Antitrem2 antibodies and methods of use thereof

Abstract

The present invention relates to anti-TREM2 antibodies and methods of use thereof. The present disclosure relates generally to compositions comprising antibodies, e.g., monoclonal antibodies, antibody fragments, etc., that specifically bind to a TREM2 protein, e.g., mammalian TREM2 or human TREM2, and the use of such compositions in the prevention, risk reduction, or treatment of an individual in need thereof.

Description

[0001] This application is a divisional application of the invention application with an application date of August 2, 2018, Chinese application number 201880027792.8, and invention name “Anti-TREM2 Antibodies and Methods of Use Thereof”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 541,019, filed on August 3, 2017, and U.S. Provisional Application No. 62 / 636,095, filed on February 27, 2018, which are incorporated herein by reference in their entireties.

[0004] Submission of sequence listings in ASCII text files

[0005] The content submitted on the following ASCII text file is incorporated herein by reference in its entirety: Sequence Listing in Computer Readable Form (CRF) (File Name: 735022001840SEQLIST.TXT, Record Date: August 2, 2018, Size: 238KB). Field of the Invention

[0006] The present disclosure relates to anti-TREM2 antibodies and therapeutic uses of said antibodies. Background of the Invention

[0008] Triggering receptor expressed on myeloid cells-2 (TREM2) is an immunoglobulin-like receptor expressed on, for example, cells of the myeloid lineage.

[0009] TREM2 activity has been implicated in diseases, disorders and conditions such as frontotemporal dementia (FTD), Alzheimer's disease, Parkinson's disease, stroke / ischemic brain injury, multiple sclerosis and Nasu-Hakola disease (Neumann, H et al., (2007) J Neuroimmunol 184:92-99; Takahashi, K et al., (2005) J Exp Med 201:647-657; Takahashi, K et al., (2007) PLoS Med 4:e124; and Hsieh, CL et al., (2009) J Neurochem 109:1144-1156; Malm, TM et al., Neurotherapeutics. 2014 Nov 18; Paloneva, J et al., (2002) Am J Hum Genet 71:656-662; and Paloneva, J et al., (2003) J Exp Med 198:669-675; Guerreiro, RJ et al., (2013) JAMA Neurol 70:78-84; Guerreiro, RJ et al., (2012) Arch Neurol: 1-7; Guerreiro, R et al., (2013) N Engl J Med 368:117-127; Jonsson, T et al., (2013) N Engl J Med 368:107-116; and Neumann, H et al., (2013) N Engl J Med 368:182-184; and Wang Y, Cell. 2015;160(6):1061-71).

[0010] Therefore, there is a need in the industry for therapeutic anti-TREM2 antibodies to treat diseases, disorders and conditions associated with reduced TREM2 activity.

[0011] All references cited herein, including patent applications and publications, are hereby incorporated by reference in their entirety. Summary of the invention

[0012] The present disclosure generally relates to compositions comprising antibodies (e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc.) that specifically bind to a TREM2 protein (e.g., mammalian TREM2 (e.g., any non-human mammal) or human TREM2), and to methods of using the same.

[0013] Certain aspects of the present disclosure are based, at least in part, on the identification of anti-TREM2 antibodies with improved affinity and functional properties. Surprisingly, the functional properties of anti-TREM2 antibodies cannot be predicted from the increase in affinity. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to both human and cynomolgus monkey TREM2 with an affinity at least about 1-fold higher than that of an anti-TREM2 antibody selected from the following: an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56 (e.g., antibody AL2p-h50); an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103 (e.g., antibody AL2p-h77); and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120 (e.g., antibody AL2). In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to primary human immune cells with an affinity at least about 10 times higher than that of an anti-TREM2 antibody selected from: an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120. In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate and activate TREM2 signaling in an amount at least about 1-fold greater than that of an anti-TREM2 antibody selected from: an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.In some embodiments, the anti-TREM2 antibodies of the present disclosure increase the survival of immune cells in vitro to a greater extent than an anti-TREM2 antibody selected from the group consisting of an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present disclosure may also have an improved half-life in vivo. In some embodiments, the anti-TREM2 antibodies of the present disclosure may also reduce the plasma levels of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibodies of the present disclosure may also reduce soluble TREM2. In some embodiments, soluble TREM2 is reduced by about any of 10%, 20%, 30%, 40%, 50%, or 60%.

[0014] Thus, certain aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1, comprising a light chain variable region according to Formula I: 1 X 2 X 3 The sequence of WMNs, where X 1 Is S or W, X 2 is S, L, or R, and X 3 is S, D, H, Q or E (SEQ ID NO: 121); HVR-H2 comprises a residue according to Formula II: RIYPGX 1 GX 2 TNYAX 3 KX 4 X 5 G sequence, where X 1 is D, G, E, Q or V, X 2 It is D or Q, X 3 is Q, R, H, W, Y or G, X 4 is F, R, or W, and X 5 is Q, R, K or H (SEQ ID NO: 122); and HVR-H3 comprises a polypeptide according to Formula III: ARLLRNX 1 PGX 2 SYAX 3 DY sequence, where X 1 It is Q or K, X 2 is E, S, or A, and X3 is M or H (SEQ ID NO: 123), and wherein the antibody is not an antibody comprising a heavy chain variable region comprising: HVR-H1 comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2 comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3 comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126). Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises: HVR-L1 comprising a heavy chain variable region according to Formula IV: RX 1 SX 2 SLX 3 HSNX 4 The sequence of YTYLH, where X 1 Is S or T, X 2 is Q, R or S, X 3 is V or I, and X 4 is G, R, W, Q or A (SEQ ID NO: 127); HVR-L2 comprises a polypeptide according to Formula V: KVSNRX 1 S sequence, where X 1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3, comprising a sequence according to Formula V: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not an antibody comprising a light chain variable region comprising: HVR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1, comprising a sequence according to Formula I: YAFX 1 X 2 X 3 The sequence of WMNs, where X 1 Is S or W, X 2 is S, L, or R, and X 3 is S, D, H, Q or E (SEQ ID NO: 121); HVR-H2 comprises a residue according to Formula II: RIYPGX 1 GX 2 TNYAX 3 KX 4 X 5 G sequence, where X1 is D, G, E, Q or V, X 2 It is D or Q, X 3 is Q, R, H, W, Y or G, X 4 is F, R, or W, and X 5 is Q, R, K or H (SEQ ID NO: 122); and HVR-H3 comprises a polypeptide according to Formula III: ARLLRNX 1 PGX 2 SYAX 3 DY sequence, where X 1 It is Q or K, X 2 is E, S, or A, and X 3 is M or H (SEQ ID NO: 123), and the light chain variable region comprises: HVR-L1, comprising according to Formula IV: RX 1 SX 2 SLX 3 HSNX 4 The sequence of YTYLH, where X 1 Is S or T, X 2 is Q, R or S, X 3 is V or I, and X 4 is G, R, W, Q or A (SEQ ID NO: 127); HVR-L2 comprises a polypeptide according to Formula V: KVSNRX 1 S sequence, where X 1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3, comprising the sequence: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not the following antibody: comprising a heavy chain variable region comprising the following items: HVR-H1, comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2, comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3, comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126) and comprising a light chain variable region comprising the following items: HVR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0015] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1 comprising a sequence selected from the group consisting of SEQ ID NOs: 132 and 136; HVR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 133, 135, 137, and 141; and HVR-H3 comprising a sequence selected from the group consisting of SEQ ID NOs: 126 and 138; and / or the light chain variable region comprises: HVR-L1 comprising a sequence selected from the group consisting of 130, 139, 142, and 144; HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 131, 134, and 140; and HVR-L3 comprising a sequence selected from the group consisting of SEQ ID NO: 129. Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1 comprising a sequence of SEQ ID No: 132; HVR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 133, 135, and 141; and HVR-H3 comprising a sequence of SEQ ID No: 126; and / or the light chain variable region comprises: HVR-L1 comprising a sequence selected from the group consisting of 130, 142, and 144; HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 131 and 134; and HVR-L3 comprising a sequence of SEQ ID NO: 129.

[0016] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 of the following antibodies: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38 28. AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, A L2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p- 47. AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, A L2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 2A through Table 2C). Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region,wherein the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 of the following antibodies: AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 3A to 3C). Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region,wherein the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 of the following antibodies: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 30. AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47 , AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (such as 2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-63, AL2p-64, AL2p-65 3A to 3C). Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein,wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2 and HVR-H3 and a light chain variable region comprising HVR-L1, HVR-L2 and HVR-L3, wherein the antibody comprises HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 of the following antibodies: AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 -6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p- 16. AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL 2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-35, AL2p-3 6. AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2 p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (as shown in Tables 2A to 2C and Tables 3A to 3C).

[0017] In some embodiments that may be combined with any of the preceding embodiments, the heavy chain variable region comprises one, two, three or four framework regions selected from VH FR1, VH FR2, VH FR3 and VH FR4, wherein: the VH FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 9-11, the VH FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 12 and 13, the VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and the VH FR4 comprises the sequence SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, wherein: the VL FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 17-20, the VL FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, the VL FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: NO: 23 and 24, and the VL FR4 comprises a sequence selected from the group consisting of SEQ ID NO: 25 and 26. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 27-71 and 91; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 92-113 and 118. In some embodiments that may be combined with any of the preceding embodiments, the antibody comprises the heavy chain variable region of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38 -18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2 p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL 2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2 p-62 (as shown in Table 6A); and / or the antibody comprises the light chain variable region of the following antibodies: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19 , AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 , AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41 , AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (as shown in Table 7A). In some embodiments that may be combined with any of the preceding embodiments: (a) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 135);NO:129); (b) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO:132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO:135), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO:130), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO:131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO:129); (c) HVR-H1 comprises the amino acid sequence of YAFSSDWMN (SEQ ID NO:136), HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYARKFHG (SEQ ID NO:137), and HVR-H3 comprises the amino acid sequence of ARLLRNKPGESYAMDY (SEQ ID NO:126). (d) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYARKFQG (SEQ ID NO: 141), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142), HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (e) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYAGKFQG (SEQ ID NO: 143), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142), and HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 144).NO: 131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (f) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), and HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); or (g) HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 135). NO:133), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO:134), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO:129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), and HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 136).NO:126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO:130), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO:131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO:129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSDWMN (SEQ ID NO: 136), HVR-H2 comprises the amino acid sequence of RIYPG EGDTNYARKFHG (SEQ ID NO: 137), HVR-H3 comprises the amino acid sequence of ARLLRNKPGESYAMDY (SEQ ID NO: 138), HVR-L1 comprises the amino acid sequence of RTSQSLVHSNAYTYLH (SEQ ID NO: 139), HVR-L2 comprises the amino acid sequence of KVSNRVS (SEQ ID NO: 140), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYARK FQG (SEQ ID NO: 141), HVR-H3 comprises the amino acid sequence of ARLLRNQPGE SYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLV HSNQYTYLH (SEQ ID NO: 142), HVR-L2 comprises the amino acid sequence of KVSN RRS (SEQ ID NO: 134), and HVR-L3 comprises the amino acid sequence of SQSTRVP YT (SEQ ID NO: 129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYAGKFQG (SEQ ID NO: 143), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 1NO: 129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments that may be combined with any of the preceding embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144), HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 comprises the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144), HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129).

[0018] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat CDR; and / or the light chain variable region comprises a Kabat CDR. In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); CDR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); CDR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0019] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat CDR; and / or the light chain variable region comprises a Kabat CDR. In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence of SDWMN (SEQ ID NO: 196); CDR-H2, comprising the sequence of RIYPGEGDTNYARKFHG (SEQ ID NO: 137); and CDR-H3, comprising the sequence of LLRNKPGESYAMDY (SEQ ID NO: 197). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence of RTSQSLVHSNAYTYLH (SEQ ID NO: 139); CDR-L2, comprising the sequence of KVSNRVS (SEQ ID NO: 140); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence of SDWMN (SEQ ID NO: 196); CDR-H2, comprising the sequence of RIYPGEGDTNYARKFHG (SEQ ID NO: 137); and CDR-H3, comprising the sequence of LLRNKPGESYAMDY (SEQ ID NO: 197); and the light chain variable region comprises: CDR-L1, comprising the sequence of RTSQSLVHSNAYTYLH (SEQ ID NO: 139); CDR-L2, comprising the sequence of KVSNRVS (SEQ ID NO: 140); and CDR-L3, comprising the sequence SQSTRVPYT (SEQID NO: 129).

[0020] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat CDR; and / or the light chain variable region comprises a Kabat CDR. In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); CDR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and Kabat CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); CDR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0021] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat CDR; and / or the light chain variable region comprises a Kabat CDR. In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); CDR-L2, comprising the sequence KVSNRRS (SEQ ID NO: 134); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); CDR-L2, comprising the sequence KVSNRRS (SEQ ID NO: 134); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0022] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a Kabat CDR; and / or the light chain variable region comprises a Kabat CDR. In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142); CDR-L2, comprising the sequence KVSNRRS (SEQ ID NO: 134); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chain variable region comprises: CDR-H1, comprising the sequence SQWMN (SEQ ID NO: 194); CDR-H2, comprising the sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141); and CDR-H3, comprising the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region comprises: CDR-L1, comprising the sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142); CDR-L2, comprising the sequence KVSNRRS (SEQ ID NO: 134); and CDR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0023] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-71 and 91; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-113 and 118. In some embodiments, the antibody comprises the heavy chain variable region of the following antibodies: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55 p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p- 47. AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55 , AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 6A);and / or the antibody comprises the light chain variable region of the following antibodies: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52 1. AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47 , AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 7A). In some embodiments: (a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:97; (b) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:59; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:104; (c) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:108; (d) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:70; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:110; (e) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:71; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:111; (f) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:59; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:112; or (g) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53;And / or the light chain variable region comprises the amino acid sequence of SEQ ID NO: 113. In some embodiments, the antibody comprises an Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-156. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 146. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 147. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 148. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 150. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 151. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 152. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 153. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 154. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 155. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 156. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 198-213; and / or a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214-218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 198 and 199; and a light chain comprising the amino acid sequence of SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 200 and 201; and a light chain comprising the amino acid sequence of SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 202 and 203; and a light chain comprising the amino acid sequence SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 204 and 205;and a light chain comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 206 and 207; and a light chain comprising the amino acid sequence of SEQ ID NO: 216. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 208 and 209; and a light chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 210 and 211; and a light chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 212 and 213; and a light chain comprising the amino acid sequence of SEQ ID NO: 217. ;

[0024] In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53, and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:97. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:59; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:104. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:64; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:108. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:70; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:71; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:11. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:59; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:112. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:53; and / or the light chain variable region comprises the amino acid sequence of SEQ ID NO:113.

[0025] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 56, and 72-90; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 104, and 114-117. In some embodiments, the antibody comprises the heavy chain variable region of AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, or AL2p-h90 (as shown in Table 6A). 7A); and / or the antibody comprises a light chain variable region of AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, or AL2p-h90 (as shown in Table 7A).

[0026] Other aspects of the present disclosure relate to antibodies that bind to a TREM2 protein, wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 198-213; and / or a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 214-218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 198 and 199; and a light chain comprising the amino acid sequence SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 200 and 201; and a light chain comprising the amino acid sequence SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 202 and 203; and a light chain comprising the amino acid sequence SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 204 and 205; and a light chain comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 206 and 207; and a light chain comprising the amino acid sequence of SEQ ID NO: 216. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 208 and 209; and a light chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 210 and 211; and a light chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 212 and 213; and a light chain comprising the amino acid sequence of SEQ ID NO:217.

[0027] In some embodiments that can be combined with any one of the preceding embodiments, the antibody is IgG class, IgM class or IgA class. In some embodiments that can be combined with any one of the preceding embodiments, the antibody is IgG class and has IgG1, IgG2, IgG3 or IgG4 isotype. In some embodiments that can be combined with any one of the preceding embodiments, the antibody comprises one or more amino acid substitutions at residue positions selected from the group consisting of the following in the Fc region: C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering. In some embodiments that may be combined with any of the preceding embodiments: (a) the Fc region comprises amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue positions are numbered according to EU numbering; (b) the Fc region comprises amino acid substitutions at positions E430G and P331S, wherein the residue positions are numbered according to EU numbering; (c) the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue positions are numbered according to EU numbering; (d) the Fc region comprises amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue positions are numbered according to EU numbering; (e) the Fc region comprises amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein The residue position numbering is according to EU numbering; (f) the Fc region comprises amino acid substitutions at positions E430G, K322A and A330S, wherein the residue position numbering is according to EU numbering; (g) the Fc region comprises amino acid substitutions at positions E430G, K322A and P331S, wherein the residue position numbering is according to EU numbering; (h) the Fc region comprises amino acid substitutions at positions S267E and L328F, wherein the residue position numbering is according to EU numbering; (i) the Fc region comprises amino acid substitutions at position C127S, wherein the residue position numbering is according to EU numbering; (j) the Fc region comprises amino acid substitutions at positions E345R, E430G and S440Y, wherein the residue position numbering is according to EU numbering; or (k) the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-156. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue position numbering is according to EU numbering.In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 146. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 147. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 148. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 149. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 150. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 151. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 152. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 153. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 154. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 155. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 156.

[0028] In some embodiments that can be combined with any of the preceding embodiments, the TREM2 protein is a human protein. In some embodiments that can be combined with any of the preceding embodiments, the TREM2 protein is a wild-type protein. In some embodiments that can be combined with any of the preceding embodiments, the TREM2 protein is a natural variant. In some embodiments that can be combined with any of the preceding embodiments, the antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of: human TREM2, natural variants of human TREM2, and disease variants of human TREM2, and optionally wherein the antibody fragment is cross-linked with a second antibody fragment that binds to one or more human proteins selected from the group consisting of: human TREM2, natural variants of human TREM2, and disease variants of human TREM2. In some embodiments that can be combined with any of the preceding embodiments, the fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In some embodiments that can be combined with any of the preceding embodiments, the antibody is a monoclonal antibody. In some embodiments that can be combined with any of the preceding embodiments, the antibody is a humanized antibody.

[0029] In some embodiments that may be combined with any of the preceding embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen, wherein the first antigen is human TREM2 or a natural variant thereof, and the second antigen is: (a) an antigen that promotes transport across the blood-brain barrier; (b) an antigen that promotes transport across the blood-brain barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and LPR-2), diphtheria toxin receptor CRM197, llama single domain antibody TMEM 30(A), protein transduction domain TAT, Syn-B, penetratin, polyarginine peptide, angiopeptide and ANG1005; (c) a pathogenic agent selected from the group consisting of pathogenic peptides or proteins or pathogenic nucleic acids, wherein the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat expansion RNA, and the pathogenic protein is selected from the group consisting of amyloid β, oligomeric amyloid β, amyloid β plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, α -Synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body body), atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, β2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation products, dipeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides;(d) ligands and / or proteins expressed on immune cells, wherein the ligands and / or proteins are selected from the group consisting of CD40, OX40, ICOS, CD28, CD137 / 4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, and phosphatidylserine; and (e) proteins, lipids, polysaccharides, or glycolipids expressed on one or more tumor cells. In some embodiments that may be combined with any of the preceding embodiments, the antibody specifically binds to both human TREM2 and cynomolgus monkey TREM2. In some embodiments that may be combined with any of the preceding embodiments, the dissociation constant (K) of the antibody for human TREM2 and / or cynomolgus monkey TREM2 is D ) is at least 1-fold lower than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56; or at least 1-fold lower than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103. In some embodiments that may be combined with any of the preceding embodiments, the dissociation constant (K) of the antibody for human TREM2 D ) is in the range of about 9 μM to about 100 pM or less than 100 pM, wherein K D is determined at a temperature of about 25° C. In some embodiments that may be combined with any of the preceding embodiments, the dissociation constant (K) of the antibody for cynomolgus monkey TREM2 is D ) is in the range of about 50 nM to about 100 pM or less than 100 pM, wherein K Dis determined at a temperature of about 25°C. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to primary human immune cells with an affinity that is at least 10 times greater than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; or at least 10 times greater than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103. In some embodiments that may be combined with any of the preceding embodiments, the antibody aggregates and activates TREM2 signaling in an amount that is at least 1 times greater than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; or at least 1 times greater than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103. In some embodiments that may be combined with any of the preceding embodiments, the antibody increases in vitro immune cell survival to a greater extent than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56; or an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103. In some embodiments that may be combined with any of the preceding embodiments, the antibody has a lower in vivo half-life than a human control IgG1 antibody. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces plasma levels of soluble TREM2 in vivo by at least 25% greater than a human control IgG1 antibody. In some embodiments that may be combined with any of the preceding embodiments, the antibody reduces plasma levels of soluble TREM2 in vivo by blocking cleavage, by inhibiting one or more metalloproteinases, and / or by inducing internalization. In some embodiments, soluble TREM2 is reduced by about any of 10%, 20%, 30%, 40%, or 50%.In some embodiments that may be combined with any of the preceding embodiments, the antibody competes for binding to TREM2 with one or more antibodies selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 18. AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p- 30. AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p- 42. AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p- 54. AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2 AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, AL2p-h90, and any combination thereof.In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to substantially the same TREM2 epitope as an antibody selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35 -18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2 p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL 2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, A L2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h2 In some embodiments, the antibody binds to one or more amino acids within amino acid residues 149-157 of SEQ ID NO: 1. In some embodiments that may be combined with any of the preceding embodiments, the antibody binds to one or more amino acid residues selected from the group consisting of E151, D152, and E156 of SEQ ID NO:1.

[0030] Other aspects of the disclosure relate to isolated nucleic acids, comprising nucleic acid sequences encoding antibodies of any of the foregoing embodiments. Other aspects of the disclosure relate to vectors, comprising nucleic acids of any of the foregoing embodiments. Other aspects of the disclosure relate to isolated host cells, comprising vectors of any of the foregoing embodiments. Other aspects of the disclosure relate to methods of producing antibodies that bind to TREM2, comprising culturing cells of any of the foregoing embodiments, thereby producing antibodies. In some embodiments, the method further comprises recovering antibodies produced by cells. Other aspects of the disclosure relate to isolated antibodies that bind to TREM2 produced by the methods of any of the foregoing embodiments. Other aspects of the disclosure relate to pharmaceutical compositions, comprising antibodies of any of the foregoing embodiments and pharmaceutically acceptable carriers.

[0031] Other aspects of the present disclosure relate to methods of achieving prevention, risk reduction or treatment of an individual suffering from a disease, disorder or injury selected from the group consisting of: dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, cognitive impairment, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis and cancer, comprising administering to an individual in need thereof a therapeutically effective amount of an antibody of the aforementioned embodiments. In some embodiments, the disease, disorder or injury is Alzheimer's disease.

[0032] Other aspects of the present disclosure relate to antibodies comprising an Fc region, wherein the antibody comprises an amino acid substitution at position E430G and one or more amino acid substitutions at residue positions in the Fc region selected from the group consisting of: L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, and any combination thereof, wherein the residue numbering is according to EU or Kabat numbering. In some embodiments: (a) the Fc region comprises amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering is according to EU numbering; (b) the Fc region comprises amino acid substitutions at positions E430G and P331S, wherein the residue position numbering is according to EU numbering; (c) the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue position numbering is according to EU numbering; (d) the Fc region comprises amino acid substitutions at positions E430G, A330S, and P331S , wherein the residue position numbering is according to EU numbering; (e) the Fc region comprises amino acid substitutions at positions E430G, K322A, A330S and P331S, wherein the residue position numbering is according to EU numbering; (f) the Fc region comprises amino acid substitutions at positions E430G, K322A and A330S, wherein the residue position numbering is according to EU numbering; (g) the Fc region comprises amino acid substitutions at positions E430G, K322A and P331S, wherein the residue position numbering is according to EU numbering; or (h) the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 146-156. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, L243A, L235A and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, A330S and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, K322A, A330S and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, K322A and A330S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, K322A and P331S, wherein the residue position numbering is according to EU numbering.In some embodiments, the Fc region increases aggregation without complement activation compared to a corresponding antibody comprising an Fc region without the amino acid substitutions. In some embodiments, the antibody induces one or more activities of a target to which the antibody specifically binds. In some embodiments, the antibody binds to TREM2.

[0033] It should be understood that one, some or all of the properties of the various embodiments described herein can be combined to form other embodiments of the present invention. Those skilled in the art will appreciate these and other aspects of the present invention. These and other embodiments of the present invention are further described by the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1A Showing increased agonistic activity of Fc variant anti-TREM2 antibodies. Luciferase activity after 6 h of culture with Fc variants of anti-TREM2 antibodies. Figure 1B Figure 3. Luciferase activity of Fc variant anti-TREM2 antibodies after co-culture of Fc variant antibodies with BWZ reporter cells and THP-1 cells at a 1:1 ratio for 6 hours.

[0035] Figure 2A Fc variant anti-TREM2 antibody induced C3b deposition is shown. Fold change in C3b deposition of AL2p Fc variants on a TREM2 expressing HEK cell line relative to a human IgG1 isotype control antibody at 10 μg / mL. Figure 2B Fc variant anti-TREM2 antibody induced C3b deposition is shown. Fold change in C3b deposition of AL2p affinity matured variants with the listed Fc mutations relative to their parental IgG1 Fc variants.

[0036] Figure 3A Showing increased activity of soluble anti-TREM2 antibodies. Figure 3B Showing increased activity of plate-bound anti-TREM2 antibodies. Figure 3C Reporter gene activity of affinity matured anti-TREM2 antibodies at 5 μg / ml plate-bound is shown (grey bars) compared to parental humanized antibody Alp2-h50 (h50), parental humanized antibody AL2p-77 (h77), and parental murine antibody AL2p (AL2p msIgG1 parent) clones (black bars). Clones as grey bars with black outlines represent AL2p-h50 antibody variants containing different amino acid substitutions.

[0037] Figure 4A Showing increased activity of soluble anti-TREM2 antibodies. Figure 4B Showing increased activity of plate-bound anti-TREM2 antibodies.

[0038] Figure 5A Shown is sTREM2 secretion by primary human dendritic cells from donor 534 over 48 h when incubated with anti-TREM2 or control antibodies. Figure 5B Shown is sTREM2 secretion by primary human dendritic cells from donor 535 over 48 h when incubated with anti-TREM2 or control antibodies.

[0039] Fig. 6A It was shown that there was no change in cell number when primary human dendritic cells from donor 534 were incubated with anti-TREM2 or control antibodies. Figure 6B Showing no change in cell number when primary human dendritic cells from donor 535 were incubated with anti-TREM2 or control antibodies.

[0040] Fig. 7A Plasma sTREM2 as % of baseline levels is shown after a single injection of 15 mg / kg TREM2 antibodies AL2p-47huIgG1, AL2p-47huIgG1ASPSEG, AL2p-58huIgG1, or control huIgG1. Figure 7B Plasma sTREM2 as % of baseline levels is shown after a single injection of 15 mg / kg TREM2 antibody AL2p-58huIgG1, AL2p-58huIgG1 PSEG, or control huIgG1. Figure 7C Plasma sTREM2 as % of baseline levels is shown after a single injection of 15 mg / kg TREM2 antibodies AL2p-61huIgG1 PSEG, AL2p-47huIgG1, AL2p-58huIgG1, or control huIgG1. Fig.7D Plasma sTREM2 in ng / ml is shown after a single injection of 20 mg / kg TREM2 antibody AL2p msIgG1, T21-9 msIgG1, or control msIgG1.

[0041] Fig. 8A and Figure 8B Figure 2 shows the expression of primary human macrophages ( Fig. 8A ) or primary human dendritic cells ( Figure 8B ) increased viability (increase in cellular ATP) after 48 h of stimulation. Figure 8C , Fig.8D , Fig. 8E and Figure 8F Figure 2 shows the expression of primary human dendritic cells ( Figure 8C and Fig.8D ) or primary human macrophages from two donors ( Fig. 8E and Figure 8F) increased viability (increase in cellular ATP) after 48 h of stimulation.

[0042] Fig. 9 Western blot showing Dap12 phosphorylation in peritoneal macrophages after treatment of WT or TREM2Bac-Tg mice with AL2p-58huIgG1, AL2p-58huIgG1 PSEG, or control huIgG1. Cell lysates were immunoprecipitated with anti-TREM2; the upper panel of bars shows staining with a phosphotyrosine antibody and the lower panel shows total human TREM2 content. DETAILED DESCRIPTION

[0043] General techniques

[0044] The techniques and procedures described or referred to herein are generally well known and commonly employed by those skilled in the art using routine methods, for example, such as the widely used methods described in the following references: Sambrook et al., Molecular Cloning: A Laboratory Manual 3rd Edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Current Protocols in Molecular Biology (FM Ausubel et al., eds. (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (MJ MacPherson, BD Hames and GR Taylor, eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (RI Freshney, ed. (1987)); Oligonucleotide Synthesis (MJ Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual, ed. (2003); Notebook (JE Cellis, 1998) Academic Press; Animal Cell Culture (RI Freshney, 1987); Introduction to Cell and Tissue Culture (JPMather and PE Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, JB Griffiths and DG Newell, 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (DM Weir and CC Blackwell, 1993-8) J. Wiley and Sons; Gene Transfer Vectors for Mammalian Cells (JMMiller and MP1987); PCR: The Polymerase Chain Reaction, (Mullis et al., 1994); Current Protocols in Immunology (J.E. Coligogan et al., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (CA Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, ed., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, ed., Harwood Press, 1996); Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (VT DeVita et al., eds., JB Lippincott Company, 1993).

[0045] definition

[0046] As used herein, the term "preventing" includes providing prevention of the occurrence or recurrence of a particular disease, disorder or condition with respect to an individual. An individual may be predisposed, susceptible to, or at risk of developing a particular disease, disorder or condition, but has not yet been diagnosed with the disease, disorder or condition.

[0047] As used herein, an individual who is "at risk" of developing a particular disease, disorder, or condition may or may not have detectable disease or disease symptoms, and may or may not have exhibited detectable disease or disease symptoms prior to the treatment methods described herein. "At risk" means that the individual has one or more risk factors, which are measurable parameters associated with the occurrence of a particular disease, disorder, or condition as known in the art. An individual who has one or more of these risk factors has a higher chance of developing a particular disease, disorder, or condition than an individual who does not have one or more of these risk factors.

[0048] As used herein, the term "treatment" refers to a clinical intervention designed to alter the natural course of the treated individual during the course of clinical pathology. Desired therapeutic effects include reducing the rate of progression of a particular disease, disorder or condition, ameliorating or alleviating the pathological state, and alleviating or improving the prognosis. For example, if one or more symptoms associated with a particular disease, disorder or condition are alleviated or eliminated, then the individual is successfully "treated".

[0049] "Effective amount" refers to the amount that effectively achieves the desired treatment or prevention result at least at the desired dosage and within the desired time period. The effective amount can be provided by one or more administrations. The effective amount herein may vary according to factors such as the following: the disease state, the age, sex and weight of the individual, and the ability of the treatment to induce the desired response in the individual. The effective amount is also the amount in which the beneficial effect of the treatment outweighs any toxic or harmful effects of the treatment. For preventive use, the beneficial or desired results include, for example, the results of eliminating or reducing the risk of the disease, reducing its severity or delaying its onset, the disease including the biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presented during the disease development. For therapeutic use, the beneficial or desired results include, for example, the following clinical results: for example, via targeting, delaying the progression of the disease and / or prolonging survival to reduce one or more symptoms caused by the disease, increase the quality of life of the patient, reduce the dosage of other agents required for treating the disease, and enhance the effect of another agent. The effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered to be in the context of administering one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if the desired result can be achieved or achieved in conjunction with one or more other agents.

[0050] "Subject" for purposes of treatment, prevention, or risk reduction refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo animals, sports animals, or pets, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. In some embodiments, the subject is a human.

[0051] As used herein, administration "in conjunction" with another compound or composition includes simultaneous administration and / or administration at different times. Administration in conjunction also encompasses administration as a co-formulation or administration as separate compositions, including at different dosing frequencies or intervals and using the same administration route or different administration routes.

[0052] The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein. The term "antibody" herein is used in the broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0053] The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. H With V L The pairs together form a single antigen binding site. For the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th edition, Daniel P. Stites, Abba I. Terr, and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6.

[0054] Based on the amino acid sequence of its constant domain, the L chain from any vertebrate species can be classified into one of two clearly distinct types, called kappa ("κ") and lambda ("λ"). According to the amino acid sequence of its heavy chain (CH) constant domain, immunoglobulins can be classified into different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, whose heavy chains are designated alpha ("α"), delta ("δ"), epsilon ("ε"), gamma ("γ"), and muon ("μ"), respectively. The gamma and alpha classes are further divided into subclasses (isotypes) based on relatively minor differences in CH sequence and function, for example humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and generally described in, for example, Abbas et al., Cellular and Molecular Immunology, 4th ed. (WB Saunders Co., 2000).

[0055] "Native antibodies" are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies in the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V H ), followed by multiple constant domains. Each light chain has a variable domain (V L ) and at its other end has a constant domain; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain. It is believed that specific amino acid residues form an interface between the light chain and the heavy chain variable domain.

[0056] An "isolated" antibody (e.g., an isolated anti-TREM2 antibody of the present disclosure) is an antibody that has been identified, separated, and / or recovered from a component of its production environment (e.g., natural or recombinant). Preferably, an isolated polypeptide is free of association with all other contaminating components from its production environment. Contaminating components from its production environment (e.g., those derived from recombinant transfected cells) are substances that would typically interfere with the research, diagnostic, or therapeutic use of the antibody, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In preferred embodiments, the polypeptide is purified (1) to greater than 95% by weight of the antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 N-terminal or internal amino acid sequence residues by use of a spinning cup sequencer, or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or, preferably, silver stain. Since at least one component of the antibody's natural environment will not be present, an isolated antibody includes an antibody in situ within a recombinant T cell. Ordinarily, however, an isolated polypeptide or antibody will be prepared by at least one purification step.

[0057] The “variable region” or “variable domain” of an antibody (e.g., an anti-TREM2 antibody of the present disclosure) refers to the amino-terminal domain of the heavy chain or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as “V H ” and “V L These domains are usually the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding site.

[0058] The term "variable" refers to the fact that the sequences of certain segments of the variable domains differ greatly between antibodies (e.g., the anti-TREM2 antibodies of the present disclosure). The V domain mediates antigen binding and defines the specificity of a particular antibody for its specific antigen. However, variability is not evenly distributed across the span of the variable domain. Instead, it is concentrated in three segments called hypervariable regions (HVRs) in both the light and heavy chain variable domains. The more highly conserved portions of the variable domains are called framework regions (FRs). The variable domains of native heavy and light chains each contain four FR regions that are primarily in a β-sheet configuration, connected by three HVRs, which form loops that connect and in some cases form a portion of the β-sheet structure. The HVRs in each chain are kept in close proximity by the FR region and, together with the HVRs from the other chain, contribute to the formation of the antigen binding site of the antibody (see Kabat et al., Sequences of Immunological Interest, 5th ed., National Institute of Health, Bethesda, MD (1991)). The constant domains are not directly involved in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0059] The term "monoclonal antibody" as used herein refers to an antibody (e.g., a monoclonal anti-TREM2 antibody of the present disclosure) obtained from a population of substantially homologous antibodies, that is, the individual antibodies constituting the population are all identical except for possible natural mutations and / or post-translational modifications (e.g., isomerization, amidation, etc.) that may be present in small amounts. Monoclonal antibodies are highly specific for a single antigenic site. Compared to polyclonal antibody preparations that typically include different antibodies for different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to its specificity, the advantage of monoclonal antibody preparations is that they are synthesized by hybridoma cultures and are not contaminated by other immunoglobulins. The modifier "monoclonal" indicates that the antibody is characterized in that it is obtained from a substantially homologous antibody population and should not be interpreted as requiring the antibody to be produced by any particular method. For example, the monoclonal antibodies used in accordance with the present invention can be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd edition 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (see, for example, U.S. Pat. No. 4,816,567), phage display technology (see, for example, Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2):299-310 (2004); Lee et al., J. Mol. Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Nat'l Acad. Sci. USA 101(34):12467-472(2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132(2004)), yeast presentation technology (for example, see WO2009 / 036379A2; WO2010105256; WO2012009568, and Xu et al., Protein Eng. Des. Sel., 26(10):663-70(2013), and techniques for producing human or human-like antibodies in animals having partial or complete human immunoglobulin loci or genes encoding human immunoglobulin sequences (e.g., see WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Nat'l Acad. Sci. USA 90:2551(1993); Jakobovits et al., Nature 362:255-258(1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13:65-93 (1995)). .

[0060] The terms "full-length antibody," "intact antibody," or "whole antibody" are used interchangeably and refer to an antibody (e.g., an anti-TREM2 antibody of the present disclosure) in its substantially intact form, as opposed to an antibody fragment. Specifically, whole antibodies include those having heavy and light chains and including an Fc region. The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or an amino acid sequence variant thereof. In some cases, an intact antibody may have one or more effector functions.

[0061] "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding region and / or variable region of an intact antibody. Examples of antibody fragments include Fab, Fab', F(ab'), 2 and Fv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995)); single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

[0062] Papain digestion of antibodies (e.g., anti-TREM2 antibodies of the present disclosure) produces two identical antigen-binding fragments (referred to as "Fab" fragments) and a residual "Fc" fragment, whose nomenclature reflects the ability to crystallize readily. The Fab fragment is composed of the entire L chain and the variable region domain (V H ) and the first constant domain of a heavy chain (C H 1) Composition. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen binding site. Antibodies are treated with pepsin to produce a single large F(ab') 2 A fragment that roughly corresponds to two Fab fragments with different antigen binding activities linked by disulfide bonds and still capable of cross-linking antigens. The Fab' fragment differs from the Fab fragment in that H The carboxyl terminus of the constant domain has several additional residues including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which one or more cysteine ​​residues of the constant domains bear a free thiol group. F(ab') 2 Antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them.Other chemical couplings of antibody fragments are also known.

[0063] The Fc fragment comprises the carboxyl terminal portions of two H chains held together by disulfide bonds.The effector functions of antibodies are determined by sequences in the Fc region, which is also recognized by Fc receptors (FcR) found on certain cell types.

[0064] "Fv" is the smallest antibody fragment containing a complete antigen recognition and binding site. This fragment consists of a dimer in a tight non-covalent association form with a heavy chain variable region domain and a light chain variable region domain. Six hypervariable loops (3 loops each from the H chain and the L chain) are generated from the folding of the two domains, and the hypervariable loops contribute amino acid residues for antigen binding and give the antibody antigen binding specificity. However, even if a single variable domain (or half of an Fv, which contains only three HVRs specific for an antigen) also has the ability to recognize and bind to an antigen, its affinity is lower than that of a complete binding site.

[0065] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is an antibody fragment comprising the VH and VL antibody domains linked into a single polypeptide chain. Preferably, the sFv polypeptide also comprises a V H With V LA polypeptide linker between domains that enables the sFv to form the desired antigen binding structure. For a review of sFv, see Plückthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag-3, New York, pp. 269-315 (1994).

[0066] A "functional fragment" of an antibody (e.g., an anti-TREM2 antibody of the present disclosure) comprises a portion of an intact antibody, which portion generally includes the antigen binding region or variable region of the intact antibody or an F region of an antibody that retains or has modified FcR binding ability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0067] The term "diabodies" refers to small antibody fragments prepared by: H With V L The sFv fragments (see the preceding paragraph) are constructed by short linkers (about 5-10 residues) between the domains, which allow interchain but not intrachain pairing of the V domains, thereby generating a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific bivalent antibodies are heterodimers of two "crossover" sFv fragments, in which the V domains of the two antibodies are H and V L The domains are present on different polypeptide chains. Diabodies are described in more detail in, for example, EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Nat'l Acad. Sci. USA 90:6444-48 (1993).

[0068] As used herein, "chimeric antibody" refers to an antibody (immunoglobulin) in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, and the rest of the chain is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass (e.g., a chimeric anti-TREM2 antibody of the present disclosure), as well as fragments of the antibody, as long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81: 6851-55 (1984)). Chimeric antibodies related herein include Antibodies, wherein the antigen binding region of the antibody is derived from antibodies produced by, for example, immunizing macaques with the relevant antigen. As used herein, "humanized antibodies" are used as a subgroup of "chimeric antibodies".

[0069] "Humanized" forms of non-human (e.g., murine) antibodies (e.g., humanized forms of anti-TREM2 antibodies of the present disclosure) are chimeric antibodies containing minimal sequences derived from non-human immunoglobulins. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient's HVR are replaced with residues from a non-human species (e.g., mouse, rat, rabbit, or non-human primate) HVR (donor antibody) with the desired specificity, affinity, and / or ability. In some cases, the FR residues of a human immunoglobulin are replaced by corresponding non-human residues. In addition, a humanized antibody may include residues that are not present in the recipient antibody or the donor antibody. These modifications may be made to further improve antibody performance, such as binding affinity. Typically, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, wherein all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, but the FR regions may include one or more individual FR residue substitutions that improve antibody performance (e.g., binding affinity, isomerization, immunogenicity, and the like). The number of these amino acid substitutions in the FR is typically no more than 6 in the H chain, and no more than 3 in the L chain. The humanized antibody will optionally also comprise at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin constant region. For additional details, see, for example, Jones et al., Nature 321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992). See also, e.g., Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1: 105-115 (1998); Harris, Biochem. Soc. Transactions 23: 1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5: 428-433 (1994); and U.S. Pat. Nos. 6,982,321 and 7,087,409.

[0070] A "human antibody" is an antibody having an amino acid sequence corresponding to the amino acid sequence of an antibody produced by a human (e.g., an anti-TREM2 antibody of the present disclosure) and / or prepared using any of the techniques for preparing human antibodies as disclosed herein. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991); Marks et al., J. Mol. Biol., 222: 581 (1991). The methods described in the following literature can also be used to prepare human monoclonal antibodies: Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147 (1): 86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce the antibody in response to antigenic challenge but whose endogenous loci have been disabled, e.g., by immunization with a xenomice (About XENOMOUSE TM Technology, see, for example, U.S. Pat. Nos. 6,075,181 and 6,150,584. For human antibodies produced via human B cell hybridoma technology, see, for example, Li et al., Proc. Nat'l Acad. Sci. USA, 103: 3557-3562 (2006). Alternatively, human antibodies can also be prepared by using yeast libraries and methods disclosed in, for example, WO2009 / 036379A2; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10): 663-70 (2013).

[0071] The term "hypervariable region", "HVR" or "HV" as used herein refers to a region of an antibody variable domain (e.g., a variable domain of an anti-TREM2 antibody of the present disclosure) that is hypervariable in sequence and / or forms a structurally defined loop. Typically, an antibody comprises 6 HVRs; 3 in VH (H1, H2, H3) and 3 in VL (L1, L2, L3). In natural antibodies, H3 and L3 display most of the diversity of the 6 HVRs, and H3 in particular is believed to play a unique role in conferring good specificity to antibodies. For example, see Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, Methods in Molecular Biology 248:1-25 (Lo ed., Human Press, Totowa, NJ, 2003)). In fact, natural camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. See, for example, Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0072] The description of many HVRs is used and covered herein. In some embodiments, HVR can be the Kabat complementary determining region (CDR) based on sequence variability and is most widely used (Kabat et al., above document). In some embodiments, HVR can be Chothia CDR. And Chothia refers to the position of the structural loop (Chothia and Lesk, J.Mol.Biol.196:901-917 (1987)). In some embodiments, HVR can be AbM HVR. AbM HVR represents a compromise between Kabat CDR and Chothia structural loops, and is used in the AbM antibody modeling software of Oxford Molecular. In some embodiments, HVR can be "contact" HVR. "Contact" HVR is based on the determination of the complex crystal structure available. The residues from each of these HVRs are as described below.

[0073]

[0074] The HVR may comprise an "extended HVR" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2), and 89-97 or 89-96 (L3) in VL and 26-35 (H1), 50-65 or 49-65 (preferred embodiments) (H2), and 93-102, 94-102, or 95-102 (H3) in VH. For each of these extended HVR definitions, the variable domain residues are numbered according to Kabat et al. (supra).

[0075] "Framework" or "FR" residues are those variable domain residues other than the HVR residues as herein defined.

[0076] The phrase "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat" and variations thereof refer to the numbering system used for the heavy chain variable domain or light chain variable domain of the compiled antibodies in Kabat et al. (supra). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertion of the FR or HVR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and an inserted residue after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues for a given antibody can be determined by aligning the homologous region of the antibody sequence with the "standard" Kabat numbering sequence.

[0077] The Kabat numbering system is often used when referring to residues in the variable domain (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Edition, Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The "EU or Kabat numbering system" or "EU index" is often used when referring to residues in the constant region of an immunoglobulin heavy chain (e.g., the EU index reported in Kabat et al., supra). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. References to residue numbering in an antibody variable domain are intended to refer to the residue numbering of the Kabat numbering system. References to residue numbering in an antibody constant domain are intended to refer to the residue numbering of the EU or Kabat numbering system (e.g., see U.S. Patent Publication No. 2010-280227).

[0078] As used herein, an "acceptor human framework" is a framework comprising an amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In the case of pre-existing amino acid changes in VH, those changes preferably occur only at three, two, or one of positions 71H, 73H, and 78H; for example, the amino acid residues at those positions may be 71A, 73T, and / or 78A. In one embodiment, the sequence of the VL acceptor human framework is consistent with the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0079] "Human consensus framework" is a framework that represents the most frequently occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Typically, the subgroup of sequences is a subgroup such as Kabat et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include, for VL, the subgroup may be, for example, Kabat et al., subgroups κI, κII, κIII or κIV in the above literature. In addition, for VH, the subgroup may be, for example, Kabat et al., subgroup I, subgroup II or subgroup III in the above literature.

[0080] An "amino acid modification" at a specified position of, for example, an anti-TREM2 antibody of the present disclosure refers to a substitution or deletion of the specified residue or an insertion of at least one amino acid residue adjacent to the specified residue. Insertion "adjacent" to a specified residue means insertion within one to two residues thereof. Insertion can be to the N-terminus or C-terminus of the specified residue. A preferred amino acid modification herein is a substitution.

[0081] An "affinity matured" antibody (e.g., an affinity matured anti-TREM2 antibody of the present disclosure) is an antibody with one or more alterations in one or more of its HVRs that result in an improvement in the antibody's affinity for the antigen compared to a parent antibody that does not have those alterations. In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinities for the target antigen. Affinity matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by shuffling of VH and VL domains. Random mutagenesis of HVR and / or framework residues is described, for example, in Barbas et al., Proc Nat. Acad. Sci, USA 91:3809-3813 (1994); Schier et al., Gene 169:147-155 (1995); Yelton et al., J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol. 226:889-896 (1992).

[0082] As used herein, the term "specific recognition" or "specific binding" refers to a measurable and reproducible interaction, such as attraction or binding between a target and an antibody (e.g., between an anti-TREM2 antibody and TREM2), that determines the presence of a target in the presence of a heterologous population of molecules (including biomolecules). For example, an antibody (e.g., an anti-TREM2 antibody of the present disclosure) that specifically or preferentially binds to a target or epitope is an antibody that binds to this target or epitope with greater affinity, avidity, and / or for a longer duration than it binds to other targets or other epitopes of a target. It should also be understood by reading this definition that, for example, an antibody (or portion) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Thus, "specific binding" or "preferential binding" does not necessarily require (but it may include) exclusive binding. An antibody that specifically binds to a target may have at least about 10 3 M -1 or 10 4 M -1 , sometimes about 10 5 M -1 or 10 6 M -1 , in other cases about 10 6 M -1 or 10 7 M -1 , about 10 8 M -1Up to 10 9 M -1 or about 10 10 M -1 Up to 10 11 M -1 or higher association constant. A variety of immunoassay formats can be used to select antibodies that specifically immunoreact with a particular protein. For example, solid phase ELISA immunoassays are often used to select monoclonal antibodies that specifically immunoreact with a protein. For a description of immunoassay formats and conditions for determining specific immunoreactivity, see, for example, Harlow and Lane (1988), Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0083] As used herein, an "interaction" between a TREM2 protein and a second protein encompasses, but is not limited to, protein-protein interactions, physical interactions, chemical interactions, binding, covalent binding, and ionic binding. As used herein, an antibody "inhibits an interaction between two proteins" when it disrupts, reduces, or completely eliminates the interaction between the two proteins. An antibody or fragment thereof of the present disclosure "inhibits an interaction between the two proteins" when it binds to one of the two proteins.

[0084] An "agonist" antibody or "activating" antibody is an antibody that induces (eg, increases) one or more activities or functions of an antigen after the antibody binds to the antigen.

[0085] An "antagonist" antibody or "blocking" antibody is an antibody that reduces or eliminates (e.g., reduces) the binding of the antigen to one or more ligands and / or reduces or eliminates (e.g., reduces) one or more activities or functions of the antigen after the antibody binds to the antigen. In some embodiments, an antagonist antibody or blocking antibody substantially or completely inhibits the binding of the antigen to one or more ligands and / or one or more activities or functions of the antigen.

[0086] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype.

[0087] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain, including a native sequence Fc region and a variant Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine in the Fc region (residue 447 according to the EU or Kabat numbering system) may be removed during, for example, the production or purification of an antibody or by recombinant engineering of a nucleic acid encoding an antibody heavy chain. Therefore, the composition of a complete antibody may include an antibody population that has all K447 residues removed, an antibody population that has not had K447 residues removed, and an antibody population that has an antibody mixture that contains and does not contain K447 residues. Suitable native sequence Fc regions for use in antibodies of the present disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0088] A "native sequence Fc region" comprises an amino acid sequence that is identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes); native sequence human IgG2 Fc regions; native sequence human IgG3 Fc regions; and native sequence human IgG4 Fc regions, as well as natural variants thereof.

[0089] A "variant Fc region" comprises an amino acid sequence that differs from a native sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region or compared to the Fc region of a parent polypeptide, e.g., from about 1 to about 10 amino acid substitutions in a native sequence Fc region or the Fc region of a parent polypeptide, and preferably from about 1 to about 5 amino acid substitutions. The variant Fc region herein will preferably have at least about 80% homology with a native sequence Fc region and / or with the Fc region of a parent polypeptide, and most preferably at least about 90% homology therewith, more preferably at least about 95% homology therewith.

[0090] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferably, the FcR is a native sequence human FcR. In addition, preferably, the FcR is an FcR (gamma receptor) that binds to an IgG antibody and includes receptors of the FcγRI, FcγRII and FcγRIII subclasses, including allelic variants and alternative splicing forms of these receptors, and the FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibiting receptor"), both of which have similar amino acid sequences that differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif ("ITAM") in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain. (See, e.g., M. Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). The term "FcR" herein encompasses other FcRs, including those to be identified in the future. FcRs may also extend the serum half-life of antibodies.

[0091] In vivo binding and serum half-life of human FcRn high affinity binding polypeptides to FcRn can be determined, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which polypeptides having variant Fc regions are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or reduced binding to FcRs. See also, for example, Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0092] As used herein, "percent (%) amino acid sequence identity" and "homology" with respect to peptide, polypeptide or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in a particular peptide or polypeptide sequence, after aligning the sequences and introducing gaps (if necessary) to achieve the maximum percentage of sequence identity, and not considering any conservative substitutions as part of the sequence identity. For the purpose of determining the percentage of amino acid sequence identity, alignment can be achieved in various ways well known to those skilled in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN TM(DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.

[0093] An "isolated" nucleic acid molecule encoding an antibody (e.g., an anti-TREM2 antibody of the present disclosure) is a nucleic acid molecule that is identified and separated from at least one contaminating nucleic acid molecule with which it is normally associated in its production environment. Preferably, the isolated nucleic acid is not associated with all components associated with the production environment. The isolated nucleic acid molecules encoding the polypeptides and antibodies herein are not in the form or arrangement in which they are found in nature. Thus, the isolated nucleic acid molecules distinguish nucleic acids encoding the polypeptides and antibodies herein from those naturally present in cells.

[0094] The term "vector" as used herein is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid connected thereto. One type of vector is a "plasmid", which refers to a circular double-stranded DNA to which other DNA segments can be connected. Another type of vector is a bacteriophage vector. Another type of vector is a viral vector, in which other DNA segments can be connected to the viral genome. Certain vectors are capable of autonomous replication in the host cell into which they have been introduced (e.g., bacterial vectors and free mammalian vectors with bacterial replication origins). Other vectors (e.g., non-free mammalian vectors) can be integrated into the genome of the host cell when introduced into the host cell, and thus replicated with the host genome. In addition, certain vectors can guide the expression of genes operably connected thereto. The vector is referred to herein as a "recombinant expression vector" or simply "expression vector". In general, expression vectors available in recombinant DNA technology are usually in the form of plasmids. Since plasmids are the most commonly used form of vectors, "plasmids" and "vectors" are used interchangeably in this specification.

[0095] "Polynucleotide" or "nucleic acid" as used interchangeably herein refers to nucleotide polymers of any length, and includes 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 polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides can contain modified nucleotides, such as methylated nucleotides and their analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Non-nucleotide components can interrupt the sequence of nucleotides. Polynucleotides can contain one or more modifications performed after synthesis, such as conjugation to a label. Other types of modifications include, for example, "caps", substitution of one or more of the natural nucleotides with an analog, internucleotide modifications, such as those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), those containing side moieties (e.g., proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those with intercalators (e.g., acridine, psoralen, etc.), those containing chelators (e.g., The polynucleotides may be modified by alkylating agents, those containing modified linkages (e.g., α-mutator nucleic acids, etc.), those containing alkylating agents, those having modified linkages (e.g., α-mutator nucleic acids, etc.), and unmodified forms of polynucleotides. In addition, any of the hydroxyl groups typically present in sugars may be replaced by, for example, phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages with additional nucleotides, or may be conjugated to a solid or semisolid support. The 5' and 3' terminal OH groups may be partially phosphorylated or substituted with amines or organic capping groups of 1 to 20 carbon atoms. Other hydroxyl groups may also be derivatized with standard protecting groups. The polynucleotides may also contain analogous forms of ribose or deoxyribose sugars generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl, 2'-fluoro- or 2'-azido-ribose, carbocyclic sugar analogs, α-mutanosaccharides, epimeric sugars (e.g., arabinose, xylose, or lyxose), pyranose sugars, furanose sugars, sedoheptulose, acyclic analogs, and basic nucleoside analogs (e.g., methyl riboside). One or more phosphates The diester linkage may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which the phosphate is replaced by P(O)S ("thioester"), P(S)S ("dithioester"), (O)NR2 ("amidate"), P(O)R, P(O)OR', CO or CH2 ("methyl acetal"), wherein each R or R' is independently H or a substituted or unsubstituted alkyl (1-20 C), aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl group optionally containing an ether (-O-) linkage.Not all linkages in a polynucleotide need be identical.The foregoing description applies to all polynucleotides mentioned herein, including RNA and DNA.

[0096] "Host cell" includes an individual cell or cell culture that can be or has been a recipient of a vector for incorporating a polynucleotide insert. Host cells include progeny of a single host cell, and the progeny may not necessarily be completely identical (in morphology or in genomic DNA complement) to the original parent cell due to natural, accidental, or deliberate mutation. Host cells include cells transfected in vivo with a polynucleotide of the invention.

[0097] As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients or stabilizers that are non-toxic to exposed cells or mammals at the dosages and concentrations employed. Typically, a physiologically acceptable carrier is a pH buffered aqueous solution. Examples of physiologically acceptable carriers include buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN TM , polyethylene glycol (PEG) and PLURONICS TM .

[0098] The term "about" as used herein refers to the general error range for the corresponding value that is readily known to those skilled in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments with respect to the value or parameter itself.

[0099] As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, a reference to an "antibody" is a reference to one to many antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, etc.

[0100] It should be understood that aspects and embodiments of the present disclosure described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0101] Overview

[0102] The present disclosure relates to anti-TREM2 antibodies (e.g., monoclonal antibodies) with improved affinity and functional properties; methods of making and using the antibodies; pharmaceutical compositions containing the antibodies; nucleic acids encoding the antibodies; and host cells containing nucleic acids encoding the antibodies.

[0103] Thus, certain aspects of the present disclosure are based, at least in part, on the identification of anti-TREM2 antibodies that are capable of binding to both human and cynomolgus monkey TREM2 with high affinity (e.g., see Examples 2 and 6); capable of binding to primary human immune cells with high affinity (e.g., see Examples 1 to 3); have improved ability to aggregate and activate TREM2 signaling in vitro and in vivo (e.g., see Examples 3, 7, and 11); and have improved ability to increase immune cell survival in vitro (e.g., see Examples 3 and 9). Advantageously, the anti-TREM2 antibodies of the present disclosure are shown to have improved in vivo half-life and are capable of reducing plasma levels of soluble TREM2 in vitro and in vivo (e.g., see Examples 4, 8, and 10). In some embodiments, the anti-TREM2 antibodies of the present disclosure induce, increase, or otherwise enhance one or more TREM2 activities of the present disclosure. In some embodiments, the anti-TREM2 antibodies of the present disclosure have one or more of these improved affinities and functional properties compared to an anti-TREM2 antibody having a heavy chain variable region and a light chain variable region of antibody AL2p-h50 or AL2p-h77. In addition, based on the results described in Examples 2 to 11, the functional properties of the affinity matured anti-TREM2 antibodies of the present disclosure would not be predicted from their improved affinity for TREM2.

[0104] In some embodiments, the anti-TREM2 antibodies of the present disclosure have high affinity for TREM2, exhibiting the following functional properties: the ability to enhance TREM2 signaling in both soluble and plate-bound forms; the ability to promote the survival of primary human macrophages and primary human dendritic cells; the ability to reduce the production of soluble TREM2 (sTREM2) by primary human bone marrow cells in vitro and in vivo; and having a relatively low polyspecific reactivity (PSR), which is a measure of non-specific binding. As disclosed herein, affinity maturation can produce anti-TREM2 antibody variants with both increased binding affinity and increased PSR (i.e., relatively high non-specific binding). Although certain antibodies of the present disclosure (e.g., AL2p-31 and AL2p-60) have higher binding affinity and preferred functional properties than other affinity matured antibody variants, these antibodies also exhibit high PSR and have a high degree of background binding to cells (e.g., see Example 12). Surprisingly, compared to other high affinity antibody variants (e.g., AL2p-31 and AL2p-60), antibodies AL2p-58 and AL2p-47 exhibit both high binding affinity and relatively low PSR, while also having the ability to enhance TREM2 signaling, promote survival of primary human macrophages and primary human dendritic cells in both soluble and plate-bound forms; and reduce the production of soluble TREM2 (sTREM2) by primary human bone marrow cells in vitro and in vivo (e.g., see Examples 2 to 12). Based on these results, unexpectedly, antibodies AL2p-58 and AL2p-47 exhibit high affinity and good functional properties to TREM2 without showing any significant PSR or background binding to cells.

[0105] The results in Example 9 also surprisingly show that the affinity matured anti-TREM2 antibodies of the present disclosure (e.g., AL2p-58 and AL2p-47) induce a hundreds-fold increase in cell viability of primary human macrophages and dendritic cells (e.g., see Tables 14 and 14). Fig. 8A and Figure 8B This functional property is surprising because affinity-matured anti-TREM2 antibodies (e.g., AL2p-58 and AL2p-47) have a higher affinity (K) for binding to human TREM2-Fc than the parental mouse anti-TREM2 antibody AL2p. D ) only showed an improvement of about 10 times (e.g., see Tables 1 and 8), but had a several hundred-fold increase in its ability to promote cell viability. In addition, surprisingly, the antibody AL2p-37, which has a binding affinity roughly similar to that of AL2p-58 and AL2p-47, has a relatively lower efficacy in promoting cell viability than AL2p-58 and AL2p-47.

[0106] TREM2 protein

[0107] In one aspect, the present disclosure provides antibodies that bind to the TREM2 proteins of the present disclosure, which have improved affinity and induce one or more TREM2 activities and / or enhance one or more TREM2 activities upon binding to the TREM2 protein expressed in a cell.

[0108] TREM2 proteins of the present disclosure include, but are not limited to, human TREM2 protein (Uniprot Accession No. Q9NZC2; SEQ ID NO: 1) and non-human mammalian TREM2 proteins, such as mouse TREM2 protein (Uniprot Accession No. Q99NH8; SEQ ID NO: 2), rat TREM2 protein (Uniprot Accession No. D3ZZ89; SEQ ID NO: 3), rhesus monkey TREM2 protein (Uniprot Accession No. F6QVF2; SEQ ID NO: 4), cynomolgus monkey TREM2 protein (NCBI Accession No. XP_015304909.1; SEQ ID NO: 5), horse TREM2 protein (Uniprot Accession No. F7D6L0; SEQ ID NO: 6), porcine TREM2 protein (Uniprot Accession No. H2EZZ3; SEQ ID NO: 7), and dog TREM2 protein (Uniprot Accession No. E2RP46; SEQ ID NO: 8). As used herein, "TREM2 protein" refers to both wild-type sequences and naturally occurring variant sequences.

[0109] Triggering receptor expressed on myeloid cells-2 (TREM2) is variously referred to as TREM-2, TREM2a, TREM2b, TREM2c, triggering receptor expressed on myeloid cells-2a, and triggering receptor expressed on monocytes-2. TREM2 is a membrane protein of 230 amino acids. TREM2 is an immunoglobulin-like receptor expressed primarily on myeloid cells, including, but not limited to, macrophages, dendritic cells, monocytes, Langerhans cells of the skin, Kupffer cells, osteoclasts, and microglial cells. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 phosphorylation and signaling is performed via DAP12 (ITAM domain adapter protein). In some embodiments, TREM2 signaling leads to downstream activation of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signals are important for the activation of TREM2 activity, for example, in the context of an infection response. TLRs also play a key role in pathological inflammatory responses, for example, TLRs are expressed on macrophages and dendritic cells.

[0110] In some embodiments, an example of a human TREM2 amino acid sequence is shown below in SEQ ID NO: 1:

[0111]

[0112] In some embodiments, the human TREM2 is a preprotein including a signal peptide. In some embodiments, the human TREM2 is a mature protein. In some embodiments, the mature TREM2 protein does not include a signal peptide. In some embodiments, the mature TREM2 protein is expressed on a cell. In some embodiments, TREM2 contains a signal peptide at amino acid residues 1-18 of human TREM2 (SEQ ID NO: 1); an extracellular immunoglobulin-like variable (IgV) domain at amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1); an additional extracellular sequence at amino acid residues 113-174 of human TREM2 (SEQ ID NO: 1); a transmembrane domain at amino acid residues 175-195 of human TREM2 (SEQ ID NO: 1); and an intracellular domain at amino acid residues 196-230 of human TREM2 (SEQ ID NO: 1).

[0113] The transmembrane domain of human TREM2 contains a lysine at amino acid residue 186 that can interact with an aspartate in DAP12, a key adaptor protein that transduces signals from TREM2, TREM1, and other related IgV family members.

[0114] Homologs of human TREM2 include, but are not limited to, natural killer (NK) cell receptor NK-p44 (NCTR2), polymeric immunoglobulin receptor (pIgR), CD300E, CD300A, CD300C, and TREML1 / TLT1. In some embodiments, NCTR2 has similarity to TREM2 within the IgV domain.

[0115] Anti-TREM2 antibodies

[0116] Certain aspects of the present disclosure relate to antibodies (e.g., monoclonal antibodies) that specifically bind to TREM2 with improved affinity. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 proteins. In some embodiments, the antibodies of the present disclosure bind to mature TREM2 proteins, wherein the mature TREM2 proteins are expressed on cells. In some embodiments, the antibodies of the present disclosure bind to TREM2 proteins expressed on one or more human cells selected from the group consisting of human dendritic cells, human macrophages, human monocytes, human osteoclasts, Langerhans cells of human skin, human Kupffer cells, human microglia, and any combination thereof.

[0117] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to the TREM2 protein without competing with one or more TREM2 ligands for binding to the TREM2 protein, inhibiting its binding to the TREM2 protein, or otherwise blocking its binding to the TREM2 protein. Examples of suitable TREM2 ligands include, but are not limited to, TREM2 ligands expressed by Escherichia coli (E. coli) cells, apoptotic cells, nucleic acids, anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2, anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidated APOE3, lipidated APOE4, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptides. Thus, in certain embodiments, the one or more TREM2 ligands comprise Escherichia coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine (PS), sulfatides, phosphatidylcholine, sphingomyelin (SM), phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid β-peptide.

[0118] In some embodiments, the anti-TREM2 antibodies of the present disclosure do not inhibit the growth of one or more innate immune cells. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more primary immune cells with an affinity 5 to 100 times higher than that of an anti-TREM2 antibody selected from the following: an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more primary immune cells with an affinity that is at least 5-fold higher, at least 6-fold higher, at least 7-fold higher, at least 8-fold higher, at least 9-fold higher, at least 10-fold higher, at least 11-fold higher, at least 12-fold higher, at least 13-fold higher, at least 14-fold higher, at least 15-fold higher, at least 16-fold higher, at least 17-fold higher, at least 18-fold higher, at least 19-fold higher, at least 20-fold higher, at least 21-fold higher, at least 22-fold higher, at least 23-fold higher, at least 24-fold higher, at least 25-fold higher, at least 26-fold higher, at least 27-fold higher, at least 28-fold higher, at least 29-fold higher, at least 30-fold higher, at least 35-fold higher, at least 40-fold higher, at least 45-fold higher, at least 50-fold higher than an anti-TREM2 antibody selected from the group consisting of: comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: NO:56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more primary immune cells with a mean fluorescence intensity (MFI) ranging from 100 to 1500 or greater than 1500. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more primary immune cells,The mean fluorescence intensity (MFI) is at least 100, at least 110, at least 120, at least 130, at least 140, at least 141, at least 150, at least 152, at least 155, at least 159, at least 160, at least 170, at least 180, at least 187, at least 190, at least 194, at least 195, at least 200, at least 210, at least 220, at least 224, at least 230, at least 235, at least 240, at least 250, at least 260, at least 262, at least 270, at least 280, at least 288, at least 290, at least 296, at least 300, at least 310, at least 318, at least 320, at least 322, at least 327, at least 330 , at least 340, at least 350, at least 360, at least 370, at least 372, at least 380, at least 390, at least 400, at least 408, at least 410, at least 413, at least 420, at least 430, at least 440, at least 450, at least 460, at least 470, at least 480, at least 490, at least 499, at least 500, at least 510, at least 520, at least 530, at least 534, at least 540, at least 547, at least 550, at least 560, at least 570, at least 580, at least 590, at least 600, at least 610, at least 620, at least 630, at least 640, at least 650, at least 660, at least 662, at least 670, 680, at least 690, at least 700, at least 710, at least 720, at least 730, at least 740, at least 750, at least 760, at least 770, at least 780, at least 790, at least 800, at least 810, at least 820, at least 830, at least 840, at least 850, at least 860, at least 870, at least 880, at least 890, at least 900, at least 910, at least 920, at least 930, at least 940, at least 950, at least 960, at least 970, at least 980, at least 990, at least 1000, at least 1035, at least 1110, at least 1120, at least 1130, at least 1140, at least 1150, at least 1160 0, at least 1170, at least 1180, at least 1190, at least 1200, at least 1210, at least 1220, at least 1230, at least 1240, at least 1250, at least 1260, at least 1270, at least 1280, at least 1290, at least 1300, at least 1310, at least 1320, at least 1330, at least 1340, at least 1350, at least 1360, at least 1370, at least 1380, at least 1390, at least 1400, at least 1410, at least 1420, at least 1430, at least 1440, at least 1450, at least 1460, at least 1467, at least 1470, at least 1480, at least 1490, or at least 1500. In some embodiments,MFI is determined at a temperature of about 25°C. In some embodiments, K, D The method of preparing and selecting antibodies that interact with and / or specifically bind to TREM2 is described herein. (For example, see Examples 1 and 2).

[0119] In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate and activate TREM2 signaling in an amount at least 0.5-fold greater, at least 0.6-fold greater, at least 0.7-fold greater, at least 0.8-fold greater, at least 0.9-fold greater, at least 1-fold greater, at least 2-fold greater, at least 3-fold greater, at least 4-fold greater, at least 5-fold greater, at least 6-fold greater, at least 7-fold greater, at least 8-fold greater, at least 9-fold greater, or at least 10-fold greater than an anti-TREM2 antibody selected from: an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.

[0120] In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate and activate TREM2 signaling in an amount ranging from about 1 times the control (FOC) to about 30 times the control (FOC). In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate and activate TREM2 signaling in an amount of at least 1 times the control (FOC), at least 1.1 times the control (FOC), at least 1.2 times the control (FOC), at least 1.3 times the control (FOC), at least 1.4 times the control (FOC), at least 1.5 times the control (FOC), at least 1.6 times the control (FOC), at least 1.7 times the control (FOC), at least 1.8 times the control (FOC), at least 1.9 times the control (FOC), at least 2 times the control (FOC), at least 2.1 times the control (FOC), at least 2.2 times the control (FOC), at least 2.3 times the control (FOC), at least 2.4 times the control (FOC), at least 2.5 times the control (FOC), at least 2.6 times the control (FOC), at least 2.7 times the control (FOC), at least 2.8 times the control (FOC), at least 2.9 times the control (FOC), 3 times the control (FOC), at least 3.1 times the control (FOC), at least 3.2 times the control (FOC), at least 3.3 times the control (FOC), at least 3.4 times the control (FOC), at least 3.5 times the control (FOC), at least 3.6 times the control (FOC), at least 3.7 times the control (FOC), to at least 3.8 times the control (FOC), at least 3.9 times the control (FOC), 4 times the control (FOC), at least 4.1 times the control (FOC), at least 4.2 times the control (FOC), at least 4.3 times the control (FOC), at least 4.4 times the control (FOC), at least 4.5 times the control (FOC), at least 4.6 times the control (FOC), at least 4.7 times the control (FOC), at least 4.8 times the control (FOC), at least 4.9 times the control (FOC), 5 times the control (FOC), at least 5.1 times the control (FOC), at least 5.2 times the control (FOC), at least 5.3 times the control (FOC). C), at least 5.4 times the control (FOC), at least 5.5 times the control (FOC), at least 5.6 times the control (FOC), at least 5.7 times the control (FOC), at least 5.8 times the control (FOC), at least 5.9 times the control (FOC), 6 times the control (FOC), at least 6.1 times the control (FOC), at least 6.2 times the control (FOC), at least 6.3 times the control (FOC), at least 6.4 times the control (FOC), at least 6.5 times the control (FOC), at least 6.6 times the control (FOC), at least 6.7 times the control (FOC), at least 6.8 times the control (FOC), at least 6.9 times the control (FOC), 7 times the control (FOC), at least 7.1 times the control (FOC), at least 7.2 times the control (FOC), at least 7.3 times the control (FOC), at least 7.4 times the control (FOC), at least 7.5 times the control (FOC), at least 7.6 times the control (FOC), at least 7.7 times the control (FOC), at least 7.8 times the control (FOC), at least 7.9 times the control (FOC), 8 times the control (FOC), at least 8.1 times the control (FOC), at least 8.2 times the control (FOC), at least 8.3 times the control (FOC), at least 8.4 times the control (FOC), at least 8.5 times the control (FOC), at least 8.6 times the control (FOC), at least 8.7 times the control (FOC), at least 8.8 times the control (FOC), at least 8.9 times the control (FOC), 9 times the control (FOC), at least 9.1 times the control (FOC), at least 9.2 times the control (FOC), at least 9.3 times the control (FOC), at least 9.4 times the control (FOC). C), at least 9.5 times the control (FOC), at least 9.6 times the control (FOC), at least 9.7 times the control (FOC), at least 9.8 times the control (FOC), at least 9.9 times the control (FOC), at least 10 times the control (FOC), at least 11 times the control (FOC), at least 12 times the control (FOC), at least 13 times the control (FOC), at least 14 times the control (FOC), at least 15 times the control (FOC), at least 16 times the control (FOC), at least 17 times the control (FOC). OC), at least 18-fold greater than a control (FOC), at least 19-fold greater than a control (FOC), at least 20-fold greater than a control (FOC), at least 21-fold greater than a control (FOC), at least 22-fold greater than a control (FOC), at least 23-fold greater than a control (FOC), at least 24-fold greater than a control (FOC), at least 25-fold greater than a control (FOC), at least 26-fold greater than a control (FOC), at least 27-fold greater than a control (FOC), at least 28-fold greater than a control (FOC), at least 29-fold greater than a control (FOC), or at least 30-fold greater than a control (FOC). In some embodiments, aggregation and activation of TREM2 signaling is determined at 37°C using a monovalent antibody (e.g., Fab) or a full-length antibody in a monovalent form. Methods of measuring aggregation and activation of TREM2 signaling are described herein (e.g., see Example 3). .

[0121] In some embodiments, the anti-TREM2 antibodies of the present disclosure increase the survival of immune cells in vitro to a degree that is at least 1.5 times higher, at least 2 times higher, at least 3 times higher, at least 4 times higher, at least 5 times higher, at least 6 times higher, at least 7 times higher, at least 8 times higher, at least 9 times higher, at least 10 times higher, at least 11 times higher, at least 12 times higher, at least 13 times higher, at least 14 times higher, at least 15 times higher, at least 16 times higher, at least 17 times higher, at least 18 times higher, at least 19 times higher, at least 20 times higher than an anti-TREM2 antibody selected from , at least 21 times higher, at least 22 times higher, at least 23 times higher, at least 24 times higher, at least 25 times higher, at least 26 times higher, at least 27 times higher, at least 28 times higher, at least 29 times higher, at least 30 times higher, at least 35 times higher, at least 40 times higher, at least 45 times higher, at least 50 times higher, at least 55 times higher, at least 60 times higher, at least 65 times higher, at least 70 times higher, at least 75 times higher, at least 80 times higher, at least 85 times higher, at least 90 times higher, at least 95 times higher, or at least 100 times higher: comprising the amino acid sequence SEQ An anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.

[0122] In some embodiments, the ability of an anti-TREM2 antibody of the present disclosure to increase in vitro immune cell survival is measured by determining the area under the curve (AUC) of the growth curve of primary immune cells in culture treated with an anti-TREM2 antibody of the present disclosure. In some embodiments, an anti-TREM2 antibody of the present disclosure increases in vitro immune cell survival with an AUC in the range of about 200,000 to about 1,500,000. In some embodiments, the anti-TREM2 antibodies of the present disclosure increase immune cell survival in vitro with an AUC of at least 200,000, at least 210,000, at least 220,000, at least 230,000, at least 240,000, at least 250,000, at least 260,000, at least 270,000, at least 280,000, at least 290,000, at least 300,000, at least 310,000, at least 320,000, at least 330,000, at least 340,000, at least 350,000, at least 360,000, at least 370,000, at least 380,000, at least 390,000. , at least 400,000, at least 410,000, at least 420,000, at least 430,000, at least 440,000, at least 450,000, at least 460,000, at least 470,000, at least 480,000, at least 490,000, at least 500,000, at least 510,000, at least 520,000, at least 530,000, at least 540,000, at least 550,000, at least 560,000, at least 570,000, at least 580,000, at least 590,000, at least 600,000, at least 610,000, at least 620,000, at least 630,000,At least 640,000, at least 650,000, at least 660,000, at least 670,000, at least 680,000, at least 690,000, at least 700,000, at least 710,000, at least 720,000, at least 730,000, at least 740,000, at least 750,000, at least 760,000, at least 770,000, at least 780,000, at least 790,000, at least 800,000, at least 810,000, at least 820,000, at least 830,000, at least 840,000, at least 850,000, at least 860,000, at least at least 870,000, at least 880,000, at least 890,000, at least 900,000, at least 910,000, at least 920,000, at least 930,000, at least 940,000, at least 950,000, at least 960,000, at least 970,000, at least 980,000, at least 990,000, at least 1,000,000, at least 1,010,000, at least 1,020,000, at least 1,030,000, at least 1,040,000, at least 1,050,000, at least 1,060,000, at least 1,070,000, at least 1,080,000, at least 1 at least 120000, at least 1210000, at least 1220000, at least 1230000, at least 1240000, at least 1250000, at least 1260000, at least 1270000, at least 1280000, at least 1290000, at least 1300000, at least 1310000, at least 1320000, at least 1330000, at least 1340000, at least 1350000, at least 1360000, at least 1370000, at least 1380000, at least 1390000, at least 140000 At least 1300000, at least 1310000, at least 1320000, at least 1330000, at least 1340000, at least 1350000, at least 1360000, at least 1370000, at least 1380000, at least 1390000, at least 1400000, at least 1410000, at least 1420000, at least 1430000, at least 1440000, at least 1450000, at least 1460000, at least 1470000, at least 1480000, at least 1490000, or at least 1500000. In some embodiments, in vitro immune cell survival is measured at 4°C using a monovalent antibody (e.g., Fab) or a full-length antibody in a monovalent form. Methods for measuring in vitro immune cell survival are described herein (e.g., see Example 3). ,

[0123] In some embodiments, the in vivo half-life of an anti-TREM2 antibody of the present disclosure is lower than that of a human control IgG1 antibody. In some embodiments, the in vivo half-life of an anti-TREM2 antibody of the present disclosure is at least 1.5 times lower, at least 2 times lower, at least 3 times lower, at least 4 times lower, at least 5 times lower, at least 6 times lower, at least 7 times lower, at least 8 times lower, at least 9 times lower, at least 10 times lower, at least 11 times lower, at least 12 times lower, at least 13 times lower, at least 14 times lower, at least 15 times lower, at least 16 times lower, at least 17 times lower, at least 18 times lower, at least 19 times lower, at least 20 times lower, at least 21 times lower, at least 22 times lower, at least 23 times lower, at least 24 times lower, at least 25 times lower, at least 26 times lower, at least 27 times lower, at least 28 times lower, at least 29 times lower, at least 30 times lower, at least 31 times lower, at least 32 times lower, at least 33 times lower, at least 34 times lower, at least 35 times lower, at least 36 times lower, at least 37 times lower, at least 38 times lower, at least 39 times lower, at least 40 times lower, at least 41 times lower, at least 42 times lower, at least 43 times lower, at least 44 times lower, at least 45 times lower, at least 46 times lower, at least 47 times lower, at least 48 times lower, at least 49 times lower, at least 50 times lower, at least 51 times lower, at least 52 times lower, fold, at least 21 fold lower, at least 22 fold lower, at least 23 fold lower, at least 24 fold lower, at least 25 fold lower, at least 26 fold lower, at least 27 fold lower, at least 28 fold lower, at least 29 fold lower, at least 30 fold lower, at least 35 fold lower, at least 40 fold lower, at least 45 fold lower, at least 50 fold lower, at least 55 fold lower, at least 60 fold lower, at least 65 fold lower, at least 70 fold lower, at least 75 fold lower, at least 80 fold lower, at least 85 fold lower, at least 90 fold lower, at least 95 fold lower, or at least 100 fold lower: comprising an amino acid sequence of SEQ An anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:103; and an anti-TREM2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.

[0124] In some embodiments, the in vivo half-life of an anti-TREM2 antibody of the present disclosure is in the range of about 0.1 day to about 10 days. In some embodiments, the in vivo half-life of an anti-TREM2 antibody of the present disclosure is about 0.1 day, about 0.2 day, about 0.3 day, about 0.4 day, about 0.5 day, about 0.6 day, about 0.7 day, about 0.8 day, about 0.9 day, about 1 day, about 1.1 day, about 1.2 day, about 1.3 day, about 1.4 day, about 1.5 day, about 1.6 day, about 1.7 day, about 1.8 day, about 1.9 day, about 2 days, about 2.1 day, about 2.2 day, about 2.3 day, about 2.4 day, about 2.5 day, about 2.6 day, about 2.7 day, about 2.8 day, about 2.9 day, about 2.1 day, about 2. .2 days, about 2.3 days, about 2.4 days, about 2.5 days, about 2.6 days, about 2.7 days, about 2.8 days, about 2.9 days, about 3 days, about 3.1 days, about 3.2 days, about 3.3 days, about 3.4 days, about 3.5 days, about 3.6 days, about 3.7 days, about 3.8 days, about 3.9 days, about 4 days, about 4.1 days, about 4.2 days, about 4.3 days, about 4.4 days, about 4.5 days, about 4.6 days, about 4.7 days, about 4 .8 days, about 4.9 days, about 5 days, about 5.1 days, about 5.2 days, about 5.3 days, about 5.4 days, about 5.5 days, about 5.6 days, about 5.7 days, about 5.8 days, about 5.9 days, about 6 days, about 6.1 days, about 6.2 days, about 6.3 days, about 6.4 days, about 6.5 days, about 6.6 days, about 6.7 days, about 6.8 days, about 6.9 days, about 7 days, about 7.1 days, about 7.2 days, about 7.3 days, about 7.4 In some embodiments, the half-life in vivo is measured using a monovalent antibody (e.g., Fab) or a full-length antibody in a monovalent form. Methods for measuring the half-life in vivo are described herein (e.g., see Example 4).

[0125] The anti-TREM2 antibodies of the present disclosure are generally bound to one or more TREM2 proteins expressed on cells with high affinity. For example, it is believed that TREM2 receptors need to aggregate on the cell surface to transduce signals. Therefore, agonist antibodies may have unique features to stimulate (for example) TREM2 receptors. For example, it may have the correct epitope specificity compatible with receptor activation, as well as the ability to induce or retain receptor aggregation on the cell surface. In addition, the anti-TREM2 antibodies of the present disclosure may show the ability to bind to TREM2 without blocking the simultaneous binding of one or more TREM2 ligands. The anti-TREM2 antibodies of the present disclosure may further show additive and / or synergistic functional interactions with one or more TREM2 ligands. Therefore, in some embodiments, when combined with the anti-TREM2 antibodies of the present disclosure and the combination of one or more TREM2 ligands of the present disclosure, the maximum activity of TREM2 may be greater than (for example, enhanced) the maximum activity of TREM2 when exposed to a saturated concentration of a single ligand or a saturated concentration of a single antibody. In addition, the activity of TREM2 under a given concentration of TREM2 ligand may be greater (for example, enhanced) in the presence of an antibody. Therefore, in some embodiments, the anti-TREM2 antibodies of the present disclosure have an additive effect with one or more TREM2 ligands to enhance one or more TREM2 activities when bound to the TREM2 protein. In some embodiments, the anti-TREM2 antibodies of the present disclosure synergistically enhance one or more TREM2 activities with one or more TREM2 ligands. In some embodiments, compared with the efficacy of one or more TREM2 ligands inducing one or more TREM2 activities in the absence of antibodies, the anti-TREM2 antibodies of the present disclosure increase the efficacy of one or more TREM2 ligands inducing one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities in the absence of cell surface aggregation of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure enhance one or more TREM2 activities by inducing or retaining cell surface aggregation of TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate through one or more Fc-γ receptors expressed on one or more immune cells, including, but not limited to, B cells and microglia. In some embodiments, the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein is measured on primary cells, including but not limited to dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, Langerhans cells of the skin, and Kupffer cells, or on cell lines, and the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein is measured, for example, using an in vitro cell assay.

[0126] In vivo, the anti-TREM2 antibodies of the present disclosure can activate receptors by a variety of potential mechanisms. In some embodiments, due to the correct epitope specificity, the anti-TREM2 antibodies of the present disclosure have the ability to activate TREM2 in solution without having to aggregate with secondary antibodies, bind to plates, or aggregate via Fcg receptors. In some embodiments, the anti-TREM2 antibodies of the present disclosure have an isotype of a human antibody (e.g., IgG2) that has an intrinsic ability to aggregate receptors or retain receptors in an aggregated configuration due to its unique structure, thereby activating receptors (e.g., TREM2) without binding to Fc receptors (e.g., White et al., (2015) Cancer Cell 27, 138-148).

[0127] In some embodiments, the anti-TREM2 antibodies of the present disclosure aggregate receptors (e.g., TREM2) by binding to Fcg receptors on adjacent cells. Binding of the constant IgG Fc portion of the antibody to the Fcg receptor causes antibody aggregation, and the antibody in turn aggregates the receptors bound via its variable region (Chu et al. (2008) Mol Immunol, 45: 3926-3933; and Wilson et al., (2011) Cancer Cell 19, 101-113). Binding to inhibitory Fcg receptors FcgR (FcgRIIB) that do not induce cytokine secretion, oxidative burst, increased phagocytosis, and enhanced antibody-dependent, cell-mediated cytotoxicity (ADCC) is generally a preferred way to aggregate antibodies in vivo, because binding to FcgRIIB is not associated with immunoadverse effects. Any suitable assay described herein can be used to determine antibody aggregation.

[0128] Other mechanisms can also be used to aggregate receptors (e.g., TREM2). For example, in some embodiments, antibody fragments (e.g., Fab fragments) that are cross-linked together can be used to aggregate receptors (e.g., TREM2) in a manner similar to antibodies with Fc regions that bind to Fcg receptors, as described above. In some embodiments, if the cross-linked antibody fragment (e.g., Fab fragment) induces receptor aggregation on the cell surface and binds to the appropriate epitope on the target (e.g., TREM2), it can function as an agonist antibody.

[0129] In some embodiments, antibodies binding to TREM2 proteins of the present disclosure may include antibodies that specifically bind to TREM2 due to their epitopes and activate one or more TREM2 activities. In some embodiments, the antibody may bind to a ligand binding site on TREM2 and mimic the effects of one or more TREM2 ligands, or stimulate target antigen transduction signals by binding to one or more domains that are not ligand binding sites. In some embodiments, the antibody does not compete with the ligand for binding to TREM2 or otherwise blocks its binding to TREM2. In some embodiments, the antibody acts additively or synergistically with one or more TREM2 ligands to activate and / or enhance one or more TREM2 activities.

[0130] In some embodiments, TREM2 activities that may be induced and / or enhanced by the anti-TREM2 antibodies of the present disclosure and / or one or more TREM2 ligands of the present disclosure include, but are not limited to, TREM2 binding to DAP12; DAP12 phosphorylation; activation of Syk kinase; modulation of one or more pro-inflammatory mediators selected from the group consisting of IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1 / CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-γ, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23, wherein the modulation may be in one or more the activity of one or more TREM2-dependent genes, wherein the one or more TREM2-dependent genes comprise the nuclear factor of activated T cells (NFAT) transcription factor; the survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells of the skin, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof, is increased; the expression of one or more stimulatory molecules selected from the group consisting of: CD83, class II CD86 MHC, CD40, and any combination thereof, wherein CD40 may be expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and wherein the dendritic cells may comprise bone marrow-derived dendritic cells; increasing memory; and reducing cognitive deficits.

[0131] As used herein, an anti-TREM2 antibody of the present disclosure enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to a TREM2 protein if it induces an increase in one or more TREM2 activities by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, at least 20-fold, or more compared to the extent of the one or more TREM2 activities induced by binding of the one or more TREM2 ligands to the TREM2 protein in the absence of the anti-TREM2 antibody. In some embodiments, an increase in one or more TEM2 activities can be measured by any suitable in vitro cell-based assay or suitable in vivo model described herein or known in the art, for example, by measuring TREM2-dependent gene expression using a luciferase-based reporter assay, measuring TREM2-induced phosphorylation increases of downstream signaling partners (e.g., Syk) using a Western blot assay, or by measuring changes in cell surface levels of TREM2 activation markers using flow cytometry (e.g., fluorescence activated cell sorting (FACS)). Any in vitro cell-based assay or suitable in vivo model described herein or known in the art can be used to measure the interaction (e.g., binding) between TREM2 and one or more TREM2 ligands.

[0132] In some embodiments, when the TREM2 ligand is in its EC 50 If an anti-TREM2 antibody of the present disclosure induces an increase in ligand-induced TREM2-dependent gene transcription by about 1-fold to about 6-fold or more than 6-fold when used at a concentration in the range of about 0.5 nM to about 50 nM or greater than 50 nM, and compared to the extent of TREM2-dependent gene transcription induced by binding of a TREM2 ligand to a TREM2 protein in the absence of the anti-TREM2 antibody, then it enhances one or more TREM2 activities induced by binding of a TREM2 ligand to a TREM2 protein. In some embodiments, when a TREM2 ligand is present at its EC 50In some embodiments, the ligand-induced TREM2-dependent gene transcription is increased by at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 11-fold, at least 12-fold, at least 13-fold, at least 14-fold, at least 15-fold, at least 16-fold, at least 17-fold, at least 18-fold, at least 19-fold, at least 20-fold, or more when used at a concentration in the range of about 0.5 nM to about 50 nM or greater than 50 nM, and compared to the extent of TREM2-dependent gene transcription induced by binding of the TREM2 ligand to the TREM2 protein in the absence of an anti-TREM2 antibody. In some embodiments, anti-TREM2 antibodies are used at a concentration of at least 0.5 nM, at least 0.6 nM, at least 0.7 nM, at least 0.8 nM, at least 0.9 nM, at least 1 nM, at least 2 nM, at least 3 nM, at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, at least 30 nM, at least 35 nM, at least 40 nM, at least 45 nM, at least 46 nM, at least 47 nM, at least 48 nM, at least 49 nM, or at least 50 nM. In some embodiments, the TREM2 ligand is phosphatidylserine (PS). In some embodiments, the TREM2 ligand is sphingomyelin (SM). In some embodiments, the increase in one or more TEM2 activities can be measured by any suitable in vitro cell-based assay or suitable in vivo model described herein or known in the industry. In some embodiments, a luciferase-based reporter gene assay is used to measure the fold increase in ligand-induced TREM2-dependent gene expression in the presence and absence of an antibody.

[0133] As used herein, an anti-TREM2 antibody of the present disclosure does not compete with, inhibit, or otherwise block the interaction (e.g., binding) between one or more TREM2 ligands and TREM2 if it reduces the binding of the ligand to TREM2 by less than 20% using any in vitro assay or cell-based culture assay described herein or known in the art at saturating antibody concentrations. In some embodiments, an anti-TREM2 antibody of the present disclosure inhibits the interaction (e.g., binding) between one or more TREM2 ligands and TREM2 by less than 20%, less than 19%, less than 18%, less than 17%, less than 16%, less than 15%, less than 14%, less than 13%, less than 12%, less than 11%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% using any in vitro assay or cell-based culture assay described herein or known in the art at saturating antibody concentrations.

[0134] In some embodiments, the anti-TREM2 antibodies of the present disclosure induce one or more TREM2 activities. In some embodiments, the antibody induces one or more activities of TREM2 after binding to a TREM2 protein expressed on a cell. In some embodiments, the antibody induces one or more activities of TREM2 after binding to a soluble TREM2 protein that is not bound to a cell membrane. In certain embodiments, TREM2 protein is expressed on the cell surface. In certain embodiments, soluble TREM2 protein (sTREM2) can be found in (but not limited to) the interstitial space in the extracellular environment, serum, cerebrospinal fluid (CSF), and tissue. In certain embodiments, soluble TREM2 protein (sTREM2) is a non-cellular protein. In some embodiments, soluble TREM2 (sTREM2) protein of the present disclosure corresponds to amino acid residues 19-160 of SEQ ID NO: 1. In some embodiments, soluble TREM2 (sTREM2) protein of the present disclosure corresponds to amino acid residues 19-159 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) proteins of the present disclosure correspond to amino acid residues 19-158 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) proteins of the present disclosure correspond to amino acid residues 19-157 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) proteins of the present disclosure correspond to amino acid residues 19-156 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) proteins of the present disclosure correspond to amino acid residues 19-155 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) proteins of the present disclosure correspond to amino acid residues 19-154 of SEQ ID NO: 1.

[0135] In some embodiments, a soluble TREM2 (sTREM2) protein of the present disclosure may be an inactive variant of a cellular TREM2 receptor. In some embodiments, sTREM2 may be present in the periphery, such as in the plasma or in the brain of a subject.

[0136] In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce plasma levels of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce plasma levels of soluble TREM2 in vivo by blocking cleavage, by inhibiting one or more metalloproteinases, or by inducing internalization.

[0137] In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce the plasma levels of soluble TREM2 in vivo by an amount ranging from about 5% to about 50% higher than a human control IgG1 antibody. In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce the plasma levels of soluble TREM2 in vivo by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, At least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49% or at least 50%.

[0138] In some embodiments, the anti-TREM2 antibodies of the present disclosure reduce plasma levels of soluble TREM2 in vivo such that plasma levels of soluble TREM2 as a percentage of baseline 6 days after antibody treatment are at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least %, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80%. In some embodiments, the plasma level of soluble TREM2 in vivo is measured using a monovalent antibody (e.g., Fab) or a full-length antibody in a monovalent form. Methods for measuring the plasma level of soluble TREM2 in vivo are described herein (e.g., see Example 4).

[0139] The anti-TREM2 antibodies of the present disclosure can be used to prevent, reduce the risk of, or treat the following diseases: dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive deficits, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome. syndrome), progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epilepsy, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget's disease of bone, solid and blood cancers, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocythemia, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid neoplasms, tumors expressing TREM2, thyroid cancer, infections, CNS herpes, parasitic infections, trypanosome infections, trypanosoma cruzi infections, Pseudomonas aeruginosa infections, Leishmania donovani infections, group B Streptococcus infections, Campylobacter jejuni infections, Neisseria meningitidis infectionsmeningiditis) infection, type I HIV and Haemophilus influenza. The methods provided herein can also be used to induce or promote the survival, maturation, functionality, migration or proliferation of one or more immune cells in individuals in need. The methods provided herein can be further used to reduce the activity, functionality or survival of regulatory T cells, tumor-embedded immunosuppressive dendritic cells, tumor-embedded immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL) cells or chronic myeloid leukemia (CML) cells in individuals in need. The methods provided herein can be further used to increase memory and / or reduce cognitive deficits.

[0140] The anti-TREM2 antibodies of the present disclosure may also be used for advanced wound care. In some embodiments, the anti-TREM2 antibodies of the present disclosure are monoclonal antibodies. The anti-TREM2 antibodies of the present disclosure may be tested for inducing one or more TREM2 activities. Useful assays may include Western blots (e.g., for tyrosine phosphorylated DAP12 or threonine / serine phosphorylated PI3K-kinase substrates); ELISA (e.g., for secreted interleukins or cytokine secretion); FACS (e.g., for anti-TREM2 binding to TREM2); immunocytochemistry (e.g., for tyrosine phosphorylated DAP12 or threonine / serine phosphorylated PI3K-kinase substrates); reporter gene assays (e.g., for TLR activation); increasing the survival and / or function of dendritic cells, macrophages, monocytes, osteoclasts, Langerhans cells of the skin, Kupffer cells and / or microglia; increasing apoptotic neurons, damaged synapses, amyloid beta or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxia, Lewy bodies, atrial natriuretic factor The invention also provides methods for increasing phagocytosis of tumor cells by macrophages, dendritic cells, Langerhans cells of the skin, Kupffer cells, monocytes, osteoclasts and / or microglia; increasing cytoskeletal reorganization and decreasing the pro-inflammatory response of microglia, or other assays known in the art.

[0141] If an antibody that relies on binding to an FcgR receptor to activate a targeted receptor is engineered to eliminate FcgR binding, it may lose agonist activity (e.g., see Wilson et al., (2011) Cancer Cell 19, 101-113; Armour et al., (2003) Immunology 40 (2003) 585-593); and White et al., (2015) Cancer Cell 27, 138-148). Therefore, when an anti-TREM2 antibody of the present disclosure with the correct epitope specificity has an Fc domain (CH1 and hinge region) from a human IgG2 isotype or another type of Fc domain that is capable of preferentially binding to an inhibitory FcgRIIB r receptor or a variant thereof, it is believed that the antibody can activate the target antigen with minimal adverse effects.

[0142] Exemplary antibody Fc isotypes and modifications are provided below in Table A. In some embodiments, the antibody has an Fc isotype listed in Table A below.

[0143] Table A: Exemplary antibody Fc isotypes capable of binding to Fcγ receptors

[0144]

[0145]

[0146] In addition to the isotypes described in Table A, and without wishing to be bound by theory, it is believed that antibodies with human IgG1 or IgG3 isotypes and mutants thereof that bind to activating Fcg receptors I, IIA, IIC, IIIA, IIIB in humans and / or Fcg receptors I, III and IV in mice (e.g., Strohl (2009) Current Opinion in Biotechnology 2009, 20: 685-691) can also be used as agonist antibodies in vivo, but may be associated with adverse effects associated with ADCC. However, compared to the inhibitory Fcg receptor FcgRIIB, the Fcg receptors appear to be less available for in vivo antibody binding (e.g., see White et al., (2013) Cancer Immunol. Immunother. 62, 941-948; and Li et al., (2011) Science 333(6045): 1030-1034.).

[0147] In some embodiments, the antibody is of IgG class, IgM class, or IgA class. In some embodiments, the antibody has an IgG1, IgG2, IgG3, or IgG4 isotype.

[0148] In certain embodiments, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region includes an Fc region. In some embodiments, the antibody is independent of binding to an Fc receptor to induce one or more TREM2 activities, DAP12 activities, or both. In some embodiments, the antibody binds to inhibitory Fc receptors. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from V234A (Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A (Cole et al., (1999) Transplantation, 68:563-571), H268Q, V309L, A330S, P331S (US2007 / 0148167; Armour et al., (1999) Eur J Immunol 29:2613-2624; Armour et al., (2000) The Haematology Journal 1(Suppl 1):27; Armour et al., (2000) The Haematology Journal 1(Suppl 1):27), C232S and / or C233S (White et al., (2015) Cancer Cell 27, 138-148), S267E, L328F (Chu et al., (2008) Mol Immunol, 45:3926-3933), M252Y, S254T and / or T256E, where the amino acid positions are according to the EU or Kabat numbering convention.

[0149] In some embodiments, the antibody is of the IgG2 isotype with a heavy chain constant domain containing a C127S amino acid substitution, wherein the amino acid positions are according to the EU or Kabat numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0150] In some embodiments, the antibody is of the IgG2 isotype with a kappa light chain constant domain containing a C214S amino acid substitution, wherein the amino acid positions are according to the EU or Kabat numbering convention (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0151] In certain embodiments, the antibody has an IgG1 isotype. In some embodiments, the antibody contains a mouse IgG1 constant region. In some embodiments, the antibody contains a human IgG1 constant region. In some embodiments, the human IgG1 constant region includes an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from N297A (Bolt S et al., (1993) Eur J Immunol 23:403-411), D265A (Shields et al., (2001) RJ Biol. Chem. 276, 6591-6604), L234A, L235A (Hutchins et al., (1995) Proc Natl Acad Sci USA, 92: 11980-11984; Alegre et al., (1994) Transplantation 57: 1537-1543.31; Xu et al., (2000) Cell Immunol, 200: 16-26), G237A (Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchern et al., (2007) Blood, 109:1185-1192), P331S (Sazinsky et al., (2008) Proc Natl Acad Sci USA 2008, 105:20167-20172), S267E, L328F, A330L, M252Y, S254T and / or T256E, wherein the amino acid positions are according to the EU or Kabat numbering convention.

[0152] In some embodiments, the antibody includes an IgG2 isotype heavy chain constant domain 1 (CH1) and a hinge region (White et al., (2015) Cancer Cell 27, 138-148). In certain embodiments, the IgG2 isotype CH1 and hinge region contain the amino acid sequence of ASTKGPSVFPLAPCSRS TSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECP PCP (SEQ ID NO: 145). In some embodiments, the antibody Fc region contains an S267E amino acid substitution, an L328F amino acid substitution, or both and / or an N297A or N297Q amino acid substitution, wherein the amino acid positions are according to the EU or Kabat numbering convention.

[0153] In certain embodiments, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region includes an Fc region. In some embodiments, the antibody binds to an inhibitory Fc receptor. In certain embodiments, the inhibitory Fc receptor is an inhibitory Fc-γ receptor IIB (FcγIIB). In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from L235A, G237A, S228P, L236E (Reddy et al., (2000) J Immunol, 164: 1925-1933), S267E, E318A, L328F, M252Y, S254T and / or T256E, wherein the amino acid position is according to EU or Kabat numbering conventions.

[0154] In certain embodiments, the antibody has a hybrid IgG2 / 4 isotype. In some embodiments, the antibody comprises an amino acid sequence comprising amino acids 118 to 260 according to EU or Kabat numbering of human IgG2 and amino acids 261-447 according to EU or Kabat numbering of human IgG4 (WO 1997 / 11971; WO 2007 / 106585).

[0155] In certain embodiments, the antibody contains a mouse IgG4 constant region (Bartholomaeus et al., (2014). J. Immunol. 192, 2091-2098).

[0156] In some embodiments, the Fc region further contains one or more additional amino acid substitutions selected from the group consisting of A330L, L234F, L235E, or P331S according to EU or Kabat numbering, and any combination thereof.

[0157] In certain embodiments, the antibody contains one or more amino acid replacements at the residue positions selected from the group consisting of C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof in the Fc region, wherein the residue numbering is according to EU or Kabat numbering. In some embodiments, the Fc region contains amino acid replacements at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid replacements at positions E430G and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid replacements at positions E430G and K322A, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, A330S and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A and A330S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A and P331S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions S267E and L328F, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions C127S, wherein the residue position numbering is according to EU numbering. In some embodiments, the Fc region contains amino acid substitutions at positions E345R, E430G, and S440Y, wherein the residue position numbering is according to EU numbering.

[0158] Other IgG mutations

[0159] In some embodiments, one or more of the IgG1 variants described herein may be combined with an A330L mutation (Lazar et al., (2006) Proc Natl Acad Sci USA, 103:4005-4010) or one or more of the L234F, L235E and / or P331S mutations (Sazinsky et al., (2008) Proc Natl Acad Sci USA, 105:20167-20172) to eliminate complement activation, where amino acid positions are according to the EU or Kabat numbering convention. In some embodiments, the IgG variants described herein may be combined with one or more mutations to extend the antibody half-life in human serum (e.g., M252Y, S254T, T256E mutations according to the EU or Kabat numbering convention) (Dall'Acqua et al., (2006) J Biol Chem, 281:23514-23524; and Strohl et al., (2009) Current Opinion in Biotechnology, 20:685-691).

[0160] In some embodiments, the IgG4 variants of the present disclosure may be combined with an S228P mutation according to the EU or Kabat numbering convention (Angal et al., (1993) Mol Immunol, 30: 105-108) and / or with one or more mutations described in Peters et al., (2012) J Biol Chem. 13; 287(29): 24525-33) to enhance antibody stability.

[0161] Exemplary Anti-TREM2 Antibodies

[0162] In some embodiments, the isolated anti-TREM2 antibodies of the present disclosure bind to TREM2 with high affinity and enhance one or more TREM2 activities induced by the binding of one or more TREM2 ligands to TREM2 proteins, compared to one or more TREM2 activities induced by the binding of one or more TREM2 ligands to TREM2 proteins in the absence of the isolated antibody. In some embodiments, the anti-TREM2 antibodies enhance one or more TREM2 activities without competing with one or more TREM2 ligands for binding to TREM2 proteins or otherwise blocking their binding. In some embodiments, the antibody is a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. Exemplary descriptions of the antibodies can be found throughout the present disclosure. In some embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen.

[0163] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to human TREM2 or a homolog thereof, including, but not limited to, mammalian (e.g., non-human mammal) TREM2 proteins, mouse TREM2 proteins (Uniprot Accession No. Q99NH8), rat TREM2 proteins (Uniprot Accession No. D3ZZ89), rhesus monkey TREM2 proteins (Uniprot Accession No. F6QVF2), cynomolgus monkey TREM2 proteins (NCBI Accession No. XP_015304909.1), horse TREM2 proteins (Uniprot Accession No. F7D6L0), pig TREM2 proteins (Uniprot Accession No. H2EZZ3), and dog TREM2 proteins (Uniprot Accession No. E2RP46). In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to human TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to cynomolgus monkey TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure specifically bind to both human TREM2 and cynomolgus monkey TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure induce at least one TREM2 activity of the present disclosure.

[0164] Anti-TREM2 antibody binding region

[0165] Certain aspects of the present disclosure relate to anti-TREM2 antibodies that bind to a human TREM2 epitope that is identical or overlapping with a TREM2 epitope bound by an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to a TREM2 epitope that is substantially identical to that bound by an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues SFEDAHVEH (amino acid residues 149-157 of SEQ ID NO: 1). In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to one or more amino acid residues selected from E151, D152, and E156 of SEQ ID NO: 1. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to amino acid residues E151, D152, and E156 of SEQ ID NO:1.

[0166] In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120 for binding to TREM2.

[0167] In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from any of the antibodies listed in Tables 2A to 2C, 3A to 3C, 4A to 4D, 5A to 5D, 6, and 7. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of at least one antibody selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p- 31. AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL 2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54 , AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-31. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-37. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-47. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-58.In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-60. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-61. In some embodiments, the anti-TREM2 antibodies of the present disclosure competitively inhibit the binding of antibody AL2p-62.

[0168] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical to or overlaps with an epitope of TREM2 bound by at least one antibody selected from any of the antibodies listed in Tables 2A to 2C, 3A to 3C, 4A to 4D, 5A to 5D, 6, and 7. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical to or overlaps with an epitope of TREM2 bound by at least one antibody selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 -17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p- 29. AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p- 41. AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p- 53. AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is the same as or overlaps with the TREM2 epitope bound by antibody AL2p-31.In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical or overlapping with the TREM2 epitope bound by antibody AL2p-37. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical or overlapping with the TREM2 epitope bound by antibody AL2p-47. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical or overlapping with the TREM2 epitope bound by antibody AL2p-58. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical or overlapping with the TREM2 epitope bound by antibody AL2p-60. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to an epitope of human TREM2 that is identical or overlapping with the TREM2 epitope bound by antibody AL2p-61. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to an epitope of human TREM2 that is identical to or overlaps with the TREM2 epitope bound by antibody AL2p-62.

[0169] In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as at least one antibody selected from any of the antibodies listed in Tables 2A to 2C, 3A to 3C, 4A to 4D, 5A to 5D, 6, and 7. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as at least one antibody selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 , AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p- 42. AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2 p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22 , AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76 and AL2p-h90. Detailed exemplary methods for locating epitopes to which antibodies bind are provided in Morris (1996) "Epitope Mapping Protocols", Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-31. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-37. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-47. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-58. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-60. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-61. In some embodiments, the anti-TREM2 antibodies of the present disclosure bind to substantially the same TREM2 epitope as that bound by antibody AL2p-62.

[0170] In some embodiments, the anti-TREM2 antibodies of the present disclosure compete for binding to TREM2 with one or more antibodies selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32 , AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-3 1. AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p -43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2 p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h2 3, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90, and any combination thereof. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-31 for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-37 for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-47 for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-58 for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-60 for binding to TREM2.In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-61 for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present disclosure compete with antibody AL2p-62 for binding to TREM2.

[0171] In an exemplary competition assay, immobilized TREM2 or cells expressing TREM2 on the cell surface are incubated in a solution comprising a first labeled antibody that binds to TREM2 (e.g., human or non-human primate) and a second unlabeled antibody that is being tested for its ability to compete with the first antibody for binding to TREM2. The second antibody may be present in the hybridoma supernatant. As a control, immobilized TREM2 or cells expressing TREM2 are incubated in a solution comprising the first labeled antibody without the second unlabeled antibody. After incubation under conditions that allow the first antibody to bind to TREM2, excess unbound antibody is removed, and the amount of label associated with immobilized TREM2 or cells expressing TREM2 is measured. If the amount of label associated with immobilized TREM2 or cells expressing TREM2 is substantially reduced in the test sample relative to the control sample, this indicates that the second antibody competes with the first antibody for binding to TREM2. See Harlow and Lane (1988) Antibodies: A Laboratory Manual Chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

[0172] Anti-TREM2 antibody light chain and heavy chain variable regions

[0173] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises (a) a heavy chain variable region comprising at least one, two, or three HVRs selected from HVR-H1, HVR-H2, and HVR-H3 of any one of the antibodies listed in Tables 2A to 2C or selected from the following: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38 8. AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39 , AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, A , AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62, and any combination thereof; and / or (b) a light chain variable region comprising at least one, two or three HVRs,The HVRs are selected from HVR-H1, HVR-H2 and HVR-H3 of any one of the antibodies listed in Tables 3A to 3C or selected from AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45 In some embodiments, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62, and any combination thereof.HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprise EU or Kabat HVRs, Chothia HVRs, or Contact HVRs as shown in Tables 2A to 2C, Tables 3A to 3C, Tables 6 and 7, or from an antibody selected from HVR sequences: AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2 p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p- AL2p-32, AL2p-33, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62, and any combination thereof.

[0174] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1, comprising a light chain variable region according to Formula I: 1 X 2 X 3 The sequence of WMNs, where X 1 Is S or W, X 2 is S, L, or R, and X 3 is S, D, H, Q or E (SEQ ID NO: 121); HVR-H2 comprises a residue according to Formula II: RIYPGX 1 GX 2 TNYAX 3 KX 4 X 5 G sequence, where X 1 is D, G, E, Q or V, X 2 It is D or Q, X 3 is Q, R, H, W, Y or G, X4 is F, R, or W, and X 5 is Q, R, K or H (SEQ ID NO: 122); and HVR-H3 comprises a polypeptide according to Formula III: ARLLRNX 1 PGX 2 SYAX 3 DY sequence, where X 1 It is Q or K, X 2 is E, S, or A, and X 3 is M or H (SEQ ID NO: 123), and wherein the antibody is not an antibody comprising a heavy chain variable region comprising: HVR-H1 comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2 comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3 comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126).

[0175] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises: HVR-L1, comprising a heavy chain variable region according to Formula IV: RX 1 SX 2 SLX 3 HSNX 4 The sequence of YTYLH, where X 1 Is S or T, X 2 is Q, R or S, X 3 is V or I, and X 4 is G, R, W, Q or A (SEQ ID NO: 127); HVR-L2 comprises a polypeptide according to Formula V: KVSNRX 1 S sequence, where X 1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3 comprises a sequence according to Formula V: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not an antibody comprising a light chain variable region comprising: HVR-L1 comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2 comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0176] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1 comprising a sequence according to Formula I, wherein X 1 Is S or W, X2 is S, L, or R, and X 3 is S, D, H, Q or E; HVR-H2 comprises a sequence according to Formula II, wherein X 1 is D, G, E, Q or V, X 2 It is D or Q, X 3 is Q, R, H, W, Y or G, X 4 is F, R, or W, and X 5 is Q, R, K or H; and HVR-H3 comprises a sequence according to Formula III, wherein X 1 It is Q or K, X 2 is E, S, or A, and X 3 is M or H, and the light chain variable region comprises: HVR-L1 comprising a sequence according to Formula IV, wherein X 1 Is S or T, X 2 is Q, R or S, X 3 is V or I, and X 4 is G, R, W, Q or A; HVR-L2 comprises a sequence according to Formula V, wherein X 1 is F, R, V or K; and HVR-L3, comprising the sequence: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not the following antibody: comprising a heavy chain variable region comprising: HVR-H1, comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2, comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3, comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126) and comprising a light chain variable region comprising: HVR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

[0177] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises one or more of the following: (a) an HVR-H1 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, at least 120%, at least 121%, at least 122%, at least 123%, at least 124%, at least 125%, at least 126%, at least 127%, at least 128%, at least 129%, at least 130%, at least 131%, at least 132%, at least 133%, at least 134%, at least 135%, at least 136%, at least 137%, at least 138%, at least 139%, at least 140%, at least 141%, An amino acid sequence that is 96%, at least 97%, at least 98%, at least 99% or 100% identical to: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p -20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p- 30. AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-4 2. AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52 , AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62;(b) HVR-H2 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of HVR-H2 of AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p -35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p- 44. AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-5 3. AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62;and (c) HVR-H3 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of HVR-H3 of AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p -35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p- 44. AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-5 3. AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62;and / or wherein the light chain variable domain comprises one or more of: (a) an HVR-L1 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to an HVR-L1 of Unique amino acid sequence: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-2 2. AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL 2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43 , AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2 p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62;(b) HVR-L2 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of HVR-L1 of AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p -35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p- 44. AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-5 3. AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62;and (c) HVR-L3 comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of HVR-L3 of AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p -35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p- 44. AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-5 3. AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62. ;

[0178] In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2 comprising the amino acid sequence of KVSNRRS (SEQ ID NO: 134); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2 comprising the amino acid sequence of KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSDWMN (SEQ ID NO: 136); HVR-H2 comprising the amino acid sequence of RIYPGEGDTNYARKFHG (SEQ ID NO: 137); HVR-H3 comprising the amino acid sequence of ARLLRNKPGESYAMDY (SEQ ID NO: 138), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RTSQSLVHSNAYTYLH (SEQ ID NO: 139); HVR-L2 comprising the amino acid sequence of KVSNRVS (SEQ ID NO: 140); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129).In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGEGDTNYARKFQG (SEQ ID NO: 141); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142); HVR-L2 comprising the amino acid sequence of KVSNRRS (SEQ ID NO: 134); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGEGDTNYAGKFQG (SEQ ID NO: 143); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142); HVR-L2 comprising the amino acid sequence of KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144); HVR-L2 comprising the amino acid sequence of KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129).In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1 comprising the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132); HVR-H2 comprising the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133); HVR-H3 comprising the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1 comprising the amino acid sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144); HVR-L2 comprising the amino acid sequence of KVSNRRS (SEQ ID NO: 134); and HVR-L3 comprising the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129). In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one, two, three or four framework regions selected from VH FR1, VH FR2, VH FR3 and VH FR4, wherein: the VH FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 9-11, the VH FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 12 and 13, the VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and the VH FR4 comprises the sequence SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, wherein: the L FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 17-20, the VL FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, the VL FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: NO:23 and 24, and the VLFR4 comprises a sequence selected from the group consisting of SEQ ID NO:25 and 26.

[0179] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable region of any one of the antibodies listed in Table 6A or selected from the group consisting of: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35 2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-4 2. AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p -54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90;and / or a light chain variable region of any of the antibodies listed in Table 7A or selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-34, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42 L2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p- 32. AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p -55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p- In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a heavy chain variable region comprising an amino acid sequence selected from any one of SEQ ID NOs: 27-71 and 91; and / or a light chain variable domain comprising an amino acid sequence selected from any one of SEQ ID NOs: 92-113 and 118. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from any one of SEQ ID NOs: 27, 56, and 72-90; and / or a light chain variable domain comprising an amino acid sequence selected from any one of SEQ ID NOs: 92, 104, and 114-117. ;

[0180] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO: 28; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO: NO:92 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-2, or to the amino acid sequence of SEQ ID NO:28, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-2. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-2, or to the amino acid sequence of SEQ ID NO:92, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-2.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence of SEQ ID NO: 28 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence of SEQ ID NO: 28. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence SEQ ID NO: 28. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-2 or SEQ ID NO: 28, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-2, (b) the HVR-H2 amino acid sequence of antibody AL2p-2, and (c) the HVR-H3 amino acid sequence of antibody AL2p-2. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO: 92 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence of SEQ ID NO:92.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-2 or SEQ ID NO: 92, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody AL2p-2, (b) the HVR-L2 amino acid sequence of antibody AL2p-2, and (c) the HVR-L3 amino acid sequence of antibody AL2p-2.

[0181] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO: 29; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO: NO:92 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:29, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-3. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:92, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-3.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence of SEQ ID NO: 29 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence of SEQ ID NO: 29. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence SEQ ID NO: 29. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-3 or SEQ ID NO: 29, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-3, (b) the HVR-H2 amino acid sequence of antibody AL2p-3, and (c) the HVR-H3 amino acid sequence of antibody AL2p-3. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO: 92 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence of SEQ ID NO:92.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-3 or SEQ ID NO: 92, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-3, (b) the HVR-L2 amino acid sequence of antibody AL2p-3, and (c) the HVR-L3 amino acid sequence of antibody AL2p-3.

[0182] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:30; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:30. NO:92 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-4, or to the amino acid sequence of SEQ ID NO:30, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-4. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-4, or to the amino acid sequence of SEQ ID NO:92, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-4.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence of SEQ ID NO: 30 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence of SEQ ID NO: 30. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence SEQ ID NO: 30. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-4 or SEQ ID NO: 30, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-4, (b) the HVR-H2 amino acid sequence of antibody AL2p-4, and (c) the HVR-H3 amino acid sequence of antibody AL2p-4. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO: 92 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence of SEQ ID NO:92.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-4 or SEQ ID NO: 92, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody AL2p-4, (b) the HVR-L2 amino acid sequence of antibody AL2p-4, and (c) the HVR-L3 amino acid sequence of antibody AL2p-4.

[0183] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:31; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO: NO:95 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-7, or to the amino acid sequence of SEQ ID NO:31, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-7. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:95, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-7.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO: 31 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence of SEQ ID NO: 31. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence SEQ ID NO: 31. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-7 or SEQ ID NO: 31, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-7, (b) the HVR-H2 amino acid sequence of antibody AL2p-7, and (c) the HVR-H3 amino acid sequence of antibody AL2p-7. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO: 95 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence of SEQ ID NO: 95. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence of SEQ ID NO:95.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-7 or SEQ ID NO: 95, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-7, (b) the HVR-L2 amino acid sequence of antibody AL2p-7, and (c) the HVR-L3 amino acid sequence of antibody AL2p-7.

[0184] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO: 32; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO: NO:95 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:32, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-8. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:95, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-8.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO: 32 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO: 32. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO: 32. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-8 or SEQ ID NO: 32, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-8, (b) the HVR-H2 amino acid sequence of antibody AL2p-8, and (c) the HVR-H3 amino acid sequence of antibody AL2p-8. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO: 95 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO: 95. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO:95.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-8 or SEQ ID NO: 95, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-8, (b) the HVR-L2 amino acid sequence of antibody AL2p-8, and (c) the HVR-L3 amino acid sequence of antibody AL2p-8.

[0185] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO: 33; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO: NO:96 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-9, or to the amino acid sequence of SEQ ID NO:33, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-9. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO:96, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-9.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence of SEQ ID NO: 33 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence of SEQ ID NO: 33. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence SEQ ID NO: 33. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-9 or SEQ ID NO: 33, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-9, (b) the HVR-H2 amino acid sequence of antibody AL2p-9, and (c) the HVR-H3 amino acid sequence of antibody AL2p-9. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO: 96 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence of SEQ ID NO: 96. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence of SEQ ID NO:96.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-9 or SEQ ID NO: 96, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-9, (b) the HVR-L2 amino acid sequence of antibody AL2p-9, and (c) the HVR-L3 amino acid sequence of antibody AL2p-9.

[0186] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO:34; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO: NO:97 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-10, or to the amino acid sequence of SEQ ID NO:34, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-10. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-10, or to the amino acid sequence of SEQ ID NO:97, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-10.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence of SEQ ID NO: 34 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence of SEQ ID NO: 34. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence SEQ ID NO: 34. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-10 or SEQ ID NO: 34, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-10, (b) the HVR-H2 amino acid sequence of antibody AL2p-10, and (c) the HVR-H3 amino acid sequence of antibody AL2p-10. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO: 97 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence of SEQ ID NO: 97. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence of SEQ ID NO:97.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-10 or SEQ ID NO: 97, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-10, (b) the HVR-L2 amino acid sequence of antibody AL2p-10, and (c) the HVR-L3 amino acid sequence of antibody AL2p-10.

[0187] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:35; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO: NO:98 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:35, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-11. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:98, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-11.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence of SEQ ID NO: 35 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence of SEQ ID NO: 35. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence SEQ ID NO: 35. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-11 or SEQ ID NO: 35, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-11, (b) the HVR-H2 amino acid sequence of antibody AL2p-11, and (c) the HVR-H3 amino acid sequence of antibody AL2p-11. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO: 98 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence of SEQ ID NO: 98. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence of SEQ ID NO:98.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-11 or SEQ ID NO: 98, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-11, (b) the HVR-L2 amino acid sequence of antibody AL2p-11, and (c) the HVR-L3 amino acid sequence of antibody AL2p-11.

[0188] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:36; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:36. NO:97 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of the heavy chain variable domain of antibody AL2p-12, or to the amino acid sequence of SEQ ID NO:36, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-12. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:97, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-12.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence of SEQ ID NO: 36 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence of SEQ ID NO: 36. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence SEQ ID NO: 36. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-12 or SEQ ID NO: 36, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-12, (b) the HVR-H2 amino acid sequence of antibody AL2p-12, and (c) the HVR-H3 amino acid sequence of antibody AL2p-12. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO: 97 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence of SEQ ID NO: 97. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence of SEQ ID NO:97.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-12 or SEQ ID NO: 97, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-12, (b) the HVR-L2 amino acid sequence of antibody AL2p-12, and (c) the HVR-L3 amino acid sequence of antibody AL2p-12.

[0189] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO: 37; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO: NO:95 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-13, or to the amino acid sequence of SEQ ID NO:37, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-13. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO:95, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-13.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence of SEQ ID NO: 37 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence of SEQ ID NO: 37. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence SEQ ID NO: 37. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-13 or SEQ ID NO: 37, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-13, (b) the HVR-H2 amino acid sequence of antibody AL2p-13, and (c) the HVR-H3 amino acid sequence of antibody AL2p-13. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO: 95 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence of SEQ ID NO: 95. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence of SEQ ID NO:95.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-13 or SEQ ID NO: 95, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-13, (b) the HVR-L2 amino acid sequence of antibody AL2p-13, and (c) the HVR-L3 amino acid sequence of antibody AL2p-13.

[0190] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:38. NO:99 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-14, or to the amino acid sequence of SEQ ID NO:38, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-14. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-14, or to the amino acid sequence of SEQ ID NO:99, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-14.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence of SEQ ID NO: 38 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence of SEQ ID NO: 38. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence SEQ ID NO: 38. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-14 or SEQ ID NO: 38, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-14, (b) the HVR-H2 amino acid sequence of antibody AL2p-14, and (c) the HVR-H3 amino acid sequence of antibody AL2p-14. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO: 99 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence of SEQ ID NO: 99. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence of SEQ ID NO:99.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-14 or SEQ ID NO: 99, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-14, (b) the HVR-L2 amino acid sequence of antibody AL2p-14, and (c) the HVR-L3 amino acid sequence of antibody AL2p-14.

[0191] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO: NO:100 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-15, or to the amino acid sequence of SEQ ID NO:38, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-15. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO: 100, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-15.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence of SEQ ID NO: 38 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence of SEQ ID NO: 38. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence SEQ ID NO: 38. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-15 or SEQ ID NO: 38, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-15, (b) the HVR-H2 amino acid sequence of antibody AL2p-15, and (c) the HVR-H3 amino acid sequence of antibody AL2p-15. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO: 100 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence of SEQ ID NO: 100. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence of SEQ ID NO: 100.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-15 or SEQ ID NO: 100, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-15, (b) the HVR-L2 amino acid sequence of antibody AL2p-15, and (c) the HVR-L3 amino acid sequence of antibody AL2p-15.

[0192] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO:39; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO: NO:96 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-16, or to the amino acid sequence of SEQ ID NO:39, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-16. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-16, or to the amino acid sequence of SEQ ID NO:96, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-16.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence of SEQ ID NO: 39 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence of SEQ ID NO: 39. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence SEQ ID NO: 39. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-16 or SEQ ID NO: 39, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-16, (b) the HVR-H2 amino acid sequence of antibody AL2p-16, and (c) the HVR-H3 amino acid sequence of antibody AL2p-16. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO: 96 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibodies comprising the sequence retain the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence of SEQ ID NO: 96. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the light chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence of SEQ ID NO:96.In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-16 or SEQ ID NO: 96, including post-translational modifications of the sequence. In specific embodiments, the VL comprises one, two or three HVRs selected from the following: (a) the HVR-L1 amino acid sequence of antibody AL2p-16, (b) the HVR-L2 amino acid sequence of antibody AL2p-16, and (c) the HVR-L3 amino acid sequence of antibody AL2p-16.

[0193] In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:40; and / or the light chain variable domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:40. NO:98 has an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a heavy chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-17, or to the amino acid sequence of SEQ ID NO:40, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-17. In some embodiments, an anti-TREM2 antibody of the present disclosure comprises a light chain variable domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid sequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:98, wherein the light chain variable domain comprises HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-17.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the heavy chain variable domain amino acid sequence of antibody AL2p-17 or the amino acid sequence of SEQ ID NO: 40 and contains substitutions (e.g., conservative substitutions, insertions, or deletions relative to the reference sequence), but the anti-TREM2 antibody comprising the sequence retains the ability to bind to TREM2. In certain embodiments, a total of 1 to 10 amino acids are substituted, inserted, and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-17 or the amino acid sequence of SEQ ID NO: 40. In certain embodiments, a total of 1 to 5 amino acids are substituted, inserted and / or deleted in the heavy chain variable domain amino acid sequence of antibody AL2p-17 or the amino acid sequence SEQ ID NO: 40. In certain embodiments, the substitution, insertion or deletion occurs in a region outside the HVR (ie, in the FR region). In some embodiments, the substitution, insertion or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VH sequence of antibody AL2p-17 or SEQ ID NO: 40, including post-translational modifications of the sequence. In specific embodiments, the VH comprises one, two or three HVRs selected from the following: (a) the HVR-H1 amino acid sequence of antibody AL2p-17, (b) the HVR-H2 amino acid sequence of antibody AL2p-17, and (c) the HVR-H3 amino acid sequence of antibody AL2p-17. In some embodiments, the anti-TREM2 antibodies of the present disclosure comprise a light chain variable domain (VL) sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the light chain variable domain amino acid se...

Claims

1. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1, comprising a sequence according to Formula I: YAFX1X2X3WMN, wherein X1 is S or W, X2 is S, L or R, and X3 is S, D, H, Q or E (SEQ ID NO: 121); HVR-H2, comprising a sequence according to Formula II: RIYPGX1GX2TNYAX3KX4X5G, wherein X1 is D, G, E, Q or V, X2 is D or Q, X3 is Q, R, H, W, Y or G, X4 is F, R or W, and X5 is Q, R, K or H (SEQ ID NO: 122); and HVR-H3, comprising a sequence according to Formula III: ARLLRNX1PGX2SYAX3DY, wherein X1 is Q or K, X2 is E, S or A, and X3 is M or H (SEQ ID NO: 123), and wherein the antibody is not an antibody comprising a heavy chain variable region comprising: HVR-H1 comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2 comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3 comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126).

2. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises: HVR-L1, comprising a sequence according to Formula IV: RX1SX2SLX3HSNX4YTYLH, wherein X1 is S or T, X2 is Q, R or S, X3 is V or I, and X4 is G, R, W, Q or A (SEQ ID NO: 127); HVR-L2, comprising a sequence according to Formula V: KVSNRX1S, wherein X1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3, comprising a sequence according to Formula V: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not an antibody comprising a light chain variable region comprising: HVR-L1 comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2 comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

3. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises: HVR-H1, comprising a sequence according to Formula I: YAFX1X2X3WMN, wherein X1 is S or W, X2 is S, L or R, and X3 is S, D, H, Q or E (SEQ ID NO: 121); HVR-H2, comprising a sequence according to Formula II: RIYPGX1GX2TNYAX3KX4X5G, wherein X1 is D, G, E, Q or V, X2 is D or Q, X3 is Q, R, H, W, Y or G, X4 is F, R or W, and X5 is Q, R, K or H (SEQ ID NO: 122); and HVR-H3, comprising a sequence according to Formula III: ARLLRNX1PGX2SYAX3DY, wherein X1 is Q or K, X2 is E, S or A, and X3 is M or H (SEQ ID NO: 123), and The light chain variable region comprises: HVR-L1, comprising a sequence according to Formula IV: RX1SX2SLX3HSNX4YTYLH, wherein X1 is S or T, X2 is Q, R or S, X3 is V or I, and X4 is G, R, W, Q or A (SEQ ID NO: 127); HVR-L2, comprising a sequence according to Formula V: KVSNRX1S, wherein X1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3, comprising the sequence: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is not an antibody comprising a heavy chain variable region comprising: HVR-H1 comprising the sequence YAFSSSWMN (SEQ ID NO: 124); HVR-H2 comprising the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO: 125); and HVR-H3 comprising the sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and comprising a light chain variable region comprising: HVR-L1 comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2 comprising the sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3 comprising the sequence SQSTRVPYT (SEQ ID NO: 129).

4. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 of the following antibodies: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2 p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-4 7. AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, A L2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 2A to Table 2C).

5. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises HVR-L1, HVR-L2, and HVR-L3 of the following antibodies: AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (as shown in Tables 3A to 3C).

6. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HVR-H1, HVR-H2, and HVR-H3 of the following antibodies: AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2 p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-4 7. AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, A L2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 2A to Table 2C);and the light chain variable region comprises HVR-L1, HVR-L2 and HVR-L3 of the following antibodies: AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30 , AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (as shown in Tables 3A to 3C). ; 7. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2, and HVR-H3 and a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein the antibody comprises HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 of the following antibodies: AL2p-2, AL2p-3, AL2p- 4. AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL 2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, A L2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45 , AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61 or AL2p-62 (as shown in Tables 2A to 2C and Tables 3A to 3C).

8. The antibody of any one of claims 1 to 7, wherein the heavy chain variable region comprises one, two, three or four framework regions selected from VH FR1, VH FR2, VH FR3 and VH FR4, wherein: The VH FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 9-11, The VH FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 12 and 13, The VH FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and The VH FR4 comprises the sequence SEQ ID NO: 16; and / or The light chain variable region comprises one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, wherein: The VL FR1 comprises a sequence selected from the group consisting of SEQ ID NOs: 17-20, The VL FR2 comprises a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, The VL FR3 comprises a sequence selected from the group consisting of SEQ ID NOs: 23 and 24, and The VL FR4 comprises a sequence selected from the group consisting of SEQ ID NOs: 25 and 26.

9. The antibody according to any one of claims 1 to 8, wherein: (a) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNGYTYLH (SEQ ID NO: 130), the HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (b) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNGYTYLH (SEQ ID NO: 130), the HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (c) the HVR-H1 comprises the amino acid sequence of YAFSSDWMN (SEQ ID NO: 136), the HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYARKFHG (SEQ ID NO: 137), the HVR-H3 comprises the amino acid sequence of ARLLRNKPGESYAMDY (SEQ ID NO: 138), the HVR-L1 comprises the amino acid sequence of RTSQSLV HSNAYTYLH (SEQ ID NO: 139), the HVR-L2 comprises the amino acid sequence of KVSNRVS (SEQ ID NO: 140), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (d) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYARKFQG (SEQ ID NO: 141), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNQYTYLH (SEQ ID NO: 142), the HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (e) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGEGDTNYAGKFQG (SEQ ID NO: 143), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNQYTYLH (SEQ ID NO: 142), the HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); (f) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNRYTYLH (SEQ ID NO: 144), the HVR-L2 comprises the amino acid sequence of KVSNRFS (SEQ ID NO: 131), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129); or (g) the HVR-H1 comprises the amino acid sequence of YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequence of RIYPGGGDTNYARKFQG (SEQ ID NO: 133), the HVR-H3 comprises the amino acid sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acid sequence of RSSQSL VHSNRYTYLH (SEQ ID NO: 144), the HVR-L2 comprises the amino acid sequence of KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprises the amino acid sequence of SQSTRVPYT (SEQ ID NO: 129).

10. An antibody that binds to a TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-71 and 91; and / or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-113 and 118.

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