Anti-TREM2 antibodies and methods of use thereof

Abstract

To provide therapeutic agents that modulate the activity of a triggering receptor expressed on myeloid cells 2 (TREM2) or the levels of soluble TREM2 (sTREM2).SOLUTION: The present invention provides an isolated antibody or an antigen-binding portion thereof that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2) protein, where the antibody or antigen-binding portion thereof decreases levels of soluble TREM2 protein (sTREM2).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application Nos. 62 / 558,803, filed September 14, 2017, 62 / 583,379, filed November 8, 2017, and 62 / 621,380, filed January 24, 2018, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] background Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor expressed on microglia and is thought to function in regulating phagocytosis, cell survival, and the production of pro-inflammatory cytokines. Mutations in TREM2 have been identified in neurodegenerative diseases, including Alzheimer's disease, Nasu-Hakola disease, Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. Furthermore, altered levels of soluble TREM2 (sTREM2) have been reported in the cerebrospinal fluid of patients with Alzheimer's disease or frontotemporal dementia who have mutations in TREM2.

[0003] There remains a need for therapeutic agents that modulate TREM2 activity or sTREM2 levels. Summary of the Invention

[0004] Quick Overview In one aspect, an isolated antibody or antigen-binding portion thereof that specifically binds to triggering receptor 2 (TREM2) protein expressed on human myeloid cells is provided. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., decreases or increases) the level of sTREM2. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., decreases or increases) the level of sTREM2 and further modulates (e.g., enhances or inhibits) one or more TREM2 activities. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., increases or inhibits) spleen tyrosine kinase (Syk) phosphorylation. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) phagocytosis. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) the migration of myeloid cells, macrophages, microglia, or disease-associated microglia. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) the differentiation of myeloid cells, macrophages, microglia, or disease-associated microglia. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) survival of myeloid cells, macrophages, microglia, or disease-associated microglia. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) one or more TREM2 activities without blocking binding of a native TREM2 ligand. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) one or more TREM2 activities induced by a TREM2 ligand. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., selectively enhances or selectively inhibits) one or more TREM2 activities induced by a TREM2 ligand. In some embodiments, the antibody or antigen-binding portion thereof modulates (e.g., enhances or inhibits) one or more TREM2 activities induced by a TREM2 ligand, butIn some embodiments, the antibody or antigen-binding portion thereof blocks the activation of TREM2 by a TREM2 ligand. In some embodiments, the antibody or antigen-binding portion thereof blocks the binding of a TREM2 ligand to TREM2. In some embodiments, the TREM2 ligand is selected from the group consisting of 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkyl Acylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhC) er), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocobalamin (LYS) Phosphorus (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N-acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC),palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (SalP), sphingomyelin (SM), sphingosine, sphingosine-1-phosphate (SolP), and sulfatide.

[0005] In another aspect, an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 and recognizes an epitope of human TREM2 that is the same or substantially the same as an epitope recognized by an antibody clone described herein. In some embodiments, the antibody or antigen-binding portion is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2. .D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 4 2E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 5 The antibody clone recognizes an epitope of human TREM2 that is the same as or substantially the same as an epitope recognized by an antibody clone selected from the group consisting of 5B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. In some embodiments, the antibody or antigen-binding portion recognizes an epitope on human TREM2 that is the same as or substantially the same as the epitope recognized by RS9.F6. In some embodiments, the antibody or antigen-binding portion binds to an epitope on human TREM2 that includes amino acid residues 140-144. In some embodiments, the antibody or antigen-binding portion makes direct contact with one or more of residues Asp140, Leu141, Trp142, Phe143, and Pro144. In some embodiments, the antibody or antigen-binding portion makes direct contact with residue Trp142.In some embodiments, the antibody or antigen-binding portion makes direct contact with each of residues Asp140, Leu141, Trp142, Phe143, and Pro144. In some embodiments, the antibody or antigen-binding portion binds to a TREM2 fragment comprising or consisting of amino acid residues 140-148.

[0006] In some embodiments, an antibody or antigen-binding portion thereof having one or more TREM2-related activities described herein also can be selected from the antibody clones described herein (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21 D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 3 0F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F1 0, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS The antibody or antigen-binding portion also recognizes an epitope on human TREM2 that is the same as or substantially the same as the epitope recognized by RS9.F6 (an antibody clone selected from the group consisting of RS9.11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10). In some embodiments, the antibody or antigen-binding portion recognizes an epitope on human TREM2 that is the same as or substantially the same as the epitope recognized by RS9.F6. In some embodiments, the antibody or antigen-binding portion binds to an epitope on human TREM2 that includes amino acid residues 140-144. In some embodiments, the antibody or antigen-binding portion makes direct contact with one or more of residues Asp140, Leu141, Trp142, Phe143, and Pro144. In some embodiments, the antibody or antigen-binding portion makes direct contact with residue Trp 142. In some embodiments, the antibody or antigen-binding portion makes direct contact with each of residues Asp 140, Leu 141, Trp 142, Phe 143, and Pro 144.In some embodiments, the antibody or antigen-binding portion binds to a TREM2 fragment comprising or consisting of amino acid residues 140-148.

[0007] In another aspect, an antibody or antigen-binding portion thereof is provided having the sequence of one or more CDRs, heavy chain variable region, and / or light chain variable region of an antibody described herein. In some embodiments, the antibody or antigen-binding portion is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D6.G2, 26D11, 26D8.B1, 26D9 ... 6D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2. H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4 .B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11 .4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1 , RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10, and comprises one or more complementarity determining regions (CDRs) (e.g., all CDRs) that have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the CDRs of an antibody clone selected from the group consisting of RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D 2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 4 2E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55 It comprises one or more CDRs (e.g., all CDRs) with up to two amino acid substitutions based on the CDRs of an antibody clone selected from the group consisting of B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E 2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11. B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F1 0, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C1 and CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that are identical to the heavy chain CDR1 (CDR-H1), heavy chain CDR2 (CDR-H2), heavy chain CDR3 (CDR-H3), light chain CDR1 (CDR-L1), light chain CDR2 (CDR-L2), and light chain CDR3 (CDR-L3) of an antibody clone selected from the group consisting of:

[0008] In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5. A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F 1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4 A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, The antibody clone comprises a heavy chain variable region having an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of an antibody clone selected from the group consisting of RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38 E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 5 5B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.The antibody clones comprise a light chain variable region comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of an antibody clone selected from the group consisting of: RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 30F3.A3, 30F4.A4, 30F5.A5, 30F6.A6, 30F7.A7, 30F8.A8, 30F9.A9, 30F10.A1, 30F11.A1, 30F12.A2, 30F13.A3, 30F14.A4, 30F15.A5, 30F16.A6, 30F17.A7, 30F18.A8, 30F19.A9, 30F20.A1, 30F21.A1, 30F22.A1, 30F23.A1, 30F24.A1, 30F25.A2, 30F26.A1, 30F27.A1, 30F28.A1, 30F29.A2, 30F30.A1, 30F31.A1, 30F32.A1, 30F33.A1, 30F34.A1 8E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11 and a nucleotide sequence encoding at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 1109%, 1110%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, 140%, 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%, 150%, 151%, 152%, 153%, 154%, 155%, 156%, 157%, 158%, 159%, 160%, 161%, 162%, 163%, 164%, 165%, 166%, 167%, 168%, 169%, 170%, 171%, 172%, 173%, 174%, 175%, 176%, 177%, 178%, 179%, 180%, 181%, 182%, 183%, 184%, 185%, 186%, 187%, 188%, 189%, 189%, 190%, %, 98%, or 99% sequence identity, and the heavy chain variable region includes 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55 B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, R The antibody clone comprises a light chain variable region comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of an antibody clone selected from the group consisting of S11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0009] In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of (i) 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2. A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51 D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11. 1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. and (ii) a heavy chain variable region that has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of the antibody clone selected from the group consisting of:In some embodiments, the antibody or antigen-binding portion thereof is selected from the group consisting of (i) 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2. A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51 D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11. 1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. and (ii) a light chain variable region that has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of the antibody clone selected from the group consisting of:

[0010] In some embodiments, the antibody or antigen-binding portion thereof (i)2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2 , 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E 9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D 3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, R an antibody clone selected from the group consisting of S11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10; a heavy chain variable region having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of the antibody clone, and (ii) an amino acid sequence comprising CDR-H1, CDR-H2, and CDR-H3 that are identical to CDR-H1, CDR-H2, and CDR-H3 of the antibody clone; (i)2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2 , 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9 .E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3 , 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS1 1.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. and (ii) a light chain variable region having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region, and (iii) an amino acid sequence comprising CDR-L1, CDR-L2, and CDR-L3 that is identical to CDR-L1, CDR-L2, and CDR-L3 of the antibody clone.

[0011] In some embodiments, an antibody or antigen-binding portion thereof having one or more TREM2-related activities described herein also comprises an antibody described herein (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D 6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51 D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS 9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11. The antibody clones may comprise one or more CDRs, heavy chain variable region, and / or light chain variable region sequences of an antibody clone selected from the group consisting of: RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0012] In some embodiments, an antibody or antigen-binding portion thereof that specifically binds to human TREM2 is (a) a heavy chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 75, 79, 82, 86, 308, and 316, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317; (d) a light chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. The amino acid sequence comprises one or more (e.g., one, two, three, four, five, or all six) CDRs selected from the group consisting of:

[0013] In some embodiments, the antibody or antigen-binding portion thereof (a) a heavy chain CDR1 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317; (d) a light chain CDR1 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. The amino acid sequence comprises one or more (e.g., one, two, three, four, five, or all six) CDRs selected from the group consisting of:

[0014] In some embodiments, the antibody or antigen-binding portion thereof (a) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 12, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (b) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 37, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (c) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 39, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 40, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 41, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 42, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 43, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 44, or (d) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 45, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 47, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 49, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50, or (e) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 51, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 52, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 53, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 54, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 55, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 56, or (f) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 59, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 61, or (g) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 62, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 63, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 64, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 65, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 66, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 67, or (h) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 68, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 69, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 70, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 71, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 72, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 73, or (i) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 75, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 78, or (j) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 79, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 80, or (k) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 81, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 82, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 83, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 84, or (l) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 86, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 87, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 88, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 89, or (m) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 307, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 308, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 309, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 311, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 312, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 313, or (n) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 315, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 316, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 317, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 319, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50 Includes:

[0015] In some embodiments, the antibody or antigen-binding portion thereof a heavy chain variable region comprising (i) an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 6, and (ii) CDR-H1, CDR-H2, and CDR-H3 of SEQ ID NOs: 8, 9, and 10, respectively; and / or a light chain variable region comprising: (i) an amino acid sequence having at least 75% sequence identity to SEQ ID NO: 7; and (ii) CDR-L1, CDR-L2, and CDR-L3 of SEQ ID NOs: 11, 12, and 13, respectively. Includes:

[0016] In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, and 314. In some embodiments, the antibody or antigen-binding portion thereof comprises a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, and 318. In some embodiments, the antibody or antigen-binding portion thereof comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, and 314, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, and 318.

[0017] In some embodiments, the antibody or antigen-binding portion thereof (a) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7; or (b) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 14, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 25; or (c) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 26; or (d) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 16, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27; or (e) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 28; or (f) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 18, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 29; or (g) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 19, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30; or (h) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 20, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 31; or (i) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 21, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 32; or (j) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 22 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33; or (k) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 23, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34; or (l) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 24, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 35; or (m) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 306, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 310; or (n) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 314, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 318. Includes:

[0018] In some embodiments, in any of the anti-TREM2 antibodies described herein, the antibody comprises a first Fc polypeptide and, optionally, a second Fc polypeptide. In some embodiments, the antibody comprises a first Fc polypeptide and a second Fc polypeptide. In some embodiments, the first Fc polypeptide is a modified Fc polypeptide and / or the second Fc polypeptide is a modified Fc polypeptide.

[0019] In some embodiments, for any of the anti-TREM2 antibodies described herein, the antibody (a) a first antigen-binding moiety comprising a first variable region that specifically binds to a TREM2 protein (e.g., human TREM2), the first antigen-binding moiety comprising (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain; (b) a second antigen-binding portion comprising a second variable region that specifically binds to a TREM2 protein (e.g., human TREM2), the second antigen-binding portion comprising (i) a second heavy chain comprising a first Fc polypeptide and (ii) a second light chain; The first Fc polypeptide and the second Fc polypeptide form an Fc dimer.

[0020] In some embodiments, the first Fc polypeptide is a modified Fc polypeptide and / or the second Fc polypeptide is a modified Fc polypeptide.

[0021] In some embodiments, the first variable region and the second variable region recognize the same epitope in the TREM2 protein. In some embodiments, the first variable region and the second variable region recognize different epitopes in the TREM2 protein.

[0022] In some embodiments, the first Fc polypeptide and the second Fc polypeptide each contain a modification that promotes heterodimerization, in some embodiments, one of the Fc polypeptides has a T366W substitution and the other Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering.

[0023] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises a native FcRn-binding site, hi some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises a modification that alters FcRn binding.

[0024] In some embodiments, the first Fc polypeptide and the second Fc polypeptide have no effector function. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises a modification that reduces effector function. In some embodiments, the modification that reduces effector function comprises a substitution of Ala at position 234 and Ala at position 235, according to EU numbering.

[0025] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises amino acid changes that increase serum half-life relative to the native Fc sequence. In some embodiments, the amino acid changes comprise substitutions of Tyr at position 252, Thr at position 254, and Glu at position 256, according to EU numbering. Alternatively, in other embodiments, the amino acid changes comprise substitutions of Leu at position 428 and Ser at position 434, according to EU numbering. Alternatively, in further embodiments, the amino acid changes comprise substitutions of Ser or Ala at position 434, according to EU numbering.

[0026] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide specifically binds to the transferrin receptor. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises at least two substitutions at positions selected from the group consisting of 384, 386, 387, 388, 389, 390, 413, 416, and 421, according to EU numbering. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises substitutions at at least 3, 4, 5, 6, 7, 8, or 9 positions.

[0027] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide further comprises one, two, three, or four substitutions at positions including, according to EU numbering, 380, 391, 392, and 415. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide further comprises one, two, or three substitutions at positions including, according to EU numbering, 414, 424, and 426.

[0028] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises a Trp at position 388. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises an aromatic amino acid at position 421. In some embodiments, the aromatic amino acid at position 421 is Trp or Phe.

[0029] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises at least one position selected from the following: position 380 is Trp, Leu, or Glu, position 384 is Tyr or Phe, position 386 is Thr, position 387 is Glu, position 388 is Trp, position 389 is Ser, Ala, Val, or Asn, position 390 is Ser or Asn, position 413 is Thr or Ser, position 415 is Glu or Ser, position 416 is Glu, and position 421 is Phe.

[0030] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 positions selected from the following: position 380 is Trp, Leu, or Glu, position 384 is Tyr or Phe, position 386 is Thr, position 387 is Glu, position 388 is Trp, position 389 is Ser, Ala, Val, or Asn, position 390 is Ser or Asn, position 413 is Thr or Ser, position 415 is Glu or Ser, position 416 is Glu, and position 421 is Phe.

[0031] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises the following 11 positions: position 380 is Trp, Leu, or Glu, position 384 is Tyr or Phe, position 386 is Thr, position 387 is Glu, position 388 is Trp, position 389 is Ser, Ala, Val, or Asn, position 390 is Ser or Asn, position 413 is Thr or Ser, position 415 is Glu or Ser, position 416 is Glu, and position 421 is Phe.

[0032] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide has a CH3 domain having at least 85% identity, at least 90% identity, or at least 95% identity to amino acids 111 to 217 of any one of SEQ ID NOs: 100 to 185, 219 to 298, and 337 to 460. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 100 to 185, 219 to 298, and 337 to 460. In some embodiments, at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues at positions corresponding to EU index positions 380, 384, 386, 387, 388, 389, 390, 391, 392, 413, 414, 415, 416, 421, 424, and 426 of any one of SEQ ID NOs: 100-185, 219-298, and 337-460 are not deleted or substituted.

[0033] In some embodiments, any of the anti-TREM2 antibodies described herein comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs: 219-298 and 351-460. In some embodiments, the antibody comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs: 219, 220, 221, 222, 227, 228, 229, 230, 231, 232, 239, 240, 241, 242, 243, 244, 251, 252, 253, 254, 255, 256, 263, 264, 265, 266, 267, 268, 275, 276, 277, 278, 279, 280, 287, 288, 289, 290, 291, 292, 351, 352, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 375, 376, 277, 278, 279, 280, 287, 288, 289, 290, 291, 292, 351, 352, 355, 356, 357, 358, 359, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 38 420, 421, 422, 427, 428, 429, 434, 435, 436, 441, 442, 443, 448, 449, 450, 455, 456, and 457. and peptides with SEQ ID NOs: 223, 224, 225, 226, 233, 234, 235, 236, 237, 238, 245, 246, 247, 248, 249, 250, 257, 258, 259, 260, 261, 262, 269, 270, 271, 272, 273, 274, 281, 282, 283, 284, 285, 286, 293, 294, 295, 296, 297, 298, 353, 354, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, ​​383, 384, 385, 386, 387, 388, 389, 390, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, and a second Fc polypeptide selected from the group consisting of: 66, 373, 374, 375, 376, 377, 378, 385, 386, 387, 388, 389, 390, 395, 396, 397, 402, 403, 404, 409, 410, 411, 416, 417, 418, 423, 424, 425, 430, 431, 432, 437, 438, 439, 444, 445, 446, 451, 452, 453, 458, 459, and 460.In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 219, 220, 221, 222, 351, 352, 406, 407, and 408, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 223, 224, 225, 226, 353, 354, 409, 410, and 411. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 227, 228, 229, 230, 231, 232, 392, 393, and 394, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 233, 234, 235, 236, 237, 238, 395, 396, and 397. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 239, 240, 241, 242, 243, 244, 434, 435, and 436, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 245, 246, 247, 248, 249, 250, 437, 438, and 439. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 251, 252, 253, 254, 255, 256, 448, 449, and 450, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 257, 258, 259, 260, 261, 262, 451, 452, and 453. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 263, 264, 265, 266, 267, 268, 455, 456, and 457, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 269, 270, 271, 272, 273, 274, 458, 459, and 460. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 275, 276, 277, 278, 279, 280, 413, 414, and 415, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 281, 282, 283, 284, 285, 286, 416, 417, and 418.In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 287, 288, 289, 290, 291, 292, 420, 421, and 422, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 293, 294, 295, 296, 297, 298, 423, 424, and 425. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 355, 356, 357, 358, 360, 399, 400, and 401, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 361, 362, 363, 364, 365, 366, 402, 403, and 404. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 367, 368, 369, 370, 371, 372, 441, 442, and 443, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 373, 374, 375, 376, 377, 378, 444, 445, and 446. In some embodiments, the antibody comprises a first Fc polypeptide selected from the group consisting of SEQ ID NOs: 379, 380, 381, 382, ​​383, 384, 427, 428, and 429, and a second Fc polypeptide selected from the group consisting of SEQ ID NOs: 385, 386, 387, 388, 389, 390, 430, 431, and 432.

[0034] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide binds to the apical domain of the transferrin receptor. In some embodiments, binding of the bispecific antibody to the transferrin receptor does not substantially inhibit binding of transferrin to the transferrin receptor.

[0035] In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide have at least 75%, or at least 80%, 90%, 92%, or 95% amino acid sequence identity compared to a corresponding wild-type Fc polypeptide (e.g., a wild-type Fc polypeptide that is a human IgG1, IgG2, IgG3, or IgG4 Fc polypeptide).

[0036] In some embodiments, brain uptake of the antibody or antigen-binding portion thereof is greater than the uptake of an antibody or antigen-binding portion thereof lacking a modification on the first Fc polypeptide and / or second Fc polypeptide that confers transferrin receptor binding, hi some embodiments, brain uptake of the antibody or antigen-binding portion thereof is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 times greater than the uptake of an antibody or antigen-binding portion thereof lacking a modification on the first Fc polypeptide and / or second Fc polypeptide that confers transferrin receptor binding.

[0037] In some embodiments, one of the Fc polypeptides is not modified to bind to a blood-brain barrier receptor, and the other of the Fc polypeptides is modified to specifically bind to the transferrin receptor.

[0038] In some embodiments, the antibody or antigen-binding portion thereof exhibits cross-reactivity with mouse TREM2 protein. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a fully human antibody. In some embodiments, the antigen-binding portion is a Fab, F(ab')2, scFv, or bivalent scFv.

[0039] In another aspect, an antigen-binding fragment that specifically binds to a TREM2 protein (e.g., human TREM2) is provided. In some embodiments, the antigen-binding fragment further comprises an Fc polypeptide. In some embodiments, the Fc polypeptide is a modified Fc polypeptide. In some embodiments, the Fc polypeptide contains one or more of the modifications described herein, e.g., for promoting heterodimerization, reducing effector function, extending serum half-life, and / or binding to the transferrin receptor. As a non-limiting example, the antigen-binding fragment may comprise a Fab fragment, e.g., a Fab-Fc fusion, further comprising an Fc polypeptide. In other embodiments, the antigen-binding fragment further comprises a first Fc polypeptide and a second Fc polypeptide. In some embodiments, the first Fc polypeptide is a modified Fc polypeptide and / or the second Fc polypeptide is a modified Fc polypeptide. In some embodiments, the first Fc polypeptide and / or the second Fc polypeptide contain one or more of the modifications described herein, e.g., to promote heterodimerization, reduce effector function, increase serum half-life, and / or bind to the transferrin receptor. As a non-limiting example, the antigen-binding fragment can include an F(ab')2 fragment, e.g., an F(ab')2-Fc fusion, further comprising a first Fc polypeptide and a second Fc polypeptide.

[0040] In some embodiments, the antibody or antigen-binding portion thereof is a multispecific antibody. In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody recognizes two different TREM2 epitopes. In some embodiments, the bispecific antibody is capable of inducing TREM2 clustering on the surface of cells. In some embodiments, the bispecific antibody has an EC2 that is at least 2-fold (e.g., at least 5-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 200-fold, 500-fold, or 1000-fold) lower than a bivalent monospecific antibody comprising the same sequence as a single arm of the bispecific antibody. 50 In some embodiments, each of the two arms of the bispecific antibody has one of the following: 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24 B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A 1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D and RS12.3C10, wherein the two arms are different epitope bins.

[0041] In another aspect, pharmaceutical compositions are provided. In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to human TREM2. In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that has one or more TREM2-related activities described herein, recognizes an epitope of human TREM2 that is the same or substantially the same as an epitope recognized by an antibody clone described herein, and / or comprises one or more CDRs, heavy chain, and / or light chain sequences of an antibody clone described herein.

[0042] In another aspect, an isolated polynucleotide is provided. In some embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 as described herein. In another aspect, vectors and host cells comprising the isolated polynucleotide are provided.

[0043] In yet another embodiment, the antibody clones described herein (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22D11.G2, 22D11.G ...1, 22D11.G2, 22D11.G1, 22D11.G1, 22D11.G1, 22D11.G1, B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2 , 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4 , 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10).

[0044] In yet another aspect, kits are provided for the therapeutic and prognostic uses described herein. In some embodiments, the kits comprise an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 as described herein, and further comprise instructions for therapeutic or prognostic use.

[0045] In another aspect, methods of treating neurodegenerative diseases are provided. In some embodiments, the methods comprise administering an antibody or pharmaceutical composition described herein to a subject with a neurodegenerative disease. In some embodiments, the neurodegenerative disease is Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, argyrophilic grain dementia, amyotrophic lateral sclerosis, Guam amyotrophic lateral sclerosis / parkinsonism dementia complex (ALS-PDC), corticobasal degeneration, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Schaffer syndrome, or Gerstmann-Straussler-Schaffer syndrome. Inker's disease, glial globular inclusion body tauopathy, Guadeloupe dementia parkinsonism, Guadeloupe PSP, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with spheroids (HDLS), Huntington's disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Nasu-Hakola disease, neurofibrillary tangle-predominant dementia, Niemann-Pick disease type C, pallidopontinigral degeneration, Parkinson's disease, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, and neurofibrillary senile dementia. In some embodiments, the neurodegenerative disease is Alzheimer's disease.

[0046] In yet another aspect, methods are provided for reducing the level of sTREM2 in a subject with a neurodegenerative disease. In some embodiments, the method comprises administering to the subject an antibody or pharmaceutical composition described herein.

[0047] In yet another aspect, methods are provided for increasing the level of sTREM2 in a subject with a neurodegenerative disease. In some embodiments, the method comprises administering to the subject an antibody or pharmaceutical composition described herein.

[0048] In yet another aspect, methods are provided for enhancing TREM2 activity in a subject with a neurodegenerative disease. In some embodiments, the method comprises administering to the subject an antibody or pharmaceutical composition described herein. In some embodiments, the antibody is an antibody that enhances TREM2 activity in the presence of a TREM2 ligand. In some embodiments, the antibody is an antibody that enhances TREM2 activity in the presence of a TREM2 ligand but not in its absence.

[0049] In yet another aspect, a method for inhibiting TREM2 activity in a subject with a neurodegenerative disease is provided. In some embodiments, the method comprises administering to the subject an antibody or pharmaceutical composition described herein. In some embodiments, the antibody is an antibody that inhibits TREM2 activity in the presence of a TREM2 ligand. In some embodiments, the antibody is an antibody that inhibits TREM2 activity in the presence of a TREM2 ligand but not in its absence. In some embodiments, the antibody is an antibody that inhibits TREM2 activity in the absence of a TREM2 ligand and inhibits ligand activation of TREM2.

[0050] In yet another aspect, methods are provided for reducing plaque accumulation in a subject with a neurodegenerative disease. In some embodiments, the method comprises administering to the subject an antibody or pharmaceutical composition described herein. In some embodiments, the subject has Alzheimer's disease.

[0051] In yet another aspect, a method is provided for identifying a subject with a neurodegenerative disease as a candidate for treatment with an anti-TREM2 antibody.

[0052] In some embodiments, the method comprises: measuring the level of sTREM2 in a sample from the subject; comparing the level of sTREM2 in the sample from the subject to a control value, wherein if the level of sTREM2 in the sample from the subject is increased relative to the control value, the subject is identified as a candidate for treatment; For a subject identified as a candidate for treatment, administering to the subject an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein (e.g., any antibody described herein); In some embodiments, the isolated antibody or antigen-binding portion thereof is an antibody that reduces the level of sTREM2.

[0053] In some embodiments, the method comprises: measuring the level of sTREM2 in a sample from the subject; comparing the level of sTREM2 in the sample from the subject to a control value, wherein if the level of sTREM2 in the sample from the subject is decreased relative to the control value, the subject is identified as a candidate for treatment; and for a subject identified as a candidate for treatment, administering to the subject an isolated antibody or antigen-binding portion thereof (e.g., any antibody described herein) that specifically binds to human TREM2 protein. In some embodiments, the isolated antibody or antigen-binding portion thereof is an antibody that increases the level of sTREM2.

[0054] In another aspect, methods are provided for treating a subject with a neurodegenerative disease who has been identified as a candidate for treatment with an anti-TREM2 antibody. The method comprises administering to a subject an isolated antibody or antigen-binding portion thereof (e.g., any antibody described herein) that specifically binds to human TREM2 protein, wherein the subject has been identified as having an increased level of sTREM2 relative to a control value. In some embodiments, the isolated antibody or antigen-binding portion thereof is an antibody that reduces the level of sTREM2.

[0055] In some embodiments, the method comprises: The method includes administering to the subject an isolated antibody or antigen-binding portion thereof (e.g., any antibody described herein) that specifically binds to human TREM2 protein, wherein the subject has been identified as having a decreased level of sTREM2 relative to a control value. In some embodiments, the isolated antibody or antigen-binding portion thereof is an antibody that increases the level of sTREM2.

[0056] In yet another aspect, methods are provided for monitoring the effectiveness of treatment of a subject with a neurodegenerative disease with an anti-TREM2 antibody. In some embodiments, the methods include: measuring the level of sTREM2 in a first sample from the subject taken prior to administration of an anti-TREM2 antibody (e.g., a first administration to the subject); treating a subject with an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein (e.g., any antibody described herein); measuring the level of sTREM2 in a second sample from the subject taken after administration of the anti-TREM2 antibody; A change in the level of sTREM2 in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody.

[0057] In some embodiments, a decrease in sTREM2 levels in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody, hi some embodiments, an increase in sTREM2 levels in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody. [The present invention 1001] An isolated antibody or antigen-binding portion thereof that specifically binds to triggering receptor 2 (TREM2) protein expressed on human myeloid cells, and reduces levels of soluble TREM2 protein (sTREM2). [The present invention 1002] 1001. An isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 42E8.H1. [The present invention 1003] 1001. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof enhances TREM2 activity. [The present invention 1004] 1003. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof induces spleen tyrosine kinase (Syk) phosphorylation. [The present invention 1005] 1005. The isolated antibody of claim 1003 or 1004, wherein said antibody or antigen-binding portion thereof enhances phagocytosis, or enhances the migration, differentiation, function, or survival of myeloid cells, microglia, or macrophages. [The present invention 1006] 1005. The isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof enhances microglial function without increasing neuroinflammation. [The present invention 1007] 1007. The isolated antibody of any of claims 1003 to 1006, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 42E8.H1. [The present invention 1008] 1003. The isolated antibody of the invention, wherein said antibody increases TREM2 activity in the absence of a TREM2 ligand. [The present invention 1009] 1003. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity without blocking binding of native TREM2 ligand. [The present invention 1010] 1003. The isolated antibody of the present invention, wherein said antibody enhances TREM2 activity induced by a TREM2 ligand. [The present invention 1011] 1010. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence of a TREM2 ligand. [The present invention 1012] 1003. The isolated antibody of claim 1003, wherein said antibody selectively enhances the activity of a TREM2 ligand. [The present invention 1013] 1003. The isolated antibody of claim 1003, wherein said antibody blocks activation of TREM2 by a TREM2 ligand. [The present invention 1014] 1003. The isolated antibody of claim 1003, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [The present invention 1015] 1007. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity induced by a TREM2 ligand, but does not enhance TREM2 activity in the absence of a TREM2 ligand. [The present invention 1016] 1015. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence but not in the absence of a TREM2 ligand. [The present invention 1017] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of any of claims 1008 to 1016, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (So1P), and sulfatide. [The present invention 1018] 1001. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof inhibits TREM2 activity. [The present invention 1019] 1018. The isolated antibody of the invention, wherein said antibody blocks activation of TREM2 by a TREM2 ligand. [The present invention 1020] 1018. The isolated antibody of the invention, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [The present invention 1021] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of claim 1019 or 1020, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (SolP), and sulfatide. [The present invention 1022] 1018. The isolated antibody of the invention, wherein the antibody or antigen-binding portion thereof reduces Syk phosphorylation. [The present invention 1023] 1. An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, wherein the antibody or antigen-binding portion thereof increases levels of sTREM2. [The present invention 1024] 1023. An isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 21D4.D1. [The present invention 1025] 1023. The isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof enhances TREM2 activity. [The present invention 1026] 1025. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation. [The present invention 1027] 1027. The isolated antibody of claim 1025 or 1026, wherein the antibody or antigen-binding portion thereof enhances phagocytosis or enhances the migration, differentiation, function, or survival of myeloid cells, microglia, or macrophages. [The present invention 1028] 1027. The isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof enhances microglial function without increasing neuroinflammation. [The present invention 1029] 1025. The isolated antibody of the invention, wherein said antibody increases TREM2 activity in the absence of a TREM2 ligand. [The present invention 1030] 1025. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity without blocking binding of native TREM2 ligand. [The present invention 1031] 1025. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity induced by a TREM2 ligand. [The present invention 1032] 1031. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence of a TREM2 ligand. [The present invention 1033] 1025. The isolated antibody of the present invention, wherein said antibody selectively enhances the activity of a TREM2 ligand. [The present invention 1034] 1025. The isolated antibody of the invention, wherein said antibody blocks activation of TREM2 by a TREM2 ligand. [This invention 1035] 1025. The isolated antibody of the invention, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [The present invention 1036] 1031. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity induced by a TREM2 ligand, but does not enhance TREM2 activity in the absence of a TREM2 ligand. [This invention 1037] 1036. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence but not in the absence of a TREM2 ligand. [The present invention 1038] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of any of claims 1029 to 1037, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (So1P), and sulfatide. [This invention 1039] 1023. The isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof inhibits TREM2 activity. [The present invention 1040] 1039. The isolated antibody of the invention, wherein said antibody blocks activation of TREM2 by a TREM2 ligand. [The present invention 1041] 1039. The isolated antibody of the invention, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [The present invention 1042] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of claim 1040 or 1041, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (SolP), and sulfatide. [This invention 1043] 1039 or 1040, an isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 21D4.D1. [This invention 1044] 1039. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof reduces Syk phosphorylation. [This invention 1045] An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, wherein the antibody or antigen-binding portion thereof enhances TREM2 activity. [The present invention 1046] 1045. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation. [This invention 1047] 1047. The isolated antibody of claim 1045 or 1046, wherein the antibody or antigen-binding portion thereof enhances phagocytosis, or enhances the migration, differentiation, function, or survival of myeloid cells, microglia, or macrophages. [This invention 1048] 1047. The isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof enhances microglial function without increasing neuroinflammation. [This invention 1049] The antibody or antigen-binding portion thereof may be selected from the group consisting of antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43E9.H1, 44E2.A3, 45E3.A1, 46E4.A1, 47E5.A1, 48E6.A1, 49E7.A1, 50E7.A1, 51E7.A1, 52E7.A1, 53E8.A1, 54E9.A1, 55E9.A1, 56E9.A1, 57E9.A1, 58E9.A1, 59E10.A1, 60E10.A1, 61E10.A1, 62E10.A1, 63E10.A1, 64E10.A1, 65E10.A1, 66E10.A1, 67E10.A1, 68E10.A1, 69E11.A1, 70E11.A1, 71E11.A1, 72E11.A1, 73E11.A1, 74E11.A1, 75E11.A1, 76E11.A1, 77E11.A1, 78E11.A1, 79E11.A1, 80E11.A1, Any of the isolated antibodies of the present invention 1045 to 1048, which recognizes an epitope that is the same as or substantially the same as the epitope recognized by .H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, or RS9.F10. [The present invention 1050] 1049. An isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone RS9.F6. [This invention 1051] 1050. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion binds to a TREM2 fragment comprising or consisting of amino acid residues 140-148. [This invention 1052] 1050. The isolated antibody of the present invention, wherein said antibody or antigen-binding portion thereof binds to an epitope on human TREM2 comprising amino acid residues 140-144. [This invention 1053] 1052. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof makes direct contact with one or more of residues Asp140, Leu141, Trp142, Phe143, and Pro144. [This invention 1054] 1053. An isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof makes direct contacts with each of residues Asp140, Leu141, Trp142, Phe143, and Pro144. [This invention 1055] 1045. The isolated antibody of the invention, wherein said antibody increases TREM2 activity in the absence of a TREM2 ligand. [This invention 1056] 1045. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity without blocking binding of native TREM2 ligand. [This invention 1057] 1045. The isolated antibody of the invention, wherein said antibody enhances TREM2 activity induced by a TREM2 ligand. [This invention 1058] 1057. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence of a TREM2 ligand. [This invention 1059] 1045. The isolated antibody of the present invention, wherein said antibody selectively enhances the activity of a TREM2 ligand. [The present invention 1060] 1045. The isolated antibody of the invention, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [This invention 1061] 1045. The isolated antibody of the invention, wherein the antibody or antigen-binding portion thereof enhances TREM2 activity induced by a TREM2 ligand, but does not enhance TREM2 activity in the absence of a TREM2 ligand. [This invention 1062] 1061. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof induces Syk phosphorylation in the presence but not in the absence of a TREM2 ligand. [This invention 1063] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of any of claims 1055 to 1062, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (So1P), and sulfatide. [This invention 1064] 1057. An isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as that recognized by antibody clones 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, or RS9.F10. [This invention 1065] An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, wherein the antibody or antigen-binding portion thereof inhibits TREM2 activity. [The present invention 1066] 1065. An isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 21D4.D1. [This invention 1067] 1065. The isolated antibody of the invention, wherein said antibody blocks activation of TREM2 by a TREM2 ligand. [The present invention 1068] 1065. The isolated antibody of the invention, wherein said antibody blocks binding of a TREM2 ligand to TREM2. [The present invention 1069] The TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosylceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol (FC), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside Glycoside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidylglycerol (LPG), lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N- Acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (Sa1P), sphingomyelin (SM),The isolated antibody of claim 1067 or 1068, wherein the antibody is selected from the group consisting of sphingosine, sphingosine-1-phosphate (SolP), and sulfatide. [The present invention 1070] 1067. An isolated antibody of the present invention, wherein the antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as that recognized by antibody clones 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, or RS9.E2. [This invention 1071] 1065. The isolated antibody of the invention, wherein said antibody or antigen-binding portion thereof reduces Syk phosphorylation. [This invention 1072] An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, comprising antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4. A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 4 0H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 5 The antibody or antigen-binding portion thereof recognizes the same or substantially the same epitope as that recognized by 4C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10. [This invention 1073] The antibodies or antigen-binding portions thereof are selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 2 6E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2 .H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59 1072. An isolated antibody of the present invention, having at least 50% overlap with an epitope recognized by an antibody clone selected from the group consisting of C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. [This invention 1074] 1072. An isolated antibody of the invention, wherein said antibody or antigen-binding portion recognizes the same or substantially the same epitope as the epitope recognized by antibody clone RS9.F6. [This invention 1075] 1074. The isolated antibody of the invention, wherein said antibody or antigen-binding portion binds to an epitope on human TREM2 comprising amino acid residues 140-144. [This invention 1076] 1075. The isolated antibody of the invention, wherein the antibody or antigen-binding portion makes direct contacts with one or more of Asp140, Leu141, Trp142, Phe143, and Pro144. [This invention 1077] 1076. The isolated antibody of the invention, wherein the antibody or antigen-binding portion makes direct contacts with each of Asp140, Leu141, Trp142, Phe143, and Pro144. [This invention 1078] 1074. The isolated antibody of the invention, wherein said antibody or antigen-binding portion binds to a TREM2 fragment comprising or consisting of amino acid residues 140-148. [This invention 1079] the antibody or antigen-binding portion thereof, Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, and 26E2 .A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E 2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7. one or more CDRs having at least 90% sequence identity to the complementarity determining regions (CDRs) of RS9.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10; or Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H 1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A one or more CDRs with up to two amino acid substitutions based on the CDRs of 1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10 The isolated antibody of any of claims 1001 to 1078, comprising: [The present invention 1080] 1. An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, and 26E2 .A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E 2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7. one or more CDRs having at least 90% sequence identity to the complementarity determining regions (CDRs) of RS9.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10; or Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H 1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A one or more CDRs with up to two amino acid substitutions based on the CDRs of 1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10 The antibody or antigen-binding portion thereof comprising: [This invention 1081] The antibody or antigen-binding portion thereof may be selected from the group consisting of antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A1, 30F3.A1, 30F4.A1, 30F5.A1, 30F6.A1, 30F7.A1, 30F8.A1, 30F9.A1, 30F9.A1, 30F9.A1, 30F10.A1, 30F11.A1, 30F12.A1, 30F13.A1, 30F14.A1, 30F15.A1, 30F16.A1, 30F17.A1, 30F18.A1, 30F19 ... 2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 5 3H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11 the heavy chain CDR1(s) of RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10 The isolated antibody of the present invention 1079 or 1080, wherein each of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 is identical to heavy chain CDR2 (CDR-H1), heavy chain CDR3 (CDR-H3), light chain CDR1 (CDR-L1), light chain CDR2 (CDR-L2), and light chain CDR3 (CDR-L3). [This invention 1082] the antibody or antigen-binding portion thereof, Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, and 26E2. A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2. H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to the heavy chain variable region of 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10; and / or 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2 , 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H 1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1 a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to the light chain variable region of any of the following: 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10. The isolated antibody of any one of claims 1001 to 1081, comprising: [This invention 1083] the antibody or antigen-binding portion thereof, (i) Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, and 30F 2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D 4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, R and / or (ii) a heavy chain variable region comprising an amino acid sequence having at least 75% sequence identity to the heavy chain variable region of S9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10; and (i) Antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30 F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 5 1D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F and (ii) a light chain variable region comprising an amino acid sequence having at least 75% sequence identity to the light chain variable region of RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10; and (iii) a light chain variable region comprising CDR-L1, CDR-L2, and CDR-L3 identical to the CDR-L1, CDR-L2, and CDR-L3 of the antibody clone. 1082. An isolated antibody of the present invention comprising: [This invention 1084] the antibody or antigen-binding portion thereof, (a) a heavy chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317; (d) a light chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. The isolated antibody of any of claims 1001 to 1083, comprising one or more CDRs selected from the group consisting of: [This invention 1085] the antibody or antigen-binding portion thereof, (a) a heavy chain CDR1 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, and 317; (d) a light chain CDR1 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. 1084. An isolated antibody of the present invention, comprising one or more CDRs selected from the group consisting of: [The present invention 1086] (a) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 12, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (b) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 37, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (c) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 39, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 40, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 41, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 42, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 43, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 44, or (d) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 45, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 47, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 49, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50, or (e) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 51, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 52, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 53, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 54, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 55, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 56, or (f) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 59, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 61, or (g) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 62, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 63, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 64, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 65, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 66, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 67, or (h) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 68, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 69, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 70, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 71, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 72, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 73, or (i) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 75, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 78, or (j) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 79, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 80, or (k) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 81, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 82, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 83, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 84, or (l) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 86, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 87, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 88, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 89, or (m) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 307, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 308, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 309, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 311, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 312, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 313, or (n) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 315, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 316, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 317, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 319, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50 1085. An isolated antibody of the present invention comprising: [This invention 1087] 1085. An isolated antibody of the present invention comprising a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, and 314. [This invention 1088] 1085. An isolated antibody of the invention comprising a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, and 318. [This invention 1089] (a) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7; or (b) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 14, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 25; or (c) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 26; or (d) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 16, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27; or (e) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 28; or (f) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 18, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 29; or (g) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 19, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30; or (h) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 20, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 31; or (i) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 21, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 32; or (j) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 22 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33; or (k) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 23, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34; or (l) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 24, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 35; or (m) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 306, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 310; or (n) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 314, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 318. 1085. An isolated antibody of the present invention comprising: [The present invention 1090] 1. An isolated antibody or antigen-binding portion thereof that specifically binds to a human TREM2 protein, comprising: (a) a light chain variable region; and (b) a heavy chain variable region comprising a heavy chain CDR1 (CDR-H1), a heavy chain CDR2 (CDR-H2), and a heavy chain CDR3 (CDR-H3), (i) CDR-H1 is a CDR of the formula GX2X3X4X5X6X7X8X9X 10 X 11 (I) (wherein X2 is Y or F, X3 is T, N, or S, X4 is F, L, or I, X5 is T, S, or K, X6 is D, S, or E, X7 is D or absent, X8 is H, Y, or T, X9 is A, N, G, V, W, T, or Y, and X 10 is M, I, or W, and X 11 is H, Q, or N) Including, (ii) CDR-H2 has the formula X1X2X3X4X5X6X7X8X9X 10 YX 12 X 13 X 14 X 15 X 16 X 17 (V) (Wherein, X1 is D, V, Y, R, G, or T, X2 is I, S, or V, X3 is L, S, N, D, I, or Y, X4 is P, T, or absent, X5 is S, Y, N, T, A, G, or F, X6 is I, S, N, T, or D, X7 is G or D, X8 is G, D, N, R, or S, X9 is R, T, or A, and X 10 is I, G, S, K, T, N, or R, and X 12 is G, N, D, or T, and X 13 is V, Q, E, or P, and X 14 is K or S, and X 15 is F, Y or L, and X 16 is K, R, Q, or absent, and X 17 is G, T, D, S, or absent) Including, (iii) CDR-H3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 47, SEQ ID NO: 53, SEQ ID NO: 59, SEQ ID NO: 70, SEQ ID NO: 76, SEQ ID NO: 83, SEQ ID NO: 87, SEQ ID NO: 319, and SEQ ID NO: 317, or has the formula ARX3X4X5X6X7X8X9X 10 YAX 13 DY(VIII) (wherein X3 is G or N, X4 is D or G, X5 is D or I, X6 is S or T, X7 is Y or T, X8 is R or A, X9 is R or G, and X 10 is G or Y, and X 13 is L or M) The heavy chain variable region comprising: [This invention 1091] 1090. The isolated antibody of the present invention, wherein the amino acids of formula I are further defined as follows: X2 is Y, X3 is T or S, X5 is T or S, X8 is H or Y, and X9 is A, N, G, V, W, or T. [This invention 1092] The isolated antibody of the present invention 1090 or 1091, wherein X7 is absent in CDR-H1. [This invention 1093] In CDR-H1, X 10 The isolated antibody of any of 1090 to 1092 of the present invention, wherein X11 is W and X12 is N. [This invention 1094] The amino acids of formula I are as follows: X3 is T or N, X7 is absent, and X 10 is M or I, and X 11 is H or Q. [This invention 1095] CDR-H2, formula GYTX4X5X6X8X9X 10 X 11 (IV) (wherein X4 is F or L, X5 is T or S, X6 is D, S, or E, X8 is H or Y, X9 is A, N, G, V, W, or T, and X 10 is M or I, and X 11 is H or Q) 1091 or 1092, an isolated antibody of the present invention, having the formula: [This invention 1096] The isolated antibody of any of 1090 to 1095 of the present invention, wherein X4 of CDR-H1 is F. [This invention 1097] The isolated antibody of any of 1090 to 1096, wherein X5 of CDR-H1 is T. [This invention 1098] The isolated antibody of the present invention 1096 or 1097, wherein X4 and X5 of CDR-H1 are F and T, respectively. [This invention 1099] The isolated antibody of any of 1090 to 1098, wherein X6 of CDR-H1 is D or S. [The present invention 1100] 1099. The isolated antibody of the present invention, wherein X6 of CDR-H1 is D. [The present invention 1101] 1099. The isolated antibody of the present invention, wherein X6 of CDR-H1 is S. [The present invention 1102] The isolated antibody of any of claims 1090 to 1101, wherein X8 of CDR-H1 is Y. [The present invention 1103] CDR-H1 X 10 The isolated antibody of any of 1090 to 1102, wherein [The present invention 1104] CDR-H1 X 11 The isolated antibody of any of 1090 to 1103 of the present invention, wherein [This invention 1105] CDR-H1 X 10 and X 11 The isolated antibody of the present invention 1103 or 1104, wherein are M and H, respectively. [The present invention 1106] CDR-H1 X 10 and X 11 and Q are I and Q, respectively. [This invention 1107] The amino acids of formula V are as follows: X1 is V, Y, R, G, or T; X3 is S, N, D, I, or Y; X5 is Y, N, T, A, G, or F; X6 is S, N, T, or D; X9 is T or A; and X 12 is N, D, or T, and X13 is Q, E, or P, and X 16 is K, R, or Q, and X 17 is G, T, D, or S. [This invention 1108] The amino acids of formula V are as follows: X4 is P or T, X5 is Y, N, T, A, or G, X8 is G, D, or N, and X 10 is G, S, K, T, N, or R, and X 14 is K and X 15 is F or Y and X 17 is G, T, or D. [This invention 1109] the antibody comprises a light chain variable region comprising a light chain CDR1 (CDR-L1), a light chain CDR2 (CDR-L2), and a light chain CDR3 (CDR-L3); (i) CDR-L1 is of the formula X1SSX4SLX7X8X9X 10 X 11 X 12 X 13 X 14 X 15 LX 17 (IX) wherein X1 is R or K, X4 is Q or K, X7 is V or L, X8 is H, D, or Y, X9 is I, N, or S, and X 10 is S or absent, X 11 is D or N, and X 12 is G or Q, and X 13 is N, I, or K, and X 14 is T or S, and X 15 is Y or F, and X 17 is Q, H, Y, N, or A) or CDR-L1 comprises a compound having the formula X1ASX4X5IX7X8X9LX 11 (X) (wherein X1 is R, K, or S, X4 is E or Q, X5 is N, D, or G, X7 is Y or S, X8 is S or N, X9 is N, R, or Y, and X 11 is A or N) Including, (ii) CDR-L2 has the formula X1X2SX4X5X6S(XI) (wherein X1 is K, Q, Y, V, or L, X2 is V, M, or T, X4 is N, K, or Y, X5 is R or L, and X6 is F, A, H, or D). or CDR-L2 comprises the amino acid sequence of SEQ ID NO: 43, SEQ ID NO: 55, or SEQ ID NO: 66; (iii) CDR-L3 has the formula X1X2X3X4X5X6X7X8T(XII) (wherein X1 is S, W, or Q, X2 is Q or H, X3 is S, T, G, Y, or F, X4 is T, F, W, or S, X5 is H, S, G, or N, X6 is V, A, F, Y, T, or L, X7 is P, T, or L, and X8 is Y, F, P, or W). or CDR-L3 comprises the amino acid sequence of SEQ ID NO: 73; An isolated antibody according to any one of 1090 to 1108 of the present invention. [The present invention 1110] 1109. An isolated antibody of the present invention, wherein X4 of formula IX is Q. [The present invention 1111] The isolated antibody of claim 1109 or 1110, wherein X8 of formula IX is H. [The present invention 1112] An isolated antibody according to any one of claims 1109 to 1111, wherein X9 of formula IX is I or S. [The present invention 1113] X in Formula IX 10 The isolated antibody of any of 1109 to 1112, wherein [This invention 1114] X in Formula IX 11 The isolated antibody of any of 1109 to 1113 of the present invention, wherein [This invention 1115] X in Formula IX 12 The isolated antibody of any of 1109 to 1114 of the present invention, wherein [The present invention 1116] X in Formula IX 13 The isolated antibody of any of 1109 to 1115, wherein is N or K. [This invention 1117] X in Formula IX 14 The isolated antibody of any of 1109 to 1116, wherein [This invention 1118] X in Formula IX 15 The isolated antibody of any one of 1109 to 1111 of the present invention, wherein [This invention 1119] An isolated antibody according to any one of claims 1109 to 1118, wherein X2 of formula XI is V. [The present invention 1120] An isolated antibody according to any one of claims 1109 to 1119, wherein X4 of formula XI is N. [This invention 1121] An isolated antibody of any of claims 1109 to 1120, wherein X5 of formula XI is R. [This invention 1122] An isolated antibody according to any one of claims 1109 to 1121, wherein X5 of formula XI is L. [This invention 1123] The isolated antibody of any of claims 1109 to 1122, wherein the amino acids of formula XII are further defined as follows: X1 is Q, X3 is Y or F, X4 is F, W, or S, X5 is S, G, or N, X6 is Y, T, or L, X7 is P, and X8 is P, Y, or W. [This invention 1124] An isolated antibody according to any one of claims 1109 to 1123, wherein X2 of formula XII is Q. [Invention 1125] The isolated antibody of any of claims 1109 to 1124, wherein X4 of formula XII is T. [The present invention 1126] An isolated antibody according to any one of claims 1109 to 1125, wherein X5 of formula XII is H. [This invention 1127] The isolated antibody of any of claims 1109 to 1122, wherein the amino acids of formula XII are further defined as follows: X1 is S or W, X2 is Q, X3 is S, T, or G, X4 is T, X5 is H, X6 is V, A, or F, X7 is P, T, or L, and X8 is Y, F, or P. [This invention 1128] 1127. The isolated antibody of the present invention, wherein X6 of formula XII is V or F. [This invention 1129] 1. An isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein, (a) a heavy chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 319, and 317, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 319, and 317; (d) a light chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. The antibody or antigen-binding portion thereof, comprising one or more CDRs selected from the group consisting of: [The present invention 1130] (a) a heavy chain CDR1 comprising any one of the amino acid sequences of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, and 315; (b) a heavy chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, and 316; (c) a heavy chain CDR3 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 319, and 317; (d) a light chain CDR1 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, and 311; (e) a light chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, and 319; and (f) a light chain CDR3 sequence comprising any one of the amino acid sequences of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, and 313. 1129. An isolated antibody of the present invention, comprising one or more CDRs selected from the group consisting of: [This invention 1131] (a) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 12, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (b) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 37, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13, or (c) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 39, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 40, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 41, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 42, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 43, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 44, or (d) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 45, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 46, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 47, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 49, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50, or (e) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 51, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 52, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 53, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 54, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 55, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 56, or (f) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 57, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 58, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 59, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 61, or (g) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 62, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 63, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 64, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 65, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 66, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 67, or (h) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 68, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 69, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 70, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 71, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 72, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 73, or (i) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 75, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 78, or (j) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 74, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 79, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 76, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 77, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 80, or (k) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 81, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 82, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 83, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 60, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 84, or (l) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 85, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 86, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 87, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 88, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 89, or (m) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 307, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 308, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 309, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 311, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 312, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 313, or (n) a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 315, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 316, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 317, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 48, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 319, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 50 1130. An isolated antibody of the present invention comprising: [This invention 1132] 1130 or 1131, an isolated antibody of the invention comprising a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, and 314. [This invention 1133] 1130 or 1131, an isolated antibody of the invention comprising a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, and 318. [This invention 1134] (a) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 7; or (b) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 14, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 25; or (c) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 15, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 26; or (d) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 16, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 27; or (e) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 17, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 28; or (f) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 18, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 29; or (g) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 19, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 30; or (h) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 20, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 31; or (i) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 21, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 32; or (j) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 22 and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 33; or (k) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 23, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 34; or (l) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 24, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 35; or (m) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 306, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 310; or (n) a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 314, and a light chain variable region comprising an amino acid sequence having at least 90% sequence identity to SEQ ID NO: 318. An isolated antibody according to any one of claims 1129 to 1131 of the present invention, comprising: [This invention 1135] The isolated antibody of any of claims 1001 to 1134, wherein said antibody comprises a first Fc polypeptide and, optionally, a second Fc polypeptide. [This invention 1136] 1135. The isolated antibody of the present invention, wherein said antibody comprises said first Fc polypeptide and said second Fc polypeptide. [This invention 1137] 1135 or 1136, wherein said first Fc polypeptide is a modified Fc polypeptide and / or said second Fc polypeptide is a modified Fc polypeptide. [This invention 1138] The antibody (a) a first antigen-binding moiety comprising a first variable region that specifically binds to the human TREM2 protein, the first antigen-binding moiety comprising (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain; (b) a second antigen-binding portion comprising a second variable region that specifically binds to human TREM2, the second antigen-binding portion comprising (i) a second heavy chain comprising a first Fc polypeptide and (ii) a second light chain; the first Fc polypeptide and the second Fc polypeptide form an Fc dimer; An isolated antibody according to any one of claims 1001 to 1137 of the present invention. [This invention 1139] 1138. The isolated antibody of the invention, wherein said first Fc polypeptide is a modified Fc polypeptide and / or said second Fc polypeptide is a modified Fc polypeptide. [This invention 1140] The isolated antibody of the invention 1138 or 1139, wherein said first variable region and said second variable region recognize the same epitope in said human TREM2 protein. [This invention 1141] The isolated antibody of claim 1138 or 1139, wherein the first variable region and the second variable region recognize different epitopes in the human TREM2 protein. [This invention 1142] 1137-1141. The isolated antibody of any of claims 1137-1141, wherein said first Fc polypeptide and said second Fc polypeptide each contain a modification that promotes heterodimerization. [This invention 1143] 1142. The isolated antibody of the invention, wherein one of said Fc polypeptides has a T366W substitution and the other of said Fc polypeptides has T366S, L368A, and Y407V substitutions according to EU numbering. [This invention 1144] The isolated antibody of any of claims 1137 to 1143, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises a native FcRn binding site. [Invention 1145] The isolated antibody of any of claims 1137 to 1143, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises a modification that alters FcRn binding. [Invention 1146] The isolated antibody of any of claims 1137 to 1145, wherein the first Fc polypeptide and the second Fc polypeptide do not have an effector function. [This invention 1147] The isolated antibody of any of claims 1137 to 1145, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises a modification that reduces effector function. [Invention 1148] 1147. The isolated antibody of the invention, wherein said modification that reduces effector function comprises a substitution of Ala at position 234 and Ala at position 235, according to EU numbering. [This invention 1149] The isolated antibody of any of claims 1137 to 1148, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises amino acid changes relative to the native Fc sequence that extend serum half-life. [This invention 1150] 1149. The isolated antibody of the invention, wherein said amino acid changes comprise substitutions of Tyr at position 252, Thr at position 254, and Glu at position 256, according to EU numbering. [This invention 1151] 1149. The isolated antibody of the invention, wherein said amino acid changes comprise a substitution of Leu at position 428 and Ser at position 434 according to EU numbering. [This invention 1152] 1149. The isolated antibody of the invention, wherein said amino acid alteration comprises a substitution of Ser or Ala at position 434 according to EU numbering. [This invention 1153] The isolated antibody of any of claims 1137 to 1152, wherein the first Fc polypeptide and / or the second Fc polypeptide specifically binds to a transferrin receptor. [This invention 1154] 1153. The isolated antibody of the present invention, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises at least two substitutions at positions selected from the group consisting of 384, 386, 387, 388, 389, 390, 413, 416, and 421, according to EU numbering. [This invention 1155] 1154. The isolated antibody of the invention, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises substitutions at at least 3, 4, 5, 6, 7, 8, or 9 positions. [Invention 1156] The isolated antibody of the invention 1154 or 1155, wherein the first Fc polypeptide and / or the second Fc polypeptide further comprises one, two, three, or four substitutions at positions including 380, 391, 392, and 415, according to EU numbering. [This invention 1157] An isolated antibody of any of claims 1154 to 1156, wherein the first Fc polypeptide and / or the second Fc polypeptide further comprises one, two, or three substitutions at positions including 414, 424, and 426, according to EU numbering. [This invention 1158] 1158. The isolated antibody of any of claims 1154 to 1157, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises Trp at position 388. [This invention 1159] 1159. The isolated antibody of any of claims 1154 to 1158, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises an aromatic amino acid at position 421. [The present invention 1160] 1159. The isolated antibody of the invention, wherein said aromatic amino acid at position 421 is Trp or Phe. [This invention 1161] The isolated antibody of any of claims 1154 to 1160, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises at least one position selected from the following: position 380 is Trp, Leu, or Glu, position 384 is Tyr or Phe, position 386 is Thr, position 387 is Glu, position 388 is Trp, position 389 is Ser, Ala, Val, or Asn, position 390 is Ser or Asn, position 413 is Thr or Ser, position 415 is Glu or Ser, position 416 is Glu, and position 421 is Phe. [This invention 1162] 1161. The isolated antibody of the present invention, wherein said first Fc polypeptide and / or said second Fc polypeptide comprises at 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 positions selected from the following: position 380 is Trp, Leu, or Glu; position 384 is Tyr or Phe; position 386 is Thr; position 387 is Glu; position 388 is Trp; position 389 is Ser, Ala, Val, or Asn; position 390 is Ser or Asn; position 413 is Thr or Ser; position 415 is Glu or Ser; position 416 is Glu; and position 421 is Phe. [This invention 1163] 1162. An isolated antibody of the present invention, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises the following 11 positions: position 380 is Trp, Leu, or Glu, position 384 is Tyr or Phe, position 386 is Thr, position 387 is Glu, position 388 is Trp, position 389 is Ser, Ala, Val, or Asn, position 390 is Ser or Asn, position 413 is Thr or Ser, position 415 is Glu or Ser, position 416 is Glu, and position 421 is Phe. [This invention 1164] The isolated antibody of the present invention 1162 or 1163, wherein the first Fc polypeptide and / or the second Fc polypeptide has a CH3 domain having at least 85% identity, at least 90% identity, or at least 95% identity to amino acids 111 to 217 of any one of SEQ ID NOs: 100 to 185, 219 to 298, and 337 to 460. [Invention 1165] The isolated antibody of the present invention 1162 or 1163, wherein the first Fc polypeptide and / or the second Fc polypeptide comprises any one of the amino acid sequences of SEQ ID NOs: 100 to 185, 219 to 298, and 337 to 460. [Invention 1166] 1164 or 1165. An isolated antibody of the invention, wherein at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 residues at positions corresponding to EU index positions 380, 384, 386, 387, 388, 389, 390, 391, 392, 413, 414, 415, 416, 421, 424, and 426 of any one of SEQ ID NOs: 100 to 185, 219 to 298, and 337 to 460 are not deleted or substituted. [This invention 1167] The isolated antibody of any of claims 1153 to 1166, wherein the first Fc polypeptide and / or the second Fc polypeptide binds to the apical domain of the transferrin receptor. [Invention 1168] 1167. The isolated antibody of claim 1167, wherein said binding of said antibody or antigen-binding portion thereof to said transferrin receptor does not substantially inhibit binding of transferrin to said transferrin receptor. [This invention 1169] An isolated antibody of any of claims 1135 to 1168, wherein the first Fc polypeptide and / or the second Fc polypeptide have at least 75%, or at least 80%, 90%, 92%, or 95% amino acid sequence identity compared to the corresponding wild-type Fc polypeptide. [This invention 1170] 1169. The isolated antibody of the invention, wherein said corresponding wild-type Fc polypeptide is a human IgG1, IgG2, IgG3, or IgG4 Fc polypeptide. [This invention 1171] 11. The isolated antibody of any of claims 1153 to 1121, wherein brain uptake of said antibody or antigen-binding portion thereof is at least 10-fold greater than uptake of an antibody or antigen-binding portion thereof that does not have a modification on said first Fc polypeptide and / or said second Fc polypeptide that confers transferrin receptor binding. [This invention 1172] An isolated antibody according to any one of claims 1135 to 1171, wherein one of the Fc polypeptides is not modified to bind to a blood-brain barrier receptor, and the other of the Fc polypeptides is modified to specifically bind to a transferrin receptor. [This invention 1173] The isolated antibody of any of claims 1001 to 1172, wherein said antibody or antigen-binding portion thereof exhibits cross-reactivity with mouse TREM2 protein. [This invention 1174] The isolated antibody of any of claims 1001 to 1173, wherein the antibody is a monoclonal antibody. [This invention 1175] The isolated antibody of any of claims 1001 to 1173, wherein the antibody is a chimeric antibody. [Invention 1176] The isolated antibody of any of claims 1001 to 1173, wherein the antibody is a humanized antibody. [This invention 1177] The isolated antibody of any of claims 1001 to 1173, wherein the antibody is a fully human antibody. [This invention 1178] The isolated antibody of any of claims 1001 to 1173, wherein the antigen-binding portion is Fab, F(ab')2, scFv, or bivalent scFv. [This invention 1179] The isolated antibody of any of claims 1001 to 1178, wherein the antibody is a multispecific antibody. [This invention 1180] 1179. The isolated antibody of the present invention, wherein said multispecific antibody is a bispecific antibody. [This invention 1181] 1180. The isolated antibody of the present invention, wherein said bispecific antibody recognizes two different TREM2 epitopes. [This invention 1182] 1180. The isolated antibody of claim 1181, wherein said bispecific antibody is capable of inducing TREM2 clustering on the surface of a cell. [This invention 1183] The bispecific antibody has an EC2 that is at least 2-fold lower than a bivalent monospecific antibody comprising the same sequence as a single arm of the bispecific antibody. 50 The isolated antibody of any of claims 1180 to 1182 of the present invention, [This invention 1184] Each of the two arms of the bispecific antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8 An isolated antibody of any of the present inventions 1180 to 1183, selected from an antibody clone selected from the group consisting of RS9.E2, RS9.F6, and RS9.F10, wherein the two arms are different epitope bins. [This invention 1185] A pharmaceutical composition comprising any of the isolated antibodies of the present inventions 1001 to 1184 and a pharmaceutically acceptable carrier. [Invention 1186] An antibody that competes with any of the isolated antibodies of the present inventions 1001 to 1184 for binding to the human TREM2 protein. [This invention 1187] An isolated antibody according to any one of claims 1001 to 1184 of the present invention or a pharmaceutical composition according to claim 1185 of the present invention; Instructions for its use and Includes a kit. [This invention 1188] A method for treating a neurodegenerative disease, comprising administering to a subject having a neurodegenerative disease an isolated antibody of any one of 1001 to 1184 of the present invention or a pharmaceutical composition of 1185 of the present invention. [This invention 1189] The neurodegenerative disease may be Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia linked to chromosome 17 with parkinsonism, argyrophilic grain dementia, amyotrophic lateral sclerosis, Guam amyotrophic lateral sclerosis / parkinsonism dementia complex (ALS-PDC), corticobasal degeneration, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Scheinker disease, glial cytoplasmic leukemia, and the like. 1188. The method of the present invention, wherein the senile dementia is selected from the group consisting of: cerebral inclusion body tauopathy, Guadeloupe dementia parkinsonism, Guadeloupe PSP, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with spheroids (HDLS), Huntington's disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Nasu-Hakola disease, neurofibrillary tangle-predominant dementia, Niemann-Pick disease type C, pallidopons-nigral degeneration, Parkinson's disease, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, and neurofibrillary senile dementia. [This invention 1190] 1189. The method of claim 1189, wherein the neurodegenerative disease is Alzheimer's disease. [This invention 1191] A method for reducing the level of sTREM2 in a subject having a neurodegenerative disease, the method comprising administering to the subject an isolated antibody of any of 1001-1022 or 1072-1184 of the present invention. [This invention 1192] A method for increasing the level of sTREM2 in a subject having a neurodegenerative disease, the method comprising administering to the subject an isolated antibody of any of 1023-1044 or 1072-1184 of the present invention. [This invention 1193] A method for enhancing TREM2 activity in a subject having a neurodegenerative disease, the method comprising administering to the subject an isolated antibody of any of 1045 to 1064 or 1072 to 1184 of the present invention. [This invention 1194] 1193. The method of claim 1193, wherein said isolated antibody or antigen-binding portion thereof is an antibody that enhances ligand-induced TREM2 activity. [This invention 1195] 1193. The method of claim 1193, wherein said isolated antibody or antigen-binding portion thereof is an antibody that selectively enhances TREM2 activity. [Invention 1196] 1193. The method of claim 1193, wherein said isolated antibody or antigen-binding portion thereof is an antibody that enhances TREM2 activity without blocking binding of native TREM2 ligand. [This invention 1197] A method for inhibiting TREM2 activity in a subject having a neurodegenerative disease, the method comprising administering to the subject an isolated antibody of any of claims 1065 to 1184 of the present invention. [This invention 1198] 1198. The method of any of claims 1193 to 1197, wherein said isolated antibody or antigen-binding portion thereof is an antibody that reduces the level of sTREM2. [This invention 1199] 1198. The method of any of claims 1193 to 1197, wherein said isolated antibody or antigen-binding portion thereof is an antibody that increases the level of sTREM2. [The present invention 1200] 1. A method for identifying a subject having a neurodegenerative disease as a candidate for treatment with an anti-TREM2 antibody, comprising: measuring the level of sTREM2 in a sample from the subject; comparing the level of sTREM2 in the sample from the subject to a control value, wherein if the level of sTREM2 in the sample from the subject is increased relative to the control value, the subject is identified as a candidate for treatment; For a subject identified as a candidate for treatment, administering to said subject an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein; Including, The method, wherein the isolated antibody or antigen-binding portion thereof reduces the level of sTREM2. [The present invention 1201] 1. A method of treating a subject having a neurodegenerative disease who has been identified as a candidate for treatment with an anti-TREM2 antibody, comprising: the subject is identified as having an increased level of sTREM2 relative to a control value; The method includes administering to the subject an isolated antibody, or antigen-binding portion thereof, that specifically binds to human TREM2 protein; The method, wherein the isolated antibody or antigen-binding portion thereof reduces the level of sTREM2. [This invention 1202] The method of any one of claims 1200 and 1201, wherein said isolated antibody or antigen-binding portion thereof is any one of antibodies 1001 to 1022 or 1072 to 1184 of the present invention. [This invention 1203] 1. A method for identifying a subject having a neurodegenerative disease as a candidate for treatment with an anti-TREM2 antibody, comprising: measuring the level of sTREM2 in a sample from the subject; comparing the level of sTREM2 in the sample from the subject to a control value, wherein the subject is identified as a candidate for treatment if the level of sTREM2 in the sample from the subject is decreased relative to the control value; For a subject identified as a candidate for treatment, administering to said subject an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein; Including, The above method, wherein the isolated antibody or antigen-binding portion thereof increases the level of sTREM2. [The present invention 1204] 1. A method of treating a subject having a neurodegenerative disease who has been identified as a candidate for treatment with an anti-TREM2 antibody, comprising: the subject is identified as having a decreased level of sTREM2 relative to a control value; The method includes administering to the subject an isolated antibody, or antigen-binding portion thereof, that specifically binds to human TREM2 protein; The above method, wherein the isolated antibody or antigen-binding portion thereof increases the level of sTREM2. [This invention 1205] The method of any one of claims 1203 to 1204, wherein said isolated antibody or antigen-binding portion thereof is any one of antibodies 1023 to 1044 or 1072 to 1184 of the present invention. [This invention 1206] 1. A method for monitoring the effectiveness of treatment of a subject with a neurodegenerative disease with an anti-TREM2 antibody, comprising: measuring the level of sTREM2 in a first sample from the subject taken prior to administration of an anti-TREM2 antibody; treating the subject with an isolated antibody or antigen-binding portion thereof that specifically binds to human TREM2 protein; measuring the level of sTREM2 in a second sample from the subject taken after administration of the anti-TREM2 antibody; Including, The method, wherein a change in the level of sTREM2 in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody. [This invention 1207] The method of claim 1071, wherein said isolated antibody or antigen-binding portion thereof is any one of the antibodies of claims 1001 to 1184. [This invention 1208] 1206. The method of claim 1206, wherein a decrease in sTREM2 levels in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody. [This invention 1209] 1206. The method of claim 1206, wherein an increase in sTREM2 levels in the second sample from the subject compared to the first sample from the subject indicates that the subject is responding to treatment with the anti-TREM2 antibody. [The present invention 1210] The neurodegenerative disease may be Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia linked to chromosome 17 with parkinsonism, argyrophilic grain dementia, amyotrophic lateral sclerosis, Guam amyotrophic lateral sclerosis / parkinsonism dementia complex (ALS-PDC), corticobasal degeneration, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangle disease with calcifications, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Scheinker disease, glial globular inclusion body tangles, and / or gliomas. Any of the methods of the present inventions 1191 to 1209, wherein the disease is selected from the group consisting of leukoencephalopathy, Guadeloupe dementia parkinsonism, Guadeloupe PSP, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with spheroids (HDLS), Huntington's disease, inclusion body myositis, multiple system atrophy, myotonic dystrophy, Nasu-Hakola disease, neurofibrillary tangle-predominant dementia, Niemann-Pick disease type C, pallidopontine-nigral degeneration, Parkinson's disease, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, and neurofibrillary senile dementia. [The present invention 1211] 1210. The method of claim 1210, wherein said neurodegenerative disease is Alzheimer's disease. [Brief explanation of the drawings]

[0058] [Figure 1-1]Anti-TREM2 antibodies bind to surface TREM2 on cells. (A) Anti-TREM2 antibodies were screened for binding to human TREM2-expressing HEK cells (unlabeled) and mouse TREM2-expressing HEK cells (labeled with NucBlue). Antibody binding was detected with an APC-conjugated secondary anti-mouse multi-adsorbent antibody. RS9.F6 shows binding to both mouse and human TREM2 cells. 57D7.A1 specifically binds to human TREM2 cells. (B) To exclude nonspecific binding, parental HEK-GFP cells were used as a negative control. (C) Dose response of anti-TREM2 antibody surface binding on hTREM2-HEK cells. Anti-TREM2 antibodies were titrated for binding to human TREM2-expressing HEK cells. Antibody binding was detected with an APC-conjugated secondary anti-mouse multi-adsorbent antibody. RS9.F6 and RS9.F10 show EC50 binding of less than 2 nM to human TREM2 cells. (D) Dose response of anti-TREM2 antibody surface binding on mTREM2-293F cells. Mouse TREM2 HEK cells were titrated for binding as in (C). RS9.F6 and RS9.F10 show EC50 binding of less than 8 nM to mouse TREM2 HEK cells. [Figure 1-2] See description of Figure 1-1. [Figure 2] Anti-TREM2 antibody binding to primary human macrophages. Anti-TREM2 antibodies were screened by FACS for binding to primary human monocyte-derived macrophages. Antibody binding was detected with an APC-conjugated secondary anti-mouse polyadsorbent antibody. Gray line = secondary antibody only. Black line = TREM2 antibody. [Figure 3A] P-Syk activation by anti-TREM2 antibodies. (A) Addition of 30 nM anti-TREM2 antibodies to human TREM2-expressing HEK cells induces pSyk. pSyk is calculated as fold-induction relative to the buffer control. (B-C) The dose-response of anti-TREM2 antibodies to p-Syk activation was determined. Anti-TREM2 antibodies were dose-titrated in human TREM2-expressing HEK cells, and pSyk induction was calculated as fold-induction relative to the buffer control. EC50 values ​​indicate the potency of each antibody in nM and the fold-induction of pSyk. [Figure 3B]See legend to Figure 3A. [Figure 3C] See legend to Figure 3A. [Figure 4] Modulation of soluble TREM2 by anti-TREM2 antibodies. Human TREM2-expressing cells were treated overnight (18 h) with the indicated concentrations of antibody in solution. After denaturation in SDS, soluble TREM2 concentrations were measured by ELISA. Absolute quantification of sTREM2 was determined based on a standard curve. Data fitting was performed using a four-parameter logistic equation. [Figure 5] Anti-TREM2 antibodies induce survival of human macrophages. Human monocytes isolated from peripheral blood were incubated with 5 ng / mL M-CSF (A) or no M-CSF (B) in the presence of titrated concentrations of plate-coated anti-TREM2 antibodies or isotype control. On day 6, cell viability was determined by CellTiter Glo viability assay. Anti-TREM2 antibodies increased survival of human macrophages cultured with or without limiting M-CSF. [Figure 6A] Anti-TREM2 antibodies induced signaling pathways. (A-D) Human macrophages were stimulated with 30 nM antibody or control for 15 minutes. Cell lysates were measured for p-Y525 / 526-SYK (A), p-T202 / Y204-ERK1 / 2 (B), p-S9-GSK3-β (C), and p-S473-AKT (D) by Alpha-LISA. Anti-TREM2 antibodies induced Syk phosphorylation, ERK phosphorylation, GSK3-β phosphorylation, and AKT phosphorylation. [Figure 6B] See legend to Figure 6A. [Figure 6C] See legend to Figure 6A. [Figure 6D] See legend to Figure 6A. [Figure 7]Anti-TREM2 antibody epitope bins. Anti-TREM2 antibody epitopes were characterized by competition binning, showing multiple epitope bins. Cross-competition was assessed using a biotinylated detection antibody, and binding was measured with a streptavidin-binding reagent in an ELISA format. The distance between the connecting lines indicates the similarity of the bins. The circular line indicates self-competition, which served as a positive control to validate the method. [Figure 8A] TREM2 p-Syk induction by novel lipid ligands. (A-B) HEK293 cells stably overexpressing human TREM2 (black bars) and DAP12 (gray bars) (A) or mutant TREM2 R47H (black bars) and DAP12 (gray bars) (B) were stimulated with 0.5 mg / mL liposomes containing 30% of the indicated lipid and 70% phosphatidylcholine (PC), except for Kdo2-lipid A (KLA), which contains 10% KLA and 90% PC. pSyk was measured by AlphaLISA, and data are shown as fold change relative to the buffer control (HBSS). Each bar represents the mean ± standard deviation from one to two independent experiments. (C) Human macrophages were stimulated with 0.5 mg / mL liposomes containing 30% of the indicated lipid and 70% phosphatidylcholine (PC). However, Kdo2-lipid A (KLA) contains 10% KLA and 90% PC. pSyk was measured by AlphaLISA, and data are graphed as fold change relative to buffer control. Data points represent the mean of two to three technical replicates from three independent human donors. Each bar represents the mean ± standard deviation. ***p<0.001, **p<0.01, *p<0.05. One-way ANOVA with Dunnett's post-hoc test comparison relative to 100% PC liposomes. See Table 9 for lipid abbreviation legend. [Figure 8B] See legend to Figure 8A. [Figure 8C] See legend to Figure 8A. [Figure 9A]Characterization of anti-TREM2 antibody interactions with lipid ligands to activate or block p-Syk. (A) Antibody induction of pSyk in the presence of a TREM2 lipid ligand. Anti-TREM2 antibodies were administered at 30 nM to human TREM2-expressing HEK cells with or without liposomes containing 30% phosphatidylserine (PS) / 70% phosphatidylcholine (PC) at EC20 (0.046 mg / mL), EC50 (0.212 mg / mL), or EC80 (0.967 mg / mL). pSyk activation was calculated as fold activation over the buffer-only control. 21D6.G2 and 3D3.A1 define the class of TREM2 antibodies that are additive with lipid TREM2 activators. (B) Antibody induction of pSyk in the presence of a TREM2 lipid ligand. Anti-TREM2 antibodies were administered to human macrophages at 10 nM with or without liposomes containing 30% phosphatidylserine (PS) / 70% phosphatidylcholine (PC) at EC20 (0.046 mg / mL), EC50 (0.212 mg / mL), or EC80 (0.967 mg / mL) concentrations. The signal from liposomes alone was subtracted from each value to determine whether the antibody had a synergistic, neutral, or inhibitory effect on lipid ligand-induced pSyk activation. (C) Anti-TREM2 antibodies (30 nM) or buffer were incubated with human macrophages for 30 min at 37°C, the antibody was removed, and then liposomes or buffer were added for 5 min at 37°C. pSyk detection in lysed cells by AlphaLISA was used to determine antibodies that synergized with or blocked the liposomal ligand. (D) Percentage of inhibition or synergy was determined by preincubating cells with antibodies and quantifying the resulting blockade or enhancement of liposome-mediated pSyk signaling. 100% inhibition was defined as complete blockade of liposome-mediated pSyk increase. (E) Antibody inhibition of pSyk in the presence of TREM2 lipid ligand. 21D4 significantly reduced liposome-induced TREM2 activation compared to control. (F-G) Antibody inhibition by antibodies 21D4 (F) and 21D11 (G) at increasing antibody concentrations. [Figure 9B] See legend to Figure 9A. [Figure 9C] See legend to Figure 9A. [Figure 9D] See legend to Figure 9A. [Figure 9E] See legend to Figure 9A. [Figure 9F] See legend to Figure 9A. [Figure 9G] See legend to Figure 9A. [Figure 10] ATV-anti-TREM2 Biacore analysis of TREM2 and hTfR binding. (A) TREM2 binding of RS9.F6 / 3C35.21.17_LALAPG. (B) TREM2 binding of RS9.F6. (C) Human TfR binding of RS9.F6 / 3C35.21.17_LALAPG. [Figure 11A] 465。 (B-D) Heatmap showing a portion of the differential heatmap shown in (A). (B) Differential heatmap showing residues 1-68 of the TREM2 protein. (C) Differential heatmap showing residues 69-144 of the TREM2 protein. (D) Differential heatmap showing residues 145-193 of the TREM2 protein. [Figure 11B] See legend to Figure 11A. [Figure 11C] See legend to Figure 11A. [Figure 11D] See legend to Figure 11A. [Figure 12]F6 Fab-TREM2 peptide co-complex structure. (A) Cartoon representation of the Fab:peptide complex. The Fab light chain (VL, left), Fab heavy chain (VH, right), and TREM2 peptide (center) are shown. (B) Interactions at the binding site. The TREM2 peptide (center), light chain (left), and heavy chain (right) are shown. Consecutive numbering of Fab residues. [Figure 13A] Interface residues of the F6-TREM2 complex. (A) Amino acid sequence of the light chain variable domain (residues 1-112 of SEQ ID NO: 112) and heavy chain variable domain (SEQ ID NO: 24) of the F6 Fab according to Chothia numbering. Kabat-defined CDRs are underlined. Residues in direct contact with the TREM2 peptide are shown in red. (B) Direct contacts between the TREM2 peptide and the Fab. Peptide residues are circled and Fab residues are boxed. Fab residues are numbered consecutively. [Figure 13B] See legend to Figure 13A. DETAILED DESCRIPTION OF THE INVENTION

[0059] Detailed Description I. Introduction Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor expressed on the cell surface of microglia, dendritic cells, macrophages, and osteoclasts. Without being bound by any particular theory, TREM2 is thought to form a signaling complex with the transmembrane adaptor protein DNAX-activating protein 12 (DAP12) upon ligand binding, which is then tyrosine phosphorylated by the protein kinase SRC. The activated TREM2 / DAP12 signaling complex is thought to regulate intracellular signaling by recruiting and phosphorylating kinases such as Syk kinase. TREM2 / DAP12 signaling regulates activities such as phagocytosis, cell growth and survival, pro-inflammatory cytokine secretion, and migration of cells such as microglia and macrophages.

[0060] TREM2 undergoes regulated intramembrane proteolysis, during which membrane-bound full-length TREM2 is cleaved by the metalloprotease ADAM10 to separate the sTREM2 moiety, which is released from the cell, and a membrane-retaining C-terminal fragment that is further degraded by γ-secretase. Altered levels of sTREM2 have been reported in patients with Alzheimer's disease or frontotemporal dementia who have mutations in TREM2. Furthermore, TREM2 mutations are associated with functional changes, including reduced phagocytosis and impaired microglial function.

[0061] As detailed in the Examples section below, antibodies have been generated that specifically bind to human TREM2 and modulate one or more downstream functions of the TREM2 / DAP12 signaling complex, such as phosphorylation of Syk kinase. Accordingly, in one aspect, the present disclosure provides anti-TREM2 antibodies and antigen-binding portions thereof.

[0062] In some embodiments, the anti-TREM2 antibodies enhance TREM2 activity. Thus, in another aspect, methods of enhancing TREM2 activity in a subject, for example, having a neurodegenerative disease, are provided.

[0063] In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity. Thus, in another aspect, a method of inhibiting TREM2 activity in a subject, for example, having a neurodegenerative disease, is provided.

[0064] In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce sTREM2 shedding. Thus, in yet another aspect, methods are provided for reducing sTREM2 levels in a subject, for example, with a neurodegenerative disease.

[0065] In some embodiments, the anti-TREM2 antibodies of the present disclosure increase the release of sTREM2. Thus, in yet another aspect, methods are provided for increasing the levels of sTREM2 in a subject, for example, having a neurodegenerative disease.

[0066] II. Definition As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to an "antibody" optionally includes a combination of two or more such molecules, and the like.

[0067] As used herein, the terms "about" and "approximately," when used to modify a numerical value or a number specified in a range, refer not only to that numerical value but also to reasonable variations from that value that would be known to one of ordinary skill in the art, e.g., ±20%, ±10%, or ±5%, within the intended meaning of the recited value.

[0068] As used herein, the term "TREM2 protein" refers to the triggering receptor 2 protein expressed on myeloid cells, encoded by the gene Trem2. As used herein, "TREM2 protein" refers to the native (i.e., wild-type) TREM2 protein of any vertebrate, including, but not limited to, humans, non-human primates (e.g., cynomolgus monkeys), rodents (e.g., mice, rats), and other mammals. In some embodiments, the TREM2 protein is a human TREM2 protein having the sequence identified by UniprotKB accession number Q9NZC2 (SEQ ID NO: 96).

[0069] As used herein, the term "anti-TREM2 antibody" refers to an antibody that specifically binds to a TREM2 protein (eg, human TREM2).

[0070] As used herein, the term "antibody" refers to a protein that specifically binds to an antigen via its variable region and possesses an immunoglobulin fold. This term encompasses intact polyclonal antibodies, intact monoclonal antibodies, single-chain antibodies, multispecific antibodies, e.g., bispecific antibodies, monospecific antibodies, monovalent antibodies, chimeric antibodies, humanized antibodies, and human antibodies. The term "antibody" as used herein also includes antibody fragments that retain binding specificity, including, but not limited to, Fab, F(ab'), Fv, scFv, and bivalent scFv. Antibodies may contain light chains classified as either kappa or lambda. Antibodies may contain heavy chains classified as gamma, mu, alpha, delta, or epsilon, which define the immunoglobulin classes IgG, IgM, IgA, IgD, and IgE, respectively.

[0071] An exemplary immunoglobulin (antibody) structural unit consists of a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light" chain (approximately 25 kD) and one "heavy" chain (approximately 50-70 kD). The N-terminus of each chain defines a variable region of about 100-110 or more amino acids primarily responsible for antigen recognition. The terms "variable light chain" (VL) and "variable heavy chain" (VH) refer to these light and heavy chains, respectively.

[0072] The term "variable region" or "variable domain" refers to the domain in an antibody heavy or light chain that is derived from germline variable (V), diversity (D), or joining (J) genes (and not from constant (Cμ and Cδ) gene segments) and confers antigen-binding specificity to the antibody. Typically, antibody variable regions contain four conserved "framework" regions, which are sandwiched between three hypervariable "complementarity-determining regions."

[0073] The term "complementarity-determining region" or "CDR" refers to the three hypervariable regions in each chain that separate the four framework regions established by the light and heavy chain variable regions. The CDRs are primarily responsible for antibody binding to an antigen epitope. The CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus, and are also typically identified by the chain in which the individual CDR is located. Thus, a VH CDR3 or CDR-H3 is located in the heavy chain variable region of the antibody in which it is found, while a VL CDR1 or CDR-L1 is the CDR1 from the light chain variable region of the antibody in which it is found.

[0074] The "framework regions" or "FRs" of different light or heavy chains are relatively conserved within a species. The framework region of an antibody, taken together with the framework regions of the constituent light and heavy chains, functions to position and align the CDRs in three-dimensional space. Framework sequences can be obtained from public DNA databases or published references, including germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in "VBASE2," a germline variable gene sequence database of human and mouse sequences.

[0075] The amino acid sequences of CDRs and framework regions can be determined using various definitions well known in the art, including, for example, Kabat, Chothia, the International ImMunoGeneTics database (IMGT), AbM, and observed antigen contact ("Contact"). In some embodiments, CDRs are defined according to the Contact definition. See MacCallum et al., J. Mol. Biol., 262:732-745 (1996). In some embodiments, CDRs are defined by a combination of the Kabat, Chothia, and / or Contact CDR definitions.

[0076] The terms "antigen-binding portion" and "antigen-binding fragment" are used interchangeably herein and refer to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., a TREM2 protein) via its variable region. Examples of antigen-binding fragments include, but are not limited to, a Fab fragment (a monovalent fragment consisting of the VL, VH, CL, and CH1 domains), a F(ab')2 fragment (a bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region), a single-chain Fv (scFv), a disulfide-linked Fv (dsFv), complementarity-determining regions (CDRs), a VL (light chain variable region), and a VH (heavy chain variable region).

[0077] The term "epitope" refers to a portion or region of an antigen to which an antibody CDR specifically binds, and can include a few amino acids or a portion of a few amino acids, e.g., 5 or 6 or more, e.g., 20 or more amino acids, or a portion of those amino acids. For example, if the target is a protein, the epitope can consist of consecutive amino acids (e.g., a linear epitope) or can consist of amino acids from different parts of the protein that are brought into proximity by protein folding (e.g., a discontinuous or conformational epitope). In some embodiments, the epitope is phosphorylated at one amino acid (e.g., a serine or threonine residue).

[0078] As used herein, the phrase "recognizes an epitope," when used in reference to an anti-TREM2 antibody, means that the CDRs of the antibody interact with or specifically bind to an antigen (i.e., a TREM2 protein) at that epitope or a portion of the antigen that contains that epitope.

[0079] As used herein, the term "multispecific antibody" refers to an antibody comprising two or more different antigen-binding portions, each of which comprises a different variable region that recognizes a different antigen, or a fragment or portion of an antibody that binds to two or more different antigens via its variable region. As used herein, the term "bispecific antibody" refers to an antibody comprising two different antigen-binding portions, each of which comprises a different variable region that recognizes a different antigen, or a fragment or portion of an antibody that binds to two different antigens via its variable region.

[0080] "Monoclonal antibody" refers to an antibody produced by a single cell clone or single cell line and consisting of or consisting essentially of antibody molecules which are identical in their primary amino acid sequence.

[0081] A "polyclonal antibody" refers to an antibody obtained from a heterogeneous antibody population, the different antibodies of which bind to different antigenic epitopes.

[0082] A "chimeric antibody" refers to an antibody molecule in which the constant region or a portion thereof has been altered, substituted, or exchanged so that its antigen-binding site (i.e., variable region, CDR, or portion thereof) is linked to a constant region of a different or altered class, effector function, and / or species, or the variable region or a portion thereof has been altered, substituted, or exchanged with a variable region (e.g., CDR and framework regions from a different species) with a different or altered antigen specificity. In some embodiments, a chimeric antibody is a monoclonal antibody comprising variable regions from one source or species (e.g., mouse) and a constant region from a second source or species (e.g., human). Methods for making chimeric antibodies have been described in the art.

[0083] A "humanized antibody" is a chimeric antibody derived from a non-human source (e.g., murine) that contains minimal sequences derived from the non-human immunoglobulin other than the CDRs. Generally, a humanized antibody will comprise at least one (e.g., two) antigen-binding variable domain(s), the CDR regions of which correspond substantially to those of a non-human immunoglobulin and the framework regions of which correspond substantially to those of a human immunoglobulin sequence. In some cases, certain framework region residues of the human immunoglobulin can be replaced with corresponding residues from the non-human species to, for example, improve specificity, affinity, and / or serum half-life. A humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically at least a portion of a human immunoglobulin sequence. Methods for humanizing antibodies are known in the art.

[0084] A "human antibody" or "fully human antibody" is an antibody having human heavy and light chain sequences, typically derived from human germline genes. In some embodiments, the antibody is produced by human cells, by non-human animals that utilize the human antibody repertoire (e.g., transgenic mice genetically engineered to express human antibody sequences), or by phage display platforms.

[0085] The term "specifically binds" refers to a molecule (e.g., an antibody (or antigen-binding portion thereof) or modified Fc polypeptide (or target-binding portion thereof)) that binds to an epitope or target in a sample with greater affinity, greater avidity, and / or for a longer period of time than it binds to another epitope or non-target compound (e.g., a structurally different antigen). In some embodiments, an antibody (or antigen-binding portion thereof) or modified Fc polypeptide (or target-binding portion thereof) that specifically binds to an epitope or target is an antibody (or antigen-binding portion thereof) or modified Fc polypeptide (or target-binding portion thereof) that binds to the epitope or target with at least 5-fold greater affinity, e.g., at least 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25-fold, 50-fold, 100-fold, 1,000-fold, 10,000-fold or more greater affinity, than to other epitopes or non-target compounds. In some embodiments, an antibody that specifically binds to a TREM2 protein (e.g., human TREM2) binds to the TREM2 protein with at least 5-fold greater affinity (e.g., at least 10-fold, 50-fold, 100-fold, 1,000-fold, 10,000-fold or more affinity) than it binds to a non-TREM2 protein. The terms "specific binding," "specifically binds," or "specific for," as used herein, with respect to a particular epitope or target, refer to, for example, the equilibrium dissociation constant K for the epitope or target to which the molecule binds. D For example, 10 -4 M or less, e.g., 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M. Those skilled in the art will recognize that an antibody that specifically binds to a TREM2 protein from a species may also specifically bind to an orthologue of that TREM2 protein.

[0086] The term "binding affinity" is used herein to refer to the strength of a non-covalent interaction between two molecules, e.g., between an antibody (or antigen-binding portion thereof) and an antigen, or between a modified Fc polypeptide (or target-binding portion thereof) and a target. Thus, for example, the term can refer to a 1:1 interaction between an antibody (or antigen-binding portion thereof) and an antigen, or between a modified Fc polypeptide (or target-binding portion thereof) and a target, unless otherwise specified or clear from the context. Binding affinity is measured by the dissociation rate constant (k d ,time -1 ) to the association rate constant (k a ,time -1 M -1 ) divided by the equilibrium dissociation constant (K D ) can be quantified by measuring the K D can be determined by measuring the kinetics of complex formation and dissociation using, for example, surface plasmon resonance (SPR) methods, e.g., the Biacore™ system; equilibrium exclusion assays such as KinExA®; and BioLayer interferometry (e.g., using the ForteBio® Octet platform). As used herein, "binding affinity" refers not only to formal binding affinity, e.g., the binding affinity that reflects a 1:1 interaction between an antibody (or antigen-binding portion thereof) and an antigen, or between a modified Fc polypeptide (or target-binding portion thereof) and a target, but also to K D is calculated and may also include apparent affinities that may reflect multivalent binding.

[0087] "Transferrin receptor" or "TfR," as used herein, refers to transferrin receptor protein 1. The human transferrin receptor 1 polypeptide sequence is set forth in SEQ ID NO: 97. Transferrin receptor protein 1 sequences from other species are also known (e.g., chimpanzee: accession numbers XP_003310238.1, rhesus monkey: NP_001244232.1, dog: NP_001003111.1, cow: NP_001193506.1, mouse: NP_035768.1, rat: NP_073203.1, and chicken: NP_990587.1). The term "transferrin receptor" also encompasses allelic variants of exemplary reference sequences, e.g., human sequences, encoded by genes at the transferrin receptor protein 1 chromosomal locus. The full-length transferrin receptor protein includes a short N-terminal intracellular region, a transmembrane region, and a large extracellular domain. The extracellular domain is characterized by three domains: a protease-like domain, a helical domain, and an apical domain.

[0088] As used herein, the term "Fc polypeptide" refers to the C-terminal region of a native immunoglobulin heavy chain polypeptide, which has the Ig fold as a structural domain. An Fc polypeptide contains constant region sequences, including at least a CH2 domain and / or a CH3 domain, and may contain at least a portion of the hinge region, but does not contain any variable region.

[0089] A "modified Fc polypeptide" refers to an Fc polypeptide that has at least one mutation, e.g., a substitution, deletion, or insertion, compared to a wild-type immunoglobulin heavy chain Fc polypeptide sequence, but retains the overall Ig fold or structure of a native Fc polypeptide.

[0090] As used herein, the term "FcRn" refers to the fetal Fc receptor. Binding of an Fc polypeptide to FcRn reduces the clearance of the Fc polypeptide and extends its serum half-life. The human FcRn protein is a heterodimer consisting of a protein approximately 50 kDa in size similar to major histocompatibility complex (MHC) class I proteins and β2-microglobulin, approximately 15 kDa in size.

[0091] As used herein, "FcRn-binding site" refers to the region of an Fc polypeptide that binds to FcRn. In human IgG, the FcRn-binding site includes L251, M252, I253, S254, R255, T256, M428, H433, N434, H435, and Y436, as numbered using the EU index. These positions correspond to positions 21-26, 198, and 203-206 of SEQ ID NO:98.

[0092] As used herein, a "native FcRn-binding site" refers to a region of an Fc polypeptide that binds to FcRn and has the same amino acid sequence as a region of a naturally occurring Fc polypeptide that binds to FcRn.

[0093] As used herein, the terms "CH3 domain" and "CH2 domain" refer to immunoglobulin constant region domain polypeptides. For purposes of this application, a CH3 domain polypeptide refers to the amino acid segment from approximately position 341 to approximately position 447 when numbered according to the EU numbering scheme, and a CH2 domain polypeptide refers to the amino acid segment from approximately position 231 to approximately position 340 when numbered according to the EU numbering scheme, excluding the hinge region sequence. CH2 and CH3 domain polypeptides may also be numbered according to the IMGT (ImMunoGeneTics) numbering scheme, in which the CH2 domain is numbered from 1 to 110 and the CH3 domain is numbered from 1 to 107 according to the IMGT Scientific chart numbering (IMGT website). The CH2 and CH3 domains are part of the Fc region of an immunoglobulin. The Fc region, as used herein, refers to the amino acid segment from approximately position 231 to approximately position 447 when numbered according to the EU numbering scheme, but may also include at least a portion of the hinge region of an antibody. An exemplary hinge region sequence is the human IgG1 hinge sequence EPKSCDKTHTCPPCP (SEQ ID NO: 99).

[0094] The terms "wild-type," "native," and "naturally occurring," when used in reference to a CH3 or CH2 domain, refer to a domain having a sequence that occurs in nature.

[0095] As used herein, the term "mutant" is used interchangeably with "variant" when used in reference to a mutant polypeptide or mutant polynucleotide. Variants relative to a given wild-type CH3 or CH2 domain reference sequence can include naturally occurring allelic variants. A "non-naturally occurring" CH3 or CH2 domain is one that does not occur in natural cells and refers to a variant or mutant domain of a native CH3 or CH2 domain polynucleotide or polypeptide that has been created by genetic modification, e.g., using genetic engineering or mutagenesis techniques. "Variant" includes any domain that contains at least one amino acid mutation relative to the wild-type. Mutations can include substitutions, insertions, and deletions.

[0096] The term "cross-reactivity," as used herein, refers to the ability of an antibody to bind to an antigen other than the antigen against which the antibody was raised. In some embodiments, cross-reactivity refers to the ability of an antibody to bind to an antigen from a species other than the antigen against which the antibody was raised. As a non-limiting example, an anti-TREM2 antibody described herein raised against a human TREM2 peptide may exhibit cross-reactivity with a TREM2 peptide or protein from a different species (e.g., monkey or mouse).

[0097] The term "isolated," when used with respect to a nucleic acid or protein (e.g., an antibody), indicates that the nucleic acid or protein is essentially free from other cellular components with which it is naturally associated. Purity and homogeneity are typically determined using analytical chemistry techniques such as electrophoresis (e.g., polyacrylamide gel electrophoresis) or chromatography (e.g., high performance liquid chromatography). In some embodiments, an isolated nucleic acid or protein (e.g., an antibody) is at least 85% pure, at least 90% pure, at least 95% pure, or at least 99% pure.

[0098] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to naturally occurring amino acids. Naturally occurring amino acids include not only those encoded by the genetic code, but also subsequently modified amino acids, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. "Amino acid analog" refers to a compound having the same basic chemical structure as a naturally occurring amino acid, i.e., an α-carbon bonded to a hydrogen, a carboxyl group, an amino group, and an R group, such as homoserine, norleucine, methionine sulfoxide, and methionine methylsulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. "Amino acid mimetics" refer to compounds that have a structure different from the general chemical structure of an amino acid but function similarly to a naturally occurring amino acid. Amino acids may be referred to herein by either the commonly known three-letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0099] The terms "polypeptide" and "peptide" are used interchangeably herein to refer to a single-chain polymer of amino acid residues. This term applies to naturally occurring and unnatural amino acid polymers, as well as to amino acid polymers in which one or more amino acid residues are artificial chemical mimetics of the corresponding naturally occurring amino acids. An amino acid polymer can contain exclusively L-amino acids, exclusively D-amino acids, or a mixture of L and D amino acids.

[0100] As used herein, the term "protein" refers to either a dimer (i.e., two) or multimer (i.e., three or more) of a polypeptide or single-chain polypeptide. Proteins in single-chain polypeptides can be linked by covalent bonds, e.g., disulfide bonds, or by non-covalent interactions.

[0101] The terms "polynucleotide" and "nucleic acid" refer interchangeably to a chain of nucleotides of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and / or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase. Polynucleotides can include modified nucleotides, such as methylated nucleotides and their analogs. Examples of polynucleotides contemplated herein include single- and double-stranded DNA, single- and double-stranded RNA, and hybrid molecules comprising mixtures of single- and double-stranded DNA and RNA.

[0102] The terms "conservative substitution" and "conservative variation" refer to alterations that result in the substitution of an amino acid with another amino acid that can be classified as having similar characteristics. Examples of conservative amino acid group classifications defined in this manner include the "charged / polar group" which includes Glu (glutamic acid or E), Asp (aspartic acid or D), Asn (asparagine or N), Gln (glutamine or Q), Lys (lysine or K), Arg (arginine or R), and His (histidine or H); the "aromatic group" which includes Phe (phenylalanine or F), Tyr (tyrosine or Y), Trp (tryptophan or W), and (histidine or H); and the "aliphatic group" which includes Gly (glycine or G), Ala (alanine or A), Val (valine or V), Leu (leucine or L), Ile (isoleucine or I), Met (methionine or M), Ser (serine or S), Thr (threonine or T), and Cys (cysteine ​​or C). Within each group, subgroups may also be identified. For example, the group of charged or polar amino acids can be subdivided into subgroups including a "positively charged subgroup" containing Lys, Arg, and His; a "negatively charged subgroup" containing Glu and Asp; and a "polar subgroup" containing Asn and Gln. As another example, the aromatic or cyclic group can be subdivided into subgroups including a "nitrogen ring subgroup" containing Pro, His, and Trp; and a "phenyl subgroup" containing Phe and Tyr. As a further example, the aliphatic group can be subdivided into subgroups including, for example, an "aliphatic non-polar subgroup" containing Val, Leu, Gly, and Ala; and an "aliphatic weakly polar subgroup" containing Met, Ser, Thr, and Cys. Examples of conservative mutation classifications include amino acid substitutions of amino acids within the above subgroups, such as, but not limited to, substitution of Lys with Arg or vice versa to maintain a positive charge; substitution of Glu with Asp or vice versa to maintain a negative charge; substitution of Ser with Thr or vice versa to maintain a free -OH; and substitution of Gln with Asn or vice versa to maintain a free -NH2.In some embodiments, hydrophobic amino acids are substituted for the native hydrophobic amino acids to maintain hydrophobicity, for example, at the active site.

[0103] The terms "identical" or percent "identity," in the context of two or more polypeptide sequences, refer to two or more sequences or subsequences that, when compared and aligned for maximum correspondence over a comparison window, or designated region, have a specified percentage of amino acid residues that are the same or identical over a specified region, e.g., at least 60% identity, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% or more.

[0104] For polypeptide sequence comparison, typically, one amino acid sequence serves as a reference sequence and is compared with a candidate sequence. Alignment can be performed by various methods available to those skilled in the art, such as visual alignment, or by using publicly available software that uses known algorithms to achieve maximum alignment. Such programs include the BLAST program, ALIGN, ALIGN-2 (Genentech, South San Francisco, Calif.), or Megalign (DNASTAR). The parameters used for alignment to achieve maximum alignment can be determined by those skilled in the art. For polypeptide sequence comparison in this application, the BLASTP algorithm, standard protein BLAST, is used, which aligns two protein sequences with default parameters.

[0105] When used in the context of identifying a given amino acid residue in a polypeptide sequence, the terms "corresponding to," "determined with reference to," or "numbered with reference to" refer to the position of the residue in a particular reference sequence when the given amino acid sequence is maximally aligned and compared to the reference sequence. Thus, for example, an amino acid residue in a modified Fc polypeptide "corresponds to" an amino acid in SEQ ID NO: 98 if that residue is identical to the amino acid in SEQ ID NO: 98 when optimally aligned to SEQ ID NO: 98. A polypeptide aligned to a reference sequence need not be the same length as the reference sequence.

[0106] The terms "subject," "individual," and "patient" are used interchangeably herein and refer to mammals, including, but not limited to, humans, non-human primates, rodents (e.g., rats, mice, and guinea pigs), rabbits, cows, pigs, horses, and other mammalian species. In one embodiment, the subject, individual, or patient is a human.

[0107] The terms "treating," "treatment," and the like are used herein generally to mean obtaining a desired pharmacological and / or physiological effect. "Treating" or "treatment" can refer to any indication of successful treatment or amelioration of a neurodegenerative disease (e.g., Alzheimer's disease or another neurodegenerative disease described herein), including any objective or subjective parameter, such as alleviation, remission, improved patient survival, increased survival time or survival rate, alleviation of symptoms, or increasing the patient's tolerance of the disease, slowing the rate of degeneration or decline, or improving the patient's physical or mental health. The treatment or amelioration of symptoms can be based on objective or subjective parameters. The effect of treatment can be compared to an individual or pool of individuals not receiving treatment, or to the same patient before treatment or at different times during treatment.

[0108] The term "pharmaceutically acceptable excipient" refers to inactive pharmaceutical ingredients, such as, but not limited to, buffers, carriers, or preservatives, that are biologically or pharmacologically compatible for use in humans or animals.

[0109] As used herein, a "therapeutic amount" or "therapeutically effective amount" of an agent (e.g., an antibody described herein) is an amount of agent that treats, alleviates, relieves, or reduces the severity of symptoms of a disease in a subject. A "therapeutic amount" of an agent (e.g., an antibody described herein) may improve the patient's survival, increase survival time or rate, alleviate symptoms, increase tolerance to injury, disease, or condition (e.g., a neurodegenerative disease), slow the rate of degeneration or decline, or improve the patient's physical or mental health.

[0110] The term "administering" refers to a method of delivering an agent, compound, or composition to a desired site of biological action. These methods include, but are not limited to, topical, parenteral, intravenous, intradermal, intramuscular, intrathecal, colonic, rectal, or intraperitoneal delivery. In one embodiment, the antibodies described herein are administered intravenously.

[0111] The term "selectively enhances," when used in the context of a TREM2 antibody that enhances activity induced by a TREM2 ligand, means that the antibody significantly (e.g., at least 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, 8-fold, 10-fold, 15-fold, 20-fold, 30-fold, or 50-fold) enhances the activity of the TREM2 ligand compared to an appropriate reference, e.g., the enhancement of a reference TREM2 ligand (e.g., any of those described herein), or compared to the average enhancement of a group of TREM2 ligands (e.g., any or all of those described herein).

[0112] The term "control" or "control value" refers to a reference value or baseline value. An appropriate control can be determined by one skilled in the art. In some cases, the control value can be determined based on a baseline within the same subject or experiment; for example, a measurement of sTREM2 taken before treatment with an anti-TREM2 antibody can serve as a control value for measurements of sTREM2 levels in the same subject after treatment. In other cases, the control value can be determined based on the average value of a control subject (e.g., a healthy or diseased control) or a population of control subjects (e.g., a population of 10, 20, 50, 100, 200, 500, 1000 or more control subjects); for example, measurements of a subject's sTREM2 level at either baseline or after treatment can be compared to the healthy control value.

[0113] III. Anti-TREM2 antibody In one aspect, antibodies and antigen-binding portions thereof that specifically bind to the TREM2 protein are provided. In some embodiments, the antibodies specifically bind to human TREM2 protein. In some embodiments, the anti-TREM2 antibodies are selective for TREM2 over other TREM-like receptors (e.g., TREM1).

[0114] In some embodiments, an antibody that specifically binds to TREM2 is an antibody that has one or more TREM2 activities described herein, such as an antibody that modulates the recruitment or phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (e.g., Syk kinase), modulates phagocytosis, modulates cell migration, and / or modulates cell differentiation; an antibody that modulates the levels of sTREM2; an antibody that modulates ligand activation of TREM2; an antibody clone described herein (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A1); 1.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8. A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44 E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 5 antibodies that recognize the same or substantially the same epitope as that recognized by (RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10); and and / or the antibody clones described herein (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS 9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4 and antibodies having one or more CDRs, heavy chain variable region, and / or light chain variable region sequences of any of the following: RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, or RS12.3C10.

[0115] Anti-TREM2 antibodies that regulate sTREM2 release In some embodiments, the anti-TREM2 antibody alters the level of sTREM2 protein in a sample, e.g., the level of sTREM2 released from the cell surface into an extracellular sample. In some embodiments, the anti-TREM2 antibody decreases the level of sTREM2. In some embodiments, the anti-TREM2 antibody increases the level of sTREM2.

[0116] In some embodiments, an anti-TREM2 antibody reduces the level of sTREM2 if the amount of sTREM2 in the treated sample is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value. In some embodiments, an anti-TREM2 antibody reduces the level of sTREM2 if the amount of sTREM2 in the treated sample is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to the control value. In some embodiments, the control value is the amount of sTREM2 in an untreated sample (e.g., supernatant of TREM2-expressing cells not treated with an anti-TREM2 antibody, or a sample from a subject not treated with an anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0117] In some embodiments, an anti-TREM2 antibody increases the level of sTREM2 if the amount of sTREM2 in the treated sample is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value. In some embodiments, an anti-TREM2 antibody increases the level of sTREM2 if the amount of sTREM2 in the treated sample is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to the control value. In some embodiments, the control value is the amount of sTREM2 in an untreated sample (e.g., supernatant of TREM2-expressing cells not treated with an anti-TREM2 antibody, or a sample from a subject not treated with an anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0118] In some embodiments, sTREM2 release is measured using a sample comprising a body fluid, e.g., blood, plasma, serum, urine, or cerebrospinal fluid. In some embodiments, the sample comprises cerebrospinal fluid. In some embodiments, the sample comprises a cell culture supernatant (e.g., supernatant of primary cells or cell lines, such as human macrophages, that endogenously express TREM2, or primary cells or cell lines engineered to express TREM2, e.g., as described in the Examples section below).

[0119] In some embodiments, the level of sTREM2 in a sample is measured using an immunoassay. Immunoassays are known in the art and include, but are not limited to, enzyme immunoassays (EIAs), such as enzyme-linked immunosorbent assays (EMIAs), enzyme-linked immunosorbent assays (ELISAs), microparticle enzyme immunoassays (MEIAs), immunohistochemistry (IHC), immunocytochemistry, capillary electrophoresis immunoassays (CEIAs), radioimmunoassays (RIAs), immunofluorescence, chemiluminescence immunoassays (CLs), and electrochemiluminescence immunoassays (ECLs). In some embodiments, the level of sTREM2 is measured using an ELISA assay. In some embodiments, the level of sTREM2 is measured using the ELISA assay described in the Examples section below.

[0120] In some embodiments, anti-TREM2 antibodies that decrease levels of sTREM2 also modulate one or more TREM2 activities described below. In some embodiments, anti-TREM2 antibodies that increase levels of sTREM2 also modulate one or more TREM2 activities described below.

[0121] Anti-TREM2 antibodies that modulate TREM2 activity In some embodiments, the anti-TREM2 antibody modulates one or more TREM2 activities. For example, in some embodiments, the anti-TREM2 antibody modulates the recruitment or phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex. In some embodiments, the anti-TREM2 antibody modulates one or more downstream activities, such as phagocytosis, cell growth, cell survival, cell differentiation, cytokine secretion, or cell migration.

[0122] In some embodiments, the anti-TREM2 antibody enhances one or more TREM2 activities, including, but not limited to, inducing phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, enhancing phagocytosis (e.g., phagocytosis of cellular debris, amyloid beta particles, etc.), enhancing cell migration (e.g., migration of microglia or macrophages), enhancing cell function (e.g., of myeloid cells, microglia including disease-associated microglia, and macrophages), and / or enhancing cell survival or cell differentiation (e.g., of myeloid cells, microglia including disease-associated microglia, and macrophages).

[0123] In some embodiments, the anti-TREM2 antibody enhances one or more TREM2 activities (e.g., those described above) induced by a ligand. Anti-TREM2 antibodies that enhance one or more TREM2 activities induced by a ligand are referred to herein as "positive allosteric modulators" ("PAMs"). In some embodiments, the anti-TREM2 antibody enhances one or more TREM2 activities without blocking the binding of a native TREM2 ligand. In some embodiments, the anti-TREM2 antibody blocks the binding of a TREM2 ligand to TREM2. In some embodiments, the anti-TREM2 antibody enhances one or more TREM2 activities induced by a ligand, but does not enhance TREM2 activity in the absence of a ligand. In some embodiments, the anti-TREM2 antibody selectively enhances the activity of a TREM2 ligand. In some embodiments, the anti-TREM2 antibody blocks activation of TREM2 by a TREM2 ligand.

[0124] In some embodiments, the anti-TREM2 antibody inhibits one or more TREM2 activities, including, but not limited to, reducing or inhibiting phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex, reducing or inhibiting phagocytosis (e.g., phagocytosis of cellular debris, amyloid-beta particles, etc.), reducing or inhibiting cell migration (e.g., migration of microglia or macrophages), and / or reducing or inhibiting cell survival or cell differentiation (e.g., of myeloid cells, microglia, including disease-associated microglia, and macrophages). In some embodiments, the anti-TREM2 antibody inhibits one or more TREM2 activities induced by a ligand. Anti-TREM2 antibodies that inhibit one or more TREM2 activities induced by a ligand are referred to herein as "negative allosteric modulators" ("NAMs"). In some embodiments, the anti-TREM2 antibody inhibits one or more TREM2 activities induced by a ligand, but does not inhibit TREM2 activity in the absence of ligand. In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity in the absence of a TREM2 ligand and inhibits one or more TREM2 activities induced by the ligand. In some embodiments, the anti-TREM2 antibody blocks activation of TREM2 by a TREM2 ligand. In some embodiments, the anti-TREM2 antibody binds to TREM2 at the ligand-binding site. In some embodiments, the anti-TREM2 antibody blocks binding of a TREM2 ligand to TREM2.

[0125] Kinase phosphorylation In some embodiments, the anti-TREM2 antibody induces phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b). In some embodiments, the anti-TREM2 antibody induces phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex without blocking binding of native TREM2 ligand. In some embodiments, the anti-TREM2 antibody induces phosphorylation of Syk. In some embodiments, the anti-TREM2 antibody induces phosphorylation of Syk if the level of Syk phosphorylation in samples treated with the anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to control values. In some embodiments, an anti-TREM2 antibody induces phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value. In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells that have not been treated with an anti-TREM2 antibody, or a sample from a subject not treated with an anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0126] In some embodiments, the anti-TREM2 antibody induces phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b) in the presence of a ligand. In some embodiments, the anti-TREM2 antibody induces phosphorylation of Syk in the presence of a ligand. In some embodiments, the anti-TREM2 antibody induces phosphorylation of Syk in the presence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value. In some embodiments, an anti-TREM2 antibody induces phosphorylation of Syk in the presence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, or more compared to a control value (e.g., the level in the presence of the ligand but in the absence of the antibody). In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells that has not been treated with a TREM2 ligand or anti-TREM2 antibody, or a sample from a subject not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0127] In some embodiments, the anti-TREM2 antibody induces phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b) in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody induces phosphorylation of Syk in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody induces Syk phosphorylation in the presence of a ligand but not in the absence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value, and the level of Syk phosphorylation in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially increased compared to the control value (e.g., not increased by more than 10% or more than 5% compared to the control value). In some embodiments, the anti-TREM2 antibody induces Syk phosphorylation in the presence of a ligand but not in the absence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, or more compared to the control value, and the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody but not the TREM2 ligand is not substantially increased compared to the control value (e.g., not increased by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells not treated with a TREM2 ligand or anti-TREM2 antibody, or a sample from a subject not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0128] In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (including, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b). In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk if the level of Syk phosphorylation in samples treated with the anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to control values. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk if the level of Syk phosphorylation in samples treated with the anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to control values. In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample containing TREM2-expressing cells that have not been treated with an anti-TREM2 antibody, or a sample from a subject not treated with an anti-TREM2 antibody) or a sample treated with an appropriate non-TREM2-binding antibody.

[0129] In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of a kinase that interacts with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b) in the presence of a ligand. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the presence of a ligand. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the presence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value. In some embodiments, the anti-TREM2 antibody inhibits the phosphorylation of Syk in the presence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value. In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells that has not been treated with a TREM2 ligand or anti-TREM2 antibody, or a sample from a subject not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0130] In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b) in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody inhibits Syk phosphorylation in the presence of a ligand but not in the absence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value, and the level of Syk phosphorylation in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 10% or more than 5% compared to the control value). In some embodiments, the anti-TREM2 antibody inhibits Syk phosphorylation in the presence of a ligand but not in the absence of a ligand if the level of Syk phosphorylation in a sample treated with a TREM2 ligand and anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to the control value, and the level of Syk phosphorylation in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells not treated with a TREM2 ligand or anti-TREM2 antibody, or a sample from a subject not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0131] In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex (including but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b) in the absence of ligand and inhibits ligand-induced phosphorylation of kinases that interact with the TREM2 / DAP12 signaling complex. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the absence of ligand and inhibits ligand-induced phosphorylation of Syk. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the absence of a ligand and inhibits ligand-induced phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value in the absence of a TREM2 ligand, and the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody and a TREM2 ligand is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value. In some embodiments, the anti-TREM2 antibody inhibits phosphorylation of Syk in the absence of a ligand and inhibits ligand-induced phosphorylation of Syk if the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to the control value in the absence of a TREM2 ligand, and the level of Syk phosphorylation in a sample treated with the anti-TREM2 antibody and a TREM2 ligand is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to the control value.In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample comprising TREM2-expressing cells that have not been treated with a TREM2 ligand or anti-TREM2 antibody, or a sample from a subject not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0132] In some embodiments, immunoassays are used to detect and / or quantify phosphorylation (e.g., Syk phosphorylation) in a sample. In some embodiments, the immunoassay is an enzyme-linked immunosorbent assay (EIA), enzyme-linked immunosorbent assay (EMIA), enzyme-linked immunosorbent assay (ELISA), microparticle enzyme-linked immunosorbent assay (MEIA), immunohistochemistry (IHC), immunocytochemistry, capillary electrophoresis immunoassay (CEIA), radioimmunoassay (RIA), immunofluorescence, chemiluminescence immunoassay (CL), or electrochemiluminescence immunoassay (ECL). In some embodiments, phosphorylation is detected and / or quantified using an immunoassay that utilizes a chemically amplified luminescence proximity homogeneous assay (AlphaLISA®, PerkinElmer Inc.).

[0133] In some embodiments, phosphorylation is measured using a sample comprising one or more cells, e.g., one or more TREM2-expressing cells (e.g., primary cells or cell lines, such as human macrophages, that endogenously express TREM2, or primary cells or cell lines engineered to express TREM2, e.g., as described in the Examples section below). In some embodiments, the sample comprises a bodily fluid, e.g., blood, plasma, serum, urine, or cerebrospinal fluid. In some embodiments, the sample comprises a tissue (e.g., lung, brain, kidney, spleen, neural tissue, or skeletal muscle) or cells derived from such a tissue. In some embodiments, the sample comprises an endogenous bodily fluid, tissue, or cell (e.g., derived from a human or non-human subject).

[0134] phagocytosis In some embodiments, anti-TREM2 antibodies enhance phagocytosis of dead cell debris, tissue debris, amyloid beta particles, or foreign material. In some embodiments, anti-TREM2 antibodies enhance phagocytosis without blocking binding of native TREM2 ligands. In some embodiments, anti-TREM2 antibodies enhance phagocytosis if the level of phagocytosis in samples treated with the anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more compared to a control value. In some embodiments, anti-TREM2 antibodies enhance phagocytosis if the level of phagocytosis in samples treated with the anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value. In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0135] In some embodiments, the anti-TREM2 antibody enhances phagocytosis in the presence of a ligand. In some embodiments, the anti-TREM2 antibody enhances phagocytosis in the presence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value. In some embodiments, the anti-TREM2 antibody enhances phagocytosis in the presence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value. In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0136] In some embodiments, the anti-TREM2 antibody enhances phagocytosis in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody enhances phagocytosis in the presence of a ligand but not in the absence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value, and the level of phagocytosis in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially increased compared to the control value (e.g., not increased by more than 10% or more than 5% compared to the control value). In some embodiments, an anti-TREM2 antibody enhances phagocytosis in the presence of a ligand but not in the absence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to the control value, and the level of phagocytosis in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially increased compared to the control value (e.g., not increased by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0137] In some embodiments, an anti-TREM2 antibody reduces phagocytosis. In some embodiments, an anti-TREM2 antibody reduces phagocytosis if the level of phagocytosis in a sample treated with the anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value. In some embodiments, an anti-TREM2 antibody reduces phagocytosis if the level of phagocytosis in a sample treated with the anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value. In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0138] In some embodiments, the anti-TREM2 antibody reduces phagocytosis in the presence of a ligand. In some embodiments, the anti-TREM2 antibody reduces phagocytosis in the presence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value. In some embodiments, the anti-TREM2 antibody reduces phagocytosis in the presence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value. In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0139] In some embodiments, the anti-TREM2 antibody reduces phagocytosis in the presence of a ligand but not in the absence of a ligand. In some embodiments, the anti-TREM2 antibody reduces phagocytosis in the presence of a ligand but not in the absence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value, and the level of phagocytosis in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 10% or more than 5% compared to the control value). In some embodiments, an anti-TREM2 antibody reduces phagocytosis in the presence of a ligand but not in the absence of a ligand if the level of phagocytosis in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to the control value, and the level of phagocytosis in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of phagocytosis in an untreated sample or a sample treated with an appropriate non-TREM2-binding antibody.

[0140] In some embodiments, phagocytosis is measured using a phagocytosis assay with a labeled substrate. Phagocytosis assays are known in the art. In some embodiments, the phagocytosis assay is performed on a sample containing cells, such as human macrophages or microglia, that endogenously express TREM2. In some embodiments, the phagocytosis assay is performed on a sample containing cells engineered to express TREM2. In some embodiments, cell migration is measured using the human macrophage phagocytosis assay described in the Examples section below.

[0141] Cell migration, survival, function, and differentiation In some embodiments, the anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation (e.g., of microglia, including myeloid cells, macrophages, and disease-associated microglia). Disease-associated microglia and methods for detecting disease-associated microglia are described in Keren-Shaul et al., Cell, 2017, 169:1276-1290. In some embodiments, the anti-TREM2 antibody enhances cell migration of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody enhances cell survival of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody enhances cell differentiation of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody enhances myeloid cell migration, survival, and / or differentiation. In some embodiments, anti-TREM2 antibodies enhance macrophage migration, survival, and / or differentiation. In some embodiments, anti-TREM2 antibodies enhance microglial migration, survival, and / or differentiation. In some embodiments, anti-TREM2 antibodies enhance microglial activation. In some embodiments, anti-TREM2 antibodies enhance disease-associated microglial migration, survival, and / or differentiation. In some embodiments, anti-TREM2 antibodies enhance cell migration, cell survival, or cell differentiation without blocking binding of native TREM2 ligand.

[0142] In some embodiments, an anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation if the level of an activity (e.g., migration, survival, or differentiation) in a sample treated with the anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value. In some embodiments, an anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation if the level of an activity (e.g., migration, survival, or differentiation) in a sample treated with the anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value. In some embodiments, the control value is the level of an activity (e.g., migration, survival, or differentiation) in an untreated sample (e.g., a sample not treated with the anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0143] In some embodiments, the anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand. In some embodiments, the anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more compared to a control value. In some embodiments, the anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value. In some embodiments, the control value is the level of activity (e.g., migration, survival, or differentiation) in an untreated sample (e.g., a sample not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0144] In some embodiments, an anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand. In some embodiments, an anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand if the level of an activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value, and the level of the activity in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially increased compared to a control value (e.g., not increased by more than 10% or more than 5% compared to a control value). In some embodiments, an anti-TREM2 antibody enhances cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand if the level of the activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and anti-TREM2 antibody is increased by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to the control value, and the level of the activity in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially increased compared to the control value (e.g., not increased by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of the activity (e.g., migration, survival, or differentiation) in an untreated sample (e.g., a sample not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0145] In some embodiments, the anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation (e.g., of myeloid cells, macrophages, and microglia, including disease-associated microglia). In some embodiments, the anti-TREM2 antibody inhibits cell migration of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody inhibits cell survival of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody inhibits cell differentiation of one or more cell types (e.g., myeloid cells, macrophages, or microglia). In some embodiments, the anti-TREM2 antibody inhibits myeloid cell migration, survival, and / or differentiation. In some embodiments, the anti-TREM2 antibody inhibits macrophage migration, survival, and / or differentiation. In some embodiments, the anti-TREM2 antibody inhibits microglial migration, survival, and / or differentiation. In some embodiments, the anti-TREM2 antibody inhibits microglial activation. In some embodiments, the anti-TREM2 antibody inhibits the migration, survival, and / or differentiation of disease-associated microglia.

[0146] In some embodiments, an anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with the anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to a control value. In some embodiments, an anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with the anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold or more compared to a control value. In some embodiments, the control value is the level of Syk phosphorylation in an untreated sample (e.g., a sample not treated with an anti-TREM2 antibody) or a sample treated with an appropriate non-TREM2-binding antibody.

[0147] In some embodiments, the anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand. In some embodiments, the anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or more compared to a control value. In some embodiments, the anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to a control value. In some embodiments, the control value is the level of activity (e.g., migration, survival, or differentiation) in an untreated sample (e.g., a sample not treated with a TREM2 ligand or anti-TREM2 antibody) or a sample treated with a suitable non-TREM2-binding antibody.

[0148] In some embodiments, an anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand. In some embodiments, an anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand if the level of activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or more compared to the control value, and the level of activity in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 10% or more than 5% compared to the control value). In some embodiments, an anti-TREM2 antibody inhibits cell migration, cell survival, or cell differentiation in the presence of a ligand but not in the absence of a ligand if the level of the activity (e.g., migration, survival, or differentiation) in a sample treated with a TREM2 ligand and an anti-TREM2 antibody is reduced by at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or more compared to the control value, and the level of the activity in a sample treated with an anti-TREM2 antibody but not a TREM2 ligand is not substantially reduced compared to the control value (e.g., not reduced by more than 1.5-fold or more than 1-fold compared to the control value). In some embodiments, the control value is the level of the activity (e.g., migration, survival, or differentiation) in an untreated sample (e.g., a sample not treated with a TREM2 ligand or anti-TREM2 antibody).

[0149] In some embodiments, cell migration is measured using a chemotaxis assay. Chemotaxis assays are known in the art. In some embodiments, the cell migration assay (e.g., chemotaxis assay) is performed on a sample containing cells, such as human macrophages, that endogenously express TREM2. In some embodiments, the cell migration assay (e.g., chemotaxis assay) is performed on a sample containing cells engineered to express TREM2. In some embodiments, cell migration is measured using the human macrophage chemotaxis assay described in the Examples section below.

[0150] In some embodiments, cell survival is measured using a cell viability assay. Cell viability assays are known in the art. In some embodiments, the cell survival assay (e.g., cell viability assay) is performed on a sample containing cells, such as human macrophages, that endogenously express TREM2. In some embodiments, the cell survival assay (e.g., cell viability assay) is performed on a sample containing cells engineered to express TREM2. In some embodiments, cell survival is measured using the human macrophage viability assay described in the Examples section below.

[0151] In some embodiments, cell differentiation is measured by assessing the ability of cells that endogenously express TREM2 to differentiate. For example, in some embodiments, cell differentiation is measured by assessing the ability of macrophages to differentiate from monocytes, e.g., as described in the Examples section below.

[0152] In some embodiments, microglial activation is measured in vivo. In some embodiments, microglial activation is measured using TSPO-PET imaging. TSPO-PET imaging methods are known in the art.

[0153] In some embodiments, anti-TREM2 antibodies enhance microglial function without increasing neuroinflammation. The level of neuroinflammation can be determined by measuring the level of cytokines (e.g., pro-inflammatory cytokines), such as, but not limited to, TNF-α, IL-1β, IL-6, IL-1ra, TGFβ, IL-15, or IFN-γ. In some embodiments, cytokine levels are measured using an immunoassay, such as an enzyme-linked immunosorbent assay (EIA), enzyme-linked immunosorbent assay (EMIA), enzyme-linked immunosorbent assay (ELISA), microparticle enzyme-linked immunosorbent assay (MEIA), immunohistochemistry (IHC), immunocytochemistry, capillary electrophoresis immunoassay (CEIA), radioimmunoassay (RIA), immunofluorescence, chemiluminescence immunoassay (CL), or electrochemiluminescence immunoassay (ECL).

[0154] TREM2 ligand In some embodiments, the TREM2 ligand is a lipid ligand described herein, for example, a lipid ligand described below in Example 4. In some embodiments, the TREM2 ligand is 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC), 2-arachidonoylglycerol (2-AG), 7-ketocholesterol (7-KC), 24(S)hydroxycholesterol (24OHC), 25(S)hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), acylcarnitine (AC), alkylacylglycerophosphocholine (PAF), α-galactosyltransferase (TAT), α-galactosyltransferase (AL ... Ceramide (KRN7000), bis(monoacylglycero)phosphate (BMP), cardiolipin (CL), ceramide, ceramide-1-phosphate (C1P), cholesteryl ester (CE), cholesterol phosphate (CP), diacylglycerol 34:1 (DG34:1), diacylglycerol 38:4 (DG38:4), diacylglycerol pyrophosphate (DGPP), dihydroceramide (DhCer), dihydrosphingomyelin (DhSM), ether phosphatidylcholine (PCe), free cholesterol Fatty acid monophosphate (FAO), galactosylceramide (GalCer), galactosylsphingosine (GalSo), ganglioside GM1, ganglioside GM3, glucosylsphingosine (GlcSo), Hank's balanced salt solution (HBSS), Kdo2-lipid A (KLA), lactosylceramide (LacCer), lysoalkylacylglycerophosphocholine (LPAF), lysophosphatidic acid (LPA), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), lysophosphatidyl LPG, lysophosphatidylinositol (LPI), lysosphingomyelin (LSM), lysophosphatidylserine (LPS), N-acyl-phosphatidylethanolamine (NAPE), N-acyl-serine (NSer), oxidized phosphatidylcholine (oxPC), palmitic acid-9-hydroxy-stearic acid (PAHSA), phosphatidylethanolamine (PE), phosphatidylethanol (PEtOH), phosphatidic acid (PA), phosphatidylcholine (PC),Selected from the group consisting of phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), sphinganine, sphinganine-1-phosphate (SalP), sphingomyelin (SM), sphingosine, sphingosine-1-phosphate (SolP), and sulfatide.

[0155] In some embodiments, the anti-TREM2 antibodies described herein interact with one or more lipid ligands (e.g., lipid ligands described herein) to modulate TREM2 activity. In some embodiments, the anti-TREM2 antibodies described herein interact with one or more lipid ligands to modulate a TREM2 signaling pathway involving kinases that interact with the TREM2 / DAP12 signaling complex (such as, but not limited to, Syk, ZAP70, PI3K, Erk, AKT, or GSK3b). In some embodiments, the anti-TREM2 antibodies interact with lipid ligands to activate Syk, ZAP70, PI3K, Erk, AKT, or GSK3b. In some embodiments, the anti-TREM2 antibodies exhibit an additive effect with lipid ligands on activation of signaling pathways (e.g., Syk, ZAP70, PI3K, Erk, AKT, or GSK3b). In some embodiments, the anti-TREM2 antibodies exhibit an additive effect with lipid ligands on activation of p-Syk. In some embodiments, anti-TREM2 antibodies exhibit a blocking effect on lipid ligand activation of signaling pathways (e.g., Syk, ZAP70, PI3K, Erk, AKT, or GSK3b), hi some embodiments, anti-TREM2 antibodies exhibit a blocking effect on lipid ligand activation of p-Syk.

[0156] In some embodiments, the anti-TREM2 antibody exhibits an additive effect with lipid ligands on activation of components of the TREM2 signaling pathway (e.g., p-Syk) and recognizes an epitope that is the same as or substantially the same as the epitope recognized by antibody clones RS9.F6, 22B8.B1, 3D3.A1, 42E8.H1, 43E9.H1, 21D6.G2, 59C6.F1, 53H11.D3, 60A4.B1, 26E2.A3, 54C2.A1, 44E2.H1, 22G9.D1, 49H11.B1, 14D5.F1, 26D11.B1, 52H9.D1, or 7B10.A2. In some embodiments, the anti-TREM2 antibody exhibits a blocking effect with lipid ligands on the activation of components of the TREM2 signaling pathway (e.g., p-Syk) and recognizes an epitope that is the same as or substantially the same as the epitope recognized by antibody clones RS9.F10, 13B11.A1, 21D4.D1, 30A8.A1, 57D7.A1, 24B4.A1, 39H10.A1, 55B9.A1, 14H11.B1, 40H3.A4, 30F2.A1, 51D4.A1, 26D2.D1, 21D11.B1, 44E3.B1, 26D5.A1, 38E9.E5, RS9.E2, or 2G4.B1.

[0157] Binding characteristics of anti-TREM2 antibodies In some embodiments, antibodies that specifically bind to the TREM2 proteins described herein bind to TREM2 expressed on cells (e.g., primary cells or cell lines such as human macrophages that endogenously express TREM2, or primary cells or cell lines that have been engineered to express TREM2, e.g., as described in the Examples section below). In some embodiments, antibodies that specifically bind to the TREM2 proteins described herein bind to purified or recombinant TREM2 protein or a chimeric protein comprising TREM2 or a portion thereof (e.g., an Fc fusion protein comprising TREM2 or an Fc fusion protein comprising the ectodomain of TREM2).

[0158] In some embodiments, an antibody that specifically binds to the human TREM2 protein exhibits cross-reactivity with one or more other TREM2 proteins of other species. In some embodiments, an antibody that specifically binds to the human TREM2 protein exhibits cross-reactivity with the mouse TREM2 protein. In some embodiments, an antibody that specifically binds to the human TREM2 protein exhibits cross-reactivity with the cynomolgus monkey ("monkey") TREM2 protein. In some embodiments, an antibody that specifically binds to the human TREM2 protein exhibits cross-reactivity with the rat TREM2 protein. In some embodiments, an antibody that specifically binds to the human TREM2 protein exhibits cross-reactivity with one, two, or all three of mouse TREM2, monkey TREM2, and rat TREM2. In some embodiments, an anti-TREM2 antibody exhibits cross-reactivity with human TREM2, monkey TREM2, and mouse TREM2.

[0159] Methods for analyzing binding affinity, binding kinetics, and cross-reactivity are known in the art. These methods include, but are not limited to, solid-phase binding assays (e.g., ELISA assays), immunoprecipitation, surface plasmon resonance (e.g., Biacore™ (GE Healthcare, Piscataway, NJ)), equilibrium exclusion assays (e.g., KinExA®), flow cytometry, fluorescence-activated cell sorting (FACS), BioLayer interferometry (e.g., Octet™ (ForteBio, Inc., Menlo Park, CA)), and Western blot analysis. In some embodiments, ELISA is used to determine binding affinity and / or cross-reactivity. Methods for performing ELISA assays are known in the art and are also described in the Examples section below. In some embodiments, surface plasmon resonance (SPR) is used to determine binding affinity, binding kinetics, and / or cross-reactivity. In some embodiments, equilibrium exclusion assays are used to determine binding affinity, binding kinetics, and / or cross-reactivity. In some embodiments, BioLayer interferometry is used to determine binding affinity, binding kinetics, and / or cross-reactivity.

[0160] Epitopes recognized by anti-TREM2 antibodies In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 that is the same as or substantially the same as the epitope recognized by the antibody clones described herein. As used herein, the term "substantially the same," when used in reference to the epitope recognized by the antibody clones described herein, means that the anti-TREM2 antibody recognizes an epitope that is identical, within a range of, or nearly identical to the epitope recognized by the antibody clones described herein (e.g., an epitope having at least 90% sequence identity or one, two, or three amino acid substitutions, e.g., conservative substitutions, relative to the epitope), or has substantial overlap (e.g., at least 50%, 60%, 70%, 80%, 90%, or 95% overlap).

[0161] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D 1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42 E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55 The antibody clones recognize an epitope of human TREM2 that is the same as or substantially the same as an epitope recognized by an antibody clone selected from the group consisting of B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0162] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2 .D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1 , 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0163] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2. D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 4 2E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, The antibody clone recognizes an epitope of human TREM2 that is within the range of epitopes recognized by an antibody clone selected from the group consisting of 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0164] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D1 1.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1 , RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0165] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5. A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9. H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, The antibody clones recognize epitopes of human TREM2 with one, two, or three amino acid substitutions (e.g., conservative substitutions) based on the epitopes recognized by antibody clones selected from the group consisting of 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0166] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D 11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H 1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4 The antibody clones recognize an epitope of human TREM2 that substantially overlaps (e.g., has at least 50%, 60%, 70%, 80%, 90%, or 95% overlap) with an epitope recognized by an antibody clone selected from the group consisting of: RS9.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0167] In some embodiments, the anti-TREM2 antibody reduces sTREM2 levels and recognizes an epitope that is the same as or substantially the same as the epitope recognized by antibody clone 42E8.H1. In some embodiments, the anti-TREM2 antibody reduces sTREM2 levels and recognizes an epitope of human TREM2 that is identical to the epitope recognized by antibody clone 42E8.H1. In some embodiments, the anti-TREM2 antibody reduces sTREM2 levels and recognizes an epitope of human TREM2 that is within the range of the epitope recognized by antibody clone 42E8.H1. In some embodiments, the anti-TREM2 antibody reduces sTREM2 levels and recognizes an epitope of human TREM2 that is at least 90% identical to the epitope recognized by antibody clone 42E8.H1. In some embodiments, the anti-TREM2 antibody reduces levels of sTREM2 and recognizes an epitope of human TREM2 with one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by antibody clone 42E8.H1.

[0168] In some embodiments, the anti-TREM2 antibody increases sTREM2 levels and recognizes an epitope that is the same as or substantially the same as the epitope recognized by antibody clone 21D4.D1. In some embodiments, the anti-TREM2 antibody increases sTREM2 levels and recognizes an epitope of human TREM2 that is identical to the epitope recognized by antibody clone 21D4.D1. In some embodiments, the anti-TREM2 antibody increases sTREM2 levels and recognizes an epitope of human TREM2 that is within the range of the epitope recognized by antibody clone 21D4.D1. In some embodiments, the anti-TREM2 antibody increases sTREM2 levels and recognizes an epitope of human TREM2 that is at least 90% identical to the epitope recognized by antibody clone 21D4.D1. In some embodiments, the anti-TREM2 antibody increases the level of sTREM2 and recognizes an epitope of human TREM2 with one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by antibody clone 21D4.D1.

[0169] In some embodiments, the anti-TREM antibody enhances TREM2 activity (e.g., induces kinase phosphorylation, enhances phagocytosis, and / or enhances cell migration, differentiation, or survival), and is selected from the group consisting of antibody clones 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A1, 26E2.A1, 26E2.B ... 3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, or RS9.F10. In some embodiments, the anti-TREM2 antibody enhances TREM2 activity and is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43 It recognizes an epitope on human TREM2 that is identical to the epitope recognized by an antibody clone selected from the group consisting of E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, and RS9.F10. In some embodiments, the anti-TREM2 antibody enhances TREM2 activity and is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43E It recognizes an epitope of human TREM2 that is within the range of epitopes recognized by antibody clones selected from the group consisting of 9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, and RS9.F10.In some embodiments, the anti-TREM2 antibody enhances TREM2 activity and is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43E9.H1, 44E9.H1, 45E9.H2, 46E9.H3, 47E9.H4, 48E9.H5, 49E9.H6, 50E9.H7, 51E9.H8, 52E9.H9, 53E9.H1, 54E9.H1, 55E9.H2, 56E9.H3, 57E9.H4, 58E9.H5, 59E9.H6, 60E9.H7, 61E9.H8, 62E9.H9, 63E9.H1, 64E9.H1, 65E9.H1, 66E9.H1, 67E9.H1, 68E9.H1, 69E9.H2, 70E9.H1, 71E9.H1, 72E9.H1, 73E9.H1, 74E9.H1, 75E9.H2, 76E9.H1, 77E9.H1, 78E9.H1, 79E9.H2, 80E9.H1, 81E9.H1, 82E9.H1 It recognizes an epitope of human TREM2 that is at least 90% identical to the epitope recognized by an antibody clone selected from the group consisting of 4E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, and RS9.F10. In some embodiments, the anti-TREM2 antibody enhances TREM2 activity and is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14H11.A1, 21D6.G2, 22G9.D1, 24B4.A1, 26D2.D1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H It recognizes an epitope of human TREM2 with one, two, or three amino acid substitutions (e.g., conservative substitutions) based on the epitope recognized by an antibody clone selected from the group consisting of 11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 60A4.B1, RS9.E2, RS9.F6, and RS9.F10.

[0170] In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity (e.g., inhibits kinase phosphorylation, inhibits phagocytosis, and / or inhibits cell migration, differentiation, or survival) and recognizes the same or substantially the same epitope as the epitope recognized by antibody clone 21D4.D1 or 21D11. In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity and recognizes an epitope of human TREM2 that is identical to the epitope recognized by antibody clone 21D4.D1 or 21D11. In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity and recognizes an epitope of human TREM2 that is within the epitope recognized by antibody clone 21D4.D1 or 21D11. In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity and recognizes an epitope of human TREM2 that is at least 90% identical to the epitope recognized by antibody clone 21D4.D1 or 21D11. In some embodiments, the anti-TREM2 antibody inhibits TREM2 activity and recognizes an epitope of human TREM2 that has one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by antibody clone 21D4.D1 or 21D11.

[0171] In some embodiments, the anti-TREM2 antibody enhances ligand-induced TREM2 activity (e.g., induces kinase phosphorylation, enhances phagocytosis, and / or enhances cell migration, differentiation, or survival) and recognizes the same or substantially the same epitope as that recognized by antibody clones 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, or RS9.F10. In some embodiments, the anti-TREM2 antibody enhances ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is identical to the epitope recognized by an antibody clone selected from the group consisting of 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, and RS9.F10. In some embodiments, the anti-TREM2 antibody enhances ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is within the range of epitopes recognized by antibody clones selected from the group consisting of 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, and RS9.F10.In some embodiments, the anti-TREM2 antibody enhances ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is at least 90% identical to an epitope recognized by an antibody clone selected from the group consisting of 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, and RS9.F10. In some embodiments, the anti-TREM2 antibody enhances ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that has one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by an antibody clone selected from the group consisting of 3D3.A1, 8A11.B1, 14D5.F1, 19F10.F3, 21D6.G2, 22B8.B1, 22G9.D1, 26D11.B1, 26E.2.A3, 30A8.A1, 42E8.H1, 43E9.H1, 44E2.H1, 49H11.B1, 52H9.D1, 53H11.D3, 54C2.A1, 59C6.F1, 60A4.B1, RS9.F6, and RS9.F10.

[0172] In some embodiments, the anti-TREM2 antibody inhibits ligand-induced TREM2 activity (e.g., induces kinase phosphorylation, enhances phagocytosis, and / or enhances cell migration, differentiation, or survival) and recognizes an epitope that is the same as or substantially the same as the epitope recognized by antibody clones 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, or RS9.E2. In some embodiments, the anti-TREM2 antibody inhibits ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is identical to the epitope recognized by an antibody clone selected from the group consisting of 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, and RS9.E2. In some embodiments, the anti-TREM2 antibody inhibits ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is within the range of epitopes recognized by antibody clones selected from the group consisting of 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, and RS9.E2.In some embodiments, the anti-TREM2 antibody inhibits ligand-induced TREM2 activity and recognizes an epitope of human TREM2 that is at least 90% identical to an epitope recognized by an antibody clone selected from the group consisting of 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, and RS9.E2. In some embodiments, the anti-TREM2 antibody inhibits ligand-induced TREM2 activity and recognizes an epitope of human TREM2 with one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by an antibody clone selected from the group consisting of 2G4.B1, 13B11.A, 14H11.A1, 21D4.D1, 21D11.B1, 24B4.A1, 26D2.D1, 26D5.A1, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 44E3.B1, 51D4.A1, 55B9.A1, 57D7.A1, and RS9.E2.

[0173] In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 24-43, 44-58, 64-78, 89-103, 94-108, 124-153, 140-144, or 159-174 of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 24-43 of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 44-58 of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 64-78 of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 89-103 of SEQ ID NO:96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 94-108 of SEQ ID NO:96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 124-153 of SEQ ID NO:96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 140-148 of SEQ ID NO:96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, within, or consisting of residues 140-144 of SEQ ID NO:96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, falling within, or consisting of residues 140-144 of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibody recognizes an epitope of human TREM2 comprising, falling within, or consisting of residues 159-174 of SEQ ID NO: 96.

[0174] In some embodiments, an anti-TREM2 antibody that recognizes an epitope of human TREM2 comprising, falling within, or consisting of residues 140-148 of SEQ ID NO:96 (e.g., recognizing an epitope of human TREM2 comprising, falling within, or consisting of residues 140-144 of SEQ ID NO:96) makes direct contact with one or more of residues Asp140, Leu141, Trp142, Phe143, and Pro144. In some embodiments, the anti-TREM2 antibody makes direct contact with residue Trp142. In some embodiments, the anti-TREM2 antibody makes direct contact with each of residues Asp140, Leu141, Trp142, Phe143, and Pro144.

[0175] Anti-TREM2 antibody sequence In some embodiments, the anti-TREM2 antibody comprises one or more complementarity determining region (CDR), heavy chain variable region, and / or light chain variable region sequences of an antibody described herein. In some embodiments, the anti-TREM2 antibody comprises one or more CDR, heavy chain variable region, and / or light chain variable region sequences of an antibody described herein and further comprises one or more functional characteristics described herein (e.g., altering the level of sTREM2 and / or modulating one or more TREM2 activities).

[0176] CDR sequences In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 53H11.D3, 54C2.A1, 55B9.A1, at least 90% homology to the CDRs of an antibody clone selected from the group consisting of 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10; , 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with one or more complementarity determining regions (CDRs) of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2 .H1, 44E3.B1, 49H11.B1, 51D4, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C 6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.It comprises one or more CDRs with up to two amino acid substitutions (i.e., 0, 1, or 2 amino acid substitutions) based on the CDRs of an antibody clone selected from the group consisting of RS12.3C10, RS12.2H1, and RS12.3C10.

[0177] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 26E2.A3, 30A8.A1, 38E9. E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 53H11.D3, 54C2 .A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11 .1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. It comprises one or more of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 that are identical to the heavy chain CDR1 (CDR-H1), heavy chain CDR2 (CDR-H2), heavy chain CDR3 (CDR-H3), light chain CDR1 (CDR-L1), light chain CDR2 (CDR-L2), and light chain CDR3 (CDR-L3) of the antibody clone.In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 2 6E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3. B1, 49H11.B1, 51D4, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9 The antibody clones may comprise two, three, four, five, or all six of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of an antibody clone selected from the group consisting of RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0178] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 53H11.D3, 54C2.A1, 55B9.A1, 57D7. The antibody clones comprise CDR-H1, CDR-H2, and CDR-H3 of an antibody clone selected from the group consisting of: 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 13B11.A1, 14D5.F1, 14H11.A1, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 24G7, 26D2, 26D11.B1, 26E2.A3, 30A8.A1, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 53H11.D3, 54C2.A1, 55B9.A1, 57D7. The antibody clones include CDR-L1, CDR-L2, and CDR-L3 of an antibody clone selected from the group consisting of: RS9.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0179] In some embodiments, the anti-TREM2 antibody (a) a heavy chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, or 315, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, or 315; (b) a heavy chain CDR2 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, or 316, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, or 316; (c) a heavy chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, or 317, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, or 317; (d) a light chain CDR1 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, or 311, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, or 311; (e) a light chain CDR2 sequence having at least 90% sequence identity to, or up to two amino acid substitutions from, the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, or 319; and (f) a light chain CDR3 sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, or 313, or having up to two amino acid substitutions based on the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, 89, or 313. It comprises one or more CDRs selected from the group consisting of:

[0180] In some embodiments, the anti-TREM2 antibody comprises two, three, four, five, or all six of (a) through (f). In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 of (a), a heavy chain CDR2 of (b), and a heavy chain CDR3 of (c). In some embodiments, the anti-TREM2 antibody comprises a light chain CDR1 of (d), a light chain CDR2 of (e), and a light chain CDR3 of (f). In some embodiments, the CDRs with a maximum of two amino acid substitutions have one amino acid substitution relative to the reference sequence. In some embodiments, the CDRs with a maximum of two amino acid substitutions have two amino acid substitutions relative to the reference sequence. In some embodiments, the maximum two amino acid substitutions are conservative substitutions.

[0181] In some embodiments, the anti-TREM2 antibody (a) a heavy chain CDR1 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 8, 36, 39, 45, 51, 57, 62, 68, 74, 81, 85, 307, or 315; (b) a heavy chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 9, 37, 40, 46, 52, 58, 63, 69, 75, 79, 82, 86, 308, or 316; (c) a heavy chain CDR3 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 10, 41, 47, 53, 59, 64, 70, 76, 83, 87, 309, or 317; (d) a light chain CDR1 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 11, 42, 48, 54, 60, 65, 71, 77, 88, or 311; (e) a light chain CDR2 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 12, 38, 43, 49, 55, 66, 72, 312, or 319; and (f) a light chain CDR3 sequence comprising the amino acid sequence of any one of SEQ ID NOs: 13, 44, 50, 56, 61, 67, 73, 78, 80, 84, or 89. It comprises one or more CDRs selected from the group consisting of:

[0182] In some embodiments, the anti-TREM2 antibody comprises two, three, four, five, or all six of (a) through (f). In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 of (a), a heavy chain CDR2 of (b), and a heavy chain CDR3 of (c). In some embodiments, the anti-TREM2 antibody comprises a light chain CDR1 of (d), a light chain CDR2 of (e), and a light chain CDR3 of (f).

[0183] In some embodiments, an anti-TREM2 antibody comprises one or more sequences that are variants of one or more consensus sequences. As a non-limiting example, a consensus sequence can be identified by aligning the heavy or light chain sequences (e.g., CDRs) of antibodies derived from the same (or similar) germline. In some embodiments, a consensus sequence can be generated from antibodies containing sequences of the same (or similar) length and / or antibodies with at least one very similar CDR (e.g., a very similar CDR3). In some embodiments, such sequences in these antibodies can be aligned and compared to identify conserved amino acids or motifs (i.e., those in which changes in sequence may alter protein function) and / or regions in which sequence variation occurs (i.e., those in which sequence variation is unlikely to significantly affect protein function). Alternatively, consensus sequences can be identified by aligning the heavy or light chain sequences (e.g., CDRs) of antibodies that bind to the same or similar (e.g., overlapping) epitopes to determine conserved amino acids or motifs (i.e., those in which changes in sequence may alter protein function) and regions in which variation occurs in sequence alignment (i.e., those in which sequence variations are unlikely to significantly affect protein function). In some embodiments, one or more consensus sequences can be determined for antibodies that recognize the same or similar epitope as the anti-TREM2 antibodies disclosed herein (e.g., 3D3.A1, 7B10.A2, 21D4.D1, 21D11, 24B4.A1, 26D2.D1, 26E2.A3, 40H3.A4, 42E8.H1, 49H11.B1, 51D4, 54C2.A1, 57D7.A1, RS9.F6, or RS9.F10). Exemplary consensus sequences include SEQ ID NOs: 320 to 332. In the consensus sequences of SEQ ID NOs: 320 to 332, capital letters represent amino acid residues that are absolutely conserved among the aligned sequences (e.g., aligned CDR sequences), while "X" represents amino acid residues that are absolutely not conserved among the aligned sequences.When selecting an amino acid to be inserted at a position designated "X," it will be understood that in some embodiments the amino acid will be selected from the amino acids at the corresponding position in the aligned sequences.

[0184] In some embodiments, the antibody has the formula GX2X3X4X5X6X7X8X9X 10 X 11 (I) (SEQ ID NO: 320) (wherein X2 is Y or F, X3 is T, N, or S, X4 is F, L, or I, X5 is T, S, or K, X6 is D, S, or E, X7 is D or absent, X8 is H, Y, or T, and X9 is A, N, G, V, W, T, or Y; and X 10 is M, I, or W, and X 11 is H, Q, or N). In some embodiments, the CDR-H1 consensus sequence comprises the sequence Includes TIFF2025133893000001.tif26160.

[0185] In some embodiments, the amino acids of Formula I are further defined as follows: X2 is Y, X3 is T or S, X5 is T or S, X8 is H or Y, and X9 is A, N, G, V, W, or T. In some embodiments, X7 is absent. In some embodiments, X 10 is W and X 11 is N.

[0186] In some embodiments, the amino acids of Formula I are further defined as follows: X3 is T or N, X7 is absent, and X 10 is M, I, X 11 is H or Q.

[0187] In some embodiments, the antibody is GYX3X4X5X6X7X8X9X 10 X 11(II) (SEQ ID NO: 321) (wherein X3 is T or S, X4 is F, L, or I, X5 is T or S, X6 is D, S, or E, X7 is D or absent, X8 is H or Y, and X9 is A, N, G, V, W, T, or A; and X 10 is M, I, or W, and X 11 is H, Q, or N).

[0188] In some embodiments, the antibody has the formula GX2X3X4X5X6X8X9X 10 X 11 (III) (SEQ ID NO: 322) (wherein X2 is Y or F, X3 is T or N, X4 is F, L, or I, X5 is T, S, or K, X6 is D, S, or E, X8 is H, Y, or T, and X9 is A, N, G, V, W, T, Y, or A; and X 10 is M or I, and X 11 is H or Q).

[0189] In some embodiments, the antibody has the formula GYTX4X5X6X8X9X 10 X 11 (IV) (SEQ ID NO: 323) (wherein X4 is F or L, X5 is T or S, X6 is D, S, or E, X8 is H, Y, X9 is A, N, G, V, W, T, and X 10 is M or I, and X 11 is H or Q).

[0190] In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X4 is F. In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X5 is T. In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X4 and X5 are F and T, respectively. In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X6 is D or S. In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X8 is Y. In some embodiments, in the CDR-H1 consensus sequence of any one of Formula I, II, III, or IV, X 10 In some embodiments, in the CDR-H1 consensus sequence of any one of formulas I, II, III, or IV, X is M. 11 is H. In some embodiments, in the CDR-H1 consensus sequence of any one of formula I, II, III, or IV, X 10 and X 11 are M and H, respectively. In some embodiments, in the CDR-H1 consensus sequence of any one of formula I, II, III, or IV, X 10 and X 11 are I and Q, respectively.

[0191] In some embodiments, the antibody has the formula X1X2X3X4X5X6X7X8X9X 10 YX 12 X 13 X 14 X 15 X 16 X 17X is D, V, Y, R, G, or T; X is I, S, or V; X is L, S, N, D, I, or Y; X is P, T, or absent; X is S, Y, N, T, A, G, or F; X is I, S, N, T, or D; X is G or D; X is G, D, N, R, or S; X is R, T, or A; 10 is I, G, S, K, T, N, or R, and X 12 is G, N, D, or T, and X 13 is V, Q, E, or P, and X 14 is K or S, and X 15 is F, Y or L, and X 16 is K, R, Q, or absent, and X 17 is G, T, D, S, or absent). In some embodiments, the CDR-H1 consensus sequence comprises the heavy chain CDR2 (CDR-H2) consensus sequence comprising the sequence Includes TIFF2025133893000002.tif49166.

[0192] In some embodiments, the amino acids of formula V are further defined as follows: X1 is V, Y, R, G, or T; X3 is S, N, D, I, or Y; X5 is Y, N, T, A, G, or F; X6 is S, N, T, or D; X9 is T or A; and X 12 is N, D, or T, and X 13 is Q, E, or P, and X 16 is K, R, or Q, and X 17 is G, T, D, or S. In some embodiments, the amino acids of formula V are further defined as follows: X4 is P or T, X5 is Y, N, T, A, or G, X8 is G, D, or N, and X 10 is G, S, K, T, N, or R, and X 14 is K and X 15 is F or Y and X 17 is G, T, or D.

[0193] In some embodiments, the antibody has the formula X1X2X3X4X5X6X7X8X9X 10 YX 12 X 13 X 14 X 15 X 16 X 17 (VI) (SEQ ID NO: 325) (wherein Xi is V, Y, R, G, or T; X2 is I, S, or V; X3 is S, N, D, I, or Y; X4 is P, T, or absent; X5 is Y, N, T, A, G, or F; X6 is S, N, T, or D; X7 is G or D; X8 is G, D, N, R, or S; X9 is T or A; and X 10 is I, G, S, K, T, N, or R, and X 12 is N, D, or T, and X 13 is Q, E, or P, and X 14 is K or S, and X 15 is F, Y or L, and X 16 is K, R, or Q, and X 17 is G, T, D, or S).

[0194] In some embodiments, the antibody has the formula X1X2X3X4X5X6X7X8X9X 10 YX 12 X 13 KX 15 X 16 X 17 (VII) (SEQ ID NO: 326) (wherein Xi is V, Y, R, G, or T, X2 is I, S, or V, X3 is S, N, D, I, or Y, X4 is P or T, X5 is Y, N, T, A, or G, X6 is S, N, T, or D, X7 is G or D, X8 is G, D, or N, X9 is T or A, and X 10 is G, S, K, T, N, or R, and X 12 is N, D, or T, and X 13 is Q, E, or P, and X 15 is F or Y and X 16 is K, R, or Q, and X 17is G, T, or D).

[0195] In some embodiments, the antibody has the formula ARX3X4X5X6X7X8X9X 10 YAX 13 DY(VIII) (SEQ ID NO: 327) (wherein X3 is G or N, X4 is D or G, X5 is D or I, X6 is S or T, X7 is Y or T, X8 is R or A, X9 is R or G, and X 10 is G or Y, and X 13 is L or M). In some embodiments, the CDR-H3 consensus sequence comprises a heavy chain CDR3 (CDR-H3) consensus sequence comprising the sequence Includes TIFF2025133893000003.tif5166.

[0196] In some embodiments, the antibody has the formula X1SSX4SLX7X8X9X 10 X 11 X 12 X 13 X 14 X 15 LX 17 (IX) (SEQ ID NO: 328) (wherein X1 is R or K, X4 is Q or K, X7 is V or L, X8 is H, D, or Y, X9 is I, N, or S, and X 10 is S or absent, X 11 is D or N, and X 12 is G or Q, and X 13 is N, I, or K, and X 14 is T or S, and X 15 is Y or F, and X 17 is Q, H, Y, N, or A). In some embodiments, the CDR-L1 consensus sequence comprises the sequence Includes TIFF2025133893000004.tif27166.

[0197] In some embodiments, X4 of formula IX is Q. In some embodiments, X8 of formula IX is H. In some embodiments, X9 of formula IX is I or S. In some embodiments, X 10 In some embodiments, X in formula IX is absent. 11 is N. In some embodiments, X in formula IX 12 is G. In some embodiments, X in formula IX 13 is N or K. In some embodiments, X in formula IX 14 is T. In some embodiments, X of formula IX 15 is Y.

[0198] In some embodiments, the antibody has the formula X1ASX4X5IX7X8X9LX 11 (X) (SEQ ID NO: 329) (wherein X1 is R, K, or S, X4 is E or Q, X5 is N, D, or G, X7 is Y or S, X8 is S or N, X9 is N, R, or Y, and X 11 is A or N. In some embodiments, the CDR-L1 consensus sequence comprises the sequence Includes TIFF2025133893000005.tif12166.

[0199] In some embodiments, the antibody comprises a light chain CDR2 (CDR-L2) consensus sequence comprising the formula X1X2SX4X5X6S(XI) (SEQ ID NO: 330), where X1 is K, Q, Y, V, or L, X2 is V, M, or T, X4 is N, K, or Y, X5 is R or L, and X6 is F, A, H, or D. In some embodiments, the CDR-L2 consensus sequence comprises the sequence Includes TIFF2025133893000006.tif12159.

[0200] In some embodiments, X2 of formula XI is V. In some embodiments, X4 of formula XI is N. In some embodiments, X5 of formula XI is R. In some embodiments, X5 of formula XI is L.

[0201] In some embodiments, the antibody comprises a light chain CDR3 (CDR-L3) consensus sequence comprising the formula X1X2X3X4X5X6X7X8T(XII) (SEQ ID NO: 331), where X1 is S, W, or Q, X2 is Q or H, X3 is S, T, G, Y, or F, X4 is T, F, W, or S, X5 is H, S, G, or N, X6 is V, A, F, Y, T, or L, X7 is P, T, or L, and X8 is Y, F, P, or W. In some embodiments, the CDR-L2 consensus sequence comprises the sequence Includes TIFF2025133893000007.tif34165.

[0202] In some embodiments, the amino acids of Formula XII are further defined as follows: X1 is Q, X3 is Y or F, X4 is F, W, or S, X5 is S, G, or N, X6 is Y, T, or L, X7 is P, and X8 is P, Y, or W. In some embodiments, X2 of Formula XII is Q. In some embodiments, X4 of Formula XII is T. In some embodiments, X5 is H. In some embodiments, the amino acids of Formula XII are further defined as follows: X1 is S or W, X2 is Q, X3 is S, T, or G, X4 is T, X5 is H, X6 is V, A, or F, X7 is P, T, or L, and X8 is Y, F, or P. In some embodiments, X6 of Formula XII is V or F.

[0203] In some embodiments, the antibody comprises a CDR-L3 consensus sequence comprising the formula QX2X3X4X5X6PX8T(XIII) (SEQ ID NO: 332), where X2 is Q or H, X3 is Y or F, X4 is F, W, or S, X5 is S, G, or N, X6 is Y, T, or L, and X8 is P, Y, or W.

[0204] Variable region sequence In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 2 6D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E 2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5 , RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, R The antibody clone comprises a heavy chain variable region having an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of an antibody clone selected from the group consisting of S12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0205] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 2 6D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E 2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5 , RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, R The antibody clone comprises a light chain variable region having an amino acid sequence that has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of an antibody clone selected from the group consisting of S12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0206] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1 , 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1 , RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS 11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3 and a heavy chain variable region comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of an antibody clone selected from the group consisting of: 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E 2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.The antibody clone comprises a light chain variable region comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of an antibody clone selected from the group consisting of RS12.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10.

[0207] In some embodiments, the anti-TREM2 comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, or 314. In some embodiments, the anti-TREM2 comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 6, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 306, or 314.

[0208] In some embodiments, the anti-TREM2 comprises a light chain variable region comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, or 318. In some embodiments, the anti-TREM2 comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 7, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 310, or 318.

[0209] CDR and variable region sequences In some embodiments, the anti-TREM2 antibody is selected from the group consisting of (i) 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 3 0A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5 , RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. and (ii) a heavy chain variable region having an amino acid sequence that is identical to the CDR-H1, CDR-H2, and CDR-H3 of the antibody clone, and (iii) a heavy chain variable region having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of the antibody clone.

[0210] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of (i) 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 3 0A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5 , RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10. and (ii) a light chain variable region that has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of the antibody clone, and that comprises an amino acid sequence containing CDR-L1, CDR-L2, and CDR-L3 that is identical to CDR-L1, CDR-L2, and CDR-L3 of the antibody clone.

[0211] In some embodiments, the anti-TREM2 antibody (a)2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2 , 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E 9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D 3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, R an antibody clone selected from the group consisting of S11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10; a heavy chain variable region having at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the heavy chain variable region of the antibody clone, and (ii) an amino acid sequence comprising CDR-H1, CDR-H2, and CDR-H3 that are identical to CDR-H1, CDR-H2, and CDR-H3 of the antibody clone; (b)2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2 , 21D11, 22B8.B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E 9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4, 52H9.D1, 53H11.D 3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, R an antibody clone selected from the group consisting of S11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10; a light chain variable region that has at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the light chain variable region of the antibody clone, and (ii) an amino acid sequence that includes CDR-L1, CDR-L2, and CDR-L3 that are identical to CDR-L1, CDR-L2, and CDR-L3 of the antibody clone; Includes.

[0212] In some embodiments, the anti-TREM2 antibody is selected from the group consisting of antibodies described herein for binding (e.g., 2G4.B1, 3D3.A1, 7B10.A2, 8A11.B1, 13B11.A1, 14D5.F1, 14H11.A1, 19F10.F3, 21D4.D1, 21D6.G2, 21D11, 22B8 .B1, 22G9.D1, 24B4.A1, 26D2.D1, 26D5.A1, 26D11.B1, 26E2.A3, 30A8.A1, 30F2.A2, 38E9.E5, 39H10.A1, 40H3.A4, 42E8.H1, 43E9.H1, 44E2.H1, 44E3.B1, 49H11.B1, 51D4 , 52H9.D1, 53H11.D3, 54C2.A1, 55B9.A1, 57D7.A1, 59C6.F1, 60A4.B1, RS9.E2, RS9.F6, RS9.F10, RS11.1F5, RS11.1G6, RS11.1A10, RS11.1D11, RS11.4A5, RS11.4H6, RS11.4D7, RS11.4D9, RS11.4F11, RS12.1C6, RS12.1C10, RS12.2D1, RS12.2D4, RS12.2E1, RS12.2F2, RS12.2G1, RS12.2H1, and RS12.3C10).

[0213] RS9.F6 and RS.F10 In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:37, and a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, the anti-TREM2 antibody comprises a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:13. In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:8 or SEQ ID NO:36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:9 or SEQ ID NO:37, a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:10, a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO:11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO:12 or SEQ ID NO:38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO:13.

[0214] In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 8, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 9, and a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-TREM2 antibody comprises a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 12, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-TREM2 antibody comprises heavy chain CDR1-3 and light chain CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 8, 9, 10, 11, 12, and 13, respectively.

[0215] In some embodiments, the anti-TREM2 antibody comprises a heavy chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 36, a heavy chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 37, and a heavy chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-TREM2 antibody comprises a light chain CDR1 sequence comprising the amino acid sequence of SEQ ID NO: 11, a light chain CDR2 sequence comprising the amino acid sequence of SEQ ID NO: 38, and a light chain CDR3 sequence comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-TREM2 antibody comprises heavy chain CDR1-3 and light chain CDR1-3 comprising the amino acid sequences of SEQ ID NOs: 36, 37, 10, 11, 38, and 13, respectively.

[0216] In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable region comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to SEQ ID NO:6 or SEQ ID NO:24. In some embodiments, ...

Claims

[Claim 1] The invention described herein.

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