulating expression of CC chemokine receptor 7 (CCR7) in one or more selected cells; (r) inducing microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; (s) normalizing disrupted TREM2 / DAP12-dependent gene expression; (t) recruiting Syk, ZAP70, or both to the DAP12 / TREM2 complex; (u) increasing the activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); (v) inducing microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; (i) increasing the maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof; (ii) increasing the ability of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof to stimulate or modulate T cell function (optionally, the T cells are selected from the group consisting of CD8+ T cells, CD4+ T cells,(x) enhancing the ability of bone marrow-derived dendritic cells to stimulate or regulate the function of antigen-specific T cells, normalizing the ability of bone marrow-derived dendritic cells, or both (optionally, the antigen-specific T cells are one or more cells selected from the group consisting of CD8+ T cells, CD4+ T cells, regulatory T cells, and any combination thereof); (y) inducing osteoclast production, increasing the rate of osteoclast formation, or both; (z) increasing the activity of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 (aa) increasing the function of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (bb) increasing phagocytosis by dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (cc) clearance of apoptotic neurons, clearance of neural tissue debris, clearance of non-neural tissue debris, clearance of bacteria or other foreign bodies; Induction of one or more types of clearance selected from the group consisting of pathogen clearance, tumor cell clearance, or any combination thereof (optionally, the pathogen 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, and repeat-associated non-ATG (RAN) translation products containing dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR), antisense GGCCCC(G2C4) repeat expansions. RNA), (dd) inducing phagocytosis of one or more of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogens, tumor cells, or any combination thereof (optionally, the pathogen 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, pancreatic islet amyloid Polypeptides, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, and repeat-associated non-ATG (RAN) translation products containing dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR).antisense GGCCCC(G2C4) repeat expanded RNA), (ee) increased expression of one or more stimulatory molecules selected from the group consisting of CD83, CD86 MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells), (ff) IFN-β, IL-1α, IL-1β, CD86, TNF-α, IL-6, IL-8, CRP, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family member, modulation of secretion of one or more pro-inflammatory mediators selected from the group consisting of IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, modulation is inducible by the activation of cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells). (gg) modulation of secretion of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation occurs in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, skin Langerhans cells, inflammatory bowel disease, leukemia, and leukemia). (hh) modulation of the expression of one or more proteins selected from the group consisting of C1qa, C1qB, C1qC, C1s, C1R, C4, C2, C3, ITGB2, HMOX1, LAT2.CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, and VEGF; (ii) enhancement of memory;and (jj) reduced cognitive impairment. In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) DAP12 phosphorylation, (c) activation of Syk kinase, (d) modulation of one or more pro-inflammatory mediators selected from the group consisting of IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, the modulation is in the presence of a marker of inflammatory responses in macrophages, M1 macrophages, M2 macrophages, M3 macrophages, M4 macrophages, M5 macrophages, M6 macrophages, M7 macrophages, M8 macrophages, M9 macrophages, M10 macrophages, M11 macrophages, M12 macrophages, M13 macrophages, M14 macrophages, M15 macrophages, M16 macrophages, M17 macrophages, M18 macrophages, M19 macrophages, M28 macrophages, M29 ...30 macrophages, M31 macrophages, M32 macrophages, M33 macrophages, M41 macrophages, M42 macrophages, M43 macrophages, M44 macro (e) recruitment of Syk to the DAP12 / TREM2 complex; (f) increased activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); (g) increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; (h) increased expression of CD83, CD86 Modulation of expression of one or more stimulatory molecules selected from the group consisting of MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells); (i) increased memory; and (j) reduced cognitive impairment. In some embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, IgM class, or IgA class. In some embodiments that may be combined with any of the preceding embodiments, the antibody is of the IgG class, and is selected from the group consisting of IgG1, IgG2,In some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG3 or IgG4 isotype. In some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG2 isotype. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a human IgG2 constant region. In some embodiments that may be combined with any of the preceding embodiments, the human IgG2 constant region comprises an Fc region. In some embodiments that may be combined with any of the preceding embodiments, the antibody enhances one or more TREM2 activities independent of binding to an Fc receptor. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to an inhibitory Fc receptor. In some embodiments that may be combined with any of the preceding embodiments, the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments that may be combined with any of the preceding embodiments, (a) the isolated antibody has a human or mouse IgG1 isotype and has one or more amino acid substitutions in the Fc region, including N297A, D265A, D270A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L328F, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L328F, A330L, M252Y, S254T, T256E, L328F, P238D, S267E, L328F, A330L, M252Y, S254V ... (b) the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, wherein optionally 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: 886), and optionally the antibody Fc region has a S267E amino acid substitution, a L328F amino acid substitution, or both;and / or a N297A or N297Q amino acid substitution (residue numbering according to EU numbering); (c) the isolated antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof (residue numbering according to EU numbering); (d) the isolated antibody has a human or murine IgG4 isotype and comprises one or more amino acid substitutions or (e) the isolated antibody has a hybrid IgG2 / 4 isotype, wherein the antibody optionally comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4 (residue numbering according to EU or Kabat numbering). In some embodiments that may be combined with any of the preceding embodiments, the antibody is an inactive antibody that binds to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the antibody is an antagonist antibody that binds to the TREM2 protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a mammalian protein or a human protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a wild-type protein. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein is a naturally occurring variant. In some embodiments that may be combined with any of the preceding embodiments, the TREM2 protein isIn some embodiments that may be combined with any of the preceding embodiments, the antibody inhibits one or more TREM2 activities. In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) TREM2 phosphorylation, (c) DAP12 phosphorylation, (d) activation of one or more tyrosine kinases (optionally, the one or more tyrosine kinases are Sy, k kinase, ZAP70 kinase, or both), (e) activation of phosphatidylinositol 3-kinase (PI3K), (f) activation of protein kinase B (Akt), (g) recruitment of phospholipase C-gamma (PLC-gamma) to the cell plasma membrane, activation of PLC-gamma, or both, (h) recruitment of the TEC-family kinase dVav to the cell plasma membrane, (i) activation of nuclear factor-rB (NF-rB), (j) inhibition of MAPK signaling, (k) phosphorylation of linker for activating T cells (LAT), linker for activating B cells (LAB), or both, (l) IL-2-induced tyrosine kinase (IL-2) activation. activation of IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, the modulation is in the activation of macrophages, M1 macrophages, activated M1 macrophages, (n) modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation occurs in one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells); (o) modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR); (p) phosphorylation of extracellular signal-regulated kinase (ERK); (q) modulation of one or more cells selected from the group consisting of macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, and microglial cells; (r) increasing expression of CC chemokine receptor 7 (CCR7) in one or more cells selected from the group consisting of cutaneous alveoli, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, and any combination thereof; (s) normalizing disrupted TREM2 / DAP12-dependent gene expression; (t) recruiting Syk, ZAP70, or both to the DAP12 / TREM2 complex; (u) increasing expression of one or more TREM2 / DAP12-dependent genes; (v) increasing the activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor); (v) promoting the proliferation, maturation, migration, differentiation, or functionality of one or more cells selected from the group consisting of immunosuppressive dendritic cells, immunosuppressive macrophages, immunosuppressive neutrophils, immunosuppressive NK cells, myeloid-derived suppressor cells, tumor-associated macrophages, tumor-associated suppressor neutrophils, tumor-associated suppressor NK cells, regulatory T cells, and any combination thereof; (w) promoting the proliferation, maturation, migration, differentiation, or functionality of one or more cells selected from the group consisting of immunosuppressive dendritic cells, immunosuppressive macrophages,(x) an increase in the number of tumor-promoting myeloid immunosuppressive or tumor-promoting granulocytic immunosuppressive cells in the tumor, peripheral blood, lymphoid organs, or any combination thereof; (y) an increase in the tumor-promoting activity of myeloid-derived suppressor cells (MDSCs); (z) an increase in the expression of tumor-promoting cytokines in the tumor or peripheral blood (optionally, the tumor-promoting cytokines are selected from the group consisting of TGF-beta, IL-10, and any combination thereof); (aa) an increase in tumor infiltration of tumor-promoting FoxP3+ regulatory T lymphocytes; (bb) decreased activation of tumor-specific T lymphocytes with tumor-killing ability, (cc) decreased infiltration of one or more cells selected from the group consisting of tumor-specific T lymphocytes with tumor-killing ability, tumor-specific NK cells with tumor-killing ability, tumor-specific B lymphocytes with the ability to enhance an immune response, and any combination thereof, (dd) increased tumor volume, (ee) increased tumor growth rate, (ff) increased metastasis, (gg) increased tumor recurrence rate, (hh) decreased effectiveness of one or more immunotherapies that modulate anti-tumor T cell responses (optionally, the one or more immunotherapies are selected from the group consisting of PD1 / PDL1 blockade, CTLA-4 blockade, and cancer vaccines), (ii) inhibition of PLCγ / PKC / calcium mobilization, and (jj) inhibition of PI3K / Akt, Ras / MAPK signaling. In some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 activities are selected from the group consisting of: (a) TREM2 binding to DAP12, (b) DAP12 phosphorylation, (c) activation of Syk kinase, (d) recruitment of Syk to the DAP12 / TREM2 complex, (e) increased activity of one or more TREM2-dependent genes (optionally, the one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor), (f) increased tumor volume, and (g) increased tumor growth rate.In some embodiments that may be combined with any of the preceding embodiments, the antibody may bind to an Fc-gamma receptor (FcγR). In some embodiments that may be combined with any of the preceding embodiments, the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments that may be combined with any of the preceding embodiments, (a) the antibody has a human or mouse IgG1 isotype and has one or more amino acid substitutions in the Fc region, including N297A, N297Q, D270A, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P3 (b) the antibody comprises an amino acid deletion in the Fc region at a residue position selected from the group consisting of 31S, T394D, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L328F, E233D, G237D, H268D, P271G, A330R, and any combination thereof (residue numbering according to EU numbering), or an amino acid deletion in the Fc region at a position corresponding to glycine 236; or (c) the antibody has an I type and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof (residue numbering according to EU numbering); or In some embodiments that may be combined with any of the preceding embodiments, the (a) Fc region further comprises: a gG4 isotype and one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of E233P, F234V, L234A / F234A, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof (residue numbering according to EU numbering).(b) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F, L235E, P331S, and any combination thereof (residue numbering according to EU numbering), (b) the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof (residue numbering according to EU numbering), or (c) the Fc region further comprises a S228P amino acid substitution according to EU numbering. In some embodiments that may be combined with any of the preceding embodiments, the antibody is an antibody fragment that binds one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, and disease variants of human TREM2, and optionally the antibody fragment is crosslinked to a second antibody fragment that binds one or more human proteins selected from the group consisting of human TREM2, naturally occurring variants of human TREM2, and disease variants of human TREM2. In some 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 some embodiments that may be combined with any of the preceding embodiments, the one or more TREM2 ligands are selected from E. coli cells, apoptotic cells, nucleic acids, The antibody is selected from the group consisting of anionic lipids, anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2, anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidated APOE3, lipidated APOE4, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatide, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, lipidated amyloid beta peptides, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, the antibody is a murine antibody. In some embodiments that may be combined with any of the preceding embodiments, the antibody is a humanized antibody, a bispecific antibody, a multivalent antibody, a conjugated antibody, or a chimeric antibody. In some embodiments that may be combined with any of the preceding embodiments, the antibody is a monoclonal antibody. In some 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 some 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 (a) an antigen that facilitates transport across the blood-brain barrier, (b) an antigen that is a target of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a polyarginine peptide, an angiopeptide, and an antigen that promotes transport across the blood-brain barrier selected from the group consisting of ANG1005; (c) a pathogen selected from the group consisting of a pathogenic peptide or protein, or a pathogenic nucleic acid (the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat-expanded RNA, and the pathogenic protein is amyloid beta, oligomeric amyloid beta, amyloid beta plaque, amyloid precursor protein or a fragment thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein,C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, 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 (d) a ligand and / or protein expressed on an immune cell (the ligand and / or protein is selected from the group consisting of CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, and phosphatidylserine), and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody is selected from the group consisting of a pathogenic peptide, a pathogenic protein, amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, 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, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides, and any combination thereof. The present invention is used in combination with one or more antibodies that specifically bind to a pathogen, or one or more antibodies that bind to an immunomodulatory protein selected from the group consisting of CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, TREM1, TREM2, CD33, Siglec-5, Siglec-9, Siglec-11, phosphatidylserine, pathogenic nucleic acid, antisense GGCCCC (G2C4) repeat-expanded RNA, and any combination thereof. In some embodiments that may be combined with any of the preceding embodiments, when administered to an individual, the antibody increases memory, reduces cognitive impairment, or both. In some embodiments that may be combined with any of the preceding embodiments, the antibody specifically binds to both human TREM2 and mouse TREM2. In some embodiments that may be combined with any of the preceding embodiments, the antibody has a dissociation constant (K,) for human TREM2 and mouse TREM2 that ranges from about 12.8 nM to about 1.2 nM, or is less than 1.2 nM. D In some embodiments that may be combined with any of the preceding embodiments, the antibody has a dissociation constant (K) for human TREM2 that ranges from about 12.8 nM to about 2.9 nM, or that is less than 2.9 nM. DIn some embodiments that may be combined with any of the preceding embodiments, the antibody has a dissociation constant (K) for mouse TREM2 that ranges from about 10.4 nM to about 1.2 nM, or is 1.2 nM. D In some embodiments that may be combined with any of the preceding embodiments, K D is determined at a temperature of about 4° C. In some embodiments that may be combined with any of the preceding embodiments, the antibody does not inhibit the proliferation of innate immune cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody has a K of less than 1 nM. D In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to an extent that the blood antibody concentration is 1% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to an extent that the blood antibody concentration is 2% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to an extent that the blood antibody concentration is 3% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to an extent that the blood antibody concentration is 4% or greater.

[0042] Other aspects of the present disclosure relate to an isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of any one of the preceding embodiments. Other aspects of the present disclosure relate to a vector comprising the nucleic acid of any of the preceding embodiments. Other aspects of the present disclosure relate to an isolated host cell comprising the vector of any of the preceding embodiments. Other aspects of the present disclosure relate to a method of producing an antibody that binds to TREM2, the method comprising culturing the host cell of any of the preceding embodiments to produce the antibody. In some embodiments, the method further comprises recovering the antibody produced by the cell. Other aspects of the present disclosure relate to an isolated (e.g., monoclonal) antibody that binds to TREM2 produced by the method of any of the preceding embodiments. Other aspects of the present disclosure relate to a pharmaceutical composition comprising the antibody of any of the preceding embodiments and a pharmaceutically acceptable carrier.

[0043] Other aspects of the present disclosure include the use of a variety of therapeutic agents for dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, 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 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, retinal pigment epithelium, and the like. fibrocytosis, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, 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, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow derived tumors, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosoma infection, Pseudomonas 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: aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type 1, and Haemophilus influenza, comprising administering to an individual in need thereof a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein.Other aspects of the present disclosure include the use of a variety of therapeutic agents for dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, 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 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, retinal pigment epithelium, and the like. fibrocytosis, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, 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, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow derived tumors, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosoma infection, Pseudomonas The present invention relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein for use in preventing, reducing the risk of, or treating an individual having a disease, disorder, or injury selected from the group consisting of: Aeruginosa infection, Leishmania donovani infection, Group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type 1, and Haemophilus influenzae.Other aspects of the present disclosure include the use of a variety of therapeutic agents for dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy diseases, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, 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 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, retinal pigment epithelium, and the like. fibrocytosis, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrosis, Paget's disease of bone, 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, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, bone marrow derived tumors, thyroid cancer, infections, CNS herpes, parasitic infections, Trypanosoma infection, Pseudomonas The present invention relates to the use of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein 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: Aeruginosa infection, Leishmania donovani infection, Group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type 1, and Haemophilus influenzae.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, cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis, and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein 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, cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis, and cancer. Another aspect of the present disclosure relates to the use of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein in the manufacture of a medicament for preventing, reducing the risk of, or treating an individual with a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis, and cancer. In some embodiments, the isolated antibody is (a) an agonist antibody, (b) an inactive antibody, or (c) an antagonist antibody. In some embodiments, the isolated antibody is an antibody of any of the preceding embodiments. In some embodiments, the disease, disorder, or injury is Alzheimer's disease. In some embodiments, the isolated antibody that binds to the TREM2 protein increases expression of one or more inflammatory mediators, wherein the one or more inflammatory mediators are selected from the group consisting of IL-1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof.In some embodiments, the isolated antibody that binds to the TREM2 protein reduces expression of one or more inflammatory mediators, wherein the one or more inflammatory mediators are selected from the group consisting of FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof. In some embodiments, the isolated antibody that binds to the TREM2 protein reduces the level of Abeta peptide in the individual. In some embodiments, the isolated antibody that binds to the TREM2 protein reduces CD11b in the brain of the individual. + In some embodiments, the isolated antibody that binds to the TREM2 protein increases the number of microglial cells. In some embodiments, the isolated antibody that binds to the TREM2 protein increases memory in an individual. In some embodiments, the isolated antibody that binds to the TREM2 protein reduces cognitive impairment in an individual. In some embodiments, the isolated antibody that binds to the TREM2 protein increases motor coordination in an individual. In some 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 some embodiments, at least one antibody that specifically binds to an inhibitory checkpoint molecule is administered in combination with the isolated antibody. In some embodiments, the at least one antibody that specifically binds to an inhibitory checkpoint molecule is an anti-PD-L1 antibody, an anti-CTLA-4 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-lymphocyte and T-lymphocyte attenuator (BTLA) antibody, an anti-killer inhibitory receptor (KIR) antibody, an anti-GAL9 antibody, an anti-TIM3 antibody, The standard or investigational anti-cancer therapy is selected from the group consisting of an anti-A2AR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27 antibody, and any combination thereof. In some embodiments, the standard or investigational anti-cancer therapy is one or more therapies selected from the group consisting of radiation therapy, cytotoxic chemotherapy, targeted therapy, hormone therapy, imatinib (Gleevec®), trastuzumab (Herceptin®), bevacizumab (Avastin®), ofatumumab (Arzerra®), rituximab (Rituxan®, MabThera®, Zytux®), cryotherapy, ablation, radiofrequency ablation, adoptive cell transfer (ACT), chimeric antigen receptor T-cell transfer (CAR-T), vaccine therapy, and cytokine therapy. In some embodiments, the method further comprises administering to the individual at least one antibody that specifically binds to the inhibitory cytokine. In some embodiments, at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with the isolated antibody. In some 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 some embodiments, the method further comprises administering to the individual at least one agonist antibody that specifically binds to a stimulatory checkpoint protein. In some embodiments, the at least one agonist antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with the isolated antibody. In some 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 some embodiments, the method further comprises administering to the individual at least one stimulatory cytokine, hi some embodiments, the at least one stimulatory cytokine is administered in combination with the isolated antibody.In some 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 IL20 family member, IL-33, LIF, OSM, CNTF, TGF-beta, IL-11, IL-12, IL-17, IL-8, IL-23, IFN-α, IFN-β, IL-2, IL-18, GM-CSF, G-CSF, and any combination thereof.

[0044] Another aspect of the present disclosure relates to a method of enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein for use in enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein in the manufacture of a medicament for enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof. In some embodiments, the isolated antibody is an antibody of any of the preceding embodiments.

[0045] Another aspect of the present disclosure relates to a method of inducing one or more TREM2 activities in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein for use in inducing one or more TREM2 activities in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein in the manufacture of a medicament for inducing one or more TREM2 activities in an individual in need thereof. In some embodiments, the isolated antibody is the antibody of any of the preceding embodiments.

[0046] Another aspect of the present disclosure relates to a method of inducing one or more TREM2 activities and enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein for use in inducing one or more TREM2 activities and enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated (e.g., monoclonal) antibody that binds to a TREM2 protein in the manufacture of a medicament for inducing one or more TREM2 activities and enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof. In some embodiments, the isolated antibody is an antibody of any of the preceding embodiments.

[0047] Another aspect of the present disclosure relates to a method of reducing cellular levels of TREM2 in one or more cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein. Another aspect of the present disclosure relates to an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein for use in reducing cellular levels of TREM2 in one or more cells in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated (e.g., monoclonal) antibody that binds to the TREM2 protein in the manufacture of a medicament for reducing cellular levels of TREM2 in one or more cells in an individual in need thereof. In some embodiments, the isolated antibody is the antibody of any of the preceding embodiments.

[0048] In some 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 to stop codon substitution in a nucleic acid sequence encoding amino acid residue Glu14 of SEQ ID NO:1; ii. a glutamine to stop codon substitution in a nucleic acid sequence encoding amino acid residue Gln33 of SEQ ID NO:1; iii. a tryptophan to stop codon substitution in a nucleic acid sequence encoding amino acid residue Trp44 of SEQ ID NO:1; iv. a tryptophan to stop codon substitution in a nucleic acid sequence encoding amino acid residue Trp44 of SEQ ID NO:1; 1, v. an arginine to histidine amino acid substitution at an amino acid corresponding to amino acid residue Arg47 of SEQ ID NO: 1, v. a tryptophan to stop 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 an amino acid corresponding to amino acid residue Val126 of SEQ ID NO: 1, vii. an aspartic acid to glycine amino acid substitution at an amino acid corresponding to amino acid residue Asp134 of SEQ ID NO: 1, and viii. a lysine to asparagine amino acid substitution at an amino acid corresponding to amino acid residue Lys186 of SEQ ID NO: 1. In some 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 a nucleotide corresponding to nucleotide residue G313 of the nucleic acid sequence encoding SEQ ID NO: 1, a guanine nucleotide deletion at a nucleotide corresponding to nucleotide residue G267 of the nucleic acid sequence encoding SEQ ID NO: 1, or both.In some embodiments that may be combined with any of the preceding embodiments, the individual has a heterozygous variant of 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 of SEQ ID NO:2, ii. a glycine to arginine amino acid substitution at an 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 a nucleotide corresponding to nucleotide residue G141 of the nucleic acid sequence encoding SEQ ID NO:2.

[0049] Another aspect of the present disclosure relates to a method of inducing or promoting innate immune cell survival or wound healing in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in inducing or promoting innate immune cell survival or wound healing in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for inducing or promoting innate immune cell survival or wound healing in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0050] Another aspect of the present disclosure relates to a method of increasing memory, reducing cognitive impairment, or both, in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in increasing memory, reducing cognitive impairment, or both, in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for increasing memory, reducing cognitive impairment, or both, in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0051] Another aspect of the present disclosure relates to a method of increasing motor coordination in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in increasing motor coordination in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for increasing motor coordination in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0052] Another aspect of the present disclosure relates to a method of reducing Abeta peptide levels in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in reducing Abeta peptide levels in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for reducing Abeta peptide levels in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0053] Another aspect of the present disclosure is CD11b +

[0010] Another aspect of the present disclosure relates to a method for increasing the number of microglial cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to the TREM2 protein.

[0011] Another aspect of the present disclosure relates to a method for increasing the number of microglial cells in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to the TREM2 protein. + Another aspect of the present disclosure relates to an isolated agonist antibody that binds to the TREM2 protein for use in increasing the number of microglial cells in an individual in need thereof. + The present invention relates to the use of an isolated agonist antibody that binds to a TREM2 protein in the manufacture of a medicament for increasing the number of microglial cells in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0054] Another aspect of the present disclosure relates to a method of increasing levels of one or more of FLT1, OPNCSF1, CD11c, and AXL in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonistic antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonistic antibody that binds to TREM2 protein for use in increasing levels of one or more of FLT1, OPNCSF1, CD11c, and AXL in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonistic antibody that binds to TREM2 protein in the manufacture of a medicament for increasing levels of one or more of FLT1, OPNCSF1, CD11c, and AXL in an individual in need thereof. In some embodiments, the isolated agonistic antibody is the agonistic antibody of any of the preceding embodiments.

[0055] Another aspect of the present disclosure relates to a method of treating spinal cord injury in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in treating spinal cord injury in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds TREM2 protein in the manufacture of a medicament for treating spinal cord injury in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0056] Another aspect of the present disclosure relates to a method of treating chronic colitis or ulcerative colitis in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to TREM2 protein. Another aspect of the present disclosure relates to an isolated agonist antibody that binds to TREM2 protein for use in treating chronic colitis or ulcerative colitis in an individual in need thereof. Another aspect of the present disclosure relates to the use of an isolated agonist antibody that binds to TREM2 protein in the manufacture of a medicament for treating chronic colitis or ulcerative colitis in an individual in need thereof. In some embodiments, the isolated agonist antibody is the agonist antibody of any of the preceding embodiments.

[0057] In some embodiments that may be combined with any of the preceding embodiments, the antibody does not inhibit the proliferation of innate immune cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody has a K D In some embodiments that may be combined with any of the preceding embodiments, K D is determined at a temperature of about 4°C. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to the extent that the blood antibody concentration is 1% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to the extent that the blood antibody concentration is 2% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to the extent that the blood antibody concentration is 3% or greater. In some embodiments that may be combined with any of the preceding embodiments, the antibody accumulates in the brain, or cerebrospinal fluid (CSF), or both, to the extent that the blood antibody concentration is 4% or greater. [Brief explanation of the drawings]

[0058] [Figure 1A]1 shows an amino acid sequence alignment between the human TREM2 protein (SEQ ID NO: 1) and the human NCTR2 protein (SEQ ID NO: 851), illustrating the homology between the two proteins. The consensus sequence is SEQ ID NO: 852. [Figure 1B] Figure 1 shows structure-based sequence alignments between several TREM proteins and other members of the IgV family. The numbering of amino acid residues corresponds to the mature sequence of the human TREM1 protein. TREM1 secondary structure elements 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 by a "-". M-1 residues that disrupt the antibody-like dimerization mode are marked with a closed triangle (e.g., Radaev et al., (2003) Structure. 11(12):1527-1535). TREM-1_human (SEQ ID NO: 853), TREM-2_human (SEQ ID NO: 854), TREM-1_mouse (SEQ ID NO: 855), TREM-2_mouse (SEQ ID NO: 856), TREM-3_mouse (SEQ ID NO: 857), NKp44 (SEQ ID NO: 858), aTCR_human (SEQ ID NO: 859), bTCR_human (SEQ ID NO: 860), gTCR_human (SEQ ID NO: 861), dTCR_human (SEQ ID NO: 862), Vd_human (SEQ ID NO: 863), hIGG1_mouse (SEQ ID NO: 864), lIGG1_mouse (SEQ ID NO: 865), CD8_human (SEQ ID NO: 866), and CTLA4_human (SEQ ID NO: 867). [Figure 2] 1 shows an amino acid sequence alignment between the human TREM1 protein (SEQ ID NO: 868) and the human TREM2 protein (SEQ ID NO: 1), illustrating the homology between the two proteins. The consensus sequence is SEQ ID NO: 869. [Figure 3A] 1 shows FACS histograms demonstrating binding of TREM2 antibodies 7E5 and 2H8 to a mouse cell line (BWZ) expressing recombinant mouse TREM2. [Figure 3B] Antibodies 7E5 and 2H8 bind to wild-type (TREM2+ / +) bone marrow-derived mouse macrophages (BMMac) and TREM2-deficient (TREM2- / -) BMMac. Antibody mIgG1 represents a negative isotype control. Shaded histograms represent the TREM2-negative cell population. Black outlined histograms represent the TREM2-positive cell population. [Figure 3C] 1 shows a dose-response curve demonstrating dose-dependent binding of TREM2 antibody 7E5 to BWZ cells expressing recombinant mouse TREM2, but not to parental BWZ cells. Antibody mIgG1 represents a negative isotype control. [Figure 4A] Figure 1 shows FACS histograms demonstrating binding of TREM2 antibodies 10A9, 10C1, and 8F8 to a human cell line (293) expressing recombinant human TREM2-DAP12 fusion protein. Shaded histograms represent the TREM2-negative cell population. Black outlined histograms represent the TREM2-positive cell population. [Figure 4B] Figure 1 shows antibodies 10A9, 10C1, and 8F8 binding to primary human dendritic cells (hDCs). The shaded histogram shows binding of an isotype antibody negative control. The black outlined histogram represents binding of the TREM2 antibody. [Figure 4C]

[0023] Figure 1 shows a diagram for combining antibody light chain variable region (VL) sequences for the humanized version of anti-TREM2 antibody 9F5 (mAb T2-9F5.1). Additional variations are listed below each sequence. The diagram includes sequences for multiple versions of humanized antibody 9F5. In this diagram, IGKV2-29*02 (SEQ ID NO: 870), linking region (SEQ ID NO: 871), T2-9F5.1 (SEQ ID NO: 872), 2-29*02 (SEQ ID NO: 873), h9F5-L1 (SEQ ID NO: 874), and h9F5-L2 (SEQ ID NO: 875). [Figure 4D]

[0023] Figure 1 shows a diagram for combining antibody heavy chain variable region (VL) sequences for the humanized version of anti-TREM2 antibody 9F5 (mAb T2-9F5.1). Additional variations are listed below each sequence. This diagram includes sequences for multiple versions of humanized antibody 9F5. In this diagram, IGHV1-46*01 (SEQ ID NO: 876), linking region (SEQ ID NO: 877), T2-9F5.1 (SEQ ID NO: 878), 1-46*01 (SEQ ID NO: 879), h9F5-H1 (SEQ ID NO: 880), h9F5-H2 (SEQ ID NO: 881), and h9F5-H3 (SEQ ID NO: 882). [Figure 4E] The binding reactivity of the anti-TREM2 antibody 9F5 (MAb) to wild-type TREM2 (%WT) and the anti-TREM2 antibodies T21-9 (Fab), T22 (Fab), and T45-10 (Fab) to the indicated TREM2 mutants is shown as a percentage. [Figure 5A] Figure 1 shows Syk phosphorylation as determined by Western blot analysis in mouse bone marrow-derived macrophages after incubation with TREM2 antibodies 2F6, 11H5, 2H8, 1H7, 3A7, 3B10, 10A9, 7F8, and 7E5. Control cells were left untreated (NT) or incubated with mIgG1, an isotype control, which does not induce Syk phosphorylation. [Figure 5B] Figure 1 shows Syk phosphorylation as determined by Western blot in WT, Fc receptor common gamma chain-deficient (FcgR- / -), and TREM2-deficient (TREM2- / -) bone marrow-derived murine macrophages after incubation with TREM2 antibodies 7E5, 3A7, and 2F6. [Figure 6A] Figure 1 shows Syk phosphorylation, as determined by Western blot, in wild-type (WT) and TREM2-deficient (TREM2- / -) bone marrow-derived mouse macrophages untreated (NT) or treated with TREM2 antibodies 7E5, 3A7, 8F8, and 2F6 in the presence of the P815 cell line overexpressing the Fc receptors FcR2b and FcR3. Antibody IgG1 is an isotype control. [Figure 6B]Figure 1 shows Syk phosphorylation, as determined by Western blot, in WT bone marrow-derived mouse macrophages untreated (NT) or treated with TREM2 antibodies 7E5, 3A7, 8F8, and 2F6 in the presence of primary mouse B cells expressing the endogenous Fc receptor FcR2b. Antibody IgG1 is an isotype control. [Figure 7A] Figure 1 shows DAP12 phosphorylation (pTyr) as determined by Western blot in mouse macrophages after incubation with TREM2 antibodies 11A2, 11H5, 2F6, 3A7, 4G3, 12F9, 3B10, and 7A9 or left untreated (NT). Antibody mIgG1 is an isotype negative control. [Figure 7B] DAP12 phosphorylation, as determined by Western blot, is shown in wild-type (WT) and TREM2-deficient (TREM2- / -) mouse macrophages that were either untreated (NT) or treated with TREM2 antibodies 7E5 and 2F6. [Figure 7C] Shown is DAP12 phosphorylation as determined by Western blot immunoprecipitation in peritoneal cells from mice treated with control antibody MOPC.1 or TREM2 antibody 7E5 for 15 minutes. [Figure 7D] Fold changes compared to IP-TREM2 in MOPC1-treated mice are shown for 15 minutes of treatment. [Figure 7E] 1 shows DAP12 phosphorylation as determined by Western blot immunoprecipitation in peritoneal cells from mice treated with control antibody MOPC.1 or TREM2 antibody 7E5 for 24 hours. [Figure 7F] Fold changes compared to IP-TREM2 in MOPC1-treated mice at 24 hours of treatment are shown. [Figure 8A]Figure 1 shows induction of a mouse TREM2-dependent luciferase reporter in a cell-based assay. Cells were either untreated (NT) or treated with plate-bound full-length anti-TREM2 antibodies 1H7, 2F6, 2H8, 3A7, 3B10, 7E5, 7F8, 8F8, and 11H5. Results are expressed as fold over background. Background levels are indicated by the dotted line. [Figure 8B] Figure 1 shows induction of a human TREM2-dependent luciferase reporter in a cell-based assay. Cells were either untreated (NT) or treated with plate-bound full-length anti-TREM2 antibodies 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12D9, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, and 4D7. Results are expressed as fold over background. Antibody msIgG1 serves as an isotype negative control. Cells treated with PMA / ionomycin (P+I) represent a positive control. [Figure 8C] Figure 1 shows the induction of mouse TREM2-dependent luciferase reporter gene expression by increasing concentrations of plate-bound phosphatidylserine (PS) or sphingomyelin (SM). Results are expressed as absolute luminescence values. [Figure 8D] Figure 1 shows the induction of human TREM2-dependent luciferase reporter gene expression by increasing concentrations of plate-bound phosphatidylserine (PS) or sphingomyelin (SM). Results are expressed as absolute luminescence values. [Figure 8E] Figure 1 shows induction of human TREM2-dependent luciferase reporter gene expression by increasing concentrations of apolipoprotein E (APOE). Three different alleles of APOE (APOE2, APOE3, and APOE4) were tested. Results are expressed as absolute luminescence values. [Figure 8F] Figure 1 shows the binding of APOE2, APOE3, and APOE4 to recombinant human TREM2 protein as determined by ELISA. Results are expressed as OD450. [Figure 9A]Figure 1 shows induction of a mouse TREM2-dependent luciferase reporter in a cell-based assay. Cells were either untreated (NT) or treated with soluble full-length anti-TREM2 antibodies 1H7, 2F6, 2H8, 3A7, 3B10, 7E5, 7F8, 8F8, and 11H5. Antibody mIgG1 serves as an isotype negative control. Cells treated with PMA / ionomycin represent a positive control. Results are expressed as fold over background (represented by the dotted line). [Figure 9B] Figure 1 shows induction of human TREM2-dependent luciferase reporter expression by full-length anti-TREM2 antibodies 9F5, 9G1, 9G3, 10A9, 10C1, 11A8, 12D9, 12E2, 12F9, 12G6, 2C7, 2F5, 3C1, and 4D7 in solution. Antibody mIgG1 is an isotype negative control. Cells treated with PMA / ionomycin represent a positive control. Results are expressed as fold over background (represented by the dotted line). [Figure 9C] Figure 1 shows dose-dependent induction of the TREM2 luciferase reporter in a cell-based assay. Cells were either untreated (NT) or treated with increasing concentrations of the full-length anti-TREM2 antibody 7E5 in solution. Results are expressed as absolute luminescence values. Data were analyzed with Prism 6 software and fitted with a four-parameter variable slope of log(agonist) vs. response. EC50 = 1.52 nM. [Figure 10A] Figure 1 shows induction of mouse TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length anti-TREM2 antibody 7E5 added in solution with increasing concentrations of plate-bound phosphatidylserine (PS). [Figure 10B] Figure 1 shows induction of mouse TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length IgG1 isotype control antibody added in solution with increasing concentrations of plate-bound phosphatidylserine (PS). [Figure 10C]Figure 1 shows induction of mouse TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length anti-TREM2 antibody 7E5 added in solution with increasing concentrations of plate-bound sphingomyelin (SM). [Figure 10D] Figure 1 shows induction of mouse TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length IgG1 isotype control antibody added in solution with increasing concentrations of plate-bound sphingomyelin (SM). [Figure 10E] Figure 1 shows induction of mouse TREM2-dependent luciferase reporter gene expression by full-length anti-TREM2 antibodies 2F6, 3A7, 3B10, 8F8, and 11H5, or an IgG1 isotype control, added in solution with increasing concentrations of plate-bound phosphatidylserine (PS). Results are expressed as absolute luminescence values. [Figure 10F] Figure 1 shows the induction of mouse TREM2-dependent luciferase reporter gene expression by the full-length anti-TREM2 antibody 7E5 added in solution with increasing concentrations of plate-bound sphingomyelin (SM), compared to a commercially available antibody. Mouse IgG1 and rat IgG2b antibodies were used as isotype controls. [Figure 11A] Figure 1 shows induction of human TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length anti-TREM2 antibody 9F5 added in solution with increasing concentrations of plate-bound phosphatidylserine (PS). [Figure 11B] Shown is the induction of human TREM2-dependent luciferase reporter gene expression by the indicated amounts of full-length IgG1 isotype control antibody added in solution with increasing concentrations of plate-bound phosphatidylserine (PS). [Figure 11C] Figure 1 shows induction of human TREM2-dependent luciferase reporter gene expression by full-length anti-TREM2 antibodies 7B3, 9G1, 9G3, 9F5, and an IgG1 isotype control antibody (msIgG1) in solution with increasing concentrations of plate-bound phosphatidylserine (PS). Results are expressed as absolute luminescence values. [Figure 11D]Figure 1 shows induction of human TREM2-dependent luciferase reporter gene expression by full-length anti-TREM2 antibodies 11A8, 12F9, 3B10, 8F8, and an IgG1 isotype control antibody (msIgG1) in solution with increasing concentrations of plate-bound phosphatidylserine (PS). Results are expressed as absolute luminescence values. [Figure 11E] Binding of recombinant human TREM2 protein to APOE3 in the presence of full-length anti-TREM2 antibodies 9F5, 7B3, and 9G3 at 5 μg / ml in solution, as well as in the presence of an IgG1 isotype control antibody (msIgG1), is shown. Means and standard errors of two replicates are shown. [Figure 11F] Binding of recombinant human TREM2 protein to APOE3 in the presence of full-length anti-TREM2 antibodies 9F5, 7B3, and 9G3 at 15 μg / ml in solution, as well as in the presence of an IgG1 isotype control antibody (msIgG1), is shown. Means and standard errors of two replicates are shown. [Figure 12A] Figure 1 shows the viability of wild-type (WT) bone marrow-derived mouse macrophages after incubation with 100 nM soluble full-length anti-TREM2 antibodies 1H7, 2F6, 2H8, 3A7, 7E5, 7F8, and 8F8, or a commercially available antibody (R&D Cat# F7E57291). As negative controls, cells were incubated with mouse IgG1 and rat IgG2b isotype control antibodies. Results are expressed as % viable cells, where 100% is the viability of untreated cells and 0% is the viability of cells cultured in the absence of the cytokine M-CSF. [Figure 12B] Figure 1 shows the viability of wild-type (WT) bone marrow-derived mouse macrophages after incubation with 2.5 μg / ml or 10 μg / ml of plate-bound full-length anti-TREM2 antibodies 2F6, 3A7, 7E5, and 8F8. As a negative control, cells were incubated with mouse IgG1 (mIgG1). Results are expressed as luminescence, a measure of cell viability. The dotted line indicates the baseline mean viability when cells were left untreated. [Figure 12C]The numbers of immune cells expressing the markers CD11b or CD11b and Gr1 found in the brains of mice injected with the anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1) are shown. [Figure 13A] FIG. 1 shows an exemplary in vivo experimental design to determine the effect of TREM2 antibodies injected into the peritoneal cavity, alone or in combination with LPS, on the total number of immune cells. [Figure 13B] Shown are the percentages of neutrophils in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS. [Figure 13C] The number of neutrophil cells in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS is shown. [Figure 13D] Shown are the percentages of neutrophils in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS. [Figure 13E] The number of neutrophil cells in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS is shown. [Figure 13F] Shown is the percentage of resident macrophages (CD11b+F4 / 80high) in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS. [Figure 13G] The numbers of resident macrophage cells (CD11b+F4 / 80high) in the peritoneal cavity are shown after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS. [Figure 13H]Shown is the percentage of resident macrophages (CD11b+F4 / 80high) in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS. [Figure 13I] The numbers of resident macrophage cells (CD11b+F4 / 80high) in the peritoneal cavity are shown after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS. [Figure 13J] Shown is the percentage of small infiltrating macrophages (CD11b+F4 / 80int) in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS. [Figure 13K] The numbers of small infiltrating macrophage cells (CD11b+F4 / 80int) in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 7E5 alone, or CTR or TREM2 antibody 7E5 in combination with LPS are shown. [Figure 13L] Shown is the percentage of small infiltrating macrophages (CD11b+F4 / 80int) in the peritoneal cavity after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS. [Figure 13M] The numbers of small infiltrating macrophage cells (CD11b+F4 / 80int) in the peritoneal cavity are shown after injection of LPS, control (CTR) or TREM2 antibody 8F8 alone, or CTR or TREM2 antibody 8F8 in combination with LPS. [Figure 13N] 1 shows an exemplary in vivo experimental design to determine the effect of intraperitoneally injected TREM2 antibodies alone or in combination with LPS on the production of inflammatory mediators CCL4, IL-1β, and MCP-1 (CCL2). [Figure 13O] The concentration of CCL4 in the peritoneal cavity after injection of control (CTR) or TREM2 antibodies 7E5 and 8F8 in combination with LPS is shown in pg / ml. [Figure 13P] The concentration of IL-1β in the peritoneal cavity after injection of control (CTR) or TREM2 antibodies 7E5 and 8F8 in combination with LPS is shown in pg / ml. [Figure 13Q] The concentration of MCP-1 (CCL2) in the peritoneal cavity after injection of control (CTR) or TREM2 antibodies 7E5 and 8F8 in combination with LPS is shown in pg / ml. [Figure 14] Shown are the mean concentrations (ug / ml) of 7E5 antibody found in serum on days 2, 4, 8, and 15 after peritoneal injection of the indicated doses of antibody in three mice. Soluble 7E5 antibody was measured by standard ELISA. Data was analyzed using Prism 6 software and fitted to a one-phase exponential decay curve to calculate half-life. The half-life of the antibody is approximately 9.5 days in mouse serum. [Figure 15] Shown are the concentrations (ng / ml) of soluble TREM2 receptor (sTREM2) found in serum 2, 4, 8, and 15 days after peritoneal injection of the indicated doses of antibody. Soluble TREM2 was measured by ELISA. [Figure 16A] 1 shows downregulation of the TREM2 receptor in culture in response to plate-bound phosphatidylserine (PS) and sphingomyelin (SM). [Figure 16B] 1 shows downregulation of the TREM2 receptor in culture in response to soluble full-length anti-TREM2 antibodies 3A7 and 2F6 in solution with increasing concentrations of plate-bound phosphatidylserine (PS). [Figure 17A]Figure 1 shows changes in the expression of pro- and anti-inflammatory genes in the hippocampus of APP / PS1 mice injected with the anti-TREM2 antibody 7E5, using TaqMan assays (Applied Biosystems, Invitrogen) containing TaqMan® gene expression probes for IL-1b, IL-6, TNFa, IL-12, YM-1, IL-1Ra, MRC1, IL-10, CD86, FCGR1B, and TGFb, as described in Example 16, and real-time PCR. Fold changes are relative to gene expression in control mice (dotted line). Treatment with the anti-TREM2 antibody 7E5 significantly increased the expression of IL-1b, IL-6, TNFa, and CD86 by approximately twofold. The expression of FCGR1B increased approximately threefold, and the expression of IL-10 increased approximately fourfold. In contrast, the expression of IL-1Ra decreased by half. Expression of IL-12, YM-1, MRC1, and TGFB remained unchanged. All gene expression data were normalized to 18S rRNA expression. [Figure 17B] Figure 1 shows changes in expression of pro- and anti-inflammatory genes in the hippocampus of 5XFAD mice 24 and 72 hours after intracranial injection of the anti-TREM2 antibody 7E5, using TaqMan assays (Applied Biosystems, Invitrogen) containing TaqMan® gene expression probes for IL-1b, TNFα, YM-1, IL-1Rn, CD86, TGF-β1, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, and Rorc, as described in Example 16. Fold changes are relative to gene expression in mice treated with an isotype control antibody. The dotted line indicates the level of expression in mice treated with the control antibody. Treatment with the anti-TREM2 antibody 7E5 significantly increased the expression of IL-1b, TNFa, YM-1, CD86, CCL2, CCL3, CCR2, CXCL10, Gata3, and Rorc by approximately twofold at 72 hours after injection. CCL5 expression was increased approximately threefold. Conversely, the expression of IL-1Rn and TGFB remained unchanged. All gene expression data were normalized to 18S rRNA expression. * = P value < 0.05, ** = P value < 0.01. [Figure 17C] Changes in FLT1 expression in the brains of APP / PS1 mice intracranially injected with 5 mg / ml of 7E5 or control msIgG1 antibody are shown. *P value < 0.01, Student's t-test. [Figure 17D] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17D shows results for CCL2. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17E] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17E shows results for CXCL10. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17F]Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17F shows results for Rorc. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17G] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17G shows results for TNFα. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17H] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17H shows results for CSF-1. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17I]Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17I shows results for OPN. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17J] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17J shows results for CD11c. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17K] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17K shows results for Flt1. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17L]Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17K shows results for Flt1. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17M] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17M shows results for LDR. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17N] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17N shows results for CXCR4. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17O]Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17O shows results for Fabp5. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17P] Figures 17D-17P show cytokine and chemokine expression in the brains of 5XFAD mice 3 months after weekly injections of 50 mg / kg of the anti-TREM2 antibody 7E5, using TaqMan assays containing TaqMan® gene expression probes for CCL2, CXCL10, Rorc, TNFα, AXL, LDR, CXCR4, Fabp5, Fabp3, OPN, FLT1, CSF-1, and CD11c, as described in Example 16, and real-time PCR. Figure 17P shows results for Fabp3. For Figures 17D-17P, *P value < 0.05, **P value < 0.01, ***P value < 0.001, one-way ANOVA with Tukey post-hoc test. [Figure 17Q] Figure 1 shows quantification of Abeta peptide in the frontal cortex (FCX) and hippocampus (HPC) of APP / PS1 mice intracranially injected with anti-TREM2 antibody 7E5 or isotype control antibody (mIgG1) using free-floating immunohistochemistry for Abeta stained with rabbit polyclonal antibody Aβ1-16 (Invitrogen) as described in Example 16. ** = P value < 0.01, two-way ANOVA with Fisher's PLSD post-hoc test. [Figure 17R]Quantification of Abeta peptides in the frontal cortex (FCX) and hippocampus (HPC) of 5xFAD mice chronically injected intraperitoneally with anti-TREM2 antibody 7E5 or isotype control antibody (mIgG1) using free-floating immunohistochemistry for Abeta stained with rabbit polyclonal antibody Aβ1-16 (Invitrogen) as described in Example 16. * = P value < 0.05, ** = P value < 0.01. [Figure 17S] Figures 17S-17U show results from the analysis of insoluble protein from the frontal cortex of 5xFAD mice chronically injected intraperitoneally with anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1) using the Meso Scale Discovery Abeta kit, which measures Abeta 38 (Ab38), Abeta 40 (Ab40), and Abeta 42 (Ab42). Following treatment with 7E5, there is a significant decrease in insoluble Abeta 42. Figure 17S shows results for Abeta 38 (Ab38). [Figure 17T] Figures 17S-17U show results from analysis of insoluble protein from the frontal cortex of 5xFAD mice chronically injected intraperitoneally with anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1) using the Meso Scale Discovery Abeta Kit, which measures Abeta 38 (Ab38), Abeta 40 (Ab40), and Abeta 42 (Ab42). Following treatment with 7E5, there is a significant decrease in insoluble Abeta 42. Figure 17T shows results for Abeta 40 (Ab40). [Figure 17U] Figures 17S-17U show results from analysis of insoluble protein from the frontal cortex of 5xFAD mice chronically injected intraperitoneally with anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1) using the Meso Scale Discovery Abeta kit, which measures Abeta 38 (Ab38), Abeta 40 (Ab40), and Abeta 42 (Ab42). Following treatment with 7E5, there is a significant decrease in insoluble Abeta 42. Figure 17U shows results for Abeta 42 (Ab42). [Figure 17V]Figure 1 shows quantification of CD11b-expressing cells in the frontal cortex (FCX) and hippocampus (HPC) of APP / PS1 mice intracranially injected with anti-TREM2 antibody 7E5 or isotype control antibody (mIgG1), using free-floating immunohistochemistry for CD11b stained with a rat monoclonal antibody (Serotec, Raleigh, NC, USA) as described in Example 16. ** = P value < 0.01. [Figure 17W] Figure 1 shows quantification of CD11b-expressing cells in the frontal cortex (FCX) and hippocampus (HPC) of mice chronically injected intraperitoneally with anti-TREM2 antibody 7E5 or isotype control antibody (mIgG1), using free-floating immunohistochemistry for CD11b stained with a rat monoclonal antibody (Serotec, Raleigh, NC, USA) as described in Example 16. ** = P value < 0.01. [Figure 17X]

[0049] Figure 16 shows the results of cognitive function assessed in the radial arm water maze test for WT or 5xFAD mice chronically injected with 7E5 or control antibodies, as described in Example 16. The radial arm water maze test was performed 12 weeks after antibody treatment. The graph represents the average number of errors made to complete the task. Blocks are the average of three trials. 5XFAD transgenic mice given the control antibody were significantly impaired compared to non-transgenic wild-type mice (WT), scoring an average of more than three errors throughout the second day of testing. In contrast, WT mice treated with either antibody scored less than one error in blocks 8 to 10, as expected for mice with normal cognitive function. 5XFAD transgenic mice treated with the anti-TREM2 7E5 antibody performed significantly better than control 5XFAD transgenic mice treated with isotype antibodies and were indistinguishable from normal non-transgenic mice in blocks 5, 9, and 10, indicating recovery of cognitive function. Horizontal lines indicate standard error, *=P value <0.05, **=P value <0.05. [Figure 17Y]

[0049] Figure 16 shows cognitive function results assessed by the novel object recognition test (NORT) in WT or 5xFAD mice chronically injected with 7E5 or a control antibody, as described in Example 16. The NORT test was performed 12 weeks after antibody treatment. Bars represent the percentage of time spent on the novel object. 5XFAD mice treated with a control antibody spent only approximately 50% of their time exploring the novel object, indicating severely impaired cognitive function. In contrast, mice treated with the anti-TREM2 antibody 7E5 spent 67% of their time exploring the novel object, which is close to normal cognitive function and indicates a nearly complete recovery. For statistical analysis, a post-hoc Fisher's PLSD test was used; ** = P value < 0.01. [Figure 18] TREM2 expression in the indicated immune cell populations present in the spleen (SPL) or tumor (Tum) of naive mice or mice bearing the indicated tumor types is shown. [Figure 19A] Tumor sizes in wild-type (WT) or TREM2-deficient (KO) mice were measured on days 8 or 26 after inoculation with MC38 tumor cells. Each dot represents an individual mouse. Means and standard errors (s.e.m.) are shown. The Mann-Whitney U test was used for statistical analysis. [Figure 19B] Median growth curves of MC38 cells transplanted into wild-type (WT) or TREM2-deficient (TREM2 KO) mice are shown. [Figure 20]Figure 2 shows dose-dependent improvement in cognitive function in mice with traumatic brain injury treated with various doses of the anti-TREM2 antibody 7E5. Cognitive function was assessed with the novel object recognition test (NORT) as described in Example 25. Treatment groups were: 1 = 40 mg / kg 7E5, 2 = 20 mg / kg 7E5, 3 = 10 mg / kg 7E5, 4 = 5 mg / kg 7E5, and CTR = 40 mg / kg isotype control antibody mIgG1. The NORT test was performed 32 days after injury. The bars represent the percentage of time spent on the novel object from the total exploration time spent on the two objects. The "Baseline" bar represents the time spent exploring the two identical objects, which is similar regardless of the treatment the mice received. The "Test" bar represents the time spent exploring the novel object. Mice with traumatic brain injury treated with a control antibody spent only 57.4 ± 5.3% of their time exploring the novel object, indicating severely impaired cognitive function. In contrast, mice treated with the highest dose of the anti-TREM2 antibody 7E5 spent 73.9 ± 5.4% of their time exploring the novel object, which is close to normal cognitive function and indicates a nearly complete recovery. Post-hoc Fisher's PLSD test was used for statistical analysis. * = P value < 0.05. [Figure 21A] Figure 1 shows the amount of cytokine TNFα measured in the peritoneal cavity of TREM2 wild-type (WT) and TREM2 knockout (KO) mice injected with Brewer thioglycollate and then administered the anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1). TNFα levels were elevated approximately six-fold in mice treated with antibody 7E5 compared to mice treated with the control. [Figure 21B] Figure 1 shows the amount of cytokine CCL2 measured in the peritoneal cavity of TREM2 wild-type (WT) and TREM2 knockout (KO) mice injected with Brewer thioglycollate and then administered the anti-TREM2 antibody 7E5 or an isotype control antibody (mIgG1). CCL2 concentrations were elevated approximately two-fold in mice treated with antibody 7E5 compared to control-treated mice. These cytokine increases are specific, as they do not occur in TREM2 KO mice. [Figure 22] Figures 22A and 22B show the results of the Basso Mouse Scale (BMS) test to measure hindlimb movement in mice treated with anti-TREM2 antibody 7E5 (7E5) or an isotype control antibody (control IgG) after induction of spinal cord injury on day 0. Figure 22A shows the BMS scores. Figure 22B shows the BMS subscores. The results show that antibody 7E5 produces a transient improvement in motor function after spinal cord contusion, as measured by the BMS scoring system. *p<0.05, two-way repeated measures ANOVA with Tukey's post-hoc test. [Figure 23] Figure 1 shows the percent survival (%) of human monocyte-derived dendritic cells after incubation with soluble TREM2 antibodies 9F5 or 10A9. In contrast to antibody 10A9, incubation with antibody 9F5 does not significantly reduce dendritic cell survival. "mIgG1" refers to the mouse isotype control antibody, and "medium" refers to the culture medium only control. [Figure 24A] Figure 1 shows that treatment of chronic dextran sulfate sodium (DSS)-challenged mice with anti-TREM2 antibody 7E5 significantly reduces symptoms of chronic colitis. Figure 2 shows weight loss in chronic DSS-challenged mice treated with antibody 7E5. Statistical analysis was performed using two-way ANOVA; ***p<0.001, ****p<0.0001. [Figure 24B] Figure 1 shows that treatment of chronic dextran sulfate sodium (DSS)-challenged mice with anti-TREM2 antibody 7E5 significantly reduces symptoms of chronic colitis. Figure 2 shows the disease activity index of chronic DSS-challenged mice treated with antibody 7E5. Statistical analysis was performed using two-way ANOVA; ***p<0.001, ****p<0.0001. [Figure 24C] Figure 24C shows that treatment of chronic dextran sulfate sodium (DSS)-challenged mice with anti-TREM2 antibody 7E5 significantly reduces symptoms of chronic colitis. Figure 24C shows the colon length of chronic DSS-challenged mice treated with antibody 7E5. Statistical analysis was performed using an unpaired t-test; ***p<0.001, ****p<0.0001. [Figure 24D] Figure 1 shows that treatment of chronic dextran sulfate sodium (DSS)-challenged mice with anti-TREM2 antibody 7E5 significantly reduces symptoms of chronic colitis. Colonoscopy scores of chronic DSS-challenged mice treated with antibody 7E5 are shown. Statistical analysis was performed using an unpaired t-test; ***p<0.001, ****p<0.0001. [Figure 25A] Figure 1 shows that anti-TREM2 antibody 9F5 can bind and crosslink human TREM2 expressed by mouse macrophages. Figure 2 shows FACS histograms demonstrating the binding of human-specific TREM2 antibodies 9F5 and 10A9 to human TREM2 expressed on macrophages from humanized TEM2 BAC transgenic mice (huTREM2 Tg), but not on macrophages from wild-type mice (WT). Anti-TREM2 antibodies that bind to both human and mouse TREM2 (antibody 2F5 and a commercially available antibody from R&D) show positive binding to TREM2 expressed on macrophages from both WT and huTREM2 Tg mice. The gray-shaded plots represent isotype-stained cells, and the black histograms represent cells stained with anti-TREM2 antibodies. [Figure 25B] Figure 1 shows that the anti-TREM2 antibody 9F5 can bind to and cross-link human TREM2 expressed by mouse macrophages. Figure 2 shows TNFα secretion by macrophages from humanized TEM2 BAC transgenic mice (Bac-Tg) stimulated in vitro with plate-bound 9F5 or a control antibody. [Figure 25C] Figure 1 shows that the anti-TREM2 antibody 9F5 can bind to and crosslink human TREM2 expressed by mouse macrophages. Figure 2 shows Dap12 phosphorylation (pTyr) after in vitro clustering of anti-TREM2 antibody 9F5 on macrophages from humanized TEM2 BAC transgenic mice (Bac-Tg) or wild-type mice (WT). The control antibody did not induce Dap12 phosphorylation. [Figure 26A]Figure 1 shows the levels of soluble human Trem2 (sTREM2) measured in human TREM2 BAC transgenic mice (huTREM2 Tg) compared to wild-type mice (WT). The anti-TREM2 antibody T21-9 significantly increases plasma levels of sTREM2, whereas the anti-TREM2 antibody 9F5 does not. [Figure 26B] 1 shows that, in contrast to anti-TREM2 antibody T21-9, anti-TREM2 antibody 9F5 binds very weakly to sTREM2 in plasma samples. The X-axis shows the dilution factor of the plasma tested, and the Y-axis shows the optical density reading. DETAILED DESCRIPTION OF THE INVENTION

[0059] 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.R. 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 (J.M. Miller and M.P. Calos, eds.,1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (JEColigan 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, 1999); The Antibodies (M. Zanetti and JD Capra, eds., Harwood The techniques and procedures described or referenced herein are generally well understood and commonly used, using widely accepted methodologies such as those described in "Clinical Trials of Oncology" (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993); and "Cancer: Principles and Practice of Oncology" (V.T. DeVita et al., eds., J.B. Lippincott Company, 1995).

[0060] 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.

[0061] As used herein, an individual "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not exhibit detectable disease or disease symptoms, prior to the treatment methods described herein. "At risk" indicates that an individual has one or more risk factors, which are measurable parameters that correlate with the development of a particular disease, disorder, or condition, as known in the art. Individuals with one or more of these risk factors have a higher probability of developing a particular disease, disorder, or condition than individuals without one or more of these risk factors.

[0062] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of a treated individual's clinical pathology. Desirable therapeutic effects include reducing the rate of progression, ameliorating or alleviating morbidity, and remission or improved prognosis of a particular disease, disorder, or condition. An individual is successfully "treated," for example, if one or more symptoms associated with a particular disease, disorder, or condition are alleviated or eliminated.

[0063] An "effective amount" refers to at least an amount that is effective, at a dosage and for a period of time necessary to achieve the desired therapeutic or prophylactic result. An effective amount can be provided in one or more administrations. The effective amount herein can vary depending on factors such as the individual's condition, age, sex, and weight, as well as the ability of the treatment to induce a desired response in the individual. An effective amount is also one in which the therapeutic beneficial effects outweigh any toxic or adverse effects of the treatment. For prophylactic use, beneficial or desired results include results such as elimination or reduction of the risk, reduction in severity, or delay in onset of disease, including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes observed during the course of disease development. For therapeutic use, beneficial or desired results include clinical results, such as reduction in one or more symptoms caused by the disease, improvement in the quality of life of those suffering from the disease, reduction in the dose of other drugs required to treat the disease, enhancement of the effect of another drug, for example, via targeting, delay in disease progression, and / or prolongation of survival. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment.As understood in clinical situations, the effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.Therefore, "effective amount" can be determined in light of the administration of one or more therapeutic agents, and a single agent can be considered to be given in an effective amount when it can or does achieve the desired result in conjunction with one or more other agents.

[0064] 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, as well as the ability of the anti-TREM2 antibody to induce a desired response in an individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the anti-TREM2 antibody are outweighed by the therapeutically beneficial effects.

[0065] As used herein, administration "in conjunction with" another compound or composition includes simultaneous administration and / or administration at different times. Administering in conjunction also encompasses administration as a co-formulation or as separate compositions, including at different dosing frequencies or intervals, and using the same or different routes of administration.

[0066] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" is used herein in the broadest sense and specifically includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0067] The basic four-chain antibody unit is a heterotetrameric glycoprotein consisting of two identical light (L) chains and two identical heavy (H) chains. H and V L pairing together to form a single antigen-binding site. For the structure and properties of different classes of antibodies, see, e.g., Basic and Clinical Immunology, 8th Ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0068] Light chains from any vertebrate species can be assigned to one of two clearly distinct types, called kappa ("κ") and lambda ("λ"), based on the amino acid sequence of their constant domains. Depending on the amino acid sequence of their heavy chain constant domains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, which have heavy chains designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and mu ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function. For example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known; see, e.g., Abbas et al., Cellular and Molecular Immunology, 4 th It is generally described in Saunders Co., ed. (WBSaunders Co., 2000).

[0069] "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.

[0070] An "isolated" antibody, such as an isolated anti-TREM2 antibody of the present disclosure, is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, the isolated polypeptide is free from association with 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.

[0071] The "variable region" or "variable domain" of an antibody, such as the anti-TREM2 antibody of the present disclosure, refers to the amino-terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy and light chains, respectively, are referred to as "V H " and "V L These domains are generally the most variable parts of an antibody (compared to other antibodies of the same class) and contain the antigen-binding sites.

[0072] The term "variable" refers to the fact that certain segments of variable domains differ extensively in sequence among antibodies, such as the anti-TREM2 antibodies of the present disclosure. V domains mediate antigen binding and define the specificity of a particular antibody for a particular antigen. However, variability is not uniformly distributed throughout the span of the variable domains. Instead, variability is concentrated in three segments called hypervariable regions (HVRs) in both the light-chain and heavy-chain variable domains. The more 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 configuration and form loops that connect, and in some cases form part of, the beta-sheet structure. The HVRs of each chain are held in close proximity by the FR regions and, together with the HVRs of the other chain, contribute to the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institutes of Health, Bethesda, MD (1991)). The constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0073] As used herein, the term "monoclonal antibody" refers to an antibody, such as a monoclonal anti-TREM2 antibody of the present disclosure, obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible 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 techniques (e.g., Kohler and Milstein, Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA techniques (see, for example, U.S. Pat. No. 4,816,567), phage display techniques (e.g., Clackson et al., Nature, 352:624-628 (1991); Marks et al. al.,J.Mol.Biol.222:581-597(1992);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Nat'l Acad.Sci.USA 101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004)), as well as techniques for producing human or human-like antibodies in animals that have some or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551 (1993); Jakobovits et al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and These antibodies can be produced by a variety of techniques, including immunohistochemistry (see Huszar, Intern. Rev. Immunol. 13:65-93 (1995)).

[0074] The terms "full length antibody," "intact antibody," or "complete antibody" are used interchangeably to refer to an antibody, such as an anti-TREM2 antibody of the present disclosure, in a substantially intact form, as opposed to an antibody fragment. Specifically, a complete antibody includes an antibody having a heavy chain and a light chain, including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

[0075] 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.

[0076] Papain digestion of antibodies, such as the anti-TREM2 antibodies of the present disclosure, produces two identical antigen-binding fragments called "Fab" fragments, and a residual "Fc" fragment (a name reflecting its ability to crystallize readily). The Fab fragment contains the variable region domains of the heavy chains (V H ) and the first constant 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 is a C fragment containing one or more cysteines from the antibody hinge region. HF(ab')2 antibody fragments differ from Fab fragments by having several additional residues at the carboxy terminus of one domain. Fab'-SH is the designation used herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical linkages of antibody fragments are also known.

[0077] 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 the sequences in the Fc region, which is also recognized by Fc receptors (FcRs) found on certain types of cells.

[0078] 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.

[0079] A "single-chain Fv," also abbreviated as "sFv" or "scFv," is an antibody fragment comprising the VH and VL antibody domains linked in a single polypeptide chain. Preferably, the sFv polypeptide contains a VH domain that enables the sFv to form the desired structure for antigen binding. H Domain and V LThe sFv further comprises a polypeptide linker between the domains, which enables the sFv to form the desired structure for antigen binding. For a review of sFvs, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0080] A "functional fragment" of an antibody, such as an anti-TREM2 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 linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0081] The term "diabody" refers to a V domain in which intrachain, rather than 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 This 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 whose 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).

[0082] As used herein, a "chimeric antibody" refers to an antibody (immunoglobulin), such as a chimeric anti-TREM2 antibody of the present disclosure, in which a portion of the heavy and / or light chain is identical to or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical to or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, so long as the desired biological activity is exhibited (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies 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."

[0083] "Humanized" forms of non-human (e.g., murine) antibodies, such as humanized forms of the anti-TREM2 antibodies of the present disclosure, are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit, or non-human primate having the desired specificity, affinity, and / or capacity. In some instances, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulin sequences and all or substantially all of the FR regions are those of human immunoglobulin sequences. However, the FR region may contain one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR is typically no more than six in the H chain and no more than three in the L chain. Humanized antibodies will optionally comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0084] A "human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody, such as the anti-TREM2 antibody of the present disclosure, produced by a human and / or 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). Methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering antigen to transgenic animals that have been modified to produce such antibodies in response to antigen challenge, but whose endogenous gene loci have been disabled (see, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology). See also, e.g., Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated by human B cell hybridoma technology.

[0085] The terms "hypervariable region," "HVR," or "HV," as used herein, refer to regions of an antibody variable domain, such as the anti-TREM2 antibodies of the present disclosure, that are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies contain six HVRs: three VH (H1, H2, and H3) and three VL (L1, L2, and L3). In natural antibodies, H3 and L3 represent the most diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). In fact, naturally occurring camelid antibodies consist solely 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).

[0086] Several HVR delineations 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 by 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 shown below. JPEG0007725185000001.jpg39156

[0087] HVRs may also include "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) of the VL, and 26-35 (H1), 50-65 or 49-65 (preferred embodiment) (H2), and 93-102, 94-102, or 95-102 (H3) of the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these extended HVR definitions.

[0088] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0089] The phrases "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat," and variations thereof, refer to the numbering system used in the heavy or light chain variable domains of the antibody compilations in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, the FRs or HVRs of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). The Kabat numbering of residues for a given antibody may be determined by aligning the regions of homology of the antibody's sequence with the "standard" Kabat-numbered sequence.

[0090] 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 or Kabat 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). The "Kabat 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 or Kabat numbering system (see, e.g., U.S. Patent Application Publication No. 2010-280227).

[0091] As used herein, an "acceptor human framework" is a framework comprising the amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence or may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. When pre-existing amino acid changes are present in the VH, preferably these changes occur at only three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at these positions may be 71A, 73T, and / or 78A. In one embodiment, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or human consensus framework sequence.

[0092] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as defined in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). For example, for VL, the subgroup may be subgroup kappa I, kappa II, kappa III, or kappa IV as defined in Kabat et al., supra. Additionally, for VH, the subgroup may be subgroup I, subgroup II, or subgroup III as defined in Kabat et al., supra.

[0093] For example, an "amino acid modification" at a particular position of an anti-TREM2 antibody of the present disclosure refers to a substitution or deletion of the particular residue, or an insertion of at least one amino acid residue adjacent to the particular residue. An insertion "adjacent to" a particular residue refers to an insertion within one to two residues thereof. The insertion may be at the N-terminus or C-terminus of the particular residue. A preferred amino acid modification herein is a substitution.

[0094] An "affinity matured" antibody, such as the affinity matured anti-TREM2 antibody of the present disclosure, is an antibody with one or more modifications in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen compared to a parent antibody lacking those modification(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues has been described, for example, by Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0095] 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, 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 antibody 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, antibody 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. Thus, "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 of an antibody may be greater than or equal to 100 kJ / mL. 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 a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.

[0096] 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.

[0097] An "agonist" or "activating" antibody is an antibody, such as an agonist anti-TREM2 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.

[0098] An "antagonist" or "blocking" antibody is an antibody, such as an antagonist anti-TREM2 antibody of the present disclosure, that reduces or eliminates (e.g., decreases) antigen binding to one or more ligands and / or reduces or eliminates (e.g., decreases) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, an antagonist or blocking antibody substantially or completely inhibits antigen binding to one or more ligands and / or one or more activities or functions of the antigen.

[0099] 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.

[0100] 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 the carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU or Kabat numbering system) may be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, an intact antibody composition may include an antibody population having all K447 residues removed, an antibody population having no K447 residue removed, and an antibody population having a mixture of antibodies with and without the K447 residue. Native-sequence Fc regions suitable for use in the antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0101] 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.

[0102] 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 a 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.

[0103] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a native-sequence human FcR. Furthermore, a preferred FcR is one that binds IgG antibodies (gamma receptors) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptors") and FcγRIIB ("inhibiting receptors"), which have similar amino acid sequences that differ primarily in their cytoplasmic domains. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. (See, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, 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.

[0104] 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 transgenic human cell lines expressing human FcRn, or in primates to which polypeptides having variant Fc regions are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcR. See also, for example, Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0105] As used herein, "percent amino acid sequence identity" and "homology" with respect to peptide, polypeptide, or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to those in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, without considering conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be accomplished in a variety of ways within the skill of those in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN™ (DNASTAR) software. Those skilled in the art can determine appropriate parameters for alignment comparisons, including any algorithms known in the art necessary to achieve maximal alignment over the full length of the sequences being compared.

[0106] An "isolated" nucleic acid molecule encoding an antibody, such as the anti-TREM2 antibody of the present disclosure, is a nucleic acid molecule that is identified and separated from at least one contaminant nucleic acid molecule that is normally associated with the environment in which it is produced. Preferably, an isolated nucleic acid is free from association with 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 naturally occur in cells.

[0107] As used herein, the term "vector" refers to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, into which additional DNA segments can be ligated into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of the host cell upon introduction into the host cell, and thereby be replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." In general, expression vectors useful in recombinant DNA techniques are often in the form of plasmids. As used herein, "plasmid" and "vector" may be used interchangeably, as the plasmid is the most commonly used form of vector.

[0108] "Polynucleotide" or "nucleic acid," as used interchangeably herein, refers to a polymer of nucleotides of any length, including DNA and RNA. The nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthetic reaction. A polynucleotide can also contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. The sequence of nucleotides can also be interrupted by non-nucleotide components. A polynucleotide can also contain modification(s) that are performed after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps," substitution of one or more of the naturally occurring nucleotides with analogs, e.g., those with uncharged linkages (e.g., methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and those with 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 with intercalators (e.g., acridine, psoralens, etc.), those containing chelators (e.g., metals, radioactive metals, boron, metal oxides, etc.), those containing alkylators, those with modified linkages (e.g., alpha-anomeric nucleic acids, etc.), and unmodified forms of the polynucleotide(s). Additionally, any of the hydroxyl groups normally present on the sugars may be replaced with, for example, phosphonate groups, phosphate groups, protected with standard protecting groups, or activated to prepare further linkages to additional nucleotides, or conjugated to a solid or semi-solid support. The 5' and 3' terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of 1 to 20 carbon atoms. Other hydroxyls can also be derivatized to standard protecting groups.Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars commonly known in the art, including, for example, 2'-O-methylribose, 2'-O-allylribose, 2'-fluororibose, or 2'-azidoribose; carbocyclic sugar analogs; α-anomeric sugars; epimeric sugars such as arabinose, xylose, or lyxose; pyranose sugars; furanose sugars; sedoheptulose; acyclic analogs; and basic nucleoside analogs such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which phosphate is replaced by P(O)S ("thioate"), P(S)S ("dithioate"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO, or CH2 ("formacetal"), where each R or R' is independently H or substituted or unsubstituted alkyl (1-20C), optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl, or aralkyl. Not all linkages in a polynucleotide need be identical. The foregoing applies to all polynucleotides referred to herein, including RNA and DNA.

[0109] 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 into which a polynucleotide(s) of the invention have been transfected in vivo.

[0110] As used herein, a "carrier" includes a pharmaceutically acceptable carrier, excipient, or stabilizer that is nontoxic to cells or mammals exposed thereto at the dosages and concentrations employed. Often, 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 dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, polyethylene glycol (PEG), and PLURONICS™.

[0111] The term "about" as used herein refers to a normal range of error for the respective value, which is readily known to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that relate to that value or parameter itself.

[0112] 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.

[0113] It is understood that the aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0114] overview The present disclosure relates to anti-TREM2 antibodies (e.g., monoclonal 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.

[0115] In some embodiments, the agonist activity of an anti-TREM2 antibody of the present disclosure is due, at least in part, to the ability of the antibody to enhance one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein without competing with or otherwise blocking the binding of the one or more TREM2 ligands to the TREM2 protein. In some embodiments, the enhancement of one or more TREM2 activities by an anti-TREM2 antibody is compared to one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein in the absence of the anti-TREM2 antibody. In some embodiments, the enhancement of one or more TREM2 activities can be determined or tested in vitro or in vivo by any of several methods disclosed herein (see, e.g., Examples 3-13 and 24).

[0116] Accordingly, certain aspects of the present disclosure are based, at least in part, on the identification of anti-TREM2 antibodies that can bind to both human and mouse TREM2 with high affinity (see, e.g., Example 1) and activate and enhance TREM2 activity (e.g., by synergizing with a TREM2 ligand) (see, e.g., Examples 3-13 and 24). Advantageously, agonistic anti-TREM2 antibodies of the present disclosure have been shown to be therapeutically effective in treating Alzheimer's disease and symptoms of Alzheimer's disease in several mouse models of Alzheimer's disease (see, e.g., Example 16).

[0117] A further aspect of the present disclosure is based, at least in part, on the surprising discovery that the TREM2 antibodies of the present disclosure can also induce antagonist activity when produced or otherwise formatted such that the antibodies are unable to induce or maintain TREM2 receptor clustering. In some embodiments, the anti-TREM2 antibodies of the present disclosure exhibit one or more antagonist TREM2 activities, including, but not limited to, inhibition of TREM2-dependent gene activation (see, e.g., Examples 7 and 8).

[0118] TREM2 protein In one aspect, the present disclosure provides antibodies that bind to a TREM2 protein of the disclosure and induce one or more TREM2 activities and / or enhance one or more TREM2 activities after binding to a TREM2 protein expressed in a cell.

[0119] TREM2 proteins of the present disclosure include, but are not limited to, the human TREM2 protein (Uniprot Accession No. Q9NZC2, SEQ ID NO: 1), and non-human mammalian TREM2 proteins, such as the mouse TREM2 protein (Uniprot Accession No. Q99NH8, SEQ ID NO: 2), the rat TREM2 protein (Uniprot Accession No. D3ZZ89, SEQ ID NO: 3), the rhesus monkey TREM2 protein (Uniprot Accession No. F6QVF2, SEQ ID NO: 4), the bovine TREM2 protein (Uniprot Accession No. Q05B59, SEQ ID NO: 5), the equine TREM2 protein (Uniprot Accession No. F7D6L0, SEQ ID NO: 6), the porcine TREM2 protein (Uniprot Accession No. H2EZZ3, SEQ ID NO: 7), and the canine TREM2 protein (Uniprot Accession No. E2RP46, SEQ ID NO: 8). As used herein, "TREM2 protein" refers to both wild-type and naturally occurring variant sequences.

[0120] Triggering receptor expressed on myeloid cells 2 (TREM2) is variously referred to as TREM-2, TREM2a, TREM2b, TREM2c, triggering receptor expressed on myeloid cells-2a, and triggering receptor expressed on monocytes 2. TREM2 is a 230-amino acid membrane protein. TREM2 is an immunoglobulin-like receptor expressed primarily on myeloid cells, including, but not limited to, macrophages, dendritic cells, monocytes, dermal Langerhans cells, Kupffer cells, osteoclasts, and microglia. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 phosphorylates and signals through DAP12 (an ITAM domain adaptor protein). In some embodiments, TREM2 signaling leads to downstream activation of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signaling is important for activating TREM2 activity, for example, in the context of infection responses. TLRs, such as those expressed on macrophages and dendritic cells, also play a key role in pathological inflammatory responses.

[0121] In some embodiments, an example of a human TREM2 amino acid sequence is shown below as SEQ ID NO: 1: JPEG0007725185000002.jpg42127

[0122] 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).

[0123] 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.

[0124] Homologs of human TREM2 include, but are not limited to, the 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.

[0125] DAP12 protein In one aspect, the present disclosure provides antibodies that further bind to a DAP12 protein of the disclosure and can modulate one or more DAP12 activities after binding to DAP12 expressed in a cell.

[0126] DAP12 proteins of the present disclosure include, but are not limited to, mammalian (e.g., non-human mammalian) DAP12 proteins, human DAP12 proteins (Uniprot accession number O43914), mouse DAP12 proteins (Uniprot accession number O54885), rat DAP12 proteins (Uniprot accession number Q6X9T7), rhesus monkey DAP12 proteins (Uniprot accession number Q8WNQ8), bovine DAP12 proteins (Uniprot accession number Q95J80), and porcine DAP12 proteins (Uniprot accession number Q9TU45). As used herein, "DAP12 protein" refers to both wild-type and naturally occurring variant sequences.

[0127] 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 can 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 plays a role in signal transduction, bone formation, brain myelination, and inflammation.

[0128] 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 believed to be TREM2, which also causes PLOSL. Multiple alternative transcript variants encoding distinct 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.

[0129] In some embodiments, an example of a human DAP12 amino acid sequence is shown below as SEQ ID NO:887. JPEG0007725185000003.jpg23155

[0130] 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: 887), a transmembrane domain located at amino acid residues 41-61 of human DAP12 (SEQ ID NO: 887), and an intracellular domain located at amino acid residues 62-113 of human DAP12 (SEQ ID NO: 887). An immunoreceptor tyrosine-based activation motif (ITAM) domain is located at amino acid residues 80-118 of human DAP12 (SEQ ID NO: 887).

[0131] 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.

[0132] Anti-TREM2 antibody Certain aspects of the present disclosure relate to antibodies (e.g., monoclonal antibodies) that specifically bind to TREM2. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 protein, which is expressed on cells. In some embodiments, the antibodies of the present disclosure bind to TREM2 protein expressed on one or more human cells selected from human dendritic cells, human macrophages, human monocytes, human osteoclasts, human dermal Langerhans cells, human Kupffer cells, human microglia, and any combination thereof. In some embodiments, the antibodies of the present disclosure 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.

[0133] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the TREM2 protein without competing with, inhibiting, or otherwise blocking one or more TREM2 ligands from binding to the TREM2 protein. Examples of suitable TREM2 ligands include, but are not limited to, a TREM2 ligand expressed by E. coli cells, apoptotic cells, nucleic acids, anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2, anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidated APOE3, lipidated APOE4, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptide. Thus, in certain embodiments, the one or more TREM2 ligands include E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine (PS), sulfatides, phosphatidylcholine, sphingomyelin (SM), phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptides.

[0134] In some embodiments, the anti-TREM2 antibodies of the present disclosure do not inhibit the proliferation of one or more innate immune cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure have a K of less than 50 nM, less than 45 nM, less than 40 nM, less than 35 nM, less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 9 nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. D In some embodiments, the anti-TREM2 antibodies of the present disclosure accumulate in the brain, cerebrospinal fluid (CSF), or both, to a level that represents 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, or 10% or more of the antibody concentration in the blood. In some embodiments, the dissociation constant (K D) is determined at a temperature of about 4° C. In some embodiments, K D is determined using a monovalent antibody (e.g., Fab) or a monovalent form of the full-length antibody. Methods for preparing and selecting antibodies that interact and / or bind with specificity to TREM2 are described herein (see, e.g., Example 1).

[0135] Agonist anti-TREM2 antibodies The anti-TREM2 antibodies of the present disclosure generally bind to one or more TREM2 proteins expressed on cells. One class of antibodies is agonistic antibodies. For example, the TREM2 receptor is thought to require clustering on the cell surface to transmit signals. Thus, agonistic antibodies may have unique features that stimulate the TREM2 receptor. 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. In addition, agonistic anti-TREM2 antibodies of the present disclosure may exhibit the ability to bind to TREM2 without blocking the simultaneous binding of one or more TREM2 ligands. The anti-TREM2 antibodies of the present disclosure may also exhibit additive and / or synergistic functional interactions with one or more TREM2 ligands. Thus, in some embodiments, the maximum activity of TREM2 when bound to an anti-TREM2 antibody of the present disclosure in combination with one or more TREM2 ligands of the present disclosure may be higher (e.g., enhanced) than the maximum activity of TREM2 when exposed to a saturating concentration of the ligand alone or to a saturating concentration of the antibody alone. In addition, the activity of TREM2 at a given concentration of TREM2 ligand may be higher (e.g., enhanced) in the presence of the antibody. Thus, in some embodiments, an anti-TREM2 antibody of the present disclosure has an additive effect with one or more TREM2 ligands, enhancing one or more TREM2 activities when bound to a TREM2 protein. In some embodiments, an anti-TREM2 antibody of the present disclosure synergizes with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments, an anti-TREM2 antibody of the present disclosure increases the potency of one or more TREM2 ligands to induce one or more TREM2 activities compared to the potency of the one or more TREM2 ligands to induce one or more TREM2 activities in the absence of the antibody. In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities in the absence of cell surface clustering of TREM2.In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities by inducing or maintaining cell surface clustering of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure are clustered by one or more Fc-gamma receptors expressed on one or more immune cells, including, but not limited to, B cells and microglial cells. In some embodiments, the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein is measured in primary cells or in cell lines, including, but not limited to, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, dermal Langerhans cells, and Kupffer cells, and the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein is measured, for example, using an in vitro cell assay.

[0136] In vivo, anti-TREM2 antibodies of the present disclosure can activate receptors by multiple potential mechanisms. In some embodiments, agonistic anti-TREM2 antibodies of the present disclosure have the ability to activate TREM2 in solution, due to precise epitope specificity, without the need for clustering with a secondary antibody bound on a plate or via Fcg receptors. In some embodiments, anti-TREM2 antibodies of the present disclosure have a human antibody isotype, such as IgG2, which, due to their unique structure, has the inherent ability to cluster receptors or hold receptors in a clustered configuration, thereby activating receptors such as TREM2 without binding to Fc receptors (e.g., White et al., (2015) Cancer Cell 27, 138-148).

[0137] In some embodiments, the anti-TREM2 antibodies of the present disclosure cluster receptors (e.g., TREM2) by binding to Fcg receptors on adjacent cells. Binding of the constant IgG Fc portion of 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 a preferred means of clustering antibodies in vivo. Any suitable assay described herein (see, e.g., Example 4) may be used to determine antibody clustering.

[0138] Other mechanisms may also be used to cluster receptors (e.g., TREM2). For example, in some embodiments, antibody fragments (e.g., Fab fragments) 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. In some embodiments, 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).

[0139] In some embodiments, antibodies of the present disclosure that bind to the TREM2 protein may include agonist antibodies that, by virtue of their epitope specificity, bind to TREM2 and activate one or more TREM2 activities. In some embodiments, such antibodies may stimulate target antigens to transduce signals by binding to a ligand-binding site on TREM2 and mimicking the action of one or more TREM2 ligands, or by binding to one or more domains that are not the ligand-binding site. In some embodiments, the antibodies do not compete with or otherwise block ligand binding to TREM2. In some embodiments, the antibodies act additively or synergistically with one or more TREM2 ligands to activate and / or enhance more than one TREM2 activity.

[0140] In some embodiments, TREM2 activities that may be induced and / or enhanced by an anti-TREM2 antibody of the present disclosure and / or one or more TREM2 ligands of the present disclosure include, but are not limited to, TREM2 binding to DAP12, TREM2 phosphorylation, DAP12 phosphorylation, activation of one or more tyrosine kinases (optionally, the one or more tyrosine kinases include Syk kinase, ZAP70 kinase, or both), activation of phosphatidylinositol 3-kinase (PI3K), activation of protein kinase B (Akt), activation of plasma membrane Recruitment of phospholipase C-gamma (PLC-gamma) to the plasma membrane, activation of PLC-gamma, or both, recruitment of the TEC-family kinase dVav to the plasma membrane, activation of nuclear factor-rB (NF-rB), inhibition of MAPK signaling, phosphorylation of linker for activating T cells (LAT), linker for activating B cells (LAB), or both, activation of IL-2-inducible tyrosine kinase (Itk), IFN-β, IL-1α, IL-1β, TNF-α, YM-1, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CC modulation of one or more pro-inflammatory mediators selected from L3, CCL4, CCL5, CCR2, CXCL-10, Gata3, Rorc, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, GM-CSF, CSF-1, MHC-II, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23 (optionally, modulation is indicative of a signal transduction pathway in macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, skin Langerhans cells, or the like); modulation of one or more anti-inflammatory mediators selected from the group consisting of IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and soluble receptors for TNF or IL-6 (optionally, the modulation is in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells,and microglial cells), modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR), activation of extracellular signal-regulated kinase (ERK) phosphorylation, modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR), activation of extracellular signal-regulated kinase (ERK) phosphorylation, modulation of one or more genes whose expression is increased upon induction of inflammation (optionally, the one or more genes are selected from the group consisting of Fabp3, Fabp5, and LDR), activation of macrophages, M1 macrophages, activated M1 macrophages, Modulation of CC chemokine receptor 7 (CCR7) expression in one or more cells selected from phages, M2 macrophages, dendritic cells, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, and any combination thereof; induction of microglial cell chemotaxis toward CCL19- and CCL21-expressing cells; normalization of disrupted TREM2 / DAP12-dependent gene expression; recruitment of Syk, ZAP70, or both to the DAP12 / TREM2 complex; Increased activity of multiple TREM2-dependent genes (optionally, one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factor), increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof, stimulating or modulating the function of T cells, dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, macrophages, increasing the ability of bone marrow-derived dendritic cells to stimulate or regulate antigen-specific T cell function, or normalizing the ability of bone marrow-derived dendritic cells to stimulate or regulate antigen-specific T cell function, or both (optionally, the antigen-specific T cells are one or more cells selected from CD8+ T cells, CD4+ T cells, regulatory T cells, and any combination thereof);Induction of osteoclast production, an increase in the rate of osteoclast formation, or both, an increase in survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, dermal Langerhans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof, an increase in survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof increasing the function of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; clearance of apoptotic neurons, clearance of neural tissue debris, clearance of non-neural tissue debris, clearance of bacteria or other foreign bodies, clearance of pathogens, clearance of tumor cells, or any combination thereof; Activation of one or more types of ATP (optionally, the pathogen may be 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, gelsoli the target of the present invention is a target of apoptotic neurons, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogens, tumor cells, and the like.or any combination thereof (optionally, the pathogen 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, ribosomal protein ... zozyme, beta2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, and repeat-associated non-ATG (RAN) translation products containing dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR), antisense GGCCCC (G2C4) repeat expansion RNA, CD83, CD86 Modulation of expression of one or more stimulatory molecules selected from MHC class II, CD40, and any combination thereof (optionally, CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally, the dendritic cells comprise bone marrow-derived dendritic cells); modulation of secretion of one or more pro-inflammatory mediators (optionally, the one or more inflammatory mediators are selected from IFN-β, IL-1α, IL-1β, CD86, TNF-α, IL-6, IL-8, CRP, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-1α, IL-1β ... modulation of one or more anti-inflammatory mediators selected from the group consisting of soluble receptors for TNF, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23, and any combination thereof), IL-4, IL-10, TGF-β, IL-13, IL-35, IL-16, IFN-alpha, IL-1Ra, VEGF, G-CSF, YM, AXL, FLT1, and TNF or IL-6; C1qa, C1qB, C1qC, C1s, C1R;These include modulation of expression of one or more proteins selected from C4, C2, C3, ITGB2, HMOX1, LAT2.CASP1, CSTA, VSIG4, MS4A4A, C3AR1, GPX1, TyroBP, ALOX5AP, ITGAM, SLC7A7, CD4, ITGAX, PYCARD, and VEGF, increased memory, and reduced cognitive impairment. In some embodiments, the anti-TREM2 antibodies of the present disclosure, when administered to an individual, increase memory and / or reduce cognitive impairment.

[0141] As used herein, an anti-TREM2 antibody of the present disclosure enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to a TREM2 protein if it induces at least a 2-fold, at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, at least a 10-fold, a...

Claims

1. 1. An isolated human or humanized monoclonal antibody that binds to a TREM2 protein, comprising: HVR-L1, HVR-L2, HVR-L3, HVR-H1, HVR-H2, and HVR-H3, (a) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 11, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 26, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 36, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 51, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 69, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 88; (b) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 60, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 78, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 97; (c) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 19, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 28, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 43, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 60, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 888, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 97; or (d) HVR-L1 comprises the amino acid sequence of SEQ ID NO: 16, HVR-L2 comprises the amino acid sequence of SEQ ID NO: 29, HVR-L3 comprises the amino acid sequence of SEQ ID NO: 35, HVR-H1 comprises the amino acid sequence of SEQ ID NO: 65, HVR-H2 comprises the amino acid sequence of SEQ ID NO: 84, and HVR-H3 comprises the amino acid sequence of SEQ ID NO: 102; antibody.

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

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

4. The isolated antibody of any one of claims 1 to 3, which is of the IgG class, IgM class, or IgA class.

5. 5. The isolated antibody of claim 4, which is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.

6. (a) the isolated antibody has a human IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of N297A, D265A, D270A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, L328E, P238D, S267E, L328F, E233D, G237D, H268D, P271G, A330R, and any combination thereof, wherein residue numbering is according to EU numbering, or comprises an amino acid deletion in the Fc region at a position corresponding to glycine 236; (b) the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and hinge region, wherein optionally 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: 886); and optionally 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 (residue numbering according to EU numbering); (c) the isolated antibody has an IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at residue positions selected from the group consisting of P238S, V234A, G237A, H268A, H268Q, V309L, A330S, P331S, C214S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, H268E, N297A, N297Q, A330L, and any combination thereof, wherein residue numbering is according to EU numbering; (d) the isolated antibody has a human 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, E233P, F234V, L234A / F234A, S228P, S241P, L248E, T394D, N297A, N297Q, L235E, and any combination thereof, wherein residue numbering is according to EU numbering; or (e) The isolated antibody of claim 5, wherein 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 (residue numbering according to EU numbering).

7. i. amino acid residues 137 to 146 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 137 to 146 of SEQ ID NO: 1; ii. amino acid residues 139-147 of SEQ ID NO:1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 139-147 of SEQ ID NO:1; iii. amino acid residues 139-149 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 139-149 of SEQ ID NO: 1; iv. amino acid residues 142-152 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 142-152 of SEQ ID NO: 1; or v. amino acid residues 149-157 of SEQ ID NO:1, or amino acid residues on the TREM2 protein corresponding to amino acid residues 149-157 of SEQ ID NO:1 The isolated antibody of any one of claims 1 to 6, which binds to an epitope comprising:

8. 8. The isolated antibody of any one of claims 1 to 7, which binds to an epitope on a mammalian TREM2 protein comprising one or more amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO:1, or one or more amino acid residues corresponding to amino acid residues selected from the group consisting of E151, D152, H154, and E156 of SEQ ID NO:

1.

9. The isolated antibody of any one of claims 1 to 8, wherein the antibody is an antibody fragment, and the antibody fragment is an F(ab')2 fragment.

10. The isolated antibody of any one of claims 1 to 9, which is a bispecific antibody, a multivalent antibody, or a conjugated antibody.

11. The isolated antibody of any one of claims 1 to 10, which specifically binds to both human TREM2 and mouse TREM2.

12. (i) Dissociation constants (K) for human TREM2 ranging from 2.9 nM to 12.8 nM Ｄ ) and K Ｄ is determined at a temperature of 4°C, and / or (ii) dissociation constants (K) for mouse TREM2 ranging from 1.2 nM to 10.4 nM Ｄ ) and K Ｄ is determined at a temperature of 4°C, An isolated antibody according to any one of claims 1 to 11.

13. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of any one of claims 1 to 12.

14. A vector comprising the nucleic acid of claim 13.

15. 15. An isolated host cell comprising the vector of claim 14.

16. 16. A method for producing an antibody that binds to TREM2, comprising culturing the cell of claim 15 so that the antibody is produced.

17. 17. An isolated antibody that binds to TREM2 produced by the method of claim 16.

18. A pharmaceutical composition comprising the antibody of any one of claims 1 to 12 and a pharmaceutically acceptable carrier.

19. 13. 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, cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis, and cancer, comprising a therapeutically effective amount of the isolated antibody of any one of claims 1 to 12.

20. The method of claim 19, wherein the disease, disorder, or injury is Alzheimer's disease.

21. A medicament for inducing one or more TREM2 activities and enhancing one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein in an individual in need thereof, the medicament comprising a therapeutically effective amount of an isolated antibody of any one of claims 1 to 12.

22. A medicament for inducing or promoting survival of innate immune cells in an individual in need thereof, comprising a therapeutically effective amount of the isolated antibody of any one of claims 1 to 12.

23. The medicament of any one of claims 19 to 22, wherein 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 to stop codon substitution in the nucleic acid sequence encoding amino acid residue Glu14 of SEQ ID NO: 1; ii. A substitution of a glutamine with a stop codon in the nucleic acid sequence encoding the amino acid residue Gln33 of SEQ ID NO: 1; iii. A tryptophan to stop codon substitution in the 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 to stop codon substitution in the 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.

24. 23. The medicament of any one of claims 19 to 22, wherein 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.

25. The medicament of any one of claims 19 to 24, wherein the individual has a heterozygous variant of 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: 887; ii. a glycine to arginine amino acid substitution at the amino acid corresponding to amino acid residue Gly49 of SEQ ID NO: 887; iii. a deletion within exons 1 to 4 of the nucleic acid sequence encoding SEQ ID NO: 887; iv. an insertion of 14 amino acid residues in exon 3 of the nucleic acid sequence encoding SEQ ID NO: 887, and v. A guanine nucleotide deletion at the nucleotide corresponding to nucleotide residue G141 of the nucleic acid sequence encoding SEQ ID NO:887.

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