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 filed on August 2, 2018, with Chinese application number 201880027792.8 and entitled "Anti-TREM2 antibody and method of using the same".

[0002] Cross-references to related applications

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

[0004] Submission of sequence lists on ASCII text files

[0005] The following ASCII text file contains the following content, which is incorporated herein by full reference: Sequence List in Computer-Readable Form (CRF) (File name: 735022001840SEQLIST.TXT, Record date: August 2, 2018, Size: 238KB). Invention Field

[0006] This disclosure relates to anti-TREM2 antibodies and their therapeutic use. Background of the Invention

[0008] Trigger receptor (TREM2) expressed on bone marrow cells-2 is an immunoglobulin-like receptor expressed on, for example, bone marrow lineage cells.

[0009] TREM2 activity is associated with diseases, conditions, and symptoms, 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., Neurootherapeutics. November 18, 2014; 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) J AMANeurol 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, conditions, and symptoms associated with reduced TREM2 activity.

[0011] All references cited in this article (including patent applications and publications) are incorporated herein by full citation. Summary of the Invention

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

[0013] Certain aspects of this 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 increased affinity. In some embodiments, the anti-TREM2 antibody of this disclosure binds to both human and cynomolgus monkey TREM2 with at least about 1 times higher affinity than anti-TREM2 antibodies selected from: anti-TREM2 antibodies comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and a light chain variable region containing the amino acid sequence SEQ ID NO:56 (e.g., antibody AL2p-h50); anti-TREM2 antibodies comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and a light chain variable region containing the amino acid sequence SEQ ID NO:103 (e.g., antibody AL2p-h77); and anti-TREM2 antibodies comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:119 and a light chain variable region containing the amino acid sequence SEQ ID NO:120 (e.g., antibody AL2). In some embodiments, the anti-TREM2 antibody of this disclosure binds to primary human immune cells with an affinity at least about 10 times higher than that of anti-TREM2 antibodies selected from: an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:27 and a light chain variable region containing amino acid sequence SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:91 and a light chain variable region containing amino acid sequence SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:119 and a light chain variable region containing amino acid sequence SEQ ID NO:120. In some embodiments, the anti-TREM2 antibody of this disclosure aggregates in an amount at least about 1 times larger than that of anti-TREM2 antibodies selected from the following: an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:27 and a light chain variable region containing amino acid sequence SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:91 and a light chain variable region containing amino acid sequence SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:119 and a light chain variable region containing amino acid sequence SEQ ID NO:120.In some embodiments, the anti-TREM2 antibody of this disclosure increases the survival of in vitro immune cells to a greater extent than anti-TREM2 antibodies selected from: anti-TREM2 antibodies comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:27 and a light chain variable region containing amino acid sequence SEQ ID NO:56; anti-TREM2 antibodies comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:91 and a light chain variable region containing amino acid sequence SEQ ID NO:103; and anti-TREM2 antibodies comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:119 and a light chain variable region containing amino acid sequence SEQ ID NO:120. In some embodiments, the anti-TREM2 antibody of this disclosure may also have a modified in vivo half-life. In some embodiments, the anti-TREM2 antibody of this disclosure may also reduce the plasma level of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibody of this disclosure may also reduce soluble TREM2. In some implementations, the soluble TREM2 is reduced by approximately 10%, 20%, 30%, 40%, 50%, or 60%.

[0014] Therefore, certain aspects of this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising: 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: 121). HVR-H1, comprising the 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 said antibody is not an antibody comprising a heavy chain variable region containing the following: 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 this disclosure relate to antibodies binding to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said light chain variable region comprising: HVR-L1, comprising the 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 the sequence according to formula V: KVSNRX1S, wherein X1 is F, R, V or K (SEQ ID NO: 128); and HVR-L3, comprising the sequence according to formula V: SQSTRVPYT (SEQ ID NO: 129), and said antibody is not an antibody comprising a light chain variable region containing: HVR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 129). NO:131); and HVR-L3, which contains the sequence SQSTRVPYT (SEQ ID NO:129).Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising: 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: 121). NO:122); and HVR-H3, comprising the 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 the 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 the 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:123). NO:129), and the antibody described herein is not an antibody comprising a heavy chain variable region containing the following: 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 containing the following: 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 this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising: HVR-H1, comprising a sequence selected from the group consisting of SEQ ID NO: 132 and 136; HVR-H2, comprising a sequence selected from the group consisting of SEQ ID NO: 133, 135, 137 and 141; and HVR-H3, comprising a sequence selected from the group consisting of SEQ ID NO: 126 and 138; and / or said light chain variable region comprising: 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 NO: 131, 134 and 140; and HVR-L3, comprising a sequence consisting of SEQ ID NO: 129. Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising: HVR-H1, comprising the sequence of SEQ ID No: 132; HVR-H2, comprising the sequence selected from the group consisting of SEQ ID NO: 133, 135 and 141; and HVR-H3, comprising the sequence of SEQ ID No: 126; and / or said light chain variable region comprising: HVR-L1, comprising the sequence selected from the group consisting of 130, 142 and 144; HVR-L2, comprising the sequence selected from the group consisting of SEQ ID NO: 131 and 134; and HVR-L3, comprising the sequence of SEQ ID NO: 129.

[0016] Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region, said heavy chain variable region comprising 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, 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 this disclosure relate to antibodies that bind to the TREM2 protein, said antibody comprising a heavy chain variable region and a light chain variable region.The light chain variable region comprises the 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, and AL2p-3. 0, 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). Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein, wherein said antibody comprises a heavy chain variable region and a light chain variable region.The heavy chain variable region comprises the 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, 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 (As shown in Tables 2A to 2C); and the light chain variable region comprises the following antibodies HVR-L1, HVR-L2, and HVR-L3: 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, A L2p-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). Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein.The antibody comprises heavy chain variable regions containing HVR-H1, HVR-H2, and HVR-H3 and light chain variable regions containing 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, 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 can be combined with any of the foregoing embodiments, the heavy chain variable region comprises one, two, three, or four frame regions selected from VH FR1, VH FR2, VH FR3, and VH FR4, wherein: VH FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 9-11, VH FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 12 and 13, VH FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 14 and 15, and VH FR4 comprises the sequence SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three, or four frame regions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein: VL FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 21 and 22, and VL FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three, or four frame regions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein: VL FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 21 and 22, and VL FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 16; and VH FR4 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20. The sequence comprises the group consisting of SEQ ID NO:23 and 24, and the VL FR4 comprises the sequence selected from the group consisting of SEQ ID NO:25 and 26. In some embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing 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, 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 can be combined with any of the foregoing embodiments: (a) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 contains the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 contains the amino acid sequence KVSNRRS (SEQ ID NO: 134), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 132).(a) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 contains the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 129); (b) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137), and HVR-H3 contains the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 129). HVR-L1 contains the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO:138), HVR-L2 contains the amino acid sequence KVSNRVS (SEQ ID NO:140), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129); (d) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFQG (SEQ ID NO:141), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO:142), HVR-L2 contains the amino acid sequence KVSNRRS (SEQ ID NO:134), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:138). (e) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGEGDTNYAGKFQG (SEQ ID NO:143), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO:142), and HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:129).(f) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO:135), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-H1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129); or (g) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO:135), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-H1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129); or (g) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO:135), and HVR-H3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129); HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 contains the amino acid sequence KVSNRRS (SEQ ID NO:134), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129). In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 contains the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 contains the amino acid sequence KVSNRRS (SEQ ID NO: 134), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments that can be combined with any of the foregoing 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: 135).HVR-L1 contains the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO:130), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129). In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), HVR-H2 contains the amino acid sequence RIYPG EGDTNYARKFHG (SEQ ID NO: 137), HVR-H3 contains the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 138), HVR-L1 contains the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139), HVR-L2 contains the amino acid sequence KVSNRVS (SEQ ID NO: 140), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARK FQG (SEQ ID NO:141), HVR-H3 contains the amino acid sequence ARLLRNQPGE SYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLV HSNQYTYLH (SEQ ID NO:142), HVR-L2 contains the amino acid sequence KVSN RRS (SEQ ID NO:134), and HVR-L3 contains the amino acid sequence SQSTRVP YT (SEQ ID NO:129). In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGEGDTNYAGKFQG (SEQ ID NO: 143), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 contains the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 132).In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO:135), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129). In some embodiments that can be combined with any of the foregoing embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), HVR-L1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), HVR-L2 contains the amino acid sequence KVSNRRS (SEQ ID NO: 134), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO:132), HVR-H2 contains the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO:135), HVR-H3 contains the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO:126), HVR-L1 contains the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO:144), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO:131), and HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO:129).

[0018] Other aspects of this disclosure relate to antibodies that bind to the 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 this disclosure relate to antibodies that bind to the 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 SDWMN (SEQ ID NO: 196); CDR-H2, comprising the sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137); and CDR-H3, comprising the sequence LLRNKPGESYAMDY (SEQ ID NO: 197). In some embodiments, the light chain variable region comprises: CDR-L1, comprising the sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139); CDR-L2, comprising the sequence 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, containing the sequence SDWMN (SEQ ID NO: 196); CDR-H2, containing the sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137); and CDR-H3, containing the sequence LLRNKPGESYAMDY (SEQ ID NO: 197); and the light chain variable region comprises: CDR-L1, containing the sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139); CDR-L2, containing the sequence KVSNRVS (SEQ ID NO: 140); and CDR-L3, containing the sequence SQSTRVPYT (SEQ ID NO: 129).

[0020] Other aspects of this disclosure relate to antibodies that bind to the 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 this disclosure relate to antibodies that bind to the 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 this disclosure relate to antibodies that bind to the 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 this disclosure relate to antibodies that bind to the TREM2 protein, wherein 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, 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, AL2... 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-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, 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 contains the amino acid sequence SEQ ID NO:53, and / or the light chain variable region contains the amino acid sequence SEQ ID NO:97; (b) the heavy chain variable region contains the amino acid sequence SEQ ID NO:59; and / or the light chain variable region contains the amino acid sequence SEQ ID NO:104; (c) the heavy chain variable region contains the amino acid sequence SEQ ID NO:64; and / or the light chain variable region contains the amino acid sequence SEQ ID NO:108; (d) the heavy chain variable region contains the amino acid sequence SEQ ID NO:70; and / or the light chain variable region contains the amino acid sequence SEQ ID NO:110; (e) the heavy chain variable region contains the amino acid sequence SEQ ID NO:71; and / or the light chain variable region contains the amino acid sequence SEQ ID NO:111; (f) the heavy chain variable region contains the amino acid sequence SEQ ID NO:59; and / or the light chain variable region contains the amino acid sequence SEQ ID NO:112; or (g) the heavy chain variable region contains the amino acid sequence SEQ ID NO:53;And / or the light chain variable region contains the amino acid sequence SEQ ID NO:113. In some embodiments, the antibody contains an Fc region containing an amino acid sequence selected from the group consisting of SEQ ID NO:146-156. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:146. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:147. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:148. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:149. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:150. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:151. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:152. In some embodiments, the antibody contains an Fc region containing the amino acid sequence SEQ ID NO:153. In some embodiments, the antibody comprises an Fc region containing the amino acid sequence SEQ ID NO:154. In some embodiments, the antibody comprises an Fc region containing the amino acid sequence SEQ ID NO:155. In some embodiments, the antibody comprises an Fc region containing the amino acid sequence SEQ ID NO:156. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:198-213; and / or a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:214-218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:198 and 199; and a light chain containing the amino acid sequence SEQ ID NO:214. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:200 and 201; and a light chain containing the amino acid sequence SEQ ID NO:214. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 202 and 203; and a light chain containing the amino acid sequence SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 204 and 205;The antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:215. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:206 and 207; and a light chain containing an amino acid sequence selected from SEQ ID NO:216. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:208 and 209; and a light chain containing an amino acid sequence selected from SEQ ID NO:218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:210 and 211; and a light chain containing an amino acid sequence selected from SEQ ID NO:218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:212 and 213; and a light chain containing an amino acid sequence selected from SEQ ID NO:217.

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

[0025] Other aspects of this disclosure relate to antibodies that bind to the TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NO: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 NO:92, 104, and 114-117. In some embodiments, the antibody comprises the heavy chain variable region of the following antibodies: 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). (as shown); and / or the antibody comprises the light chain variable region of the following antibodies: 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 this disclosure relate to antibodies that bind to the TREM2 protein, wherein said antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:198-213; and / or a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:214-218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:198 and 199; and a light chain containing the amino acid sequence SEQ ID NO:214. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:200 and 201; and a light chain containing the amino acid sequence SEQ ID NO:214. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:202 and 203; and a light chain containing the amino acid sequence SEQ ID NO:215. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 204 and 205; and a light chain containing the amino acid sequence SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 206 and 207; and a light chain containing the amino acid sequence SEQ ID NO: 216. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 208 and 209; and a light chain containing the amino acid sequence SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 210 and 211; and a light chain containing the amino acid sequence SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO:212 and 213; and a light chain containing the amino acid sequence SEQ ID NO:217.

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

[0028] In some embodiments that can be combined with any of the foregoing embodiments, the TREM2 protein is a human protein. In some embodiments that can be combined with any of the foregoing embodiments, the TREM2 protein is a wild-type protein. In some embodiments that can be combined with any of the foregoing embodiments, the TREM2 protein is a natural variant. In some embodiments that can be combined with any of the foregoing embodiments, the antibody is an antibody fragment binding to one or more human proteins selected from the group consisting of: human TREM2, a natural variant of human TREM2, and a disease variant of human TREM2, and optionally wherein said 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, a natural variant of human TREM2, and a disease variant of human TREM2. In some embodiments that can be combined with any of the foregoing 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 foregoing embodiments, the antibody is a monoclonal antibody. In some embodiments that can be combined with any of the foregoing embodiments, the antibody is a humanized antibody.

[0029] In some embodiments that can be combined with any of the foregoing 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; or (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-associated proteins 1 and 2 (LPR-1 and LPR-2), diphtheria toxin receptor CRM197, and vicuña single-domain antibody TMEM. 30(A) Protein transduction domains TAT, Syn-B, penetratin, polyarginine peptide, angiopeptide, and ANG1005; (c) Pathogenic agents selected from the group consisting of pathogenic peptides, proteins, or pathogenic nucleic acids, wherein the pathogenic nucleic acid is an antisense GGCCCC (G2C4) repeat amplified RNA, and the pathogenic protein is selected from the group consisting of: amyloid β, oligoamyl β, amyloid β plaques, amyloid precursor proteins 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 diuretic natriuretic factor, pancreatic amyloid peptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, β2 microglobulin, coagulant, keratoepithelialin, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation products, dipeptide repeat (DPR) peptide, glycine-alanine (GA) repeat peptide, glycine-proline (GP) repeat peptide, glycine-arginine (GR) repeat peptide, proline-alanine (PA) repeat peptide, ubiquitin, and proline-arginine (PR) repeat peptide;(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) one or more proteins, lipids, polysaccharides, or glycolipids expressed on tumor cells. In some embodiments that can be combined with any of the foregoing embodiments, the antibody specifically binds to both human TREM2 and cynomolgus monkey TREM2. In some embodiments that can be combined with any of the foregoing embodiments, the dissociation constant (K) of the antibody for human TREM2 and / or cynomolgus monkey TREM2 is specified. D The antibody exhibits at least 1-fold lower dissociation constant (K0) than an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:27 and a light chain variable region containing amino acid sequence SEQ ID NO:56; or at least 1-fold lower dissociation constant than an anti-TREM2 antibody comprising a heavy chain variable region containing amino acid sequence SEQ ID NO:91 and a light chain variable region containing amino acid sequence SEQ ID NO:103. In some embodiments that can be combined with any of the foregoing embodiments, the antibody exhibits a dissociation constant (K0) for human TREM2. D ) is in the range of approximately 9 μM to approximately 100 pM or less than 100 pM, where K D The determination was made at a temperature of approximately 25°C. In some embodiments that can be combined with any of the foregoing embodiments, the dissociation constant (K2) of the antibody against cynomolgus monkey TREM2 is... D ) is in the range of approximately 50 nM to approximately 100 pM or less than 100 pM, where K DThe determination was performed at a temperature of approximately 25°C. In some embodiments that can be combined with any of the foregoing embodiments, the antibody binds to primary human immune cells with an affinity at least 10 times greater than that of an anti-TREM2 antibody containing the heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and the light chain variable region containing the amino acid sequence SEQ ID NO:56; or at least 10 times greater than that of an anti-TREM2 antibody containing the heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and the light chain variable region containing the amino acid sequence SEQ ID NO:103. In some embodiments that can be combined with any of the foregoing embodiments, the antibody aggregates and activates TREM2 signaling in an amount at least 1 times greater than that of an anti-TREM2 antibody containing the heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and the light chain variable region containing the amino acid sequence SEQ ID NO:56; or at least 1 times greater than that of an anti-TREM2 antibody containing the heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and the light chain variable region containing the amino acid sequence SEQ ID NO:103. In some embodiments that can be combined with any of the foregoing embodiments, the antibody increases the survival of in vitro immune cells to a greater extent than an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and a light chain variable region containing the amino acid sequence SEQ ID NO:56; or greater than an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and a light chain variable region containing the amino acid sequence SEQ ID NO:103. In some embodiments that can be combined with any of the foregoing embodiments, the antibody has a shorter in vivo half-life than a human control IgG1 antibody. In some embodiments that can be combined with any of the foregoing embodiments, the antibody reduces the plasma level of soluble TREM2 in vivo by at least 25% more than a human control IgG1 antibody. In some embodiments that can be combined with any of the foregoing embodiments, the antibody reduces the plasma level of soluble TREM2 in vivo by blocking cleavage, by inhibiting one or more metalloproteinases, and / or by inducing internalization. In some embodiments, the soluble TREM2 is reduced by any one of about 10%, 20%, 30%, 40%, or 50%.In some embodiments that can be combined with any of the foregoing embodiments, the antibody competes 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-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-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, AL2p-h90, and any combination thereof.In some embodiments that can be combined with any of the foregoing embodiments, the antibody binds to substantially the same TREM2 epitopes as 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, 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 2. 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. In some embodiments that can be combined with any of the foregoing 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 can be combined with any of the foregoing 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 this disclosure relate to isolated nucleic acids comprising nucleic acid sequences encoding antibodies of any of the foregoing embodiments. Other aspects of this disclosure relate to vectors comprising nucleic acids of any of the foregoing embodiments. Other aspects of this disclosure relate to isolated host cells comprising vectors of any of the foregoing embodiments. Other aspects of this disclosure relate to methods for generating antibodies bound to TREM2, comprising culturing cells of any of the foregoing embodiments to generate antibodies. In some embodiments, the method further includes recovering antibodies generated from the cells. Other aspects of this disclosure relate to isolated antibodies bound to TREM2 generated by methods of any of the foregoing embodiments. Other aspects of this disclosure relate to pharmaceutical compositions comprising antibodies of any of the foregoing embodiments and pharmaceutically acceptable vectors.

[0031] Other aspects of this disclosure relate to methods for preventing, reducing risk, or treating individuals suffering from diseases, conditions, or injuries 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, including administering a therapeutically effective amount of an antibody to an individual in need of the aforementioned embodiments. In some embodiments, the disease, condition, or injury is Alzheimer's disease.

[0032] Other aspects of this disclosure relate to antibodies comprising an Fc region, wherein said antibody comprises an amino acid substitution at position E430G and one or more amino acid substitutions at positions of residues selected from the group consisting of L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, and any combination thereof, wherein the residue numbers are based on EU or Kabat numbers. In some embodiments: (a) the Fc region comprises amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbers are based on EU numbers; (b) the Fc region comprises amino acid substitutions at positions E430G and P331S, wherein the residue position numbers are based on EU numbers; (c) the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue position numbers are based on EU numbers; (d) the Fc region comprises amino acid substitutions at positions E430G, A330S, and P331S. The residue positions are numbered according to EU numbers; (e) the Fc region contains amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein the residue positions are numbered according to EU numbers; (f) the Fc region contains amino acid substitutions at positions E430G, K322A, and A330S, wherein the residue positions are numbered according to EU numbers; (g) the Fc region contains amino acid substitutions at positions E430G, K322A, and P331S, wherein the residue positions are numbered according to EU numbers; or (h) the Fc region contains an amino acid sequence selected from the group consisting of SEQ ID NO: 146-156. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G and K322A, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region comprises amino acid substitutions at positions E430G, K322A, and P331S, wherein the residue positions are numbered according to EU numbers.In some embodiments, the Fc region increases aggregation without activating complement compared to corresponding antibodies containing an Fc region without amino acid substitutions. In some embodiments, the antibody induces one or more activities of the 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 invention. These and other aspects of the invention will be apparent to those skilled in the art. These and other embodiments of the invention are further described in the following detailed description. Attached Figure Description

[0034] Figure 1A Increased agonistic activity of the Fc variant of anti-TREM2 antibody was observed. Luciferase activity was also measured after 6 hours of co-culture with the Fc variant of anti-TREM2 antibody. Figure 1B Increased agonistic activity of the Fc variant anti-TREM2 antibody was observed. Luciferase activity was also measured after 6 hours of co-culturing the Fc variant antibody with BWZ reporter cells and THP-1 cells at a 1:1 ratio.

[0035] Figure 2A This study demonstrates C3b deposition induced by the Fc variant anti-TREM2 antibody. The fold change in C3b deposition of the AL2p Fc variant in a TREM2-expressing HEK cell line was shown at 10 μg / mL relative to the human IgG1 isotype control antibody. Figure 2B The image shows C3b deposition induced by the anti-TREM2 antibody in the Fc variant. The fold change in C3b deposition of the AL2p affinity mature variant with the listed Fc mutation relative to its parental IgG1 Fc variant is also shown.

[0036] Figure 3A This indicates increased activity of the soluble anti-TREM2 antibody. Figure 3B The display plate showed increased activity of the anti-TREM2 antibody. Figure 3C The reporter gene activity (gray bars) of the affinity-matured anti-TREM2 antibody bound to a 5 μg / ml plate is shown compared to the parental humanized antibody Alp2-h50 (h50), the parental humanized antibody AL2p-77 (h77), and the parental murine antibody AL2p (AL2p msIgG1 parent) clones (black bars). Clones appearing as gray bars with black outlines represent AL2p-h50 antibody variants containing different amino acid substitutions.

[0037] Figure 4A This indicates increased activity of the soluble anti-TREM2 antibody. Figure 4B The display plate showed increased activity of the anti-TREM2 antibody.

[0038] Figure 5A This shows sTREM2 secreted by primary human dendritic cells from donor 534 after 48 hours of culture with anti-TREM2 or control antibody. Figure 5B This shows sTREM2 secreted by primary human dendritic cells from donor 535 after 48 hours of culture with anti-TREM2 or control antibody.

[0039] Figure 6A The results showed no change in cell number when primary human dendritic cells from donor 534 were cultured together with anti-TREM2 or control antibodies. Figure 6B The results showed no change in cell number when primary human dendritic cells from donor 535 were cultured together with anti-TREM2 or control antibodies.

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

[0041] Figure 8A and Figure 8B The illustration shows the use of plate-bound TREM2 antibody against control IgG to transfer primary human macrophages from a donor ( Figure 8A ) or human primary dendritic cells ( Figure 8B Increased viability (increased cellular ATP) 48 hours after stimulation. Figure 8C , Figure 8D , Figure 8E and Figure 8F The illustration shows the primary human dendritic cells from two donors being treated with soluble AL2p-58huIgG1 and control human IgG1. Figure 8C and Figure 8D ) or two donor human primary macrophages ( Figure 8E and Figure 8FIncreased viability (increased cellular ATP) 48 hours after stimulation.

[0042] Figure 9 Western blot analysis of Dap12 phosphorylation in retroperitoneal macrophages of WT or TREM2Bac-Tg mice treated with AL2p-58huIgG1, AL2p-58huIgG1 PSEG, or control huIgG1. Cell lysates were immunoprecipitated with anti-TREM2; the upper bands show staining with phosphotyrosine antibody, and the lower bands show total human TREM2 content. Detailed Implementation

[0043] General Technology

[0044] The techniques and procedures described or mentioned herein are generally well-known and are often employed by those skilled in the art using conventional methods. For example, widely used methods described in the following literature include: 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 (edited by F.M. Usubel et al. (2003)); Methods in Enzymology (Academic Press): PCR 2: A Practical Approach (edited by M.J. MacPherson, B.D. Hames, and G.R. Taylor (1995)), edited by Harlow and Lane (1988); Antibodies, A Laboratory Manual, and Animal Cell Culture (edited by R.R. Freshney (1987)); Oligonucleotide Synthesis (edited by M.J. Gait, 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Manual. Notebook (edited by J.E.C.L., 1998) Academic Press; Animal Cell Culture (edited by R.I.Freshney, 1987); Introduction to Cell and Tissue Culture (J.M.P.A.T.E.T ...Calos (ed., 1987); PCR: The Polymerase Chain Reaction (Mullis et al., ed., 1994); Current Protocols in Immunology (JEColigan et al., ed., 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 JD Capra, ed., Harwood). Academic Publishers, 1995; and Cancer: Principles and Practice of Oncology (edited by VT DeVita et al., JBLippincott Company, 1993).

[0045] definition

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

[0047] As used herein, an individual at “risk” for developing a particular disease, condition, or symptom may or may not have a detectable disease or disease symptoms, and may or may not have exhibited a detectable disease or disease symptoms prior to the treatments described herein. “At risk” means that an individual has one or more risk factors, which are measurable parameters known in the art as being associated with the occurrence of a particular disease, condition, or symptom. An individual with one or more of these risk factors is more likely to develop the particular disease, condition, or symptom than an individual without 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 a treated individual during the clinicopathological process. Desired therapeutic effects include reducing the rate of progression of a particular disease, condition, or symptom, improving or alleviating the pathological state, and mitigating or improving prognosis. For example, if one or more symptoms associated with a particular disease, condition, or symptom are alleviated or eliminated, then the individual is successfully "treated."

[0049] "Effective amount" refers to the amount that is effective at at least the required dose and for at least the required time period to achieve the desired therapeutic or preventive outcome. An effective amount may be provided by one or more administrations. The effective amount described herein may vary depending on factors such as: disease state, individual age, sex, and weight, and the ability of the treatment to elicit the desired response in the individual. An effective amount is also the amount in which the beneficial effect of the treatment outweighs any toxic or harmful effects of the treatment. For prophylactic use, beneficial or desired outcomes include, for example, the elimination or reduction of the risk of disease, the reduction of its severity, or the delay of its onset, said disease including its biochemical, histological, and / or behavioral symptoms, its complications, and intermediate pathological phenotypes presented during disease development. For therapeutic use, beneficial or desired outcomes include, for example, clinical outcomes such as: reduction of one or more symptoms caused by the disease by targeting, delaying disease progression, and / or prolonging survival; increased quality of life for the patient; reduction of the dosage of other agents required to treat the disease; and enhancement of the effect of another agent. An effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve preventive or therapeutic treatment. As understood in a clinical context, an effective amount of a drug, compound, or drug composition may or may not be achieved in combination with another drug, compound, or drug composition. Therefore, an "effective amount" can be considered to be given in the context of administration of one or more therapeutic agents, and a single agent can be considered to be administered in an effective amount if the desired result can be achieved in combination with one or more other agents.

[0050] "Individual" for therapeutic, preventative, or risk-reducing purposes means any animal classified as a mammal, including humans, domestic and farm animals as well as zoo animals, sporting animals, or pets such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats, and the like. In some implementations, the individual is a human.

[0051] As used herein, administration in combination with another compound or composition includes simultaneous administration and / or administration at different times. Combination administration also covers administration as a co-prepared formulation or as separate compositions, including administration at different frequencies or intervals and using the same or different routes of administration.

[0052] The term “immunoglobulin” (Ig) may be used interchangeably with “antibody” in this document. The term “antibody” as used in the broadest sense and specifically includes monoclonal antibodies, polyvinyl antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two complete antibodies, and antibody fragments, provided 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. V H With V L They pair together to form a single antigen-binding site. For information on the structure and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th ed., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.), Appleton & Lange, Norwalk, CT, 1994, p. 71 and Chapter 6.

[0054] Based on the amino acid sequence of their constant domain, L-chains from any vertebrate species can be classified into one of two distinct types (called kappa (“κ”) and lambda (“λ”)). Immunoglobulins can be classified into different classes or isotypes based on the amino acid sequence of their heavy chain (CH) constant domain. 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 mu (“μ”), respectively. The γ and α classes are further subdivided 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 conformations of different classes of immunoglobulins are well known and are usually described in (for example) Abbas et al., Cellular and Molecular Immunology, 4th edition (WBSaunders Co., 2000).

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

[0056] "Isolated" antibodies (e.g., the isolated anti-TREM2 antibody of this disclosure) are antibodies that have been identified, isolated, and / or recovered from components (e.g., native or recombinant) of their production environment. Preferably, the isolated peptide does not associate with any other contaminating components from its production environment. Contaminating components from its production environment (e.g., those derived from recombinant transfected cells) are substances that 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 a preferred embodiment, the peptide is purified to (1) greater than 95% by weight of antibody as determined by, for example, the Lowry method, and in some embodiments, to greater than 99% by weight; (2) to the extent that at least 15 N-terminal or internal amino acid sequence residues can be obtained by using a spin-cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie blue or preferably silver staining. Since at least one component of the antibody's native environment is not present, the isolated antibody includes an in situ antibody within recombinant T cells. However, isolated peptides or antibodies are typically prepared through at least one purification step.

[0057] The "variable region" or "variable domain" of an antibody (such as the anti-TREM2 antibody disclosed herein) refers to the amino-terminal domain of the heavy or light chain of the antibody. The variable domains of the heavy and light chains can be respectively referred to as "V..." H " and "V L These domains are typically the most variable parts of an antibody (relative to other antibodies in the same class) and contain antigen-binding sites.

[0058] The term "variable" refers to the fact that certain segments of the variable domain differ significantly between antibodies (e.g., the anti-TREM2 antibody of this disclosure). The V domain mediates antigen binding and defines the specificity of a particular antibody for its specific antigen. However, variability is not uniformly distributed across the entire 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 conserved portions of the variable domain are called framework regions (FRs). The variable domains of the natural heavy and light chains each contain four FR regions, predominantly in a β-lamellar configuration, linked by three HVRs that form loops that, in some cases, form part of a β-lamellar structure. The HVRs in each chain remain closely adjacent through the FR regions and, together with HVRs from the other chain, facilitate the formation of antigen-binding sites for the antibody (see Kabat et al., Sequences of Immunological Interest, 5th ed., National Institute of Health, Bethesda, MD (1991)). Constant domains do not directly participate in the binding of antibodies to antigens, but they exhibit various effector functions, such as antibody participation in antibody-dependent cytotoxicity.

[0059] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a largely homologous population of antibodies (e.g., the monoclonal anti-TREM2 antibody of this disclosure), meaning that the individual antibodies constituting said population are 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. Each monoclonal antibody targets a single determinant on an antigen, unlike polyclonal antibody formulations which typically comprise different antibodies targeting different determinants (epitopes). In addition to their specificity, monoclonal antibody formulations have the advantage of being synthesized via hybridoma cultures, free from contamination by other immunoglobulins. The modifier "monoclonal" indicates that the antibody is characterized by being obtained from a largely homologous population of antibodies and should not be construed as requiring the production of said antibody by any particular method. For example, the monoclonal antibodies used according to the present invention can be prepared by a variety of techniques, including (e.g.) hybridoma methods (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14(3):253-260 (1995); Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd edition 1988); Hammerling et al., Monoclonal Antibodies and T-Cell Hybridomas). 563-681 (Elsevier, NY, 1981)), recombinant DNA methods (e.g., see U.S. Patent No. 4,816,567), phage display technology (e.g., see 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 techniques (e.g., see WO2009 / 036379A2; WO2010105256; WO2012009568, and Xu et al., Protein Eng. Des. Sel.,26(10):663-70 (2013), and techniques for generating 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. Patent Nos. 5,545,807, 5,545,806, 5,569,825, 5,625,126, 5,633,425, and 5,661,016; Marks et al., Bio / Technology 10:779-783 (1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature 368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851 (1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg and 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 that is in its substantially intact form as opposed to an antibody fragment (e.g., the anti-TREM2 antibody of this disclosure). Specifically, whole antibodies include those that have both a heavy chain and a light chain and include an Fc region. The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or a variant of its amino acid sequence. In some cases, an intact antibody may have one or more effector functions.

[0061] An "antibody fragment" comprises a portion of a complete antibody, preferably the antigen-binding region and / or variable region of the complete antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; bivalent antibodies; linear antibodies (see U.S. Patent 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 (such as the anti-TREM2 antibody of this disclosure) yields two identical antigen-binding fragments (referred to as the "Fab" fragment) and a residual "Fc" fragment, named to reflect their tendency to crystallize. The Fab fragment consists of the entire L chain and the variable region domain (V) of the H chain. H ) and the first constant structural domain of a heavy chain (C H 1) Composition. Each Fab fragment is monovalent in terms of antigen binding, meaning it has a single antigen-binding site. Antibody treatment with pepsin produces a single large F(ab')2 fragment, which roughly corresponds to two Fab fragments linked by disulfide bonds with different antigen-binding activities, and still retains the ability to cross-link the antigen. The difference between the Fab' fragment and the Fab fragment lies in the C... H The carboxyl terminus of the 1 domain has several additional residues, including one or more cysteine ​​residues from the antibody hinge region. Fab'-SH is the designation used herein for Fab' with one or more cysteine ​​residues in the constant domain having a free thiol group. The F(ab')2 antibody fragment was originally generated as a Fab' fragment pair with a hinge cysteine ​​residue therebetween. 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 function of an antibody is determined by the sequence in the Fc region, which is also recognized by the Fc receptor (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 composed of a heavy chain variable region domain and a light chain variable region domain in a tightly non-covalently associated form. Six hypervariable rings (three from the H chain and three from the L chain) are generated from the folding of these two domains. These hypervariable rings contribute amino acid residues for antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of Fv, containing only three antigen-specific HVRs) has the ability to recognize and bind antigens, but its affinity is lower than that of the complete binding site.

[0065] Also abbreviated as "sFv" or "scFv", "single-chain Fv" is an antibody fragment containing VH and VL antibody domains linked together to form a single polypeptide chain. Preferably, the sFv polypeptide also contains V... H With V LThe polypeptide linkers between the domains enable sFv to form the desired antigen-binding structure. For a review of sFv, see Plückthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, edited by Rosenburg and Moore, Springer-VerLAG-3, New York, pp. 269-315 (1994).

[0066] An antibody (such as the anti-TREM2 antibody of this disclosure) has a “functional fragment” comprising a portion of the complete antibody, said portion typically including the antigen-binding region or variable region of the complete antibody, or a retained or modified F region of the antibody with FcR binding capability. Examples of antibody fragments include linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0067] The term "bivalent antibody" refers to a small antibody fragment prepared by using V... H With V L Short connectives (approximately 5-10 residues) between domains construct sFv fragments (see previous paragraphs), enabling interchain rather than intrachain pairing of the V domains, thereby producing bivalent fragments, i.e., fragments with two antigen-binding sites. Bispecific bivalent antibodies are heterodimers of two "crossed" sFv fragments, where the V domains of the two antibodies... H and V L The domains are located on different polypeptide chains. Bivalent antibodies 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, a "chimeric antibody" refers to an antibody (immunoglobulin) in which a portion of its heavy chain and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass (e.g., the chimeric anti-TREM2 antibody of this disclosure), and fragments of said antibody, provided they exhibit the desired biological activity (US Patent No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). The chimeric antibodies discussed herein include... Antibodies, wherein the antigen-binding region of an antibody is derived from antibodies produced by immunizing macaques with an associated antigen, for example. As used herein, “humanized antibody” is used as a subgroup of “chimeric antibody”.

[0069] A “humanized” form of a non-human (e.g., murine) antibody (e.g., the humanized form of the anti-TREM2 antibody of this disclosure) is a chimeric antibody containing a minimal amount of sequences derived from a non-human immunoglobulin. In one embodiment, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues of the recipient’s HVR are replaced by residues of the donor antibody’s HVR with the desired specificity, affinity, and / or ability from a non-human species (e.g., mouse, rat, rabbit, or non-human primate). In some cases, FR residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, the humanized antibody may contain residues not present in the recipient antibody or donor antibody. These modifications can be made to further improve antibody performance, such as binding affinity. Typically, humanized antibodies will contain substantially all, and usually both, variable domains, wherein all or substantially all of the hypervariable loops correspond to those hypervariable loops of non-human immunoglobulin sequences, and all or substantially all of the FR regions are those FR regions of human immunoglobulin sequences, 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 FRs is generally no more than 6 in the H chain and no more than 3 in the L chain. Humanized antibodies will optionally also contain at least a portion of the immunoglobulin constant region (Fc) (typically the human immunoglobulin constant region). For further 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, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409.

[0070] "Human antibody" is an antibody having an amino acid sequence corresponding to that of an antibody produced by humans (e.g., the anti-TREM2 antibody of this disclosure) and / or prepared using any of the techniques disclosed herein for preparing human antibodies. This definition of human antibody explicitly excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the industry, 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 an antigen attack, but whose endogenous loci have been disabled, for example, by immunization with xenomice (regarding XENOMOUSE). TM For the technology, see, for example, U.S. Patents 6,075,181 and 6,150,584. Regarding human antibodies produced via human B-cell hybridoma technology, also see, for example, Li et al., Proc. Nat'l Acad. Sci. USA, 103:3557-3562 (2006). Alternatively, human antibodies can also be prepared using a yeast library and methods disclosed as, for example, WO2009 / 036379A2; WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013).

[0071] The terms “hypervariant region,” “HVR,” or “HV” as used herein refer to regions of antibody variable domains (e.g., the variable domains of the anti-TREM2 antibody of this disclosure) that are hypervariable in sequence and / or form structurally defined loops. Typically, antibodies contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). In natural antibodies, H3 and L3 exhibit the majority of the diversity among the six HVRs, and H3 is believed to play a unique role, particularly in conferring good antibody specificity. (See, for example, 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). Indeed, natural camelid antibodies consisting only of heavy chains are functional and stable in the absence of light chains. For example, see Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al., Nature Struct.Biol.3:733-736 (1996).

[0072] This document uses and covers descriptions of many HVRs. In some embodiments, the HVR can be based on the Kabat complementarity-determining region (CDR) of sequence variability, which is the most widely used (Kabat et al., above). In some embodiments, the HVR can be the Chothia CDR. Chothia refers to the location of the structural loop (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). In some embodiments, the HVR can be the AbM HVR. AbM HVR represents a compromise between the Kabat CDR and the Chothia structural loop and is used in the AbM antibody modeling software of Oxford Molecular. In some embodiments, the HVR can be the “contact” HVR. The “contact” HVR is based on the determination of the available complex crystal structure. The residues from each of these HVRs are as follows.

[0073]

[0074] HVRs may include the following “extended HVRs”: 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 embodiment) (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. (above).

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

[0076] The phrases “as in Kabat variable domain residue numbering” or “as in Kabat amino acid position numbering” and their variations refer to the numbering system used for the heavy chain or light chain variable domains of antibodies compiled in Kabat et al. (see above). Using this numbering system, the actual linear amino acid sequence may contain fewer or more shortened or inserted amino acids corresponding to 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 (according to residue 52a in Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c in Kabat). The Kabat number of a given antibody residue can be determined by comparing the homologous regions of the antibody sequence with a “standard” Kabat numbered sequence.

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

[0078] As used herein, a “receptor human framework” is a framework comprising the amino acid sequence of a VL or VH framework derived from the human immunoglobulin framework or the human common framework. A recipient human framework “derived” from the human immunoglobulin framework or the human common framework may contain the same amino acid sequence, or may contain previously existing amino acid sequence variations. In some embodiments, the number of previously existing amino acid variations 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. Where previously existing amino acid variations are present in the VH, those variations 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 recipient human framework is consistent with the VL human immunoglobulin framework sequence or the human common framework sequence.

[0079] The "human common framework" represents the framework of amino acid residues that most frequently appear in the selection of the human immunoglobulin VL or VH framework sequence. Typically, the selection of the human immunoglobulin VL or VH sequence is from a subgroup of variable domain sequences. Common subgroups are those described in 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, subgroups such as κI, κII, κIII, or κIV as described in the above literature by Kabat et al.; and for VH, subgroups such as subgroup I, subgroup II, or subgroup III as described in the above literature by Kabat et al.

[0080] In the context of the anti-TREM2 antibody of this disclosure, "amino acid modification" at a specified position refers to the substitution or deletion of a specified residue or the insertion of at least one amino acid residue adjacent to the specified residue. "Adjacent" insertion means insertion within one or two residues. The insertion can be to the N-terminus or C-terminus of the specified residue. Preferred amino acid modifications herein are substitutions.

[0081] Affinity-matured antibodies (e.g., the affinity-matured anti-TREM2 antibody of this disclosure) are antibodies with one or more alterations in one or more of their HVRs, which improve the antibody's affinity for the antigen compared to a parent antibody without those alterations. In one embodiment, the affinity-matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity-matured antibodies are produced using procedures known in the industry. For example, Marks et al., Bio / Technology 10:779-783 (1992) describe affinity maturation via VH and VL domain shuffling. Random mutagenesis of HVR and / or framework residues is described in, for example, the following literature: Barbas et al., ProcNat.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 terms “specific recognition” or “specific binding” refer to a measurable and reproducible interaction, such as the attraction or binding between a target and an antibody (e.g., between an anti-TREM2 antibody and TREM2), which is determined by the presence of the target in the presence of a heterogeneous molecular population (including biomolecules). For example, an antibody that specifically or preferentially binds to a target or epitope (e.g., the anti-TREM2 antibody of this disclosure) is an antibody that binds to a target or epitope with greater affinity, more readily, and / or for a longer duration compared to its binding to other targets or other epitopes of the target. It should also be understood from this definition that, for example, an antibody (or part thereof) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. Therefore, “specific binding” or “preferential binding” does not necessarily require (but may include) exclusive binding. Antibodies that specifically bind 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, approximately 10 6 M -1 Or 10 7 M -1 Approximately 10 8 M -1Up to 10 9 M -1 Or about 10 10 M -1 Up to 10 11 M -1 Or a higher association constant. A variety of immunoassay formats can be used to select antibodies that specifically react with a particular protein. For example, solid-phase ELISA is commonly used to select monoclonal antibodies that specifically react with a protein. For descriptions of immunoassay formats and conditions used to determine specific immunoreactivity, see, for example, Harlow and Lane (1988), Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York.

[0083] As used herein, the “interaction” between the TREM2 protein and the 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 the interaction between the two proteins” when it disrupts, reduces, or completely eliminates the interaction between the two proteins. When an antibody or fragment thereof of this disclosure binds to one of the two proteins, the antibody or fragment thereof “inhibits the interaction between the two proteins.”

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

[0085] "Antagonist" antibodies or "blocking" antibodies are antibodies that, upon binding to an antigen, reduce or eliminate (e.g., decrease) the binding of the antigen to one or more ligands and / or reduce or eliminate (e.g., decrease) one or more activities or functions of the antigen. In some embodiments, antagonist antibodies or blocking antibodies substantially or completely inhibit the binding of the antigen to one or more ligands and / or one or more activities or functions of the antigen.

[0086] Antibody "effective function" refers to the biological activity attributable to the antibody's Fc region (natural sequence Fc region or amino acid sequence variant Fc region), and varies with antibody isotype.

[0087] The term "Fc region" is used herein to define the C-terminal region of the immunoglobulin heavy chain, including the native sequence Fc region and variant Fc regions. Although the boundaries of the Fc region of the immunoglobulin heavy chain can 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 of the Fc region (residue 447 according to the EU or Kabat numbering system) may be removed, for example, during antibody production or purification or by recombinant modification of the nucleic acid encoding the antibody heavy chain. Therefore, the composition of a complete antibody may comprise a population of antibodies with all K447 residues removed, a population of antibodies with K447 residues not removed, and a population of antibodies containing and not containing K447 residues. Suitable native sequence Fc regions for use in the antibodies of this disclosure include human IgG1, IgG2, IgG3, and IgG4.

[0088] The “natural sequence Fc region” contains an amino acid sequence that is identical to the amino acid sequence of the Fc region found in nature. The natural sequence human Fc regions include the natural sequence human IgG1 Fc region (non-A and A variants); the natural sequence human IgG2 Fc region; the natural sequence human IgG3 Fc region; and the natural sequence human IgG4 Fc region, as well as their natural variants.

[0089] The “variant Fc region” comprises an amino acid sequence that differs from the native Fc region due to 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 the native Fc region or the Fc region of the parent peptide, for example, about 1 to about 10 amino acid substitutions in the native Fc region or the Fc region of the parent peptide, and more preferably about 1 to about 5 amino acid substitutions. The variant Fc region herein preferably has at least about 80% homology with the native Fc region and / or the Fc region of the parent peptide, and most preferably at least about 90% homology, more preferably at least about 95% homology.

[0090] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. Preferably, the FcR is a naturally occurring human FcR. Furthermore, the preferred FcR is an FcR (γ receptor) that binds to IgG antibodies and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternative splice forms of these receptors. FcγRII receptors include FcγRIIA ("activating receptor") and FcγRIIB ("inhibitory receptor"), both having similar amino acid sequences that differ primarily in their cytoplasmic domains. The activating receptor FcγRIIA contains an activating motif ("ITAM") based on the immunoreceptor tyrosine residue in its cytoplasmic domain. The inhibitory receptor FcγRIIB contains an inhibitory motif ("ITIM") based on the immunoreceptor tyrosine residue in its cytoplasmic domain. (See, for example, 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" used in this paper encompasses other FcRs, including those to be identified in the future. FcRs can also prolong the serum half-life of antibodies.

[0091] The in vivo binding and serum half-life of human FcRn high-affinity binding peptides to FcRn can be determined, for example, in transgenic mice expressing human FcRn or in primates transfected with peptides containing variant Fc regions. WO 2004 / 42072 (Presta) describes antibody variants with modified or reduced binding to FcR. See also, for example, Shields et al., J. Biol. Chem. 9(2):6591-6604 (2001).

[0092] As used herein, “percentage of amino acid sequence identity (%)” and “homology” for peptide, polypeptide, or antibody sequences refer to the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a specific peptide or polypeptide sequence after sequence alignment and the introduction of vacancies (if necessary) to achieve the maximum percentage of sequence identity, and without considering any conserved substitutions as part of sequence identity. For the purpose of determining the percentage of amino acid sequence identity, alignment can be performed in various ways well known to those skilled in the art, such as using publicly available computer software, such as BLAST, BLAST-2, ALIGN, or MEGALIGN. TM(DNASTAR) software. Those skilled in the art can determine the appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.

[0093] The “isolated” nucleic acid molecule encoding an antibody (e.g., the anti-TREM2 antibody of this disclosure) is a nucleic acid molecule that is identified and isolated from at least one contaminating nucleic acid molecule that normally associates with it in its production environment. Preferably, the isolated nucleic acid does not associate with any components associated with the production environment. The isolated nucleic acid molecule encoding the polypeptide and antibody described herein is in a form that is not found in nature or in any other form or configuration. Therefore, the isolated nucleic acid molecule is distinguishable from the nucleic acids encoding the polypeptide and antibody naturally present in cells.

[0094] As used herein, the term "vector" is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it is linked. One type of vector is the "plasmid," which is a circular double-stranded DNA to which other DNA segments can be linked. Another type of vector is the bacteriophage vector. Yet another type of vector is the viral vector, in which other DNA segments can be linked to the viral genome. Some vectors are capable of autonomous replication in the host cell to which they have been introduced (e.g., bacterial vectors with bacterial origins of replication and free mammalian vectors). Other vectors (e.g., non-free mammalian vectors) can be integrated into the host cell's genome upon introduction into the host cell and thereby replicate along with the host genome. Furthermore, some vectors can direct the expression of genes to which they are operatively linked. These vectors are referred to herein as "recombinant expression vectors" or simply "expression vectors." Generally, expression vectors available in recombinant DNA technology are typically in plasmid form. Because plasmids are the most commonly used form of vector, the terms "plasmid" and "vector" are used interchangeably in this specification.

[0095] As used interchangeably herein, “polynucleotide” or “nucleic acid” refers to a nucleotide polymer of any length and includes both DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and / or their analogues, or any substrate that can be incorporated into the polymer by DNA or RNA polymerase or through a synthetic reaction. Polynucleotides may contain modified nucleotides, such as methylated nucleotides and their analogues. If present, modifications to the nucleotide structure may be conferred before or after polymer assembly. Non-nucleotide components may disrupt the sequence of nucleotides. Polynucleotides may include one or more modifications performed post-synthesis, such as conjugation to a label. Other types of modifications include, for example, "capping," substitution of one or more of the natural nucleotides with analogues, internucleotide modifications such as those with non-electrolyte linkages (e.g., phosphonate methyl esters, phosphate triesters, aminophosphate esters, carbamates, etc.) and those with electrolyte linkages (e.g., thiophosphate esters, dithiophosphate esters, etc.), those containing side-linked moieties (e.g., those of proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc.), those containing intercalating agents (e.g., acridine, psoralen, etc.), and those containing chelating agents (e.g., Modifications involving metals, radioactive metals, boron, metal oxides, etc.; modifications containing alkylating agents; modifications with modified linkages (e.g., α-mutant isomers of nucleic acids); and unmodified forms of polynucleotides are permitted. Furthermore, any of the hydroxyl groups commonly found in sugars can be replaced by, for example, phosphonate groups or phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages with additional nucleotides, or conjugated to solid or semi-solid supports. The 5' and 3' terminal OH groups can be partially phosphorylated or substituted by amines or organic end-capping groups of 1 to 20 carbon atoms. Other hydroxyl groups can also be derivatized into standard protecting groups. Polynucleotides may also contain similar forms of ribose or deoxyribose commonly known in the industry, including (e.g.) 2'-O-methyl-, 2'-O-allyl, 2'-fluoro-, or 2'-azido-ribose, carbocyclic sugar analogs, α-mutantoses, epimeric sugars (e.g., arabinose, xylose, or lyxose), pyranoses, furanoses, sedoheptulose, acyclic analogs, and basic nucleoside analogs (e.g., methylriboside). 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 ester is replaced by P(O)S (“thioester”), P(S)S (“dithioester”), (O)NR2 (“amide”), P(O)R, P(O)OR', CO or CH2 (“methyl ethyl acetal”), wherein each R or R' is independently H or optionally contains an ether (-O-)-linked substituted or unsubstituted alkyl (1-20 C), aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl.Not all links in a polynucleotide need to be identical. The foregoing description applies to all polynucleotides mentioned herein, including RNA and DNA.

[0096] "Host cell" includes individual cells or cell cultures that may be or have been vector recipients, said vector being used to incorporate polynucleotide inserts. Host cells include progeny of a single host cell, and progeny may not be identical to the original parent cell (morphologically or in terms of genome-wide DNA complementarity) due to natural, accidental, or intentional mutations. Host cells include cells transfected in vivo with the polynucleotides of the present invention.

[0097] As used herein, “carrier” includes pharmaceutically acceptable carriers, excipients, or stabilizers that are non-toxic to the exposed cells or mammals at the doses and concentrations used. Typically, physiologically acceptable carriers are pH-buffered aqueous solutions. 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 dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming ions such as sodium; and / or nonionic surfactants such as TWEEN. TM Polyethylene glycol (PEG) and PLURONICS TM .

[0098] As used herein, the term "about" refers to a general range of error for a corresponding value that is readily understood by those skilled in the art. The use of "about" herein to refer to a value or parameter includes (and describes) an embodiment of the value or parameter itself.

[0099] Unless the context clearly indicates otherwise, as used herein and in the appended claims, the singular forms “a” and “the” include multiple indicators. For example, a reference to “antibody” refers to one or more antibodies, such as in molar amounts, and includes equivalents known to those skilled in the art.

[0100] It should be understood that the aspects and implementations of this disclosure described herein include aspects and implementations that "comprise", "consist of" aspects and implementations and "consist substantially of" aspects and implementations.

[0101] Overview

[0102] This disclosure relates to anti-TREM2 antibodies (e.g., monoclonal antibodies) having modified affinity and functional properties; methods for preparing and using said antibodies; pharmaceutical compositions containing said antibodies; nucleic acids encoding said antibodies; and host cells containing nucleic acids encoding said antibodies.

[0103] Therefore, certain aspects of this disclosure are based at least in part on the identification of anti-TREM2 antibodies that: can bind to both human and cynomolgus monkey TREM2 with high affinity (e.g., see Examples 2 and 6); can bind to primary human immune cells with high affinity (e.g., see Examples 1 to 3); have a modified ability to aggregate in vitro and in vivo and activate TREM2 signaling (e.g., see Examples 3, 7, and 11); and have a modified ability to increase the survival of immune cells in vitro (e.g., see Examples 3 and 9). Advantageously, the anti-TREM2 antibodies of this disclosure exhibit a modified 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 this disclosure induce, increase, or otherwise enhance one or more TREM2 activities of this disclosure. In some embodiments, the anti-TREM2 antibody of this disclosure possesses one or more of these modified affinity and functional properties compared to anti-TREM2 antibodies having heavy chain variable regions and light chain variable regions of antibody AL2p-h50 or AL2p-h77. Furthermore, based on the results described in Examples 2 through 11, the functional properties of the affinity-modified anti-TREM2 antibody of this disclosure cannot be predicted from its modified affinity for TREM2.

[0104] In some embodiments, the anti-TREM2 antibodies of this disclosure have a high affinity for TREM2 and exhibit 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) in vitro and in vivo from primary human bone marrow cells; and a relatively low multispecific reactivity (PSR), which is a measure of nonspecific binding. As disclosed herein, affinity maturation can produce anti-TREM2 antibody variants with both increased binding affinity and increased PSR (i.e., relatively high nonspecific binding). While some antibodies of this 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 high 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 enhancing TREM2 signaling in both soluble and plate-bound forms, promoting the survival of primary human macrophages and primary human dendritic cells, and reducing the production of soluble TREM2 (sTREM2) in vitro and in vivo from primary human bone marrow cells (e.g., see Examples 2 through 12). Based on these results, unexpectedly, antibodies AL2p-58 and AL2p-47 exhibit high affinity for TREM2 and favorable functional properties without showing any significant PSR or binding to the cellular background.

[0105] The results in Example 9 also surprisingly showed that the affinity-matured anti-TREM2 antibodies of this disclosure (e.g., AL2p-58 and AL2p-47) induced a several hundred-fold increase in cell viability of primary human macrophages and dendritic cells (e.g., see Table 14 and...). Figure 8A and Figure 8B This functional property is surprising because, compared to the parental mouse anti-TREM2 antibody AL2p, the affinity of mature anti-TREM2 antibodies (e.g., AL2p-58 and AL2p-47) for binding to human TREM2-Fc is significantly higher (K0). D The antibody AL2p-37 showed only about a 10-fold improvement (see Tables 1 and 8 for example), but a several hundred-fold increase in its ability to promote cell viability. Surprisingly, the antibody AL2p-37, with a binding affinity roughly similar to AL2p-58 and AL2p-47, exhibited relatively lower cell viability-promoting efficacy than AL2p-58 and AL2p-47.

[0106] TREM2 protein

[0107] In one aspect, this disclosure provides an antibody that binds to the TREM2 protein of this disclosure, said antibody having modified affinity and inducing one or more TREM2 activities and / or enhancing one or more TREM2 activities upon binding to the TREM2 protein expressed in cells.

[0108] The TREM2 proteins disclosed herein include (but are not limited to) human TREM2 protein (Uniprot accession number Q9NZC2; SEQ ID NO:1) and non-human mammalian TREM2 proteins, such as mouse TREM2 protein (Uniprot accession number Q99NH8; SEQ ID NO:2), rat TREM2 protein (Uniprot accession number D3ZZ89; SEQ ID NO:3), rhesus monkey TREM2 protein (Uniprot accession number F6QVF2; SEQ ID NO:4), cynomolgus monkey TREM2 protein (NCBI accession number XP_015304909.1; SEQ ID NO:5), horse TREM2 protein (Uniprot accession number F7D6L0; SEQ ID NO:6), pig TREM2 protein (Uniprot accession number H2EZZ3; SEQ ID NO:7), and dog TREM2 protein (Uniprot accession number E2RP46; SEQ ID NO:8). As used in this article, "TREM2 protein" refers to both the wild-type sequence and the natural variant sequence.

[0109] The trigger receptor (TREM2) expressed on bone marrow cells-2 is differently referred to as TREM-2, TREM2a, TREM2b, TREM2c, the trigger receptor expressed on bone marrow cells-2a, and the trigger receptor expressed on monocytes-2. TREM2 is a 230-amino acid membrane protein. TREM2 is an immunoglobulin-like receptor primarily expressed on bone marrow cells, including (but not limited to) macrophages, dendritic cells, monocytes, Langerhans cells, Kupffer cells, osteoclasts, and microglia of the skin. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 is phosphorylated and signaled via DAP12 (an ITAM domain transfer protein). In some embodiments, TREM2 signaling leads to downstream activation of PI3K or other intracellular signals. On bone marrow cells, TLR receptor (TLR) signaling is important for the activation of TREM2 activity, for example, in the context of an infection response. TLRs also play a crucial role in pathological inflammatory responses, for example, TLRs expressed on macrophages and dendritic cells.

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

[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 cells. In some embodiments, TREM2 contains a signal peptide located at amino acid residues 1-18 of human TREM2 (SEQ ID NO:1); an extracellular immunoglobulin-like variable (IgV) domain located at amino acid residues 29-112 of human TREM2 (SEQ ID NO:1); an additional extracellular sequence located at amino acid residues 113-174 of human TREM2 (SEQ ID NO:1); a transmembrane domain located at amino acid residues 175-195 of human TREM2 (SEQ ID NO:1); and an intracellular domain located at amino acid residues 196-230 of human TREM2 (SEQ ID NO:1).

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

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

[0115] Anti-TREM2 antibody

[0116] Certain aspects of this disclosure relate to antibodies (e.g., monoclonal antibodies) that bind specifically to TREM2 with modified affinity. In some embodiments, the antibodies of this disclosure bind to mature TREM2 protein. In some embodiments, the antibodies of this disclosure bind to mature TREM2 protein, wherein the mature TREM2 protein is expressed on a cell. In some embodiments, the antibodies of this disclosure bind to TREM2 protein expressed on one or more human cells selected from: human dendritic cells, human macrophages, human monocytes, human osteoclasts, Langerhans cells of human skin, human Kuffour cells, human microglia, and any combination thereof.

[0117] In some embodiments, the anti-TREM2 antibody of this disclosure binds 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 in *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, thiolipins, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid β-peptides. Therefore, in some embodiments, the one or more TREM2 ligands comprise E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine (PS), thiolipin, phosphatidylcholine, sphingomyelin (SM), phospholipids, lipidated proteins, protein lipids, lipidated peptides, and lipidated starch-like β-peptides.

[0118] In some embodiments, the anti-TREM2 antibody of this disclosure does not inhibit the growth of one or more innate immune cells. In some embodiments, the anti-TREM2 antibody of this disclosure binds to one or more primary immune cells with an affinity 5 to 100 times higher than that of anti-TREM2 antibodies selected from: an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and a light chain variable region containing the amino acid sequence SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and a light chain variable region containing the amino acid sequence SEQ ID NO:103; and an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO:119 and a light chain variable region containing the amino acid sequence SEQ ID NO:120. In some embodiments, the anti-TREM2 antibody of this disclosure binds to one or more primary immune cells with an affinity at least 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 21-fold, 22-fold, 23-fold, 24-fold, 25-fold, 26-fold, 27-fold, 28-fold, 29-fold, 30-fold, 35-fold, 40-fold, 45-fold, and 50-fold higher than an anti-TREM2 antibody selected from the group consisting of a heavy chain variable region containing the amino acid sequence SEQ ID NO:27 and containing the amino acid sequence SEQ ID NO:27. Anti-TREM2 antibodies comprising the light chain variable region of SEQ ID NO:56; anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and the light chain variable region containing the amino acid sequence SEQ ID NO:103; and anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:119 and the light chain variable region containing the amino acid sequence SEQ ID NO:120. In some embodiments, the anti-TREM2 antibodies of this disclosure bind to one or more primary immune cells, having a mean fluorescence intensity (MFI) in the range of 100 to 1500 or greater than 1500. In some embodiments, the anti-TREM2 antibodies of this disclosure bind to one or more primary immune cells,Its average 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. At least 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 116 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 implementations,MFI is determined at a temperature of approximately 25°C. In some implementations, K, D This is determined using a monovalent antibody (e.g., Fab) or a full-length antibody in monovalent form. Methods for preparing and selecting antibodies that interact with and / or specifically bind to TREM2 are described herein (e.g., see Examples 1 and 2).

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

[0120] In some embodiments, the anti-TREM2 antibody of this disclosure aggregates and activates TREM2 signaling in amounts ranging from about 1 fold to about 30 folds of the control (FOC). In some embodiments, the anti-TREM2 antibody of this disclosure aggregates and activates TREM2 signaling in amounts of at least 1 fold to the control (FOC), at least 1.1 fold to the control (FOC), at least 1.2 fold to the control (FOC), at least 1.3 fold to the control (FOC), at least 1.4 fold to the control (FOC), at least 1.5 fold to the control (FOC), at least 1.6 fold to the control (FOC), at least 1.7 fold to the control (FOC), at least 1.8 fold to the control (FOC), at least 1.9 fold to the control (FOC), at least 2 fold to the control (FOC), at least 2.1 fold to the control (FOC), and at least 2.2 fold to the control. (FOC), at least 2.3 times that of the control (FOC), at least 2.4 times that of the control (FOC), at least 2.5 times that of the control (FOC), at least 2.6 times that of the control (FOC), at least 2.7 times that of the control (FOC), at least 2.8 times that of the control (FOC), at least 2.9 times that of the control (FOC), 3 times that of the control (FOC), at least 3.1 times that of the control (FOC), at least 3.2 times that of the control (FOC), at least 3.3 times that of the control (FOC), at least 3.4 times that of the control (FOC), at least 3.5 times that of the control (FOC), at least 3.6 times that of the control (FOC), at least 3.7 times that of the control (FOC), to Less than 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 that of control (FOC), at least 8.3 times that of control (FOC), at least 8.4 times that of control (FOC), at least 8.5 times that of control (FOC), at least 8.6 times that of control (FOC), at least 8.7 times that of control (FOC), at least 8.8 times that of control (FOC), at least 8.9 times that of control (FOC), 9 times that of control (FOC), at least 9.1 times that of control (FOC), at least 9.2 times that of control (FOC), at least 9.3 times that of control (FOC), at least 9.4 times that of control (FOC). C) At least 9.5 times that of the control (FOC), at least 9.6 times that of the control (FOC), at least 9.7 times that of the control (FOC), at least 9.8 times that of the control (FOC), at least 9.9 times that of the control (FOC), at least 10 times that of the control (FOC), at least 11 times that of the control (FOC), at least 12 times that of the control (FOC), at least 13 times that of the control (FOC), at least 14 times that of the control (FOC), at least 15 times that of the control (FOC), at least 16 times that of the control (FOC), at least 17 times that of the control (F) The aggregation and activation of TREM2 signaling are determined at 37°C using a monovalent antibody (e.g., Fab) or a full-length antibody in monovalent form. Methods for measuring aggregation and activation of TREM2 signaling are described herein (e.g., see Example 3).

[0121] In some embodiments, the anti-TREM2 antibody of this disclosure increases the survival of in vitro immune cells to a degree at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, or at least 20 times higher than an anti-TREM2 antibody selected from the group consisting of [list of other anti-TREM2 antibodies]. 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: Contains an amino acid sequence SEQ. Anti-TREM2 antibodies comprising the heavy chain variable region of SEQ ID NO:27 and the light chain variable region containing the amino acid sequence SEQ ID NO:56; anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and the light chain variable region containing the amino acid sequence SEQ ID NO:103; and anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:119 and the light chain variable region containing the amino acid sequence SEQ ID NO:120.

[0122] In some embodiments, the ability of the anti-TREM2 antibody of this disclosure to increase the survival of in vitro immune cells is measured by determining the area under the curve (AUC) of the growth curve of primary immune cells in culture treated with the anti-TREM2 antibody of this disclosure. In some embodiments, the anti-TREM2 antibody of this disclosure increases the survival of in vitro immune cells with an AUC in the range of about 200,000 to about 1,500,000. In some embodiments, the anti-TREM2 antibody of this disclosure increases the survival of immune cells 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, and 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, to 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 090000, at least 1100000, at least 1110000, at least 1120000, at least 1130000, at least 1140000, at least 1150000, at least 1160000, at least 1170000, at least 1180000, at least 1190000, at least 1200000, 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, to The numbers are: at least 1,300,000, at least 1,310,000, at least 1,320,000, at least 1,330,000, at least 1,340,000, at least 1,350,000, at least 1,360,000, at least 1,370,000, at least 1,380,000, at least 1,390,000, at least 1,400,000, at least 1,410,000, at least 1,420,000, at least 1,430,000, at least 1,440,000, at least 1,450,000, at least 1,460,000, at least 1,470,000, at least 1,480,000, at least 1,490,000, or at least 1,500,000. In some embodiments, in vitro immune cell viability is measured at 4°C using a monovalent antibody (e.g., Fab) or a full-length antibody in monovalent form. Methods for measuring in vitro immune cell viability are described herein (e.g., see Example 3).

[0123] In some embodiments, the in vivo half-life of the anti-TREM2 antibody of this disclosure is shorter than that of the human control IgG1 antibody. In some embodiments, the in vivo half-life of the anti-TREM2 antibody of this disclosure is at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times, at least 18 times, at least 19 times, at least 20 times, or at least [missing information - likely a number] times shorter than that of the anti-TREM2 antibody selected from the group consisting of [missing information - likely a specific antibody]. At least 21 times, at least 22 times, at least 23 times, at least 24 times, at least 25 times, at least 26 times, at least 27 times, at least 28 times, at least 29 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times, at least 55 times, at least 60 times, at least 65 times, at least 70 times, at least 75 times, at least 80 times, at least 85 times, at least 90 times, at least 95 times, or at least 100 times: Contains an amino acid sequence SEQ. Anti-TREM2 antibodies comprising the heavy chain variable region of SEQ ID NO:27 and the light chain variable region containing the amino acid sequence SEQ ID NO:56; anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:91 and the light chain variable region containing the amino acid sequence SEQ ID NO:103; and anti-TREM2 antibodies comprising the heavy chain variable region containing the amino acid sequence SEQ ID NO:119 and the light chain variable region containing the amino acid sequence SEQ ID NO:120.

[0124] In some embodiments, the in vivo half-life of the anti-TREM2 antibody of this disclosure is in the range of about 0.1 days to about 10 days. In some embodiments, the in vivo half-life of the anti-TREM2 antibody of this disclosure is about 0.1 days, about 0.2 days, about 0.3 days, about 0.4 days, about 0.5 days, about 0.6 days, about 0.7 days, about 0.8 days, about 0.9 days, about 1 day, about 1.1 days, about 1.2 days, about 1.3 days, about 1.4 days, about 1.5 days, about 1.6 days, about 1.7 days, about 1.8 days, about 1.9 days, about 2 days, about 2.1 days, and about 2... 2 days, approximately 2.3 days, approximately 2.4 days, approximately 2.5 days, approximately 2.6 days, approximately 2.7 days, approximately 2.8 days, approximately 2.9 days, approximately 3 days, approximately 3.1 days, approximately 3.2 days, approximately 3.3 days, approximately 3.4 days, approximately 3.5 days, approximately 3.6 days, approximately 3.7 days, approximately 3.8 days, approximately 3.9 days, approximately 4 days, approximately 4.1 days, approximately 4.2 days, approximately 4.3 days, approximately 4.4 days, approximately 4.5 days, approximately 4.6 days, approximately 4.7 days, approximately 4... 8 days, approximately 4.9 days, approximately 5 days, approximately 5.1 days, approximately 5.2 days, approximately 5.3 days, approximately 5.4 days, approximately 5.5 days, approximately 5.6 days, approximately 5.7 days, approximately 5.8 days, approximately 5.9 days, approximately 6 days, approximately 6.1 days, approximately 6.2 days, approximately 6.3 days, approximately 6.4 days, approximately 6.5 days, approximately 6.6 days, approximately 6.7 days, approximately 6.8 days, approximately 6.9 days, approximately 7 days, approximately 7.1 days, approximately 7.2 days, approximately 7.3 days, approximately 7.4 days The in vivo half-life is approximately 7.5 days, 7.6 days, 7.7 days, 7.8 days, 7.9 days, 8 days, 8.1 days, 8.2 days, 8.3 days, 8.4 days, 8.5 days, 8.6 days, 8.7 days, 8.8 days, 8.9 days, 9 days, 9 days, 9.1 days, 9.2 days, 9.3 days, 9.4 days, 9.5 days, 9.6 days, 9.7 days, 9.8 days, 9.9 days, or 10 days. In some embodiments, the in vivo half-life is measured using a monovalent antibody (e.g., Fab) or a full-length antibody in monovalent form. Methods for measuring the in vivo half-life are described herein (e.g., see Example 4).

[0125] The anti-TREM2 antibodies of this disclosure typically bind with high affinity to one or more TREM2 proteins expressed on cells. For example, it is believed that TREM2 receptors require aggregation on the cell surface to transduce signals. Therefore, agonist antibodies may have unique characteristics to stimulate, for example, TREM2 receptors. For example, they may have the correct epitope specificity compatible with receptor activation and the ability to induce or retain receptor aggregation on the cell surface. Additionally, the anti-TREM2 antibodies of this disclosure may exhibit the ability to bind TREM2 without blocking the simultaneous binding of one or more TREM2 ligands. The anti-TREM2 antibodies of this disclosure may further exhibit additive and / or co-functional interactions with one or more TREM2 ligands. Therefore, in some embodiments, when bound to a combination of the anti-TREM2 antibody of this disclosure and one or more TREM2 ligands of this disclosure, the maximum activity of TREM2 may be greater than (e.g., enhanced) the maximum activity of TREM2 when exposed to saturation concentrations of either the single ligand or the single antibody. Furthermore, the activity of TREM2 at a given concentration of TREM2 ligand may be greater (e.g., enhanced) in the presence of the antibody. Therefore, in some embodiments, the anti-TREM2 antibody of this disclosure has an additive effect with one or more TREM2 ligands to enhance the activity of one or more TREM2 upon binding to the TREM2 protein. In some embodiments, the anti-TREM2 antibody of this disclosure synergistically enhances the activity of one or more TREM2 with one or more TREM2 ligands. In some embodiments, the anti-TREM2 antibody of this disclosure increases the efficacy of one or more TREM2 ligands in inducing one or more TREM2 activities compared to the efficacy of one or more TREM2 ligands inducing one or more TREM2 activities in the absence of the antibody. In some embodiments, the anti-TREM2 antibody of this disclosure enhances the activity of one or more TREM2 in the absence of TREM2 on the cell surface. In some embodiments, the anti-TREM2 antibody of this disclosure enhances the activity of one or more TREM2 by inducing or preserving the cell surface aggregation of TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure aggregates via 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 the binding of one or more TREM2 ligands to the TREM2 protein is measured on primary cells or cell lines, said primary cells including (but not limited to) dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts, Langerhans cells and Kuffour cells of the skin, and (for example) in vitro cytometry is used to measure the enhancement of one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein.

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

[0127] In some embodiments, the anti-TREM2 antibody of this disclosure aggregates the receptor (e.g., TREM2) by binding to an Fcg receptor on adjacent cells. Binding of the constant IgG Fc moiety of the antibody to the Fcg receptor leads to antibody aggregation, and the antibody further aggregates the receptor 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 the inhibitory Fcg receptor FcgR (FcgRIIB) that does not induce cytokine secretion, oxidative burst, increased phagocytosis, and enhanced antibody-dependent, cell-mediated cytotoxicity (ADCC) is generally a preferred mode of antibody aggregation in vivo, as binding to FcgRIIB is not associated with adverse immune 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, cross-linked antibody fragments (e.g., Fab fragments) can be used to aggregate receptors (e.g., TREM2) in a manner similar to that of antibodies having an Fc region that binds to the Fcg receptor, 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), then it can act as an agonist antibody.

[0129] In some embodiments, the antibodies of this disclosure that bind to the TREM2 protein may include antibodies that specifically bind to TREM2 due to their epitope and activate one or more TREM2 activities. In some embodiments, the antibody may bind to a ligand-binding site on TREM2 and mimic the action 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 ligands for binding to TREM2 or otherwise blocks their 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 activity induced and / or enhanced by the anti-TREM2 antibody of this disclosure and / or one or more TREM2 ligands of this disclosure includes (but is not limited to) TREM2 binding to DAP12; DAP12 phosphorylation; activation of Syk kinase; and regulation by one or more pro-inflammatory mediators selected from: 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 said regulation may be in one or more of these mediators. This mechanism of action occurs in cells selected from the following: macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, Langerhans cells of the skin, Kuffour cells, and microglia; Syk is recruited to the DAP12 / TREM2 complex; increases the activity of one or more TREM2-dependent genes, wherein one or more TREM2-dependent genes contain the activation T cell nuclear factor (NFAT) transcription factor; increases the survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells of the skin, Kuffour cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; and regulates the expression of one or more stimulatory molecules selected from the following: 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 dendritic cells may include bone marrow-derived dendritic cells; enhance memory; and reduce cognitive deficits.

[0131] As used herein, if the anti-TREM2 antibody of this disclosure induces one or more TREM2 activities 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 greater, compared to the extent that such activities are induced by the binding of one or more TREM2 ligands to the TREM2 protein in the absence of an anti-TREM2 antibody, then it enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein. 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 gene assay, by measuring TREM2-induced increases in phosphorylation of downstream signaling collaterals (e.g., Syk) using a Western ink dot assay, or by measuring changes in the cell surface content 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 interactions (e.g., binding) between TREM2 and one or more TREM2 ligands.

[0132] In some implementations, when the TREM2 ligand uses its EC 50 When used at concentrations ranging from about 0.5 nM to about 50 nM or greater, and compared to the extent of TREM2-dependent gene transcription induced by the binding of the TREM2 ligand to the TREM2 protein in the absence of an anti-TREM2 antibody, if the anti-TREM2 antibody of this disclosure, when used at concentrations ranging from about 0.5 nM to about 60 nM or greater, induces an increase of about 1 to about 60 ... 50When used at concentrations, and compared to the degree of TREM2-dependent gene transcription induced by the binding of TREM2 ligand to TREM2 protein in the absence of anti-TREM2 antibody, 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 greater. In some embodiments, anti-TREM2 antibodies are used at concentrations of at least 0.5 nM, at least 0.6 nM, at least 0.7 nM, at least 0.8 nM, at least 0.9 nM, at least 1 nM, at least 2 nM, at least 3 nM, at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least 9 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, at least 30 nM, at least 35 nM, at least 40 nM, at least 45 nM, at least 46 nM, at least 47 nM, at least 48 nM, at least 49 nM, or at least 50 nM. In some embodiments, the TREM2 ligand is phosphatidylserine (PS). In some embodiments, the TREM2 ligand is sphingomyelin (SM). In some embodiments, an increase in one or more 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. In some implementations, 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 the antibody.

[0133] As used herein, using any in vitro assay or cell culture-based assay known herein or in the art, if the anti-TREM2 antibody of this disclosure reduces the binding of the ligand to TREM2 by less than 20% at a saturated antibody concentration, then it does not compete with one or more TREM2 ligands for, inhibit, or otherwise block the interaction (e.g., binding) with TREM2. In some embodiments, using any in vitro assay or cell culture-based assay known herein or in the art, the anti-TREM2 antibody of this 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% at a saturated antibody concentration.

[0134] In some embodiments, the anti-TREM2 antibody of this disclosure induces one or more TREM2 activities. In some embodiments, the antibody induces one or more TREM2 activities upon binding to a TREM2 protein expressed on a cell. In some embodiments, the antibody induces one or more TREM2 activities upon binding to a soluble TREM2 protein that does not bind to the cell membrane. In some embodiments, the TREM2 protein is expressed on the cell surface. In some embodiments, the soluble TREM2 protein (sTREM2) may be found in (but not limited to) the extracellular environment, serum, cerebrospinal fluid (CSF), and interstitial spaces within tissues. In some embodiments, the soluble TREM2 protein (sTREM2) is a non-cellular protein. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-160 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-159 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-158 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-157 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-156 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-155 of SEQ ID NO:1. In some embodiments, the soluble TREM2 (sTREM2) protein of this disclosure corresponds to amino acid residues 19-154 of SEQ ID NO:1.

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

[0136] In some embodiments, the anti-TREM2 antibody of this disclosure reduces plasma levels of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibody of this disclosure reduces 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 antibody of this disclosure reduces plasma levels of soluble TREM2 in vivo by approximately 5% to approximately 50% higher than that of a human control IgG1 antibody. In some embodiments, the anti-TREM2 antibody of this disclosure reduces 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%, and at least 23% higher than that of a human control IgG1 antibody. 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 antibody of this disclosure reduces plasma levels of soluble TREM2 in vivo, such that the plasma level of soluble TREM2 as a baseline percentage at 6 days after antibody treatment is 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 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, plasma levels of soluble TREM2 in vivo are measured using a monovalent antibody (e.g., Fab) or a full-length antibody in monovalent form. A method for measuring plasma levels of soluble TREM2 in vivo is described herein (e.g., see Example 4).

[0139] The disclosed anti-TREM2 antibody may 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, normobaric hydrocephalus, amyotrophic lateral sclerosis (ALS), Huntington's disease, tauopathy disease, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, spontaneous tremor, central nervous system lupus, Behcet's disease, Parkinson's disease, Lewy body type dementia, multiple system atrophy, and Shy-Drager syndrome. Syndrome, progressive supranuclear palsy, corticobasal ganglia degeneration, acute disseminated encephalomyelitis, granulomatous diseases, sarcoidosis, age-related diseases, epilepsy, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory infections, sepsis, eye infections, systemic infections, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, bone formation, osteopetrotic disease, Paget's disease of bone, solid and hematologic malignancies, 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 myelocirrhosis, myeloid tumors, TREM2-expressing tumors, thyroid cancer, infections, CNS herpes, parasitic infections, trypanosome infection, Trypanosoma infection, Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, Group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningitidis infection.Infections with hepatitis B (HBeAg), HIV type I, and Haemophilus influenzae. The methods described herein can also be used to induce or promote the survival, maturation, function, migration, or proliferation of one or more immune cells in individuals in need. The methods described herein can further be used to reduce the activity, function, 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 described herein can further be used to increase memory and / or reduce cognitive deficits.

[0140] The anti-TREM2 antibody disclosed herein can also be used for advanced wound care. In some embodiments, the anti-TREM2 antibody of this disclosure is a monoclonal antibody. The anti-TREM2 antibody of this disclosure can be tested against substances that induce one or more TREM2 activities. Available assays may include Western ink dots (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); assays that increase the survival and / or function of dendritic cells, macrophages, monocytes, osteoclasts, Langerhans cells, Kuffour cells, and / or microglia of the skin; assays that increase the survival and / or function of apoptotic neurons, damaged synapses, amyloid β or fragments thereof, Tau, IAPP, α-synuclein, TDP-43, FUS protein, prion protein, PrPSc, Huntington's protein, calcitonin, superoxide dismutase, ataxia protein, Lewis bodies, and atrial diuretic natriuretic factor. Increased phagocytosis of tumor cells, including: islet amyloid peptides, insulin, apolipoprotein AI, serum amyloid A, interpeptides, prolactin, transthyretin, lysozyme, β2-microglobulin, coagulants, corneal epithelial proteins, cystatin, immunoglobulin light chain AL, S-IBM protein, repeat-associated non-ATG (RAN) translation products, dipeptide repeats (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides and proline-arginine (PR) repeat peptides, neural tissue debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acids, or macrophages, dendritic cells, Langerhans cells, Kuffour cells, monocytes, osteoclasts, and / or microglia; increased cytoskeletal remodeling and decreased pro-inflammatory responses in microglia, or other assays known in the art.

[0141] If an antibody that relies on binding to the FcgR receptor to activate the target receptor is modified to eliminate FcgR binding, it may lose its 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 the anti-TREM2 antibody of this disclosure has the correct epitope specificity and an Fc domain (CH1 and hinge region) derived from the human IgG2 isotype or another type of Fc domain that preferentially binds to the inhibitory FcgRIIB r receptor or a variant thereof, the antibody is considered to activate the target antigen with minimal adverse effects.

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

[0143] Table A: Exemplary antibodies Fc isotypes capable of binding to the Fcγ receptor

[0144]

[0145]

[0146] In addition to the isotypes described in Table A and not wishing to be limited by theory, antibodies and mutants of human IgG1 or IgG3 isotypes binding to activated 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) are also considered to be usable as agonist antibodies in vivo, but may be associated with adverse effects related to ADCC. However, the Fcg receptors appear to have lower availability for antibody binding in vivo compared to the inhibitory Fcg receptor FcgRIIB (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 an IgG, IgM, or IgA class. In some embodiments, the antibody has IgG1, IgG2, IgG3, or IgG4 isotypes.

[0148] In some 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 induces one or more TREM2 activities, DAP12 activities, or both, independently of binding to an Fc receptor. In some embodiments, the antibody binds to an inhibitory Fc receptor. In some 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 the 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 (Supplement 1):27; Armour et al., (2000) The Haematology Journal 1(Supplement 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, wherein the amino acid positions are according to EU or Kabat numbering conventions.

[0149] In some implementations, the antibody has an IgG2 isotype with a heavy chain constant domain containing a C127S amino acid substitution, wherein the amino acid position is determined according to EU or Kabat numbering conventions (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 has an IgG2 isotype with a C214S amino acid substitution in the κ light chain constant domain, wherein the amino acid positions are determined according to EU or Kabat numbering conventions (White et al., (2015) Cancer Cell 27, 138-148; Lightle et al., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

[0151] In some 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 some 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 the 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) RJBiol.Chem.276,6591-6604), L234A, L235A (Hutchins et al., (1995) Proc Natl Acad Sci USA,92:11980-11984; Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol,200:16-26), G237A (Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol,200:16-26), and G237A (Alegre et al., (1994) Transplantation 57:1537-1543.31; Xu et al., (2000) Cell Immunol,200:16-26). 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 EU or Kabat numbering conventions.

[0152] In some embodiments, the antibody comprises an IgG2 isotype heavy chain constant domain 1 (CH1) and a hinge region (White et al., (2015) Cancer Cell 27, 138-148). In some embodiments, the IgG2 isotype CH1 and hinge region contain the amino acid sequence 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 EU or Kabat numbering conventions.

[0153] In some 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 some 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 the 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 positions are according to EU or Kabat numbering conventions.

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

[0155] In some implementations, the antibody contains the 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 following: according to EU or Kabat numbers A330L, L234F, L235E or P331S and any combination thereof.

[0157] In some embodiments, the antibody contains one or more amino acid substitutions in the Fc region at positions selected from the following residues: C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the residue numbers are based on EU or Kabat numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbers are based on EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and P331S, wherein the residue position numbers are based on EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and K322A, wherein the residue position numbers are based on EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and A330S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and P331S, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains amino acid substitutions at positions S267E and L328F, wherein the residue positions are numbered according to EU numbers. In some embodiments, the Fc region contains an amino acid substitution at position C127S, wherein the residue positions are numbered according to EU numbers. In some implementations, the Fc region contains amino acid substitutions at positions E345R, E430G, and S440Y, wherein the residue position numbers are based on EU numbers.

[0158] Other IgG mutations

[0159] In some implementations, one or more of the IgG1 variants described herein may be combined with the A330L mutation (Lazar et al., (2006) Proc Natl Acad Sci USA, 103:4005-4010) or one or more of the L234F, L235E and / or P331S mutations (Sazinsky et al., (2008) Proc Natl Acad Sci USA, 105:20167-20172) to eliminate complement activation, wherein the amino acid positions are according to EU or Kabat numbering conventions. In some implementations, the IgG variants described herein may be combined with one or more mutations to prolong the antibody half-life in human serum (e.g., M252Y, S254T, T256E mutations according to EU or Kabat numbering conventions) (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 variant of this disclosure may be combined with one or more mutations as described in the EU or Kabat numbering conventions (Angal et al., (1993) Mol Immunol, 30:105-108) and / or with Peters et al., (2012) J Biol Chem. 13; 287(29):24525-33) to enhance antibody stability.

[0161] Example of anti-TREM2 antibody

[0162] In some embodiments, the isolated anti-TREM2 antibody of this disclosure binds to TREM2 with high affinity and enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to TREM2 protein in the absence of the isolated antibody, compared to such activities. In some embodiments, the anti-TREM2 antibody enhances one or more TREM2 activities without competing with or otherwise blocking the binding of one or more TREM2 ligands to the TREM2 protein. In some embodiments, the antibody is a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. Illustrative examples of the antibodies can be found throughout this 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 antibody of this disclosure binds to human TREM2 or its homologues, including (but not limited to) mammalian (e.g., non-human mammalian) TREM2 protein, mouse TREM2 protein (Uniprot accession number Q99NH8), rat TREM2 protein (Uniprot accession number D3ZZ89), rhesus monkey TREM2 protein (Uniprot accession number F6QVF2), cynomolgus monkey TREM2 protein (NCBI accession number XP_015304909.1), horse TREM2 protein (Uniprot accession number F7D6L0), porcine TREM2 protein (Uniprot accession number H2EZZ3), and dog TREM2 protein (Uniprot accession number E2RP46). In some embodiments, the anti-TREM2 antibody of this disclosure specifically binds to human TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure specifically binds to cynomolgus monkey TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure specifically binds to both human TREM2 and cynomolgus monkey TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure induces at least one of the TREM2 activities of this disclosure.

[0164] Anti-TREM2 antibody binding region

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

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

[0167] In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits 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 antibody of this disclosure competitively inhibits 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, and 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, 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 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. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-31. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-37. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-47. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-58.In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-60. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-61. In some embodiments, the anti-TREM2 antibody of this disclosure competitively inhibits the binding of antibody AL2p-62.

[0168] In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, said epitope being identical to or overlapping with a TREM2 epitope 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 antibody of this disclosure binds to an epitope of human TREM2, said epitope being identical to or overlapping with a TREM2 epitope bound by 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-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-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. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, said epitope being the same as or overlapping with the TREM2 epitope bound by antibody AL2p-31.In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, the epitope being identical to or overlapping with the TREM2 epitope bound by antibody AL2p-37. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, the epitope being identical to or overlapping with the TREM2 epitope bound by antibody AL2p-47. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, the epitope being identical to or overlapping with the TREM2 epitope bound by antibody AL2p-58. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, the epitope being identical to or overlapping with the TREM2 epitope bound by antibody AL2p-60. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, the epitope being identical to or overlapping with the TREM2 epitope bound by antibody AL2p-61. In some embodiments, the anti-TREM2 antibody of this disclosure binds to an epitope of human TREM2, said epitope being the same as or overlapping with the TREM2 epitope bound by antibody AL2p-62.

[0169] In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as an antibody selected from at least one antibody listed in Tables 2A to 2C, 3A to 3C, 4A to 4D, 5A to 5D, 6, and 7. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as an antibody selected from at least one antibody selected from the following: 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, 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 illustrative methods for locating the epitopes bound by the antibodies are provided in Morris (1996), “Epitope Mapping Protocols,” Methods in Molecular Biology, Vol. 66 (Humana Press, Totowa, NJ).In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-31. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-37. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-47. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-58. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-60. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-61. In some embodiments, the anti-TREM2 antibody of this disclosure binds to substantially the same TREM2 epitope as antibody AL2p-62.

[0170] In some embodiments, the anti-TREM2 antibody of this disclosure competes 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, and AL2p-19 for binding to TREM2. , 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 antibody of this disclosure competes with antibody AL2p-31 for binding to TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-37 for binding to TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-47 for binding to TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-58 for binding to TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-60 for binding to TREM2.In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-61 for binding to TREM2. In some embodiments, the anti-TREM2 antibody of this disclosure competes with antibody AL2p-62 for binding to TREM2.

[0171] In an exemplary competitive assay, cells immobilized with TREM2 or expressing TREM2 on their cell surface are incubated in a solution containing a first labeled antibody (which binds to TREM2 (e.g., in human or non-human primates)) and a second unlabeled antibody (tested to compete with the first antibody for binding to TREM2). The second antibody may be present in the hybridoma supernatant. As a control, cells immobilized with TREM2 or expressing TREM2 are incubated in a solution containing the first labeled antibody but without the second unlabeled antibody. After incubation under conditions allowing the first antibody to bind to TREM2, excess unbound antibody is removed, and the amount of label associated with the immobilized TREM2 or TREM2-expressing cells is measured. If the amount of label associated with the immobilized TREM2 or TREM2-expressing cells 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, the anti-TREM2 antibody of this disclosure comprises (a) a heavy chain variable region comprising at least one, two, or three HVRs, wherein the HVRs are selected from those listed in Tables 2A to 2C or from any of the following antibodies: HVR-H1, HVR-H2, and HVR-H3: 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-2 ... 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 L2p-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) light chain variable regions containing at least one, two or three HVRs.The HVR is selected from the antibodies listed in Tables 3A to 3C or selected from any of the following: HVR-H1, HVR-H2, and HVR-H3: 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 and any combination thereof. In some embodiments,HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprise EU or Kabat HVR, Chothia HVR, or Contact antibodies as shown in Tables 2A to 2C, 3A to 3C, 6, and 7, or selected from the following: 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- 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 antibody of this 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: 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: 122). (SEQ ID NO:123), and said antibody is not an antibody containing a heavy chain variable region containing the following: HVR-H1, containing the sequence YAFSSSWMN (SEQ ID NO:124); HVR-H2, containing the sequence RIYPGDGDTNYAQKFQG (SEQ ID NO:125); and HVR-H3, containing the sequence ARLLRNQPGESYAMDY (SEQ ID NO:126).

[0175] In some embodiments, the anti-TREM2 antibody of this disclosure 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 containing: HVR-L1, comprising the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the sequence KVSNRFS (SEQ ID NO: 130); ID NO:131); and HVR-L3, which contains the sequence SQSTRVPYT (SEQ ID NO:129).

[0176] In some embodiments, the anti-TREM2 antibody of this 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 X1 is S or W, X2 is S, L, or R, and X3 is S, D, H, Q, or E; and HVR-H2, comprising a sequence according to Formula II, 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. ; and HVR-H3, comprising a sequence according to Formula III, wherein X1 is Q or K, X2 is E, S or A, and X3 is M or H, and the light chain variable region comprises: HVR-L1, comprising a sequence according to Formula IV, 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; HVR-L2, comprising a sequence according to Formula V, wherein X1 is F, R, V or K; and HVR-L3, comprising the sequence: SQSTRVPYT(SEQ SEQ ID NO:129), and the antibody described herein is not an antibody comprising a heavy chain variable region containing the following: 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 containing the following: 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, the anti-TREM2 antibody of this 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) HVR-H1, comprising an HVR-H1 amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, or at least Amino acid sequences with 96%, at least 97%, at least 98%, at least 99%, or 100% identity: 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 having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the HVR-H2 amino acid sequence 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, AL2 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;(c)HVR-H3, comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence 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, AL2 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 the light chain variable domain thereof comprises one or more of the following: (a) HVR-L1, comprising an amino acid sequence of HVR-L1 having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% similarity to the HVR-L1 amino acid sequence of the antibody. Unique amino acid sequences: 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 having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the HVR-L1 amino acid sequence 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, AL2 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;(c)HVR-L3, comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the following antibodies' HVR-L3 amino acid sequences: 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, AL2 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, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130); HVR-L2, comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, comprising the amino acid sequence YAFSSDWMN (SEQ ID NO: 136); HVR-H2, comprising the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137); HVR-H3, comprising the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 138), and the light chain variable domain comprises HVR-L1, comprising the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139); HVR-L2, comprising the amino acid sequence KVSNRVS (SEQ ID NO: 140); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable region comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142); HVR-L2, comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGEGDTNYAGKFQG (SEQ ID NO: 143); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable domain comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142); HVR-L2, comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable domain comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); HVR-L2, comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises HVR-H1, comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132); HVR-H2, comprising the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133); HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable domain comprises HVR-L1, comprising the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144); HVR-L2, comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134); and HVR-L3, comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodiments, the anti-TREM2 antibody of this 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 frame regions selected from VH FR1, VH FR2, VH FR3, and VH FR4, wherein: VH FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 9-11, VH FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 12 and 13, VH FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 14 and 15, and VH FR4 comprises the sequence SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three, or four frame regions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein: VL FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 21 and 22, and VL FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 16; and / or the light chain variable region comprises one, two, three, or four frame regions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein: VL FR1 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 comprises a sequence selected from the group consisting of SEQ ID NO: 21 and 22, and VL FR3 comprises a sequence selected from the group consisting of SEQ ID NO: 16; and VH FR4 comprises a sequence selected from the group consisting of SEQ ID NO: 17-20. The sequence of group NO:23 and 24, and the VLFR4 contains a sequence selected from group NO:25 and 26.

[0179] In some embodiments, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable region of antibodies listed in Table 6A or selected from any of the following: 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-h50 ... 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 the light chain variable region of any of the antibodies listed in Table 7A or selected from the following: 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, A 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- 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. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from any of SEQ ID NO:27-71 and 91; and / or a light chain variable domain comprising an amino acid sequence selected from any of SEQ ID NO:92-113 and 118. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable region comprising an amino acid sequence selected from any of SEQ ID NO:27, 56, and 72-90; and / or a light chain variable domain comprising an amino acid sequence selected from any of SEQ ID NO:92, 104, and 114-117.

[0180] In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:28; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:28; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:28; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:28, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-2. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:92, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-2.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:28 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence SEQ ID NO:28 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-2 or in amino acid sequence SEQ ID NO:28 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:92 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-2 or the amino acid sequence SEQ ID NO:92 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:92 of antibody AL2p-2 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, 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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:29; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:29; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:29; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:29, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-3. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:92, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-3.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:29 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence SEQ ID NO:29 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-3 or in amino acid sequence SEQ ID NO:29 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:92 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-3 or the amino acid sequence SEQ ID NO:92 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:92 of antibody AL2p-3 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:30; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:30; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:30, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-4. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:92, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-4.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:30 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence SEQ ID NO:30 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-4 or in amino acid sequence SEQ ID NO:30 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:92 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-4 or the amino acid sequence SEQ ID NO:92 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:92 of antibody AL2p-4 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, 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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:31; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:31; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:31; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:31, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-7. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:95, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-7.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:31 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence SEQ ID NO:31 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-7 or in amino acid sequence SEQ ID NO:31 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:95 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-7 or the amino acid sequence SEQ ID NO:95 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:95 of antibody AL2p-7 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of SEQ ID NO:32; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of SEQ ID NO:32; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of SEQ ID NO:32. 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with 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, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:95, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-8.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence of SEQ ID NO:32 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO:32 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence of SEQ ID NO:32 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:95 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-8 or the amino acid sequence SEQ ID NO:95 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:95 of antibody AL2p-8 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:33; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 99%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:33; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:33; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:33, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-9. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:96, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-9.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the heavy chain variable domain amino acid sequence of antibody AL2p-9 or amino acid sequence SEQ ID NO:33 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-9 or amino acid sequence SEQ ID NO:33 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:33 of antibody AL2p-9 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:96 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-9 or the amino acid sequence SEQ ID NO:96 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:96 of antibody AL2p-9 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:34; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:34; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:34; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:34, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-10. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:97, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-10.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:34 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence SEQ ID NO:34 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-10 or in amino acid sequence SEQ ID NO:34 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:97 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-10 or the amino acid sequence SEQ ID NO:97 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:97 of antibody AL2p-10 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In specific embodiments, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:35; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:35; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:35; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:35, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-11. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:98, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-11.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:35 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence SEQ ID NO:35 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-11 or in amino acid sequence SEQ ID NO:35 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:98 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-11 or the amino acid sequence SEQ ID NO:98 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:98 of antibody AL2p-11 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:36; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:36; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:36, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-12. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:97, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-12.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:36 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence SEQ ID NO:36 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:36 of antibody AL2p-12 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:97 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-12 or the amino acid sequence SEQ ID NO:97 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:97 of antibody AL2p-12 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:37; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:37; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:37; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:37, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-13. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:95, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-13.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:37 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence SEQ ID NO:37 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:37 of antibody AL2p-13 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:95 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-13 or the amino acid sequence SEQ ID NO:95 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:95 of antibody AL2p-13 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-14. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:99, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-14.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:38 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence SEQ ID NO:38 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-14 or in amino acid sequence SEQ ID NO:38 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:99 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-14 or the amino acid sequence SEQ ID NO:99 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:99 of antibody AL2p-14 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:38, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-15. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:100, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-15.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:38 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence SEQ ID NO:38 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-15 or in amino acid sequence SEQ ID NO:38 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:100 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-15 or the amino acid sequence SEQ ID NO:100 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:100 of antibody AL2p-15 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In specific embodiments, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:39; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:39; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:39; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:39, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-16. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:96, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-16.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:39 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence SEQ ID NO:39 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:39 of antibody AL2p-16 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In specific embodiments, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:96 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-16 or the amino acid sequence SEQ ID NO:96 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:96 of antibody AL2p-16 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:40; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:40; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:40, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-17. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:98, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-17.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:40 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-17 or the amino acid sequence SEQ ID NO:40 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-17 or in amino acid sequence SEQ ID NO:40 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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 said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (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 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:98 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-17 or the amino acid sequence SEQ ID NO:98 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:98 of antibody AL2p-17 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, substitution, insertion, or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-17 or SEQ ID NO:98, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody AL2p-17, (b) the HVR-L2 amino acid sequence of antibody AL2p-17, and (c) the HVR-L3 amino acid sequence of antibody AL2p-17.

[0194] In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:41; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:41; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:41; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:41, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-18. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:96, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-18.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:41 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-18 or the amino acid sequence SEQ ID NO:41 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:41 of antibody AL2p-18 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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-18 or SEQ ID NO:41, including post-translational modifications of said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody AL2p-18, (b) the HVR-H2 amino acid sequence of antibody AL2p-18, and (c) the HVR-H3 amino acid sequence of antibody AL2p-18. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:96 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-18 or the amino acid sequence SEQ ID NO:96 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:96 of antibody AL2p-18 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-18 or SEQ ID NO:96, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody AL2p-18, (b) the HVR-L2 amino acid sequence of antibody AL2p-18, and (c) the HVR-L3 amino acid sequence of antibody AL2p-18.

[0195] In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 99%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; 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, the anti-TREM2 antibody of this disclosure comprises a heavy chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42, wherein the heavy chain variable domain comprises the HVR-H1, HVR-H2, and HVR-H3 amino acid sequences of the antibody AL2p-19. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain comprising an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:98, wherein the light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3 amino acid sequences of the antibody AL2p-19.In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:42 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-19 or the amino acid sequence SEQ ID NO:42 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the heavy chain variable domain amino acid sequence of antibody AL2p-19 or in amino acid sequence SEQ ID NO:42 are substituted, inserted, and / or deleted. In some embodiments, the substitution, insertion, or deletion occurs in a region outside the HVR (i.e., 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-19 or SEQ ID NO:42, including post-translational modifications of said sequence. In a specific embodiment, said VH comprises one, two, or three HVRs selected from: (a) the HVR-H1 amino acid sequence of antibody AL2p-19, (b) the HVR-H2 amino acid sequence of antibody AL2p-19, and (c) the HVR-H3 amino acid sequence of antibody AL2p-19. In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain (VL) sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence SEQ ID NO:98 and contains substitutions (e.g., conserved substitutions, insertions, or deletions relative to a reference sequence), but the anti-TREM2 antibody comprising said sequence retains its ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids in the light chain variable domain amino acid sequence of antibody AL2p-19 or the amino acid sequence SEQ ID NO:98 are substituted, inserted, and / or deleted. In some embodiments, a total of 1 to 5 amino acids in the light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO:98 of antibody AL2p-19 are substituted, inserted and / or deleted.In some embodiments, substitution, insertion, or deletion occurs in a region outside the HVR (i.e., in the FR region). In some embodiments, substitution, insertion, or deletion occurs in the FR region. Optionally, the anti-TREM2 antibody comprises the VL sequence of antibody AL2p-19 or SEQ ID NO:98, including post-translational modifications of said sequence. In a specific embodiment, the VL comprises one, two, or three HVRs selected from: (a) the HVR-L1 amino acid sequence of antibody AL2p-19, (b) the HVR-L2 amino acid sequence of antibody AL2p-19, and (c) the HVR-L3 amino acid sequence of antibody AL2p-19.

[0196] In some embodiments, the anti-TREM2 antibody of this disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; and / or the light chain variable domain comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 98%, at least 99%, or 100% identity with the amino acid sequence SEQ ID NO:42; 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%,...

Claims

1. An antibody that binds to a TREM2 protein, wherein 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 0. 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, AL2 p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-5 5. 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). ; 2. The antibody of claim 1, wherein: (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.

3. The antibody of any one of claims 1-2, 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.

4. 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, 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.

5. An antibody that binds to a TREM2 protein, wherein the antibody comprises the heavy chain variable region of the following antibodies: 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); 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).

6. The antibody of any one of claims 1-5, wherein the antibody is of the IgG class, the IgM class or the IgA class.

7. The antibody of claim 6, wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3 or IgG4 isotype.

8. The antibody of claim 7, wherein the antibody comprises one or more amino acid substitutions at residue positions in the Fc region selected from the group consisting of: 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.

9. The antibody of claim 8, wherein: (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; (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 an amino acid substitution 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.

10. The antibody of any one of claims 1-9, wherein the TREM2 protein is a human protein.

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