EA044134B1 - ANTI-TREM2 ANTIBODIES AND METHODS OF THEIR APPLICATION - Google Patents

Description

Cross reference to related applications

This application claims benefit to U.S. Provisional Application Nos. 62/541019, filed August 3, 2017, and 62/636095, filed February 27, 2018, which are incorporated herein by reference in their entirety.

Submission of a list of sequences as a text file in ASCII format

The contents of the following ASCII text file provided are incorporated herein by reference in their entirety: Sequence Listing Computer Readable Form (CRF) (file name: 735022001840SEQLIST.TXT, creation date: August 2, 2018, size: 238 kb).

Field of technology to which the present invention relates

The present invention relates to anti-TREM2 antibodies and the therapeutic use of such antibodies.

Prior Art

Trigger receptor expressed on myeloid cells-2 (TREM2) is an immunoglobulin-like receptor that is expressed, for example, on cells of myeloid origin.

TREM2 activity is associated with diseases, disorders and conditions such as frontotemporal dementia (FTD), Alzheimer's disease, Parkinson's disease, stroke/ischemic brain injury, multiple sclerosis and Nasu-Hakola disease (Neumann, H. et al. (2007) ), J. Neuroimmunol., 184:92-99; Takahashi, K. et al. (2005), J. Exp. Med., 201:647-657; Takahashi, K. et al. (2007), PLoS Med. , 4:el24; and Hsieh, C. L. et al. (2009), J. Neurochem., 109:1144-1156; Malm, T. M. et al., Neurotherapeutics., 2014 Nov 18; Paloneva, J. et al. (2002 ), Am. J. Hum. Genet., 71:656-662; and Paloneva, J. et al. (2003), J. Exp. Med., 198:669-675; Guerreiro, R. J. et al. (2013 ), JAMA Neurol., 70:78-84; Guerreiro, R. J. 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., 368:107-116; and Neumann, H. et al. (2013), N. Engl. J. Med. Med., 368:182-184; and Wang Y., Cell., 2015, 160(6):1061-71).

Accordingly, there is a need for therapeutic anti-TREM2 antibodies to treat diseases, disorders and conditions associated with reduced TREM2 activity.

All sources referenced herein, including patent applications and publications, are hereby incorporated by reference in their entirety.

Summary of the present invention

The present invention generally relates to compositions that contain antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind to a TREM2 protein, e.g., TREM2 of a mammal (e.g., any non-human mammal) or human TREM2, and methods of using such compositions.

Certain aspects of the present invention are based, at least in part, on the identification of anti-TREM2 antibodies with improved affinity and functional characteristics. Surprisingly, the functional characteristics of anti-TREM2 antibodies could not be predicted by increased affinity. In some embodiments, the anti-TREM2 antibodies of the present invention bind to both human and cynomolgus TREM2 with an affinity that is at least about 1-fold higher than an anti-TREM2 antibody selected from an anti-TREM2 antibody containing a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 27, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 56 (for example, antibody AL2p-h50);

an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103 (eg, antibody AL2p-h77); and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120 (eg, antibody AL2).

In some embodiments, the anti-TREM2 antibodies of the present invention bind to primary human immune cells with an affinity that is at least about 10 times greater than the affinity of an anti-TREM2 antibody selected from an anti-TREM2 antibody comprising a heavy chain variable region containing an amino acid the 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 comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the anti-TREM2 antibodies of the present invention collect

- 1 044134 cluster and activate the TREM2 signaling pathway in amounts that are at least about 1-fold higher than that of an anti-TREM2 antibody selected from an anti-TREM2 antibody containing a heavy chain variable region containing the amino acid sequence of 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 comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the anti-TREM2 antibodies of the present invention enhance the survival of immune cells in vitro to a greater extent than an anti-TREM2 antibody selected from an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 56;

an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the anti-TREM2 antibodies of the present invention may also have improved half-lives in vivo. In some embodiments, the anti-TREM2 antibodies of the present invention may also reduce plasma levels of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibodies of the present invention may also reduce soluble TREM2. In some embodiments, soluble TREM2 is reduced by any of about 10, 20, 30, 40, 50, or 60%.

Accordingly, certain aspects of the present invention relate to an antibody that binds to TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 (heavy chain hypervariable region-1) containing the sequence corresponding to formula I

YAFX1X2X3WMN, where X1 represents S or W,

X ₂ represents S, L or R, and

X ₃ is S, D, H, Q or E (SEQ ID NO: 121);

HVR-H2 containing the sequence corresponding to formula II

RIYPGX1GX ₂ TNYAX ₃ KX ₄ X ₅ G, where X1 represents D, G, E, Q or V,

X ₂ represents D or Q,

X3 represents Q, R, H, W, Y or G,

X4 represents F, R or W, and

X ₅ is Q, R, K or H (SEQ ID NO: 122); And

HVR-H3 containing the sequence corresponding to formula III

ARLLRNX1PGX2SYAX3DY, where X1 represents Q or K,

X ₂ represents E, S or A, and

X ₃ is M or H (SEQ ID NO: 123), and the antibody is not an antibody containing a heavy chain variable region containing 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).

Other aspects of the present invention provide an antibody that binds to TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises

HVR-L1 (light chain hypervariable region-1) containing the sequence corresponding to formula IV

RX1 SX2SLX3HSNX4YTYLH, where X1 represents S or T,

X ₂ represents Q, R or S,

- 2 044134

X ₃ represents V or I, and

X ₄ is G, R, W, Q or A (SEQ ID NO: 127);

HVR-L2 containing a sequence corresponding to formula V

KVSNRX1S where X1 is F, R, V or K (SEQ ID NO: 128); And

HVR-L3 containing a sequence corresponding to formula V

SQSTRVPYT (SEQ ID NO: 129), wherein the antibody is not an antibody containing a light chain variable region containing HVR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present invention provide an antibody that binds to TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 containing the sequence corresponding to formula I

YAFX1X ₂ X ₃ WMN, where X1 represents S or W,

X ₂ represents S, L or R, and

X ₃ is S, D, H, Q or E (SEQ ID NO: 121);

HVR-H2 containing the sequence corresponding to formula II

RIYPGX ₁ GX ₂ TNYAX ₃ KX ₄ X ₅ G, where X1 represents D, G, E, Q or V,

X2 represents D or Q,

X ₃ represents Q, R, H, W, Y or G,

X ₄ represents F, R or W, and

X ₅ is Q, R, K or H (SEQ ID NO: 122); And

HVR-H3 containing the sequence corresponding to formula III

ARLLRNX1PGX2SYAX3DY, where X ₁ represents Q or K,

X ₂ represents E, S or A, and

X ₃ is M or H (SEQ ID NO: 123); and the light chain variable region contains

HVR-L1 containing the sequence corresponding to formula IV

RX1SX2SLX3HSNX4YTYLH, where X1 represents S or T,

X ₂ represents Q, R or S,

X ₃ represents V or I, and

X ₄ is G, R, W, Q or A (SEQ ID NO: 127);

HVR-L2 containing a sequence corresponding to formula V

KVSNRX1S where X1 is F, R, V or K (SEQ ID NO: 128); And

HVR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129), wherein the antibody is not an antibody containing a heavy chain variable region containing 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), and including a light chain variable region containing HVR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR- L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 containing the sequence SQSTRVPYT (SEQ GO NO: 129).

Other aspects of the present invention provide an antibody that binds to TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 containing a sequence selected from the group consisting of SEQ ID NOs: 132 and 136,

HVR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 133, 135, 137 and 141, and

HVR-H3 containing a sequence selected from the group consisting of SEQ ID NO: 126 and 138; and/or the light chain variable region contains

HVR-L1 containing a sequence selected from the group consisting of 130, 139, 142 and 144,

- 3 044134

HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 131, 134 and 140, and

HVR-L3 containing the sequence SEQ ID NO: 129.

Other aspects of the present invention provide an antibody that binds to TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 containing the sequence SEQ ID NO: 132,

HVR-H2 comprising a sequence selected from the group consisting of SEQ ID NOs: 133, 135 and 141, and

HVR-H3 containing the sequence SEQ ID NO: 126; and/or the light chain variable region contains

HVR-L1 containing a sequence selected from the group consisting of 130, 142 and 144,

HVR-L2 comprising a sequence selected from the group consisting of SEQ ID NOs: 131 and 134, and

HVR-L3 containing the sequence SEQ ID NO: 129.

Other aspects of the present invention relate to an antibody that binds 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 HVR-H1, HVR-H2 and HVR-H3 AL2p-2 antibodies, 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 (as listed in Tables 2A-2C). Other aspects of the present invention relate to an antibody that binds to the TREM2 protein, wherein the antibody comprises a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises HVR-L1, HVR-L2 and HVR-L3 AL2p-5 antibodies, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p- 18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23,

AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38,

AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49,

AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60,

AL2p-61 or AL2p-62 (as listed in Tables 3A-3C). Other aspects of the present invention relate to an antibody that binds 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 HVR-H1, HVR-H2 and HVR-H3 AL2p-2 antibodies, 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 (as specified in Table 2A-2C); and the light chain variable region contains HVR-L1, HVR-L2 and HVR-L3 antibodies AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p- 25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p- 54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as listed in Tables 3A-3C).

Other aspects of the present invention provide an antibody that binds to the TREM2 protein, the antibody comprising a heavy chain variable region comprising HVR-H1, HVRH2 and HVR-H3 and a light chain variable region comprising HVR-L1, HVR-L2 and HVR -L3, where the antibody contains HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2 and HVR-L3 antibodies AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p- 19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p- 45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as listed in Tables 2A-2C and 3A-3C).

In some embodiments, which may be combined with any of the previously mentioned embodiments, the heavy chain variable region comprises one, two, three, or four framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4, wherein

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VH FR1 contains a sequence selected from the group consisting of SEQ ID NO: 9-11,

VH FR2 contains a sequence selected from the group consisting of SEQ ID NOs: 12 and 13,

VH FR3 contains a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and

VH FR4 contains the sequence SEQ ID NO: 16; and/or the light chain variable region comprises one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, wherein

VL FR1 contains a sequence selected from the group consisting of SEQ ID NO: 17-20,

VL FR2 contains a sequence selected from the group consisting of SEQ ID NOs: 21 and 22,

VL FR3 contains a sequence selected from the group consisting of SEQ ID NOs: 23 and 24, and

VL FR4 contains a sequence selected from the group consisting of SEQ ID NOs: 25 and 26.

In some embodiments, which may be combined with any of the above embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27-71 and 91; and/or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92-113 and 118.

In some embodiments, which may be combined with any of the above embodiments, the antibody comprises the antibody heavy chain variable region 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 listed in Table 6A); and/or the antibody contains the antibody light chain variable region 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 listed in Table 7A). In some embodiments, which may be combined with any of the above 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: 129);

(b) 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-NZ 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);

(c) HVR-H1 contains the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFHG (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);

(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: 129);

(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), HVR-L2 contains the amino acid sequence KVSNRFS (SEQ ID NO: 131) and HVR-L3 contains

- 5 044134 live amino acid sequence SQSTRVPYT (SEQ ID NO: 129);

(f) HVR-H1 contains the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVRH2 contains the amino acid sequence RIYPGGGDTNYAGKFQG (SeQ ID NO: 135), HVRH3 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); 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: 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, which may be combined with any of the above 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 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, which may be combined with any of the above 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 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). In some embodiments, which may be combined with any of the above embodiments, HVR-H1 contains the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137), HVR-H3 contains 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, which may be combined with any of the above embodiments, 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 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: 129). In some embodiments, which may be combined with any of the above 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 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: 129). In some embodiments, which may be combined with any of the above 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 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, which may be combined with any of the above 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 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 an amino acid

- 6 044134 lot 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).

Other aspects of the present invention relate to an antibody that binds 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 Kabat complementarity determining regions (Kabat CDRs); and/or the light chain variable region contains a Kabat CDR.

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194);

CDR-H2 containing the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); And

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises CDR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID nO: 130);

CDR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131); And

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194),

CDR-H2 containing the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), and

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region contains

CDR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130),

CDR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present invention relate to an antibody that binds 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 contains a Kabat CDR.

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).

In some embodiments, 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).

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 contains

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).

Other aspects of the present invention relate to an antibody that binds 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 contains a Kabat CDR.

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194);

CDR-H2 containing the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135); And

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chain variable region comprises CDR-L1 containing the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144);

- 7 044134

CDR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131); And

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194),

CDR-H2 containing the sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), and

Kabat CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region contains

CDR-L1 containing the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144),

CDR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present invention relate to an antibody that binds 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 contains a Kabat CDR.

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194);

CDR-H2 containing the sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133); And

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195).

In some embodiments, the light chain variable region comprises

CDR-L1 containing the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144);

CDR-L2 containing the sequence KVSNRRS (SEQ ID NO: 134); And

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194),

CDR-H2 containing the sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133), and

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region contains

CDR-L1 containing the sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144),

CDR-L2 containing the sequence KVSNRRS (SEQ ID NO: 134), and

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present invention relate to an antibody that binds 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 contains a Kabat CDR.

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194);

CDR-H2 containing the sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141); And

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195).

In some embodiments, the light chain variable region comprises

CDR-L1 containing the sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142);

CDR-L2 containing the sequence KVSNRRS (SEQ ID NO: 134); And

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the heavy chain variable region comprises

CDR-H1 containing the sequence SQWMN (SEQ ID NO: 194),

CDR-H2 containing the sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141), and

CDR-H3 containing the sequence LLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable region contains

CDR-L1 containing the sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142),

CDR-L2 containing the sequence KVSNRRS (SEQ ID NO: 134), and

CDR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

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

In some embodiments

- 8 044134 antibody contains the variable region of the heavy chain of the antibody 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 listed in Table 6A); and/or the antibody contains the antibody light chain variable region 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 listed in Table 7A).

In some embodiments, (a) the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 53 and/or the light chain variable region comprises the amino acid sequence of SEQ ID NO: 97;

(b) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 59 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 104;

(c) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 64 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 108;

(d) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 70 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 110;

(e) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 71 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 111;

(f) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 59 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 112; or (g) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 53 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 113.

In some embodiments, the antibody comprises an Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-156. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 146. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 147. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence sequence SEQ ID NO: 148. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence of SEQ ID NO: 149. In some embodiments, the antibody comprises an Fc region comprising the amino acid sequence SEQ ID NO: 150. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 151. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 152. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 152. 153. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 154. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 155. In some embodiments, the antibody contains an Fc region comprising the amino acid sequence of SEQ ID NO: 156. In some embodiments, the antibody contains 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 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 198 and 199, and a light chain comprising the amino acid sequence of SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 200 and 201, and a light chain comprising the amino acid sequence of SEQ ID NO: 214. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 202 and 203, and a light chain comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 204 and 205, and a light chain comprising the amino acid sequence of SEQ ID NO: 215. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 206 and 207, and a light chain comprising the amino acid sequence of SEQ ID NO: 216. In some

- 9044134 embodiments, the antibody contains 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 of SEQ ID NO: 218. In some embodiments, the antibody contains a heavy chain, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 210 and 211, and a light chain comprising the amino acid sequence of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 212 and 213, and a light chain containing the amino acid sequence of SEQ ID NO: 217.

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

Other aspects of the present invention relate to an antibody that binds to the TREM2 protein, the antibody comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 27, 56 and 72-90; and/or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 92, 104 and 114-117.

In some embodiments, the antibody comprises the antibody heavy chain variable region 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 listed in Table 6A); and/or the antibody contains the antibody light chain variable region 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 listed in Table 7A).

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

- 10 044134 activity of SEQ ID NO: 218. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 212 and 213, and a light chain comprising the amino acid sequence of SEQ ID NO: 217. In some embodiments, which may be combined with any of the above embodiments, the antibody is of the IgG class, the IgM class, or the IgA class. In some embodiments, which may be combined with any of the above embodiments, the antibody is of the IgG class and is of the IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments, which may be combined with any of the above embodiments, the antibody contains one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of C127S, L234A, L234F, L235A, L235E, S267E, K322A , L328F, A330S, P331S, E345R, E430G, S440Y and any combination thereof, with the remainder numbering following the EU or Kabat numbering scheme. In some embodiments, which may be combined with any of the above embodiments, (a) the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering follows the EU numbering scheme;

(b) the Fc region contains amino acid substitutions at positions E430G and P331S, with the residue position numbering following the EU numbering scheme;

(c) the Fc region contains amino acid substitutions at positions E430G and K322A, with the numbering of residue positions following the EU numbering scheme;

(d) the Fc region contains amino acid substitutions at positions E430G, A330S and P331S, with the residue position numbering following the EU numbering scheme;

(f) the Fc region contains amino acid substitutions at positions E430G, K322A, A330S and P331S, with the numbering of residue positions following the EU numbering scheme;

(f) the Fc region contains amino acid substitutions at positions E430G, K322A and A330S, with the residue position numbering following the EU numbering scheme;

(g) the Fc region contains amino acid substitutions at positions E430G, K322A and P331S, with the residue position numbering following the EU numbering scheme;

(h) the Fc region contains amino acid substitutions at positions S267E and L328F, with the residue position numbering following the EU numbering scheme;

(i) the Fc region contains an amino acid substitution at position C127S, wherein the residue position numbering follows the EU numbering scheme;

(j) the Fc region contains amino acid substitutions at positions E345R, E430G and S440Y, with the numbering of residue positions following the EU numbering scheme; 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 position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and K322A, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 146. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 147. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 148. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 148. in embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 149. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 150. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 151. In some embodiments, the Fc region comprises the amino acid sequence of SEQ ID NO: 151. The Fc region contains the amino acid sequence of SEQ ID NO: 152. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 153. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 154. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 154. the region contains the amino acid sequence of SEQ ID NO: 155. In some embodiments, the Fc region contains the amino acid sequence of SEQ ID NO: 156.

In some embodiments, which may be combined with any of the above embodiments, the TREM2 protein is a human protein. In some embodiments, which may be combined with any of the above embodiments, the TREM2 protein is a wild-type protein. In some embodiments, which may be combined with any of the above embodiments, the TREM2 protein is a naturally occurring variant. In some embodiments, which may be combined with any of the above embodiments, the antibody is an 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 variant of human TREM2.

- 11 044134 occurring in a disease, and optionally the antibody fragment is linked to 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 variant of human TREM2 occurring in a disease . In some embodiments, which may be combined with any of the above embodiments, the fragment is a Fab fragment, Fab', Fab'-SH, F(ab')2, Fv, or scFv. In some embodiments, which may be combined with any of the above embodiments, the antibody is a monoclonal antibody. In some embodiments, which may be combined with any of the above embodiments, the antibody is a humanized antibody.

In some embodiments, which may be combined with any of the above 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 facilitates transport across the blood-brain barrier;

(b) an antigen that facilitates transport across the blood-brain barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR- 1 and -2), diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopeptide and ANG1005;

(c) a pathogenic agent selected from the group consisting of pathogenic peptides or proteins, or pathogenic nucleic acids, wherein the pathogenic nucleic acids are antisense RNA with a GGCCCC repeat expansion (G2C4), the pathogenic proteins are selected from the group consisting of beta-amyloid , oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, tau protein (Tau), IAPP (islet amyloid polypeptide), alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72 ), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medina, prolactin, transthyretin, lysozyme, beta-2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, translation products associated with non-ATG repeats (RAN), peptides dipeptide repeats (DPR), glycine-alanine repeat peptides (GA), glycine-proline repeat peptides (GP), glycine-arginine repeat peptides (GR), proline-alanine repeat peptides (PA), ubiquitin, and peptides with proline-arginine repeats (PR);

(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) a protein, lipid, polysaccharide or glycolipid expressed on one or more tumor cells.

In some embodiments, which can be combined with any of the above embodiments, the antibody specifically binds to both human TREM2 and cynomolgus TREM2. In some embodiments, which can be combined with any of the above embodiments, the antibody has a dissociation constant (KD) with human TREM2 and/or cynomolgus TREM2 that is at least 1-fold lower than that of an anti-TREM2 variable-containing antibody a heavy chain region containing the amino acid sequence of SEQ ID NO: 27, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; or at least 1-fold lower than the value for an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103.

In some embodiments, which can be combined with any of the above embodiments, the antibody has a dissociation constant (KD) with human TREM2 that ranges from about 9 μM to about 100 pM or less than 100 pM, where the KD is determined at temperature approximately 25°C. In some embodiments, which can be combined with any of the above embodiments, the antibody has a dissociation constant (KD) with cynomolgus TREM2 that is in the range of about 50 nM to about 100 pM or less than 100 pM, where the KD is determined at temperature approximately 25°C. In some embodiments, which can be combined with any of the above embodiments, the antibody binds to primary human immune cells with an affinity that is at least 10 times greater than that of an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence SEQ ID NO: 27, and variable

- 12 044134 light chain region containing the amino acid sequence SEQ ID NO: 56; or at least 10 times higher than the value for an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103.

In some embodiments, which can be combined with any of the above embodiments, the antibody clusters and activates TREM2 signaling in an amount that is at least 1-fold greater than that of an anti-TREM2 antibody comprising a heavy chain variable region containing an amino acid the sequence SEQ ID NO: 27, and a light chain variable region containing the amino acid sequence SEQ ID NO: 56; or at least 1 times the value for an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103.

In some embodiments, which can be combined with any of the above embodiments, the antibody enhances the survival of immune cells in vitro to a greater extent than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27, and a variable a light chain region containing the amino acid sequence of SEQ ID NO: 56; or to a greater extent than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 103.

In some embodiments, which can be combined with any of the above embodiments, the antibody has an in vivo half-life that is less than that of the human IgG1 control antibody. In some embodiments, which can be combined with any of the above embodiments, the antibody reduces plasma levels of soluble TREM2 in vivo by an amount that is at least 25% greater than that of a human IgG1 control antibody. In some embodiments, which can be combined with any of the above embodiments, the antibody reduces plasma levels of soluble TREM2 in vivo by blocking cleavage, by inhibiting one or more metalloproteases, and/or by inducing internalization. In some embodiments, soluble TREM2 is reduced by any of about 10, 20, 30, 40, or 50%. In some embodiments, which may be combined with any of the above 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-hl9, AL2p-h21, AL2p-h22, AL2p-h23, AL2ph24, 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 to bind to TREM2. In some embodiments, which may be combined with any of the above embodiments, the antibody binds to substantially the same TREM2 epitope as the antibody selected from the group consisting of AL2p-h50, AL2p-2, AL2p-3, AL2p- 4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p- 29, AL2p-30, AL2p-31, AL2p-32, 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-hl9, 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, which may be combined with any of the above embodiments, the antibody binds to one or more amino acids from amino acid residues 149-157 in SEQ ID NO: 1. In some embodiments, which may be combined with any of the above embodiments implementation, the antibody binds to one or more amino acid residues selected from the group consisting of E151, D152 and E156 in SEQ ID NO: 1.

Other aspects of the present invention relate to an isolated nucleic acid containing a nucleic acid sequence encoding an antibody according to any of the above embodiments. Other aspects of the present invention relate to a vector containing a nucleic acid according to any of the above embodiments. Other aspects of the infusion

- 13 044134 of the present invention relate to an isolated host cell containing a vector according to any of the above embodiments. Other aspects of the present invention relate to a method for producing an antibody that binds to TREM2, which includes culturing cells according to any of the above embodiments so that the antibody is produced. In some embodiments, the method further includes isolating an antibody produced by the cell. Other aspects of the present invention relate to an isolated antibody that binds to TREM2 produced by a method according to any of the above embodiments. Other aspects of the present invention relate to a pharmaceutical composition comprising an antibody according to any of the above embodiments and a pharmaceutically acceptable carrier.

Other aspects of the present invention relate to a method of preventing, reducing the risk of or treating an individual with a disease, disorder or impairment selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, cognitive impairment, memory loss, damage spinal cord, traumatic brain injury, multiple sclerosis, chronic colitis, ulcerative colitis and cancer, comprising administering to the individual a therapeutically effective amount of an antibody in accordance with the preceding embodiments. In some embodiments, said disease, disorder or lesion is Alzheimer's disease.

Other aspects of the present invention relate to an antibody comprising an Fc region, wherein the antibody contains an amino acid substitution at position E430G and one or more amino acid substitutions at the Fc region at a residue position selected from the group consisting of L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S and any combination thereof, where the numbering of the remainders corresponds to the EU or Kabat numbering scheme. In some embodiments, (a) the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering follows the EU numbering scheme;

(b) the Fc region contains amino acid substitutions at positions E430G and P331S, with the residue position numbering following the EU numbering scheme;

(c) the Fc region contains amino acid substitutions at positions E430G and K322A, with the numbering of residue positions following the EU numbering scheme;

(d) the Fc region contains amino acid substitutions at positions E430G, A330S and P331S, with the residue position numbering following the EU numbering scheme;

(f) the Fc region contains amino acid substitutions at positions E430G, K322A, A330S and P331S, with the numbering of residue positions following the EU numbering scheme;

(f) the Fc region contains amino acid substitutions at positions E430G, K322A and A330S, with the residue position numbering following the EU numbering scheme;

(g) the Fc region contains amino acid substitutions at positions E430G, K322A and P331S, with the residue position numbering following the EU numbering scheme; 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 position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and K322A, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and A330S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region increases clustering without activating complement compared to a corresponding antibody comprising an Fc region that does not contain amino acid substitutions. In some embodiments, the antibody induces one or more activities of a target specifically bound by the antibody. In some embodiments, the antibody binds to TREM2.

It should be understood that any one, more, or all of the features of the various embodiments described herein can be combined to form other embodiments of the present invention. These and other aspects of the invention will be apparent to one skilled in the art. These and other embodiments of the invention are further described in the following detailed description.

- 14 044134

Brief description of graphic materials

In fig. 1A demonstrates increased agonist activity of the Fc variant of the aHTu-TREM2 antibody. Luciferase activity after a 6-hour culture with Fc-variant anti-TREM2 antibodies.

Fig. 1B demonstrates increased agonist activity of the Fc variant of the anti-TREM2 antibody. Luciferase activity after a 6-hour co-culture of the Fc variant antibody with BWZ reporter cells and THP-1 cells in a 1:1 ratio.

Fig. 2A shows C3b deposition induced by the Fc variant of the anti-TREM2 antibody. Fold change in C3b deposition on TREM2-expressing HEK cell line by AL2p Fc variants compared to human IgG1 isotype control antibody at 10 μg/ml.

Fig. 2B shows C3b deposition induced by the Fc variant of the anti-TREM2 antibody. Fold change in C3b deposition by affinity-mature AL2p variants with the listed Fc mutations compared to their original IgG1 Fc variant.

Fig. 3A demonstrates increased activity of soluble anti-TREM2 antibody.

Fig. 3B demonstrates increased activity of anti-TREM2 antibodies immobilized on the plate.

Fig. 3C shows the reporter activity of plate-coated affinity matured anti-TREM2 antibodies at 5 μg/ml (gray bars) compared to the parent humanized antibody Alp2-h50 (h50), the parent humanized antibody AL2p-77 (h77), and clones of the parent humanized antibody AL2p-77 (h77). AL2p antibodies (original variant AL2p msIgG1) (black bars). Clones in gray bars with black outlines represent variants of the AL2p-h50 antibody containing different amino acid substitutions.

Fig. 4A demonstrates increased activity of soluble anti-TREM2 antibody.

Fig. 4B demonstrates increased activity of anti-TREM2 antibody immobilized on the plate.

Fig. 5A shows sTREM2 secreted over 48 hours from primary human dendritic cells from donor 534 when incubated with anti-TREM2 or control antibodies.

Fig. 5B shows sTREM2 secreted over 48 hours from primary human dendritic cells from donor 535 when incubated with anti-TREM2 or control antibodies.

Fig. 6A shows no change in cell numbers when primary human dendritic cells from donor 534 are incubated with anti-TREM2 or control antibodies.

Fig. 6B shows no change in cell numbers when primary human dendritic cells from donor 535 are incubated with anti-TREM2 or control antibodies.

Fig. 7A shows plasma sTREM2 as % of baseline after a single injection of 15 mg/kg TREM2 antibodies AL2p-47 huIgG1, AL2p-47 huIgG1 ASPSEG, AL2p-58 huIgG1, or control huIgG1.

Fig. 7B shows plasma sTREM2 as % of baseline after a single injection of 15 mg/kg TREM2 antibodies AL2p-58 huIgG1, AL2p-58 huIgG1 PSEG, or huIgG1 control.

Fig. 7C shows plasma sTREM2 as % of baseline after a single injection of 15 mg/kg TREM2 antibodies AL2p-61 huIgG1 PSEG, AL2p-47 huIgG1, AL2p-58 huIgG1, or huIgG1 control.

Fig. 7D shows plasma sTREM2 in ng/ml after a single injection of 20 mg/kg TREM2 antibodies AL2p msIgG1, T21-9 msIgG1, or control msIgG1.

Fig. 8A and 8B depict increased viability (as increased cellular ATP) following stimulation of primary human macrophages (FIG. 8A) or human primary dendritic cells (FIG. 8B) from a single donor with TREM2 plate-captured antibodies compared to control IgG for 48 hours.

Fig. 8C, 8D, 8E and 8F depict increased viability (as increased cellular ATP) following stimulation of primary human dendritic cells from two donors (Figs. 8C and 8D) or human primary macrophages from two donors (Figs. 8E and 8F) with soluble AL2p-58 huIgG1 compared with control human IgG1 for 48 hours.

Fig. 9 shows Western blot analysis of Dap12 phosphorylation of peritoneal macrophages following administration of wild-type (WT) or TREM2 Bac-Tg mice with AL2p-58 huIgG1, AL2p-58 huIgG1 PSEG, or control huIgG1. Cell lysates were immunoprecipitated with anti-TREM2; the top series of bands demonstrates phosphotyrosine antibody staining, and the bottom series demonstrates total human TREM2 levels.

Detailed Description of the Invention

General techniques.

The methods and procedures described or referenced herein are generally well understood by those skilled in the art and are typically performed using conventional techniques, such as, for example, the widely used techniques described in Sambrook et al., Molecular Cloning: A Laboratory Manual, 3d edition (2001), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel et al. eds., (2003)); series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988), Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed.

- 15 044134 (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998), Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998), Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8), J. Wiley and Sons; Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); Antibodies (M. Zanetti and J.D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993).

Definitions.

As used herein, the term "prevention" includes the prevention of a particular disease, disorder or condition in an individual or its recurrence. An individual may be predisposed, susceptible to, or at risk of developing a particular disease, disorder, or condition prior to being diagnosed with the disease, disorder, or condition.

As used herein, an individual at risk for developing a particular disease, disorder, or condition may or may not have the disease or symptoms of a disease, and may or may not have exhibited the disease or symptoms of a disease prior to treatment methods described herein. At risk means that an individual has one or more risk factors, which are measurable parameters that are correlated with the development of a specific disease, disorder or condition, as known to those skilled in the art. An individual with one or more such risk factors has a higher likelihood of developing a particular disease, disorder or condition than an individual without one or more such risk factors.

As used herein, the term treatment refers to a clinical intervention aimed at changing the natural course of events for an individual receiving treatment for a clinical condition. Desirable effects of treatment include a reduction in the rate of progression, improvement or alleviation of a pathological condition, and remission or improved prognosis of a particular disease, disorder or condition. Treatment of an individual is successful, for example, if one or more symptoms associated with a particular disease, disorder or condition are alleviated or eliminated.

An effective amount refers to at least an amount effective in dosages and for periods of time necessary to achieve the desired therapeutic or prophylactic result. An effective amount may be provided in one or more administrations. The effective amount herein may vary depending on factors such as the disease state, age, sex and weight of the individual, and the ability of the treatment to produce a desired response in the individual. An effective amount is also one in which the therapeutically beneficial effects exceed any toxic or harmful effects of the treatment. For prophylactic use, beneficial or desirable results include results such as eliminating or reducing the risk, reducing the severity or delaying the onset of disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes observed during the progression of the disease. For therapeutic use, beneficial or desirable results include clinical results such as a reduction in one or more symptoms caused by a disease, an improvement in the quality of life of individuals suffering from a disease, a reduction in the dose of other drugs required to treat a disease, an enhancement of the effect of another drug, e.g. through targeted delivery, slowing disease progression, and/or increasing survival. An effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to provide prophylactic or therapeutic treatment, directly or indirectly. As understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, an effective amount may be considered in the context of the administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, the desired result can be or is achieved.

Individual for the purposes of treatment, prevention or risk reduction refers to any animal classified as a mammal, including humans, domestic, farm and zoo animals, sporting animals or pets such as dogs, horses, rabbits, cattle livestock, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual is a human.

As used herein, administration in combination with another compound or composition includes simultaneous administration and/or administration at a different time. Administration in combination also includes administration as a joint composition or administration as separate compositions, including at different dosing frequencies or intervals and using the same route of administration or different routes of administration.

The term immunoglobulin (Ig) is used herein interchangeably with antibody. The term antibody is used herein in its broadest sense and specifically covers monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies) formed from at least two intact antibodies, and antibody fragments, provided they exhibit the desired biological activity.

The main 4-chain portion of the antibody is a heterotetrameric glycoprotein consisting of two identical light (L) chains and two identical heavy (H) chains. When VH and VL pair, a single antigen-binding site is formed. The structure and properties of different classes of antibodies are described, for example, in 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.

The L chain of any vertebrate species can be classified into one of two distinct types, designated kappa (k) and lambda (λ), based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be classified into different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated alpha (α), delta (δ), epsilon (ε), gamma (γ) and mu (μ), respectively. The γ and α classes are further divided into subclasses (isotypes) based on relatively small differences in CH sequences and function, for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The subunit structures and three-dimensional configurations of the various classes of immunoglobulins are well known and described generally, for example, in Abbas et al., Cellular and Molecular Immunology, 4th ed. (W.B. Saunders Co., 2000).

Native antibodies are typically heterotetrameric glycoproteins, approximately 150,000 daltons, consisting of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by a single covalent disulfide bond, while the number of disulfide bonds between heavy chains varies among immunoglobulin isotypes. Each heavy and light chain also has evenly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (VH) at one end, followed by a series of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at the other end; the light chain constant domain is adjacent to the first heavy chain constant domain, and the light chain variable domain is adjacent to the heavy chain variable domain. Specific amino acid residues are believed to form the interface between the light chain and heavy chain variable domains.

An isolated antibody, such as an isolated anti-TREM2 antibody of the present invention, has been identified, separated and/or recovered from a component of the environment in which it was produced (eg, naturally or recombinantly). Preferably, the isolated polypeptide is not associated with all other contaminants from its production environment. Contaminants from its production environment, such as those produced by recombinant transfected cells, are materials that will typically interfere with research, diagnostic or therapeutic use of the antibody, and may contain enzymes, hormones, and other protein or non-protein solutes. In preferred embodiments, the polypeptide will be purified (1) to greater than 95 wt.% antibody as determined, for example, by the Lowry method, and in some embodiments to greater than 99 wt.%;

(2) to an extent sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence using a rotating beaker sequencer; or (3) to homogeneity by SDS-PAGE under non-reducing or reducing conditions using Coomassie Blue or preferably Silver staining.

The isolated antibody includes the antibody in situ in the recombinant T cells, since at least one component of the antibody's natural environment will not be present. Typically, however, the isolated polypeptide or antibody will be obtained through at least one purification step.

The variable region or variable domain of an antibody, such as the anti-TREM2 antibody of the present invention, refers to the amino-terminal domains of the heavy or light chain of the antibody. The heavy chain and light chain variable domains may be designated VH and VL, respectively. These domains are usually the most variable parts of the antibody (compared to other antibodies)

- 17 044134 antibodies of the same class) and contain antigen-binding sites.

The term variable refers to the fact that the sequences of certain segments of the variable domains differ significantly between antibodies, such as the anti-TREM2 antibodies of the present invention. The V domain mediates antigen binding and determines the specificity of a particular antibody for its particular antigen. However, variability is not distributed evenly across the entire extent of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) of both the light chain and heavy chain variable domains. The more highly conserved parts of the variable domains are called framework regions (FR). The variable domains of the native heavy and light chains each contain four FR regions, predominantly adopting a beta sheet configuration, connected by three HVRs that form loops connecting and in some cases forming part of the beta sheet structure. The HVRs on each chain are held in close proximity to each other by framework regions and, together with the HVRs of the other chain, participate in the formation of the antigen-binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). Constant domains are not directly involved in the binding of the antibody to the antigen, but exhibit various effector functions, such as the participation of the antibody in antibody-dependent cellular toxicity.

The term monoclonal antibody as used herein refers to an antibody, such as the anti-TREM2 monoclonal antibody of the present invention, derived from a population of substantially homogeneous antibodies, i.e. the individual antibodies composing the population are identical, except for possible natural mutations and/or post-translational modifications (eg, isomerization, amidation, etc.), which may be present in minor quantities. Monoclonal antibodies are highly specific, being targeted to a single antigenic site. Unlike polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single antigen determinant. In addition to their specificity, monoclonal antibodies have the advantage that they are synthesized in a hybridoma culture uncontaminated by other immunoglobulins. The definition of monoclonal refers to the nature of the antibody as being derived from an essentially homogeneous population of antibodies, and does not imply a requirement that the antibody be produced in any particular manner. For example, monoclonal antibodies for use in accordance with this invention can be prepared by various methods, including, for example, the hybridoma method (for example, 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, 2d ed. 1988); Hammerling et al., in Monoclonal Antibodies and T-Cell Hybridomas, 563-681 (Elsevier, N.Y., 1981)), recombinant DNA techniques (see, for example, US Pat. No. 4,816,567), phage display technologies (see, for example, Clackson et al., Nature, 352:624-628 (1991); Marks et al., J. Mol. Biol., 222:581-597 (1992); Sidhu et al., J. Mol. Biol., 338(2):299-310 (2004); Lee et al., J. Mol. Biol., 340(5):1073-1093 (2004);Fellouse, Proc. Nat'l Acad. Sci., USA, 101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods, 284(1-2):119-132 (2004), yeast presentation technologies (see, for example, WO 2009/036379A2; WO 2010105256; WO 2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013), and technologies for the production of human or human-like antibodies in animals having part or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, for example, 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); US Patent Nos. 5545807; 5545806; 5569825; 5625126; 5633425; and 5661016; 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., 14:845851 (1996) Neuberger, Nature Biotechnol., 14:826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol., 13:65-93 (1995).

The terms full-length antibody, intact antibody, or whole antibody are used interchangeably to refer to an antibody, such as the anti-TREM2 antibody of the present invention in its substantially intact form as opposed to an antibody fragment. More specifically, whole antibodies include antibodies with heavy and light chains, including the Fc region. The constant domains may be native sequence constant domains (eg, human native sequence constant domains) or amino acid sequence variants thereof. In some cases, an intact antibody may have one or more effector functions.

The antibody fragment includes a portion of an intact antibody, preferably an antigen binding and/or variable region of an intact antibody. Examples of antibody fragments include Fab fragments, Fab', F(ab') ₂ and Fv; diabodies; linear antibodies (see US patent 5641870, example 2; Zapata et al., Protein Eng., 8(10):1057-1062 (1995)); single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

Papain hydrolysis of antibodies, such as the anti-TREM2 antibodies of the present invention, produces

- 18 044134 two identical antigen-binding fragments, called Fab fragments, and a residual Fc fragment, the name of which reflects the ability to readily crystallize. The Fab fragment consists of the complete L chain together with an H chain variable domain (VH), and the first single heavy chain constant domain (CH1). Each Fab fragment is monovalent with respect to antigen binding, i.e. has one antigen binding site. Treatment of the antibody with pepsin produces one large F(ab')2 fragment, which approximately corresponds to two disulfide-linked Fab fragments that have different antigen-binding activities and retain the ability to cross-link antigen. Fab' fragments differ from Fab fragments by the presence of several additional residues at the carboxyl terminus of the CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is used herein to refer to Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab') ₂ antibody fragments were initially produced as pairs of Fab fragments with hinge cysteines in between. Other types of chemical bonding of antibody fragments are also known.

The Fc fragment contains the carboxy-terminal portions of both H chains, held together by disulfide bonds. The effector functions of antibodies are determined by the sequences of the Fc region, which is a region that is also recognized by Fc receptors (FcRs) present on certain types of cells.

Fv is a minimal antibody fragment containing a complete antigen recognition and binding site. This fragment consists of a dimer of variable region domains of one heavy and one light chain with strong non-covalent bonds. When these two domains are folded, six hypervariable loops are formed (3 loops in each of the H- and L-chains), the amino acid residues of which are involved in antigen binding and give the antibody antigen-binding specificity. However, even a single variable domain (or half of an Fv containing only three antigen-specific HVRs) has the ability to recognize and bind antigen, although with less affinity than the entire binding site.

Single-chain Fv, also abbreviated as sFv or scFv, are antibody fragments containing the VH and VL domains of the antibody linked into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the _VH and VL domains, which allows the sFv to form the desired structure for antigen binding. sFv is reviewed by Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-VerLAG-3, New York, p. 269-315 (1994).

Functional antibody fragments, such as the anti-TREM2 antibodies of the present invention, comprise a portion of an intact antibody, typically including an antigen binding region or variable region of an intact antibody or an F region of an antibody retaining or having a modified FcR binding capacity. Examples of antibody fragments include linear antibody, single chain antibody molecules, and multispecific antibodies formed from antibody fragments.

The term diabodies refers to small antibody fragments obtained by constructing sFv fragments (see previous paragraph) with short linkers (approximately 5-10 residues) between the VH and _VL domains so as to allow interchain, but not intrachain, pairing of the V domains , resulting in the formation of a bivalent fragment, i.e. fragment having two antigen-binding sites. Bispecific diabodies are heterodimers of two crossing-over fragments of sFv, in which the VH and VL domains of the two antibodies are located in different polypeptide chains. Diabodies are described in more detail, for example, in EP 404097; WO 93/11161; Hollinger et al., Proc. Nat'l Acad. Sci., USA, 90:6444-48 (1993).

As used herein, a chimeric antibody refers to an antibody (immunoglobulin), such as a chimeric anti-TREM2 antibody of the present invention, in which a portion of the heavy and/or light chain is identical or homologous to the corresponding sequence of antibodies derived from a specific species or belonging to specific class or subclass of antibodies, while the remaining chain(s) are identical or homologous to the corresponding sequences of antibodies derived from another species or belonging to a different class or subclass of antibodies, as well as fragments of such antibodies, provided that they exhibit desired biological activity (US Pat. No. 4,816,567; Morrison et al., Proc. Nat'l Acad. Sci., USA, 81:6851-55 (1984)). Chimeric antibodies of interest to the present invention include PRIMATIZED® antibodies, in which the antigen binding region of the antibody is derived from an antibody produced by, for example, immunizing macaques with the antigen of interest. As used herein, a humanized antibody is used as a subset of chimeric antibodies.

Humanized forms of non-human (eg, murine) antibodies, such as the humanized forms of anti-TREM2 antibodies of the present invention, are chimeric antibodies containing minimal sequence derived from non-human immunoglobulin. In one embodiment, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues from the recipient HVR are replaced with

- 19 044134 residues from an HVR of a non-human species (donor antibody), such as a mouse, rat, rabbit or non-human primate, having the desired specificity, affinity and/or functional activity. In some cases, human immunoglobulin FR residues are replaced with corresponding non-human residues. In addition, humanized antibodies may contain residues not present in the recipient or donor antibody. These modifications can be made to further improve the characteristics of the antibody, such as binding affinity. In general, a humanized antibody will contain substantially all of at least one, and typically two, variable domains in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin sequence, and all or substantially all of the FR regions belong to the human immunoglobulin sequence, although FR regions may include one or more individual substitutions of FR residues that improve characteristics of the antibody, such as binding affinity, isomerization, immunogenicity, and the like. The number of such amino acid substitutions in FR is typically no more than 6 in the H chain, and no more than 3 in the L chain. The humanized antibody will optionally also contain at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin.

Further details are given, for example, in 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.

A human antibody is an antibody having an amino acid sequence corresponding to an antibody, such as an anti-TREM2 antibody of the present invention, produced by a human and/or produced using any methods for producing human antibodies as disclosed herein. This definition of a human antibody excludes a humanized antibody containing non-human antigen-binding residues. Human antibodies can be produced using various methods known in the art, including phage display libraries. Hoogenboom and Winter, J. Mol. Biol, 227:381 (1991); Marks et al., J. Mol. Biol, 222:581 (1991) Also available for the production of human monoclonal antibodies are the methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5:368-74 (2001). Human antibodies can be produced by administering an antigen to a transgenic animal modified to produce such antibodies in response to an antigenic stimulus, but with the endogenous loci blocked, for example, immunized xenomice (see, for example, US Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE™ technology) . See also, for example, Li et al., Proc. Nat'l Acad. Sci., USA, 103:3557-3562 (2006), regarding human antibodies generated using human B-cell hybridoma technology. Alternatively, human antibodies can also be produced by using yeast libraries and methods disclosed, for example, in WO 2009/036379A2; WO 2010105256; WO 2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013).

The term hypervariable region, HVR or HV, as used herein, refers to regions of the variable domain of an antibody, such as an anti-TREM2 antibody of the present invention, that are sequence hypervariable and/or form structurally defined loops. Typically, antibodies contain six HVRs; three in VH (H1, H2, H3) and three in VL (L1, L2, L3). In native antibodies, H3 and L3 show the greatest diversity of the six HVRs, and H3 in particular is thought to play a unique role in conferring fine specificity to antibodies. See, for example, Xu et al., Immunity, 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology, 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003)). Truly natural camelid antibodies, consisting only of the heavy chain, are functional and stable in the absence of the light chain. See, for example, Hamers-Casterman et al., Nature, 363:446-448 (1993); and Sheriff et al., Nature Struct. Biol., 3:733-736 (1996).

A number of HVR definitions are used and are included in this document. In some embodiments, the HVRs may be Kabat's complementarity determining regions (CDRs), based on sequence variation and most commonly used (Kabat et al., supra). In some embodiments, the HVRs may be Chothia CDRs. The Chothia system is distinguished by its use of an arrangement of structural loops (Chothia and Lesk, J. Mol. Biol., 196:901-917 (1987)). In some embodiments, the HVRs may be AbM HVRs. AbM HVRs are a compromise between Kabat CDRs and Chotia structural loops, and are used in Oxford Molecular's AbM antibody modeling program. In some embodiments, the HVRs may be contact HVRs. Contact HVRs are based on the analysis of available structures of complex crystals. Remains of each of these HVRs are listed below.

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Loop I'm Kabat ABM Chotia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2 L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1 Н31-Н35В Н26-Н35В H26-H32 Н30-Н35В (numbering according to Kabat) H1 H31-H35 H26-H35 H26-H32 H30-H35 (numbering according to Chotia) H2 H50-H65 H50-H58 H53-H55 H47-H58 NZ N95-N102 N95-N102 N96-N101 N93-N101

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

Framework or FR residues are variable domain residues other than HVR residues as defined herein.

The phrases Kabat variable domain residue numbering or Kabat amino acid position numbering and variants thereof refer to the numbering system used for heavy chain variable domains or light chain variable domains of antibodies described in Kabat et al., supra. When using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids, corresponding to a shortening of, or insertion into, the FR or HVR variable domain. For example, a heavy chain variable domain may include the insertion of one amino acid (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc. according to Kabat) after residue 82 of the heavy chain. FR chains. Kabat numbering of residues can be determined for a given antibody by aligning regions of homology of the antibody sequence with a standard Kabat numbered sequence.

The Kabat numbering system is typically used when referring to a residue in the variable domain (approximately light chain residues 1-107 and heavy chain residues 1-113) (eg, Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). The EU or Kabat numbering system or EU index is typically used when referring to a residue in the constant region of an immunoglobulin heavy chain (eg, EU index described in Kabat et al., supra). The Kabat EU index refers to the residue numbering of the human IgG1 antibody EU. References to residue numbers in the antibody variable domain indicate residue numbering according to the Kabat numbering system. References to residue numbers in the antibody constant domain indicate residue numbering according to the EU or Kabat numbering system (for example, see US Patent Publication No. 2010-280227).

A human acceptor framework as used herein is a framework comprising an amino acid sequence of a VL or VH framework derived from a human immunoglobulin framework or a human consensus framework. A human acceptor framework derived from a human immunoglobulin framework or a human consensus framework may contain the same amino acid sequence thereof, or it may contain predetermined changes to the amino acid sequence. In some embodiments, the number of specified amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In cases where specified amino acid changes are present in VH, preferably such changes are only at three, two or one of the 71H, 73H and 78H positions; for example, the amino acid residues at these positions may be 71A, 73T and/or 78A. In one embodiment, the human VL acceptor framework is identical in sequence to a human immunoglobulin VL framework sequence or a human consensus framework sequence.

A human consensus framework is a framework that represents the most frequently occurring amino acid residues in selected human immunoglobulin VL or VH framework sequences. Typically, the selection of human immunoglobulin VL or VH sequences is made from a subset of variable domain sequences. Typically, a subset of sequences is a subset of Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for VL a subgroup that may be a kappa I, kappa II, kappa III, or kappa IV subgroup, as in Kabat et al., supra. Additionally, for VH, the subgroup may be subgroup I, subgroup II, or subgroup III, as in Kabat et al., supra.

An amino acid modification at a specific position, for example, an anti-TREM2 antibody of the present invention, refers to the substitution or deletion of a specific residue, or the insertion of at least one amino acid residue adjacent to a specific residue. Insertion next to

- 21 044134 by a specific residue means an insertion at a distance of one to two residues from it. The insertion may be N-terminal or C-terminal to a specific residue. The preferred amino acid modification herein is a substitution.

An affinity matured antibody, such as an affinity matured anti-TREM2 antibody of the present invention, is an antibody with one or more changes in one or more of its HVRs that result in increased affinity of the antibody for an antigen, compared to the parent antibody without such change(s). In one embodiment, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Affinity matured antibodies are prepared using procedures known in the art. For example, Marks et al., Bio/Technology, 10:779-783 (1992) describes affinity maturation by shuffling the VH and VL domains. Non-specific mutagenesis of HVR and/or framework residues is described, for example, in Barbas et al., Proc Nat. Acad. Sci., USA, 91:3809-3813 (1994); Schier et al., Gene, 169:147-155 (1995); Yelton et al., J. Immunol., 155:1994-2004 (1995); Jackson et al., J. Immunol., 154(7):3310-9 (1995); and Hawkins et al., J. Mol. Biol., 226:889-896 (1992).

As used herein, the term specifically recognizes or specifically binds refers to measurable and reproducible interactions, such as attraction or binding, between a target and an antibody, such as between an anti-TREM2 antibody and TREM2, that allows the presence of a target to be determined in the presence of a heterogeneous population of molecules, including biological molecules. For example, an antibody, such as an anti-TREM2 antibody of the present invention, that specifically or preferentially binds to a target or epitope is an antibody that binds that target or epitope with greater affinity, avidity, more readily and/or for a longer period of time , how it binds to other targets or other epitopes of the target. This definition also implies that, for example, an antibody (or fragment) that specifically or preferentially binds to a first target may or may not specifically or preferentially bind to a second target. As such, specific binding or preferential binding does not necessarily require (although it may include) exclusive binding. An antibody that specifically binds to a target may have an association constant of at least about 103 or 10 ⁴ M ^-1 , sometimes about 105 or 106 M ^-1 , in other cases about 106 or 10 ⁷ M ^-1 , from about 108 up to 10 ⁹ M ^-1 or from about 10 ¹⁰ to 10 ¹¹ M ^-1 or higher. Various immunoassay formats can be used to select antibodies that are specifically immunoreactive for a particular protein. For example, ELISA immunoassays are commonly used to select monoclonal antibodies that are specifically immunoreactive for a protein. See, for example, Harlow and Lane (1988), Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York, for immunoassay formats and conditions that can be used to determine specific immunoreactivity.

As used herein, an interaction between a TREM2 protein and a second protein includes, without limitation, protein-protein interaction, physical interaction, chemical interaction, binding, covalent binding, and ionic binding. As used herein, an antibody inhibits the interaction between two proteins when the antibody disrupts, weakens or completely eliminates the interaction between the two proteins. The antibody of the present invention, or a fragment thereof, inhibits the interaction between two proteins when the antibody or fragment thereof binds to one of the two proteins.

An agonistic antibody or activating antibody is an antibody that induces (eg, enhances) one or more activities or functions of an antigen upon binding of the antibody to the antigen.

An antagonistic antibody or blocking antibody is an antibody that weakens or eliminates (e.g., reduces) the binding of an antigen to one or more ligands following binding of an antibody to an antigen and/or that weakens or eliminates (e.g., reduces) one or more activities or functions of an antigen after binding of antibody to antigen. In some embodiments, antagonistic antibodies or blocking antibodies substantially or completely inhibit the binding of an antigen to one or more ligands and/or one or more activities or functions of the antigen.

Antibody effector functions refer to those biological activities that can be attributed to the Fc region (native Fc region sequence or Fc region amino acid sequence variant) of the antibody and vary depending on the isotype of the antibody.

The term Fc region is used herein to define the C-terminal region of an immunoglobulin heavy chain, including native sequence Fc regions and variant Fc regions. Although the boundaries of the immunoglobulin heavy chain Fc region may vary, the human IgG heavy chain Fc region is generally defined as extending from the amino acid residue at position Cys226, or Pro230, to its carboxyl terminus. The C-terminal lysine (residue 447 according to the EU or Kabat numbering system) of the Fc region may be removed, for example, during antibody production or purification, or by recombinant modification of the nucleic acid code

- 22 044134 heavy chain binding antibody. Accordingly, an intact antibody composition may contain antibody populations with K447 residues completely deleted, antibody populations with K447 residues not deleted, and antibody populations with a mixture of antibodies with and without the K447 residue. Suitable native sequence Fc regions for use in the antibodies of the present invention include human IgG1, IgG2, IgG3 and IgG4.

The native sequence Fc region contains an amino acid sequence identical to the native amino acid sequence of the Fc region. Native sequence human Fc regions include native sequence human IgG1 Fc region (non-A and A allotypes); Fc region of human IgG2 with native sequence; Fc region of human IgG3 with native sequence; and the Fc region of human IgG4 with the native sequence, as well as their natural variants.

The Fc region variant contains an amino acid sequence that differs from the native Fc region sequence by at least one amino acid modification, preferably one or more amino acid substitutions. Preferably, the Fc region variant has at least one amino acid substitution relative to the native Fc region sequence or the Fc region of the parent polypeptide, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in the native sequence Fc region or on the Fc region of the original polypeptide. The Fc region variant herein will preferably have at least about 80% homology to the native Fc region sequence and/or the Fc region of the parent polypeptide, and most preferably at least about 90% homology thereto, more preferably at least approximately 95% homology with them.

Fc receptor or FcR describes a receptor that binds to the Fc region of an antibody. A preferred FcR is a human FcR with a native sequence. Further preferred is an FcR that binds an IgG antibody (gamma receptor) and includes receptors of the FcyRI, FcyRII and FcyRIII subclasses, including allelic variants and alternative splice forms of these receptors, FcyRII receptors include FcyRIIA (activating receptor) and FcyRIIB (inhibitory receptor) , which have similar amino acid sequences, differing mainly in their cytoplasmic domains. The activating receptor FcyRIIA contains an immunoreceptor tyrosine-activated motif (ITAM) in its cytoplasmic domain. The inhibitory receptor FcyRIIB contains an immunoreceptor tyrosine inhibitory motif (ITIM) in its cytoplasmic domain (see, for example, M. Daeron, Annu. Rev. Immunol., 15:203-234 (1997)). Reviews of FcR are given 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 as used herein covers other FcRs, including those that will be identified in the future. FcRs may also increase the half-life of serum antibodies.

The in vivo FcRn binding and serum half-life of high affinity binding human FcRn polypeptides can be assessed, for example, in transgenic mice or transfected human cell lines expressing human FcRn, or in primates administered polypeptides having an Fc region variant. WO 2004/42072 (Presta) describes antibody variants with increased or decreased FcR binding. See also, for example, Shields et al., J. Biol. Chem., 9(2):6591–6604 (2001).

As used herein, percentage (%) amino acid sequence identity and homology to a peptide, polypeptide, or antibody sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a particular peptide or polypeptide sequence, after sequence alignment and introducing omissions if necessary to achieve the maximum percentage of sequence identity, and not taking into account any conservative substitutions when determining sequence identity. Alignment to determine percent amino acid sequence identity can be performed in a variety of ways available to those skilled in the art, for example, using publicly available computer software such as the BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) programs. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms known to those skilled in the art necessary to achieve maximum alignment over the full length of the sequences being compared.

An isolated nucleic acid molecule encoding an antibody, such as an anti-TREM2 antibody of the present invention, is a nucleic acid molecule that is identified and separated from at least one contaminating nucleic acid molecule with which it is typically associated in the environment in which it is produced . Preferably, the isolated nucleic acid is not associated with all components associated with the production environment.

- 23 044134

The isolated nucleic acid molecules encoding the polypeptides and antibodies herein are in a form different from the form or conditions in which they exist in nature. The isolated nucleic acid molecules are thus different from the nucleic acid encoding the polypeptides and antibodies of the present invention naturally present in cells.

The term vector, as used herein, shall refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a plasmid, which is a circular double-stranded DNA into which additional DNA segments can be ligated. Another type of vector is a phage vector. Another type of vector is a viral vector, in which additional DNA segments can be ligated into the viral genome. Some vectors are capable of autonomous replication in the host cell into which they are introduced (eg, bacterial vectors having a bacterial origin of replication and mammalian episomal vectors). Other vectors (eg, non-episomal mammalian vectors) can be integrated into the host cell genome upon introduction into the host cell and thus replicate along with the host genome. In addition, some vectors are capable of directing the expression of genes to which they are functionally linked. Such vectors are referred to herein as recombinant expression vectors or simply expression vectors. In general, expression vectors suitable for use in recombinant DNA techniques are often in the form of plasmids. In this description, plasmid and vector can be used interchangeably, since plasmid is the most widely used form of vector.

Polynucleotide or nucleic acid, as used interchangeably herein, refers to polymers of nucleotides of any length, and includes DNA and RNA. Nucleotides may be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or analogs thereof, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase or by a synthesis reaction. The polynucleotide may contain modified nucleotides, such as methylated nucleotides and analogs thereof. If present, modification of the nucleotide structure can be carried out before or after polymer assembly. Non-nucleotide components may be inserted into the nucleotide sequence. The polynucleotide may contain post-synthesis modification(s), such as conjugation to a tag. Other types of modifications include, for example, cap groups, replacement of one or more natural nucleotides with an analogue, intranucleotide modifications such as with uncharged bonds (e.g. methylphosphonates, phosphotriesters, phosphoamidates, carbamates, etc.) and with charged bonds (e.g. phosphorothioates, phosphorodithioates, etc.) containing side moieties such as, for example, proteins (e.g. nucleases, toxins, antibodies, signal peptides, poly-L-lysine, etc. ...), with intercalators (for example, acridine, psoralen, etc.), containing chelators (for example, metals, radioactive metals, boron, oxidizing metals, etc.), containing alkylating agents, with modified bonds ( for example, alpha-anomeric nucleic acids, etc.), as well as unmodified forms of polynucleotide(s). In addition, any of the hydroxyl groups typically present in sugars may be replaced, for example, by phosphonate groups, phosphate groups protected by standard protecting groups, or activated to prepare additional bonds with additional nucleotides, or may be conjugated to solid or semi-solid supports. The 5' and 3' terminal OHs can be phosphorylated or replaced by amines or organic cap moieties containing from 1 to 20 carbon atoms. Other hydroxyls can also be derivatized with standard protecting groups. The polynucleotides may also contain similar forms of ribose or deoxyribose sugars generally known in the art, including, for example, 2'-O-methyl-, 2'-O-allyl-, 2'-fluoro- or 2'-azidoribose, carbocyclic sugar analogues, α -anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogues, and basic nucleoside analogues such as methyl riboside. One or more phosphodiester linkages may be replaced by alternative linking groups. These alternative linking groups include, but are not limited to, embodiments in which the phosphate is replaced by P(O)S (thioate), P(S)S (dithioate), (O)NR2 (amidate), P(O)R, P(O )OR', CO, or CH2 (formacetal), wherein each R or R' independently represents H or substituted or unsubstituted alkyl (1-20 C), optionally containing an ether (-O-) bond, aryl, alkenyl, cycloalkyl , cycloalkenyl or araldyl. All bonds in a polynucleotide do not have to be identical. The foregoing description applies to all polynucleotides mentioned herein, including RNA and DNA.

A host cell includes an individual cell or cell culture that can be or has been the recipient of the vector(s) for incorporating polynucleotide inserts. Host cells include the progeny of a single host cell, and the progeny will not necessarily be completely identical (in morphology or genomic DNA complement) to the original parent cell due to natural, accidental, or intentional mutation. The host cell includes cells that have been transfected

- 24 044134 in vivo with the polynucleotide(s) of the present invention.

Carriers as used herein include pharmaceutically acceptable carriers, excipients or stabilizers that are non-toxic to the cell or mammal exposed thereto at the dosages and concentrations used. Often the physiologically acceptable carrier is an aqueous solution buffered to a certain pH value. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; toposaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or non-ionic surfactants such as TWEEN™, polyethylene glycol (PEG) and PLURONICS™.

The term "about" as used herein refers to the typical error range for the corresponding value, well known to one skilled in the art. Reference to an exemplary value or parameter herein includes (and describes) embodiments that relate to that value or parameter per se.

As used herein, the singular includes references to the plural unless the context clearly indicates otherwise. For example, a reference to an antibody is a reference to one to a plurality of antibodies, such as molar amounts, and includes equivalents thereof known to those skilled in the art, etc.

It should be understood that the aspect and embodiments of the present invention described herein include including, consisting of, and essentially consisting of aspects and embodiments.

Review.

The present invention relates to anti-TREM2 antibodies (eg, monoclonal antibodies) with improved affinity and functional characteristics; methods for obtaining and using such antibodies; pharmaceutical compositions containing such antibodies; nucleic acids encoding such antibodies; and host cells containing nucleic acids encoding such antibodies.

Accordingly, certain aspects of the present invention are based, at least in part, on the identification of anti-TREM2 antibodies capable of binding to both human and cynomolgus TREM2 with high affinity (see, for example, Examples 2 and 6); capable of binding to primary human immune cells with high affinity (see, for example, examples 1-3); having an increased ability to cluster and activate TREM2 signaling in vitro and in vivo (see, for example, examples 3, 7 and 11); and having an improved ability to increase the survival of immune cells in vitro (see, for example, examples 3 and 9). Advantageously, the anti-TREM2 antibodies of the present invention have been demonstrated to have extended half-lives in vivo and are capable of reducing plasma levels of soluble TREM2 in vitro and in vivo (see, for example, Examples 4, 8 and 10). In some embodiments, anti-TREM2 antibodies of the present invention induce, enhance, or otherwise enhance one or more TREM2 activities of the present invention. In some embodiments, the anti-TREM2 antibodies of the present invention have one or more of these increased affinity and functional characteristics compared to an anti-TREM2 antibody having a heavy chain variable region and an AL2p-h50 or AL2p-h77 antibody light chain variable region. Moreover, based on the results described in Examples 2-11, the functional characteristics of the affinity matured anti-TREM2 antibodies of the present invention cannot be predicted by their increased affinity for TREM2.

In some embodiments, anti-TREM2 antibodies of the present invention having high affinity for TREM2 exhibit the following functional properties: the ability to enhance TREM2 signaling in both soluble and plate-immobilized formats; 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) both in vitro by primary human myeloid cells and in vivo; and have relatively low polyspecific reactivity (PSR), which is a measure of nonspecific binding. As disclosed herein, affinity maturation can produce anti-TREM2 antibody variants having both increased binding affinity and increased PSR (ie, relatively high nonspecific binding). Although some antibodies of the present invention, such as AL2p-31 and AL2p-60, have higher binding affinity and better functional properties than other affinity matured antibody variants, they also exhibit high PSR and have high levels of background cell binding (see ., for example, example 12). Surprisingly, antibodies AL2p-58 and AL2p-47 exhibit both high binding affinity and relatively low PSR compared to other high-affinity antibody variants such as AL2p-31 and AL2p-60, while

- 25 044134 time also having the ability to enhance TREM2 signaling in both soluble and plate-immobilized formats, promote the survival of primary human macrophages and primary human dendritic cells; and reduce the production of soluble TREM2 (sTREM2) both in vitro by primary human myeloid cells and in vivo (see, for example, Examples 2-12). Based on these results, it was surprising that antibodies AL2p-58 and AL2p-47 exhibited high affinity for TREM2 and good functionality without exhibiting any significant PSR or background cell binding.

The results in Example 9 also unexpectedly demonstrated that the affinity matured anti-TREM2 antibodies of the present invention, such as AL2p-58 and AL2p-47, induce several hundred-fold increases in cell viability of primary human macrophages and dendritic cells (see, e.g., Table 14 and Fig. 8A and 8B). This functional property is unexpected since affinity matured anti-TREM2 antibodies, such as AL2p-58 and AL2p-47, show only an approximately 10-fold increase in binding affinity (KD) to human TREM2-Fc compared to parental mouse anti-TREM2 antibody AL2p (see, for example, Tables 1 and 8), but increase their ability to promote cell viability several hundred times. Moreover, it is surprising that antibody AL2p-37, which has approximately similar binding affinities to AL2p-58 and AL2p-47, has a relatively lower ability to promote cell viability than AL2p-58 and AL2p-47.

TREM2 proteins.

In one aspect, the present invention provides antibodies that bind to the TREM2 protein of the present invention with increased affinity and induce one or more TREM2 activities and/or enhance one or more TREM2 activities upon binding to a TREM2 protein expressed in a cell.

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

Trigger receptor expressed on myeloid cells-2 (TREM2) is variously called TREM-2, TREM2a, TREM2b, TREM2c, trigger receptor expressed on myeloid cells 2a, and trigger receptor expressed on monocytes-2. TREM2 is a membrane protein consisting of 230 amino acids. TREM2 is an immunoglobulin-like receptor expressed primarily on cells of myeloid origin, including but not limited to macrophages, dendritic cells, monocytes, skin Langerans cells, Kupffer cells, osteoclasts, and microglia. In some embodiments, TREM2 forms a receptor signaling complex with DAP12. In some embodiments, TREM2 is phosphorylated and signals through DAP12 (ITAM domain adapter protein). In some embodiments, TREM2 signaling results in subsequent activation of PI3K or other intracellular signals. On myeloid cells, Toll-like receptor (TLR) signals are important for activating TREM2 function, for example, in the context of response to infection. TLRs also play a key role in the pathological inflammatory response, such as TLRs expressed in macrophages and dendritic cells.

In some embodiments, an example human TREM2 amino acid sequence is provided below as SEQ ID NO: 1:

20 30 40 5060

MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS MKHWGRRKAW CRQLGEKGPC

£7 8 0. 90 100 11012 0

QRWSTHNLW LLSFLRRWNG STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT

13.0 14 £ 1510 160 170180

LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS RSLLEGEIPF PPTSILLLLA

190 200 210 220230

CIFLIKILAA SALWAAAWHG QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT

In some embodiments, human TREM2 is a preprotein that includes a signal peptide. In some embodiments, human TREM2 is a mature protein. In some embodiments, the mature TREM2 protein does not contain a signal peptide. In some embodiments, the mature TREM2 protein is expressed on the cell. In some embodiments, TREM2 comprises a signal peptide located at amino acid residues 1-18 of human TREM2 (SEQ ID NO: 1); extracellular immunoglobulin-like domain

- 26 044134 variable type (IgV), located in amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1); additional extracellular sequences located at amino acid residues 113-174 of human TREM2 (SEQ ID NO: 1); 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).

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

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

Ahtu-TREM2 antibodies.

Certain aspects of the present invention relate to antibodies (eg, monoclonal antibodies) that specifically bind TREM2 with increased affinity. In some embodiments, antibodies of the present invention bind mature TREM2 protein. In some embodiments, the antibodies of the present invention bind mature TREM2 protein, wherein the mature TREM2 protein is expressed on the cell. In some embodiments, the antibodies of the present invention bind TREM2 protein expressed on one or more human cells selected from human dendritic cells, human macrophages, human monocytes, human osteoclasts, human skin Langerans cells, human Kupffer cells, human microglia, and any combinations thereof .

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

In some embodiments, the anti-TREM2 antibodies of the present invention do not inhibit the growth of one or more natural immune cells. In some embodiments, the anti-TREM2 antibodies of the present invention bind to one or more primary immune cells with an affinity that is five times to 100 times higher than an anti-TREM2 antibody selected from an anti-TREM3 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 27, and containing a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present invention bind to one or multiple primary immune cells with an affinity that is at least five times higher, at least six times higher, at least seven times higher, at least eight times higher, at least nine times higher, at least 10 times higher, at least 11 times higher, at least 12 times higher, at least 13 times higher, at least 14 times higher, at least 15 times higher, at least 16 times higher, at least 17 times higher, at least 18 times higher, at least 19 times higher, at least 20 times higher, 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 than for an anti-TREM2 antibody selected from an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and comprising a light chain variable region comprising the amino acid sequence

- 27 044134 sequence SEQ ID NO: 56; aHTu-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the anti-TREM2 antibodies of the present invention bind to one or multiple primary immune cells with a mean fluorescence intensity (MFI) ranging from 100 to 1500, or greater than 1500. In some embodiments, the anti-TREM2 antibodies of the present invention bind to one or more primary immune cells with a mean fluorescence intensity (MFI) , which 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 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 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 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 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 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 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 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 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 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 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 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 at least 1160, 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 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 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 at least 1460, at least 1467, at least 1470, at least 1480, at least 1490, or at least 1500. In some embodiments, MFI is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for preparing and selecting antibodies that interact and/or bind specifically to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the anti-TREM2 antibodies of the present invention cluster and activate TREM2 signaling in amounts that are at least 0.5 times greater, at least 0.6 times greater, at least 0.7 times greater, at least 0.8 times larger, at least 0.9 times larger, at least 1 times larger, at least 2 times larger, at least 3 times larger, at least 4 times larger , at least 5 times more, at least 6 times more, at least 7 times more, at least 8 times more, at least 9 times more, or at least 10 times more, than for an anti-TREM2 antibody selected from an anti-TREM2 antibody containing a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 27, and containing a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody containing a heavy chain variable region containing the amino acid

- 28 044134 the sequence of SEQ ID NO: 119, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the anti-TREM2 antibodies of the present invention cluster and activate TREM2 signaling in amounts ranging from about 1-fold over control (FOC) to about 30-fold over control (FOC). In some embodiments, anti-TREM2 antibodies of the present invention cluster and activate TREM2 signaling in amounts that are at least 1-fold over control (FOC), at least 1.1-fold over control (FOC), at least 1.2-fold compared to control (FOC), at least 1.3-fold compared to control (FOC), at least 1.4-fold compared to control (FOC), at least at least 1.5 times the control (FOC), at least 1.6 times the control (FOC), at least 1.7 times the control (FOC), at least 1 .8-fold compared to control (FOC), at least 1.9-fold compared to control (FOC), at least 2-fold compared to control (FOC), at least 2.1-fold compared to control (FOC), at least 2.2-fold compared to control (FOC), at least 2.3-fold compared to control (FOC), at least 2.4-fold compared with control (FOC), at least 2.5-fold compared to control (FOC), at least 2.6-fold compared to control (FOC), at least 2.7-fold compared to control (FOC), at least 2.8 times the control (FOC), at least 2.9 times the control (FOC), 3 times the control (FOC), at least 3.1-fold compared to control (FOC), at least 3.2-fold compared to control (FOC), at least 3.3-fold compared to control (FOC), at least 3, 4-fold compared to control (FOC), at least 3.5-fold compared to control (FOC), at least 3.6-fold compared to control (FOC), at least 3.7- fold of control (FOC), at least 3.8 fold of control (FOC), at least 3.9 fold of control (FOC), 4 fold of control (FOC ), at least 4.1-fold compared to control (FOC), at least 4.2-fold compared to control (FOC), at least 4.3-fold compared to control (FOC), at least 4.4-fold compared to control (FOC), at least 4.5-fold compared to control (FOC), at least 4.6-fold compared to control (FOC), at least at least 4.7-fold compared to control (FOC), at least 4.8-fold compared to control (FOC), at least 4.9-fold compared to control (FOC), 5-fold compared to compared to control (FOC), at least 5.1-fold compared to control (FOC), at least 5.2-fold compared to control (FOC), at least 5.3-fold compared to control (FOC), at least 5.4-fold compared to control (FOC), at least 5.5-fold compared to control (FOC), at least 5.6-fold compared to control ( FOC), at least 5.7-fold compared to control (FOC), at least 5.8-fold compared to control (FOC), at least 5.9-fold compared to control (FOC) , 6-fold compared to control (FOC), at least 6.1-fold compared to control (FOC), at least 6.2-fold compared to control (FOC), at least 6.3 -fold over control (FOC), at least 6.4-fold over control (FOC), at least 6.5-fold over control (FOC), at least 6.6-fold compared to control (FOC), at least 6.7 times compared to control (FOC), at least 6.8 times compared to control (FOC), at least 6.9 times compared with control (FOC), 7 times compared to control (FOC), at least 7.1 times compared to control (FOC), at least 7.2 times compared to control (FOC), according to 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-fold compared to control (FOC), at least 7.7-fold compared to control (FOC), at least 7.8-fold compared to control (FOC), at least 7, 9-fold over control (FOC), 8-fold over control (FOC), at least 8.1-fold over control (FOC), at least 8.2-fold over control (FOC), at least 8.3-fold compared to control (FOC), at least 8.4-fold compared to control (FOC), at least 8.5-fold compared to control (FOC ), at least 8.6-fold compared to control (FOC), at least 8.7-fold compared to control (FOC), at least 8.8-fold compared to control (FOC), at least 8.9-fold compared to control (FOC), 9-fold compared to control (FOC), at least 9.1-fold compared to control (FOC), at least 9.2- fold of control (FOC), at least 9.3-fold of control (FOC), at least 9.4-fold of control (FOC), at least 9.5-fold of compared to control (FOC), at least 9.6-fold compared to control (FOC), at least 9.7-fold compared to control (FOC), at least 9.8-fold compared to con

- 29 044134 troll (FOC), at least 9.9-fold compared to control (FOC), at least 10-fold compared to control (FOC), at least 11-fold compared to control (FOC ), at least 12-fold compared to control (FOC), at least 13-fold compared to control (FOC), at least 14-fold compared to control (FOC), at least 15-fold compared to control (FOC), at least 16 times compared to control (FOC), at least 17 times compared to control (FOC), at least 18 times compared to control (FOC), at least 19 times the control (FOC), at least 20 times the control (FOC), at least 21 times the control (FOC), at least 22 times the control with control (FOC), at least 23 times compared to control (FOC), at least 24 times compared to control (FOC), at least 25 times compared to control (FOC), at least at least 26 times the control (FOC), at least 27 times the control (FOC), at least 28 times the control (FOC), at least 29 times the control (FOC), or at least 30-fold compared to control (FOC). In some embodiments, clustering and activation of TREM2 signaling is determined at 37°C using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for measuring clustering and activation of TREM2 signaling are described herein (for example, see Example 3).

In some embodiments, the anti-TREM2 antibodies of the present invention increase the survival of immune cells in vitro to an extent that is at least 1.5 times higher, at least 2 times higher, at least 3 times higher, at least 4 times higher, at least 5 times higher, at least 6 times higher, at least 7 times higher, at least 8 times higher, at least 9 times higher, at least 10 times higher, at least 11 times higher, at least 12 times higher, at least 13 times higher, at least 14 times higher, at least 15 times higher, at least 16 times higher , at least 17 times higher, at least 18 times higher, at least 19 times higher, at least 20 times higher, at least 21 times higher, at least 22 times higher, according to 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 than an anti-TREM2 antibody selected from an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27, and containing a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the ability of the anti-TREM2 antibodies of the present invention to enhance the survival of immune cells in vitro is determined by determining the area under the curve (AUC) of the growth curves of primary immune cells in culture that have been treated with the anti-TREM2 antibodies of the present invention.

In some embodiments, the anti-TREM2 antibodies of the present invention increase the survival of immune cells in vitro with an AUC that ranges from about 200,000 to about 1,500,000. In some embodiments, the anti-TREM2 antibodies of the present invention increase the survival of immune cells in vitro with AUC that is 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, according to 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, according 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, according 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, according 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, according to

- 30 044134 at least 680000, at least 690000, at least 700000, at least 710000, at least 720000, at least 730000, at least 740000, at least 750000, at least 760000, at least 770000, at least 780000, at least 790000, at least 800000, at least 810000, at least 820000, at least 830000, at least 840000, at least 850000, at least 860000, at least 870000, at least 880000, at least 890000, at least 900000, at least 910000, at least 920000, at least 930000, at least 940000, at least 950000, at least 960000, at least 970000, at least 980000, at least 990000, at least 1000000, at least 1010000, at least 1020000, at least 1030000, at least 1040000, at least 1050000, at least 1060000, at least 1070000, at least 1080000, at least 1090000, 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, at least 1300000, at least 1310000, at least 1320000, at least 1330000, at least 1340000, at least 1350000, at least 1360000, at least 1370000, at least 1380000, at least 1390000, at least 1400000, at least 1410000, at least 1420000, at least 1430000, at least 1440000, at least 1450000, at least 1460000, at least 1,470,000, at least 1,480,000, at least 1,490,000, or at least 1,500,000. In some embodiments, in vitro survival of immune cells is measured at 4°C using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for measuring immune cell survival in vitro are described herein (eg, see Example 3).

In some embodiments, the anti-TREM2 antibodies of the present invention have an in vivo half-life that is shorter than that of the human IgG1 control antibody. In some embodiments, the anti-TREM2 antibodies of the present invention have an in vivo half-life that is at least one and a half times lower, at least two times lower, at least three times lower, at least four times lower, at least five times lower, at least six times lower, at least seven times lower, at least eight times lower, at least nine times lower, at least 10 times lower, at least at least 11 times lower, at least 12 times lower, at least 13 times lower, at least 14 times lower, at least 15 times lower, at least 16 times lower, at least 17 times lower, at least 18 times lower, at least 19 times lower, at least 20 times lower, at least 21 times lower, at least 22 times lower, at least 23 times lower lower, at least 24 times lower, at least 25 times lower, at least 26 times lower, at least 27 times lower, at least 28 times lower, at least 29 times lower, at least 30 times lower, at least 35 times lower, at least 40 times lower, at least 45 times lower, at least 50 times lower, at least 55 times lower, at least at least 60 times lower, at least 65 times lower, at least 70 times lower, at least 75 times lower, at least 80 times lower, at least 85 times lower, at least 90 times lower, at least 95 times lower, or at least 100 times lower than an anti-TREM2 antibody selected from an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27, and comprising a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, the anti-TREM2 antibodies of the present invention have an in vivo half-life that ranges from about 0.1 day to about 10 days. In some embodiments, the anti-TREM2 antibodies of the present invention have an in vivo half-life of about 0.1 day, about 0.2 day, about 0.3 day, about 0.4 day, about 0.5 day, about 0 ,6 days, approximately 0.7 days, approximately 0.8 days, approximately 0.9 days, approximately 1 day, approximately 1.1 days, approximately 1.2 days, approximately 1.3 days, approximately 1.4 days, approximately 1.5 days, approximately 1.6 days, approximately 1.7 days, approximately 1.8 days, approximately 1.9 days, approximately 2 days, approximately 2.1 days, approximately 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,

- 31 044134 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 , approximately 7.5 days, approximately 7.6 days, approximately 7.7 days, approximately 7.8 days, approximately 7.9 days, approximately 8 days, approximately 8.1 days, approximately 8.2 days, approximately 8, 3 days, approximately 8.4 days, approximately 8.5 days, approximately 8.6 days, approximately 8.7 days, approximately 8.8 days, approximately 8.9 days, approximately 9 days, approximately 9.1 days, approximately 9.2 days, approximately 9.3 days, approximately 9.4 days, approximately 9.5 days, approximately 9.6 days, approximately 9.7 days, approximately 9.8 days, approximately 9.9 days, or approximately 10 days. In some embodiments, the in vivo half-life is measured using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for measuring half-life in vivo are described herein (eg, see Example 4).

The Ahtu-TREM2 antibodies of the present invention typically bind with high affinity to one or more TREM2 proteins expressed on the cell. For example, the TREM2 receptor is thought to require clustering on the cell surface for signal transduction. Thus, agonistic antibodies may have unique features to stimulate, for example, the TREM2 receptor. For example, they may have appropriate epitope specificity consistent with receptor activation, as well as the ability to induce or maintain receptor clustering on the cell surface. In addition, anti-TREM2 antibodies of the present invention may demonstrate the ability to bind TREM2 without simultaneously blocking the binding of one or more TREM2 ligands. The Ahtu-TREM2 antibodies of the present invention may further exhibit additive and/or synergistic functional interactions with one or more TREM2 ligands. Thus, in some embodiments, the maximum activity of TREM2 when bound to anti-TREM2 antibodies of the present invention in combination with one or more TREM2 ligands of the present invention may be greater (e.g., higher) than the maximum activity of TREM2 when exposed to saturating concentrations of a single ligand or saturating concentrations of a single antibody. Additionally, TREM2 activity at a given concentration of TREM2 ligand may be greater (eg, higher) in the presence of the antibody. Accordingly, in some embodiments, the anti-TREM2 antibodies of the present invention have an additive effect with one or more TREM2 ligands by enhancing one or more TREM2 activities upon binding to TREM2 protein. In some embodiments, the anti-TREM2 antibodies of the present invention synergistically interact with one or more TREM2 ligands to enhance one or more TREM2 activities. In some embodiments, the anti-TREM2 antibodies of the present invention increase the ability of one or more TREM2 ligands to induce one or more TREM2 activities, compared to the ability of one or more TREM2 ligands to induce one or more TREM2 activities in the absence of the antibody. In some embodiments, the anti-TREM2 antibodies of the present invention enhance one or more TREM2 activities in the absence of TREM2 clustering on the cell surface. In some embodiments, anti-TREM2 antibodies of the present invention enhance one or more activities of TREM2 by inducing or maintaining TREM2 clustering on the cell surface. In some embodiments, the anti-TREM2 antibodies of the present invention are clustered by one or more Fc gamma receptors expressed on one or more immune cells, including, but not limited to, B cells and microglial cells. In some embodiments, the enhancement of one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein is measured in primary cells, including, but not limited to, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, natural killer cells, osteoclasts, skin Langerans cells and Kupffer cells, or on cell lines, and the enhancement of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein is measured, for example, using an in vitro cell-based assay.

In vivo, the anti-TREM2 antibodies of the present invention can activate receptors through multiple potential mechanisms. In some embodiments, anti-TREM2 antibodies of the present invention have, due to appropriate epitope specificity, the ability to activate TREM2 in solution without the need for clustering by a secondary antibody immobilized on plates or clustering via Fcg receptors. In some embodiments, the anti-TREM2 antibodies of the present invention have human antibody isotypes, such as IgG2, that have, due to their unique structure, the innate ability to cluster receptors or hold receptors in a clustered configuration, thereby activating receptors, such as TREM2, without binding with the Fc receptor (e.g. White et al. (2015), Can

- 32 044134 cer Cell, 27, 138-148).

In some embodiments, the aHTu-TREM2 antibodies of the present invention cluster receptors (eg, TREM2) by binding to Fcg receptors on adjacent cells. Binding of the Fc constant portion of an IgG antibody to Fcg receptors results in antibody aggregation, and the antibodies in turn aggregate the receptors to which they bind via their variable region (Chu et al. (2008), Mol. Immunol., 45:3926-3933 ; and Wilson et al. (2011), Cancer Cell, 19, 101-113). Binding to the Fcg inhibitory receptor FcgR (FcgRIIB), which does not cause cytokine secretion, oxidative burst, increased phagocytosis, and enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), is often the preferred mode of antibody clustering in vivo, since binding to FcgRIIB is not associated with immune side effects. Any suitable assay described herein can be used to determine antibody clustering.

Other mechanisms can also be used to cluster receptors (eg TREM2). For example, in some embodiments, antibody fragments (eg, Fab fragments) fused together can be used to cluster receptors (eg, TREM2) similar to antibodies with Fc regions that bind Fcg receptors, as described above. In some embodiments, cross-linked antibody fragments (eg, Fab fragments) can function as agonistic antibodies if they induce cell surface receptor clustering and bind the corresponding epitope on a target (eg, TREM2).

In some embodiments, antibodies of the present invention that bind TREM2 protein may include antibodies that, due to their epitope specificity, bind TREM2 and activate one or more TREM2 activities. In some embodiments, such antibodies may bind to the TREM2 ligand binding site and mimic the action of one or more TREM2 ligands, or stimulate a target antigen to signal transduction by binding to one or more non-ligand binding site domains. In some embodiments, the antibodies do not compete with, or otherwise block, ligand binding to TREM2. In some embodiments, the antibodies, acting additively or synergistically with one or more TREM2 ligands, activate and/or enhance one or more activities of TREM2.

In some embodiments, the activities of TREM2 that can be induced and/or enhanced by anti-TREM2 antibodies of the present invention and/or one or more TREM2 ligands of the present invention include, but are not limited to, binding of TREM2 to DAP12; phosphorylation of DAP12; activation of Syk kinase; modulation of one or more pro-inflammatory mediators selected from IFN-β, IL-1a, IL-1e, TNF-α, IL-6, IL-8, CRP, CD86, MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2 , CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17 , IL-18 and IL-23, wherein said modulation may occur in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, cutaneous Langerans cells, Kupffer cells and microglial cells; recruitment of Syk to the DAP12/TREM2 complex; increased activity of one or more TREM2-dependent genes, wherein one or more TREM2-dependent genes include transcription factors nuclear factor of activated T cells (NFAT); increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; modulated expression of one or more stimulatory molecules selected from CD83, CD86 MHC class II, CD40, and any combination thereof, wherein CD40 may be expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and said dendritic cells may include dendritic cells bone marrow origin; increased memory; and reduction in cognitive impairment.

As used herein, an anti-TREM2 antibody of the present invention enhances one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein if it induces at least 2-fold, at least 3-fold, 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 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 An 18-fold, at least 19-fold, at least 20-fold or greater increase in one or more TREM2 activities compared to the levels of one or more TREM2 activities induced by binding of one or more TREM2 ligands to the TREM2 protein in the absence of anti- TREM2 antibodies. In some embodiments, the increase in one or more TEM2 activities can be measured using any suitable in vitro cell assay or suitable in vivo model described herein or known

- 33 044134 specialists, for example, by using a luciferase reporter assay to measure TREM2-dependent gene expression, using Western blotting to measure increases in TREM2-induced phosphorylation of downstream signaling partners such as Syk, or by using flow cytometry such as cell sorting fluorescence-activated scaffolding (FACS) to measure changes in levels of cell surface activation markers TREM2. Any in vitro cellular assay or suitable in vivo model described herein or known to those skilled in the art can be used to measure the interaction (eg, binding) between TREM2 and one or more TREM2 ligands.

In some embodiments, an anti-TREM2 antibody of the present invention enhances one or more TREM2 activities induced by binding of a TREM2 ligand to a TREM2 protein if it induces an increase that is in the range of about 1-fold to about 6-fold or greater than 6-fold -fold for ligand-induced TREM2-dependent gene transcription when used at concentrations ranging from about 0.5 nM to about 50 nM or greater than 50 nM and compared with the level of TREM2-dependent gene transcription induced by binding of TREM2 ligand to TREM2 protein in absence of anti-TREM2 antibody when TREM2 ligand is used at its EC ₅₀ concentration. In some embodiments, the increase in ligand-induced TREM2-dependent gene transcription is at least 1-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, 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 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-fold or greater when used at concentrations ranging from about 0.5 nM to about 50 nM or greater than 50 nM and compared to the level of TREM2-dependent gene transcription induced by binding of TREM2 ligand to TREM2 protein in the absence of anti-TREM2 antibody when TREM2 ligand is used at its concentration EC ₅₀ . In some embodiments, the anti-TREM2 antibody is used at a concentration of at least 0.5 nM, at least 0.6 nM, at least 0.7 nM, at least 0.8 nM, at least 0.9 nM , at least 1 nM, at least 2 nM, at least 3 nM, at least 4 nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, according at least 9 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, at least 30 nM, at least 35 nM, at least 40 nM, at least 45 nM, at least 46 nM, at least 47 nM, at least 48 nM, at least 49 nM or at least 50 nM. In some embodiments, the TREM2 ligand is phosphatidylserine (PS). In some embodiments, the TREM2 ligand is sphingomyelin (SM). In some embodiments, the increase in one or more TREM2 activities can be measured using any suitable in vitro cell assay or suitable in vivo model described herein or known to those skilled in the art. In some embodiments, a luciferase reporter assay is used to measure the fold increase in ligand-induced TREM2-dependent gene expression in the presence and absence of an antibody.

As used herein, an anti-TREM2 antibody of the present invention does not compete with, inhibit, or otherwise block the interaction (eg, binding) between one or more TREM2 ligands and TREM2 if it reduces the binding of the ligand to TREM2 by less than 20% at the saturating concentration of the antibody using any in vitro assay or cell culture assay described herein or known to those skilled in the art. In some embodiments, the anti-TREM2 antibodies of the present invention inhibit 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 saturating antibody concentration when used any in vitro assay or cell culture assay described herein or known to those skilled in the art.

In some embodiments, an anti-TREM2 antibody of the present invention induces one or more TREM2 activities. In some embodiments, the antibody induces one or more TREM2 activities upon binding to a TREM2 protein that is expressed on the cell. In some embodiments, the antibody induces one or more TREM2 activities upon binding to a soluble TREM2 protein not associated with the cell membrane. In some embodiments, the TREM2 protein is expressed on the surface of a cell. In some embodiments, soluble TREM2 protein (sTREM2) may be present without limitation in the extracellular environment, in blood serum, in cerebrospinal fluid (CSF), and in

- 34 044134 terstitial space in tissues. In some embodiments, soluble TREM2 (sTREM2) protein is noncellular. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-160 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-159 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-158 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-157 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-156 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 protein (sTREM2) of the present invention corresponds to amino acid residues 19-155 of SEQ ID NO: 1. In some embodiments, the soluble TREM2 (sTREM2) protein of the present invention corresponds to amino acid residues 19-154 of SEQ ID NO: 1.

In some embodiments, the soluble TREM2 (sTREM2) proteins of the present invention may be inactive variants of TREM2 cellular receptors. In some embodiments, sTREM2 may be present peripherally, such as in plasma, or in the brain of a subject.

In some embodiments, the anti-TREM2 antibodies of the present invention reduce plasma levels of soluble TREM2 in vivo. In some embodiments, the anti-TREM2 antibodies of the present invention reduce plasma levels of soluble TREM2 in vivo by blocking cleavage, by inhibiting one or more metalloproteases, or by inducing internalization.

In some embodiments, the anti-TREM2 antibodies of the present invention reduce plasma levels of soluble TREM2 in vivo by an amount ranging from about 5% greater to about 50% greater than the human control IgG1 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention reduce plasma levels of soluble TREM2 in vivo by an amount that is at least 5%, at least 6%, at least 7%, at least 8%, at least 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 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% exceeds the values for the human IgG1 control antibody.

In some embodiments, the anti-TREM2 antibodies of the present invention reduce plasma levels of soluble TREM2 in vivo such that the plasma level of soluble TREM2 as a percentage of baseline six 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 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 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 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 (eg, Fab) or a full-length antibody in monovalent form. Methods for measuring plasma levels of soluble TREM2 in vivo are described herein (for example, see Example 4).

- 35 044134

The Ahtu-TREM2 antibodies of the present invention can be used to prevent, reduce the risk of, or treat dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, group of tauopathies, NasuHakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, damage spinal cord, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease , osteitis deformans, solid and blood cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymph regional leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection (Cruzi infection), Pseudomonas aeruginosa infection, infection Leishmania donovani, group B Streptococcus infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type I and Pfeiffer bacillus (Haemophilus influenza), the methods proposed in the present invention also find use in inducing or promoting survival, maturation, functionality, migration, or proliferation of one or more immune cells in an individual in need thereof. The methods proposed in the present invention further find use in reducing the activity, functionality or survival of regulatory T cells, intratumoral immunosuppressive dendritic cells, intratumoral immunosuppressive macrophages, myeloid-derived suppressor cells, tumor-associated macrophages, acute myeloid leukemia (AML) cells, chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML) cells in an individual. The methods proposed in the present invention are further used to enhance memory and/or reduce cognitive impairment.

The Ahtu-TREM2 antibodies of the present invention can also be used for more effective wound care. In some embodiments, the anti-TREM2 antibodies of the present invention are monoclonal antibodies. Ahtu-TREM2 antibodies of the present invention can be tested for the induction of one or more TREM2 activities. Suitable assays may include Western blotting (eg for tyrosine phosphorylated DAP12 or threonine/serine phosphorylated PI3K kinase substrates), ELISA (eg for secreted interleukin or cytokine secretion), FACS (fluorescence activated cell sorting) (eg , for anti-TREM2 binding to TREM2), immunocytochemistry (eg, for tyrosine phosphorylated DAP12 or threonine/serine phosphorylated PI3K kinase substrates), reporter gene assays (eg, for TLR activation), enhanced survival and/or function of dendritic cells, macrophages , monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia, increased phagocytosis of apoptotic neurons, damaged synapses, beta-amyloid or its fragments, tau protein (Tau), IAPP (islet amyloid polypeptide), alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, protein S-IBM, non-ATG repeat-associated (RAN) translation products, peptides with dipeptide repeats (DPR), peptides with glycine-alanine repeats (GA), peptides with glycine-proline repeats (GP), glycine-arginine repeat peptides (GR), proline-alanine repeat peptides (PA) and proline-arginine repeat peptides (PR), neural debris, non-nervous tissue debris, bacteria, other foreign bodies, pathogenic proteins, pathogenic peptides, pathogenic nucleic acid, or tumor cells, macrophages, dendritic cells, skin Langerans cells, Kupffer cells, monocytes, osteoclasts and/or microglial cells, increased cytoskeletal remodeling, and decreased microglial proinflammatory responses, or others tests known to those skilled in the art.

- 36 044134

An antibody dependent on FcgR binding to activate target receptors may lose its agonist activity when modified to eliminate FcgR binding (see, for example, Wilson et al. (2011), Cancer Cell, 19, 101-113; Armor at al. (2003), Immunology, 40 (2003) 585-593); and White et al. (2015), Cancer Cell, 27, 138-148). As such, it is believed that an anti-TREM2 antibody of the present invention with appropriate epitope specificity can activate a target antigen with minimal undesirable effects when the antibody has a human IgG2 isotype Fc domain (CH1 and hinge region) or another type of Fc domain capable of preferentially binding inhibitory receptors FcgRIIB or its variant.

Typical examples of Fc antibody isotypes and modifications are presented in table. And lower. In some embodiments, the antibody has an Fc isotype as shown in Table 1. And lower.

Table A

Typical examples of Fc antibody isotypes capable of binding to Fc receptor gamma

Isotype Fc Mutation (EU numbering scheme) IgGl N297A IgGl D265A and N297A IgGl D270A IgGl L234AhL235A L234A and G237A L234A and L235A and G237A IgGl P238D and/or L328E and/or S267E/L328F and/or E233 and/or G237D and/or H268D and/or P271G and/or A330R IgGl P238D and L328E and E233D and G237D and H268D and P271G and A33OR IgGl P238D and L328E and G237D and H268D and P271G and A330R IgGl P238D and S267E and L328F and E233D and G237D and H268D and P271G and A330R IgGl P238D and S267E and L328F and G237D and H268D and P271G and A33OR IgG2 V234A and G237A IgG4 L235A and G237A and E318A IgG4 S228PhL236E IgG2/4 hybrid IgG2 a.k. 118-260 and IgG4 a.k. 261-447 H268Q and V309L; and A330S and RZZ1S IgGl C226S and C229S and E233P and L234V and L235A IgGl L234F and L235E and P331S IgG2 C232S or C233S IgG2 A330ShP331S IgGl S267E, and L328F S267E only IgG2 S267E and L328F IgG4 S267E and L328F IgG2 wild type heavy chain (WT HC) with kappa light chain (LC) NS C127S with kappa-LC kappa-LC C214S kappa-LC C214S and HC C233S kappa-LC C214S and HC C232S Any of the above mutations together with the A330S and P331S mutations wild type (WT) F(ab')2 IgGl fragment and any of the above mutations

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IgGl Replacement of heavy chain 1 (CH1) constant region and hinge region IgGl on CH1 and hinge region of IGg2 ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP (SEQ ID NO: 145) With Kappa-LC IgGl Any of the above mutations together with A330L/A330S and/or L234F and/or L235E and/or P331S IgGl, IgG2, or IgG4 Any of the above mutations together with M252Y and/or S254T and/or T256E Mouse IgGl For mouse models of the disease IgG4 Wild type (WT) IgGl Any of the above mutations together with E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, S440W and/or any combination thereof. IgG2 Any of the above mutations together with E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, S440W and/or any combination thereof.

In addition to the isotypes described in Table. And, without wishing to be bound by theory, it is believed that human antibodies with IgGl or IgG3 isotypes and mutant variants thereof (e.g., Strohl (2009), Current Opinion in Biotechnology, 2009, 20:685-691) bind to activating Fcg I receptors , PA, PS, ShA, ShV in humans and/or Fcg receptors I, III and IV in mice, may also act as agonistic antibodies in vivo, but may be associated with adverse effects associated with ADCC (antibody-mediated cellular cytotoxicity) . However, such Fcg receptors appear to be less accessible for antibody binding in vivo compared to the inhibitory Fcg receptor FcgRIIB (see, e.g., White et al. (2013), Cancer Immunol. Immunother., 62, 941-948; and Li et al (2011), Science, 333(6045):1030-1034).

In some embodiments, the antibody is of the IgG class, the IgM class, or the IgA class. In some embodiments, the antibody is of the IgGl, IgG2, IgG3, or IgG4 isotype.

In some embodiments, the antibody is of the IgG2 isotype. In some embodiments, the antibody comprises 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, DAP 12 activities, or both, independent of Fc receptor binding. In some embodiments, the antibody binds an inhibitory Fc receptor. In some embodiments, the inhibitory Fc receptor is an inhibitory Fc receptor gamma PV (FcyllB). 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 (eg, compared to a wild-type Fc region of the same isotype). In some embodiments, 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 (US 2007/0148167; Armor et al. (1999), Eur. J. Immunol., 29:2613 -2624; Armour et al. (2000), The Haematology Journal, 1 (Suppl 1):27; Armour et al. (2000), The Haematology Journal 1 (Suppl 1):27), C232S, and/or C233S ( White et al. (2015), Cancer Cell, 27, 138-148), S267E, L328F (Chu et al. (2008), Mol. Immunol., 45:3926-3933), M252Y, S254T, and/or T256E , with amino acid positions determined according to the EU or Kabat numbering schemes.

In some embodiments, the antibody is an IgG2 isotype with a heavy chain constant domain that contains the C127S amino acid substitution, wherein amino acid positions are defined according to the EU or Kabat numbering schemes (White et al. (2015), Cancer Cell, 27, 138-148 ; Lightle et al. (2010), PROTEIN SCIENCE, 19:753-762; and WO 2008079246).

In some embodiments, the antibody is an IgG2 isotype with a kappa light chain constant domain that contains the amino acid substitution C214S, wherein amino acid positions are defined according to the EU or Kabat numbering schemes (White et al. (2015), Cancer Cell, 27, 138- 148; Lightle et al (2010), PROTEIN SCIENCE, 19:753-762; and WO 2008079246).

-38044134

In some embodiments, the antibody is of the IgG1 isotype. In some embodiments, the antibody comprises a mouse IgG1 constant region. In some embodiments, the antibody comprises a human IgG1 constant region. In some embodiments, the human IgG1 constant region includes an Fc region. In some embodiments, the antibody binds an inhibitory Fc receptor. In some embodiments, the inhibitory Fc receptor is an inhibitory Fc receptor gamma IIB (FcyIIB). 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 (eg, compared to a wild-type Fc region of the same isotype). In some embodiments, 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), R. J. Biol. Chem ., 276, 6591-6604), L234A, L235A (Hutchins et al. (1995), Proc. Natl. Acad. Sci., USA, 92:11980-11984; Alegre et al. (1994), Transplantation, 57: 1537-1543, 31; Xu et al. (2000), Cell Immunol., 200:16-26), G237A (Alegre et al. (1994), Transplantation, 57:1537-1543, 31; Xu et al. ( 2000), Cell Immunol., 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E (McEarchern et al. (2007), Blood, 109:1185-1192), P331S (Sazinsky et al. ( 2008), Proc. Natl. Acad. Sci., USA, 2008, 105:20167-20172), S267E, L328F, A330L, M252Y, S254T, and/or T256E, where amino acid positions are determined in accordance with the EU numbering schemes or Kabata.

In some embodiments, the antibody includes an IgG2 isotype heavy chain constant domain 1 (CH1) and a hinge region (White et al. (2015), Cancer Cell, 27, 138-148). In some embodiments, the IgG2 isotype CH1 and hinge region comprise the amino acid sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP (SEQ ID NO: 145). In some embodiments, the Fc region of the antibody comprises amino acid substitution S267E, amino acid substitution L328F, or both, and/or amino acid substitution N297A or N297Q, wherein amino acid positions are defined in accordance with the EU or Kabat numbering schemes.

In some embodiments, the antibody is of the IgG4 isotype. In some embodiments, the antibody comprises a human IgG4 constant region. In some embodiments, the human IgG4 constant region includes an Fc region. In some embodiments, the antibody binds an inhibitory Fc receptor. In some embodiments, the inhibitory Fc receptor is an inhibitory Fc receptor gamma IIB (FcyIIB). 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 (eg, compared to a wild-type Fc region of the same isotype). In some embodiments, 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 amino acid positions are determined in accordance with the EU or Kabat numbering schemes.

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

In some embodiments, the antibody comprises a mouse IgG4 constant region (Bartholomaeus et al. (2014), J. Immunol., 192, 2091-2098).

In some embodiments, the Fc region further comprises one or more additional amino acid substitutions selected from A330L, L234F, L235E, or P331S according to EU or Kabat numbering; and any combination thereof.

In some embodiments, the antibody contains one or more amino acid substitutions in the Fc region at residue positions selected from C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any of these combinations, with residue numbering following the EU or Kabat numbering schemes. In some embodiments, the Fc region contains an amino acid substitution at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions E430G and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region comprises an amino acid substitution at positions E430G and K322A, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions E430G, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions E430G, K322A, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions E430G, K322A, and A330S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region comprises an amino

- 39 044134 acid substitution in positions E430G, K322A and P331S, whereby the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions S267E and L328F, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at position C127S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains an amino acid substitution at positions E345R, E430G, and S440Y, wherein the residue position numbering follows the EU numbering scheme.

Additional IgG mutations.

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

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

Typical examples of anti-TREM2 antibodies.

In some embodiments, an isolated anti-TREM2 antibody of the present invention binds to TREM2 with high affinity and enhances one or more TREM2 activities induced by the binding of one or more TREM2 ligands to the TREM2 protein relative to one or more TREM2 activities induced by the binding of one or more multiple TREM2 ligands with TREM2 protein in the absence of isolated antibody. In some embodiments, an 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. Typical examples of descriptions of such antibodies are given in the description of the present invention. In some embodiments, the antibody is a bispecific antibody that recognizes a first antigen and a second antigen.

In some embodiments, the anti-TREM2 antibodies of the present invention bind to human TREM2, or a homolog thereof, including, without limitation, mammalian (e.g., non-human mammalian) TREM2 protein, mouse TREM2 protein (Uniprot Accession No. Q99NH8), rat TREM2 protein ( Uniprot accession no. D3ZZ89), rhesus macaque TREM2 protein (Uniprot accession no. F6QVF2), cynomolgus macaque TREM2 protein (NCBI accession no. and canine TREM2 protein (Uniprot accession no. E2RP46). In some embodiments, the anti-TREM2 antibodies of the present invention specifically bind to human TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention specifically bind to cynomolgus TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention specifically bind to both human TREM2 and cynomolgus TREM2. In some embodiments, anti-TREM2 antibodies of the present invention induce at least one TREM2 activity of the present invention.

Anti-TREM2 antibody binding regions.

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

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In some embodiments, the anti-TREM2 antibodies of the present invention bind amino acid residues E151, D152, and E156 of SEQ ID NO: 1.

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

In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of at least one antibody selected from any of the antibodies listed in table. 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6A, 6B, 7A and 7B. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of at least one antibody selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p- 20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-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-hl9, 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 antibodies of the present invention competitively inhibit the binding of the AL2p-31 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-37 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-47 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-58 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-60 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-61 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention competitively inhibit the binding of the AL2p-62 antibody.

In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with a TREM2 epitope bound by at least one antibody selected from any of the antibodies listed in Table 1. 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6A, 6B, 7A and 7B. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps 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-hl9, AL2p-h21, AL2ph22, 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 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-31 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-37 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-47 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-58 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-60 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-61 antibody. In some embodiments, anti-TREM2 an

- 41 044134 antibodies of the present invention bind to a human TREM2 epitope that is the same as or overlaps with the TREM2 epitope bound by the AL2p-62 antibody.

In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by at least one antibody selected from any of the antibodies listed in Table 1. 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6A, 6B, 7A and 7B. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by at least one antibody selected from AL2ph50, 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. For a detailed description of typical methods for mapping the epitope to which an antibody binds, see Morris (1996) Epitope Mapping Protocols, in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ). In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-31 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-37 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-47 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-58 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-60 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-61 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention bind substantially the same TREM2 epitope as that bound by the AL2p-62 antibody.

In some embodiments, the anti-TREM2 antibodies of the present invention compete with one or more antibodies 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 and any combination thereof, for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-31 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-37 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-47 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-58 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-60 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-61 antibody for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention compete with the AL2p-62 antibody for binding to TREM2.

In a typical example of a competition assay, immobilized TREM2 or cells expressing TREM2 on the cell surface are incubated in a solution containing a first labeled antibody that binds to TREM2 (eg, human or non-human primate) and a second unlabeled antibody that tests for its ability to compete with the first antibody for binding to TREM2. The second antibody may be present in the supernatant of the hybridoma. As a control, immobilized TREM2 or TREM2-expressing cells were incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to TREM2, excess unbound antibody is removed and the amount of label bound to immobilized TREM2 or TREM2-expressing cells is measured. If the amount of label associated with immobilized TREM2 or cells expressing TREM2 is significantly reduced in the test sample compared to con

- 42 044134 troll 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, ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

Anti-TREM2 Antibody Light Chain and Heavy Chain Variable Regions In some embodiments, the anti-TREM2 antibodies of the present invention comprise (a) a heavy chain variable region comprising at least one, two, or three HVRs selected from HVR-H1, HVR- H2 and HVR-H3 of any of the antibodies listed in table. 2A-2C, or selected from 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 and any combination thereof; and/or (b) a light chain variable region comprising at least one, two or three HVRs selected from HVR-H1, HVR-H2 and HVR-H3 of any of the antibodies listed in table. 3A-3C, or selected from AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15 , AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p -28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-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 include EU or Kabat HVR, Chotia HVR, or contact HVR sequences as set forth in Table 1. 2A-2C, 3A-3C, 6A, 6B, 7A and 7B, or from an antibody selected from 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-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.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 containing the sequence corresponding to formula I

YAFX1X2X3WMN, where X1 represents S or W,

X ₂ represents S, L or R, and

X ₃ is S, D, H, Q or E (SEQ ID NO: 121);

HVR-H2 containing the sequence corresponding to formula II

RIYPGX1GX ₂ TNYAX ₃ KX ₄ X ₅ G, where X1 represents D, G, E, Q or V,

X ₂ represents D or Q,

X3 represents Q, R, H, W, Y or G,

X4 represents F, R or W, and

X ₅ is Q, R, K or H (SEQ ID NO: 122); And

HVR-H3 containing the sequence corresponding to formula III

ARLLRNX1PGX2SYAX3DY, where X1 represents Q or K,

X ₂ represents E, S or A, and

X ₃ is M or H (SEQ ID NO: 123), and the antibody is not an antibody containing a heavy chain variable region containing 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).

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the light chain variable region comprises

HVR-L1 containing the sequence corresponding to formula IV

RX1 SX2SLX3HSNX4YTYLH, where X1 represents S or T,

X ₂ represents Q, R or S,

X ₃ represents V or I, and

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X4 is G, R, W, Q or A (SEQ ID NO: 127);

HVR-L2 containing a sequence corresponding to formula V

KVSNRX1S where X1 is F, R, V or K (SEQ ID NO: 128); And

HVR-L3 containing a sequence corresponding to formula V

SQSTRVPYT (SEQ ID NO: 129), wherein the antibody is not an antibody containing a light chain variable region containing HVR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises

HVR-H1 containing the sequence corresponding to formula I, where X1 represents S or W, X ₂ represents S, L or R and X ₃ represents S, D, H, Q or E;

HVR-H2 containing a sequence corresponding to formula II, where X1 is D, G, E, Q or V, X ₂ is D or Q, X ₃ is Q, R, H, W, Y or G, X ₄ is F, R or W and X ₅ is Q, R, K or H; And

HVR-H3, containing a sequence corresponding to formula III, where X1 represents Q or K, X ₂ represents E, S or A and X ₃ represents M or H, and the light chain variable region contains

HVR-L1 containing the sequence corresponding to formula IV, where X1 represents S or T, X ₂ represents Q, R or S, X ₃ represents V or I and X represents G, R, W, Q or A;

HVR-L2 containing a sequence corresponding to formula V, where X1 represents F, R, V or K; And

HVR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129), wherein the antibody is not an antibody containing a heavy chain variable region containing 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), and including a light chain variable region containing HVR-L1 containing the sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR- L2 containing the sequence KVSNRFS (SEQ ID NO: 131), and HVR-L3 containing the sequence SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises one or more of (a) HVR-H1 comprising an amino acid sequence of 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%, according to 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 HVR-H1 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;

(b) HVR-H2 comprising an amino acid sequence of 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 HVR-H2 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; and (c) HVR-H3 comprising an amino acid sequence of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least

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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 HVR-H3 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; and/or the light chain variable domain comprises one or more of (a) HVR-L1 comprising an amino acid sequence of 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 HVR-L1 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 ;

(b) HVR-L2 comprising an amino acid sequence of 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 HVR-L1 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; and (c) HVR-L3 comprising an amino acid sequence of at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 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 HVR-L3 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.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise 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 contains HVR-L1, including 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 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises HVRH1 comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), HVR-H2 comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), HVRH3, including the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region contains HVR-L1, including the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), HVR-L2, including 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 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain,

- 45 044134 wherein the variable region of the heavy chain contains HVR-H1, including the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), HVR-H2, including the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137), HVR-H3, including the amino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 138), and the light chain variable region 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 antibodies of the present invention comprise 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 contains HVR-L1, including 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 antibodies of the present invention comprise 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 RIYPGEGDTNYAGKFQG (SEQ ID NO: 143), HVR-H3, comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), and the light chain variable region contains HVR-L1, including 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 antibodies of the present invention comprise 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 contains HVR-L1, including 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 antibodies of the present invention comprise 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 contains HVR-L1, including 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 antibodies of the present invention comprise a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises one, two, three, or four framework regions selected from VH FR1, VH FR2, VH FR3, and VH FR4, wherein VH FR1 contains a sequence selected from the group consisting of SEQ ID NOs: 9-11, VH FR2 contains a sequence selected from the group consisting of SEQ ID NOs: 12 and 13, VHFR3 contains a sequence selected from the group consisting of SEQ ID NOs: 14 and 15, and VH FR4 contains the sequence SEQ ID NO: 16; and/or the light chain variable region contains one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, wherein VL (L) FR1 contains a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 contains a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, VL FR3 contains a sequence selected from the group consisting of SEQ ID NOs: 23 and 24, and VL FR4 contains the sequence, selected from the group consisting of SEQ ID NOs: 25 and 26.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise the heavy chain variable region of any of the antibodies listed in Table 1. 6A, or 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,

- 46 044134

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 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 antibodies of the present invention comprise a heavy chain variable region comprising an amino acid sequence selected from any of SEQ ID NOs: 27-71 and 91; and/or a light chain variable domain comprising an amino acid sequence selected from any of SEQ ID NOs: 92-113 and 118.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable region comprising an amino acid sequence selected from any of SEQ ID NOs: 27, 56 and 72-90; and/or a light chain variable domain comprising an amino acid sequence selected from any of SEQ ID NOs: 92, 104 and 114-117.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-2 or with the amino acid sequence of SEQ ID NO: 28; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-2 antibody or with the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-2 or with the amino acid sequence of SEQ ID NO: 28, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-2 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-2 or with the amino acid sequence of SEQ ID NO: 92, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-2. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-2 or with the amino acid sequence of SEQ ID NO: 28, and contains substitutions (e.g., conservative substitutions, insertions, or deletions compared with the reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the variable

- 47 044134 of the heavy chain domain of the AL2p-2 antibody or the amino acid sequence of SEQ ID NO: 28. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the heavy chain variable domain of the AL2p-2 antibody. 2 or the amino acid sequence of SEQ ID NO: 28. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the AL2p-2 antibody or SEQ ID NO: 28, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-2 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-2 antibody, and (c) the HVR-H3 amino acid sequence AL2p-2 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 AL2p-2 antibody light chain variable domain or with the amino acid sequence of SEQ ID NO: 92, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-2 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 92. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-2 antibody light chain variable domain or amino acid sequence SEQ ID NO: 92. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the AL2p-2 antibody or SEQ ID NO: 92, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-2 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-2 antibody, and (c) the HVR-L3 amino acid sequence AL2p-2 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-3 or with the amino acid sequence of SEQ ID NO: 29; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-3 antibody or with the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-3 or with the amino acid sequence of SEQ ID NO: 29, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-3 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-3 or with the amino acid sequence of SEQ ID NO: 92, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2

- 48 044134 and HVR-L3 antibodies AL2p-3. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-3 or with the amino acid sequence of SEQ ID NO: 29, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-3 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 29. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-3 or the amino acid sequence of SEQ ID NO: 29. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-3 or SEQ ID NO: 29, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-3 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-3 antibody, and (c) the HVR-H3 amino acid sequence AL2p-3 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-3 or with the amino acid sequence of SEQ ID NO: 92, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-3 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 92. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-3 antibody light chain variable domain or amino acid sequence SEQ ID NO: 92. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the AL2p-3 antibody or SEQ ID NO: 92, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-3 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-3 antibody, and (c) the HVR-L3 amino acid sequence AL2p-3 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-4 or with the amino acid sequence of SEQ ID NO: 30; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-4 antibody or with the amino acid sequence of SEQ ID NO: 92. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising an amino acid sequence of 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%,

- 49 044134 at least 96%, at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-4 or with the amino acid sequence of SEQ ID NO: 30 , wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-4 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-4 or with the amino acid sequence of SEQ ID NO: 92, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-4. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-4 or with the amino acid sequence of SEQ ID NO: 30, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-4 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 30. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-4 or the amino acid sequence of SEQ ID NO: 30. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the AL2p-4 antibody or SEQ ID NO: 30, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-4 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-4 antibody, and (c) the HVR-H3 amino acid sequence AL2p-4 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 AL2p-4 antibody light chain variable domain or with the amino acid sequence of SEQ ID NO: 92, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-4 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 92. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-4 antibody light chain variable domain or amino acid sequence SEQ ID NO: 92. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the AL2p-4 antibody or SEQ ID NO: 92, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-4 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-4 antibody, and (c) the HVR-L3 amino acid sequence AL2p-4 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%

- 50 044134 or 100% identity with the amino acid sequence of the variable domain of the heavy chain of the antibody AL2p-7 or with the amino acid sequence of SEQ ID NO: 31; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-7 antibody or with the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-7 or with the amino acid sequence of SEQ ID NO: 31, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-7 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-7 or with the amino acid sequence of SEQ ID NO: 95, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-7. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-7 or with the amino acid sequence of SEQ ID NO: 31, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-7 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 31. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-7 or the amino acid sequence of SEQ ID NO: 31. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-7 or SEQ ID NO: 31, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-7 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-7 antibody, and (c) the HVR-H3 amino acid sequence AL2p-7 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the AL2p-7 antibody or with the amino acid sequence of SEQ ID NO: 95, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-7 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 95. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-7 antibody light chain variable domain or amino acid sequence SEQ ID NO: 95. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments of the replacement, in

- 51 044134 series or deletions are located in FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-7 or SEQ ID NO: 95, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-7 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-7 antibody, and (c) the HVR-L3 amino acid sequence AL2p-7 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-8 or with the amino acid sequence of SEQ ID NO: 32; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-8 antibody or with the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-8 or with the amino acid sequence of SEQ ID NO: 32, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-8 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-8 or with the amino acid sequence of SEQ ID NO: 95, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-8. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-8 or with the amino acid sequence of SEQ ID NO: 32, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-8 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 32. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-8 or the amino acid sequence of SEQ ID NO: 32. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the AL2p-8 antibody or SEQ ID NO: 32, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-8 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-8 antibody, and (c) the HVR-H3 amino acid sequence AL2p-8 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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%,

- 52 044134 at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-8 or with the amino acid sequence of SEQ ID NO: 95, and containing substitutions (for example , conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-8 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 95. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-8 antibody light chain variable domain or amino acid sequence SEQ ID NO: 95. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the AL2p-8 antibody or SEQ ID NO: 95, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-8 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-8 antibody, and (c) the HVR-L3 amino acid sequence AL2p-8 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-9 or with the amino acid sequence of SEQ ID NO: 33; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-9 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-9 or with the amino acid sequence of SEQ ID NO: 33, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-9 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-9 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-9. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-9 or with the amino acid sequence of SEQ ID NO: 33, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-9 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 33. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the anti heavy chain variable domain

- 53 044134 AL2p-9 body or amino acid sequence SEQ ID NO: 33. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-9 or SEQ ID NO: 33, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-9 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-9 antibody, and (c) the HVR-H3 amino acid sequence AL2p-9 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 AL2p-9 antibody light chain variable domain or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-9 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-9 antibody light chain variable domain or amino acid sequence SEQ ID NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-9 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-9 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-9 antibody, and (c) the HVR-L3 amino acid sequence AL2p-9 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-10 or with the amino acid sequence of SEQ ID NO: 34; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-10 antibody or with the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-10 or with the amino acid sequence of SEQ ID NO: 34, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-10 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-10 or with the amino acid sequence of SEQ ID NO: 97, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-10. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85% of

- 54 044134 our 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 heavy chain variable domain of the antibody AL2p-10 or with the amino acid sequence of SEQ ID NO: 34, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody comprising such sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-10 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 34. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-10 or the amino acid sequence of SEQ ID NO: 34. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-10 or SEQ ID NO: 34, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-10 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-10 antibody, and (c) the HVR-H3 amino acid sequence AL2p-10 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the AL2p-10 antibody or with the amino acid sequence of SEQ ID NO: 97, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-10 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 97. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-10 antibody light chain variable domain or amino acid sequence SEQ ID NO: 97. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-10 or SEQ ID NO: 97, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-10 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-10 antibody, and (c) the HVR-L3 amino acid sequence AL2p-10 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-11 or with the amino acid sequence of SEQ ID NO: 35; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-11 antibody or with the amino acid sequence of SEQ ID NO: 98. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-11 or with the amino acid sequence of SEQ ID NO: 35, wherein variable

- 55 044134 the heavy chain domain includes the amino acid sequences of the HVR-H1, HVR-H2 and HVR-H3 antibody AL2p-11. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-11 or with the amino acid sequence of SEQ ID NO: 98, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVRL3 antibodies AL2p-11. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-11 or with the amino acid sequence of SEQ ID NO: 35, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-11 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 35. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-11 or the amino acid sequence of SEQ ID NO: 35. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-11 or SEQ ID NO: 35, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two, or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-11 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-11 antibody, and (c) the HVR-H3 amino acid sequence AL2p-11 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 at least 98%, at least 99%, or 100% identity with the amino acid sequence of the AL2p-11 antibody light chain variable domain or with the amino acid sequence of SEQ ID NO: 98, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-11 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 98. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-11 antibody light chain variable domain or amino acid sequence SEQ ID NO: 98. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-11 or SEQ ID NO: 98, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-11 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-11 antibody, and (c) the HVR-L3 amino acid sequence AL2p-11 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-12 or with the amino acid sequence of SEQ ID NO: 36; and/or the light chain variable domain contains an amino acid sequence with at least 85% of at least

- 56 044134 at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, according 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 light chain variable domain of the antibody AL2p-12, or with the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of at least 85%, at least 86%, at least 87%, at least 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 heavy chain variable domain of the antibody AL2p-12 or with the amino acid sequence of SEQ ID NO: 36, wherein the heavy chain variable domain includes the amino acid sequences of HVR-H1, HVR-H2 and HVR-H3 of the AL2p-12 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-12 or with the amino acid sequence of SEQ ID NO: 97, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-12. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-12 or with the amino acid sequence of SEQ ID NO: 36, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-12 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 36. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-12 or the amino acid sequence of SEQ ID NO: 36. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-12 or SEQ ID NO: 36, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-12 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-12 antibody, and (c) the HVR-H3 amino acid sequence AL2p-12 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-12 or with the amino acid sequence of SEQ ID NO: 97, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-12 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 97. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-12 antibody light chain variable domain or amino acid sequence SEQ ID NO: 97. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-12 or SEQ ID NO: 97, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a)

- 57 044134 amino acid sequence of the HVR-L1 antibody AL2p-12, (b) the amino acid sequence of the HVR-L2 antibody AL2p-12 and (c) the amino acid sequence of the HVR-L3 antibody AL2p-12.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-13 or with the amino acid sequence of SEQ ID NO: 37; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-13 antibody or with the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-13 or with the amino acid sequence of SEQ ID NO: 37, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-13 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of antibody AL2p-13 or with the amino acid sequence of SEQ ID NO: 95, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-13. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-13 or with the amino acid sequence of SEQ ID NO: 37, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-13 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 37. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-13 or the amino acid sequence of SEQ ID NO: 37. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-13 or SEQ ID NO: 37, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-13 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-13 antibody, and (c) the HVR-H3 amino acid sequence AL2p-13 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-13 or with the amino acid sequence of SEQ ID NO: 95, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody that includes such

- 58 044134 sequence, retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-13 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 95. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-13 antibody light chain variable domain or amino acid sequence SEQ ID NO: 95. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-13 or SEQ ID NO: 95, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-13 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-13 antibody, and (c) the HVR-L3 amino acid sequence AL2p-13 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-14 or with the amino acid sequence of SEQ ID NO: 38; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-14 antibody or with the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-14 or with the amino acid sequence of SEQ ID NO: 38, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-14 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-14 or with the amino acid sequence of SEQ ID NO: 99, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-14. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-14 or with the amino acid sequence of SEQ ID NO: 38, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-14 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 38. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-14 or the amino acid sequence of SEQ ID NO: 38. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-14 or SEQ ID NO: 38, including post-translational modifications of this sequence. In a specific embodiment, VH

- 59 044134 contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-14 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-14 antibody, and (c) the HVR-H3 amino acid sequence of the AL2p- antibody 14. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-14 or with the amino acid sequence of SEQ ID NO: 99, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-14 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 99. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-14 antibody light chain variable domain or amino acid sequence SEQ ID NO: 99. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-14 or SEQ ID NO: 99, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-14 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-14 antibody, and (c) the HVR-L3 amino acid sequence AL2p-14 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-15 or with the amino acid sequence of SEQ ID NO: 38; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-15 antibody or with the amino acid sequence of SEQ ID NO: 100. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-15 or with the amino acid sequence of SEQ ID NO: 38, wherein the heavy chain variable domain includes the amino acid sequences of the HVR-H1, HVR-H2 and HVR-H3 antibody AL2p-15. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-15 or with the amino acid sequence of SEQ ID NO: 100, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-15. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-15 or with the amino acid sequence of SEQ ID NO: 38, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference after

- 60 044134 efficiency), but an aHTu-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-15 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 38. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-15 or the amino acid sequence of SEQ ID NO: 38. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-15 or SEQ ID NO: 38, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-15 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-15 antibody, and (c) the HVR-H3 amino acid sequence AL2p-15 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-15 or with the amino acid sequence of SEQ ID NO: 100, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-15 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 100. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-15 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 100. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-15 or SEQ ID NO: 100, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-15 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-15 antibody, and (c) the HVR-L3 amino acid sequence AL2p-15 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-16 or with the amino acid sequence of SEQ ID NO: 39; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-16 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-16 or with the amino acid sequence of SEQ ID NO: 39, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-16 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least

- 61 044134

98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-16 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences of HVR-L1, HVR-L2 and HVR-L3 antibody AL2p-16. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-16 or with the amino acid sequence of SEQ ID NO: 39, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-16 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 39. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-16 or the amino acid sequence of SEQ ID NO: 39. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-16 or SEQ ID NO: 39, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-16 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-16 antibody, and (c) the HVR-H3 amino acid sequence AL2p-16 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-16 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-16 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-16 antibody light chain variable domain or amino acid sequence SEQ ID NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-16 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-16 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-16 antibody, and (c) the HVR-L3 amino acid sequence AL2p-16 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-17 or with the amino acid sequence of SEQ ID NO: 40; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-17 antibody or with the amino acid sequence of SEQ ID NO: 98. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of at least 85 % at least

- 62 044134

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 heavy chain variable domain of the antibody AL2p-17 or with the amino acid sequence of SEQ ID NO: 40, wherein the heavy chain variable domain includes the amino acid sequences of the HVR-H1, HVR-H2 and HVR-H3 antibody AL2p-17. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-17 or with the amino acid sequence of SEQ ID NO: 98, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-17. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-17 or with the amino acid sequence of SEQ ID NO: 40, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-17 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 40. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-17 or the amino acid sequence of SEQ ID NO: 40. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-17 or SEQ ID NO: 40, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-17 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-17 antibody, and (c) the HVR-H3 amino acid sequence AL2p-17 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-17 or with the amino acid sequence of SEQ ID NO: 98, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-17 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 98. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-17 antibody light chain variable domain or amino acid sequence SEQ ID NO: 98. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-17 or SEQ ID NO: 98, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-17 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-17 antibody, and (c) the HVR-L3 amino acid sequence AL2p-17 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%,

- 63 044134 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 heavy chain variable domain of the antibody AL2p-18 or with the amino acid sequence of SEQ ID NO: 41; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-18 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-18 or with the amino acid sequence of SEQ ID NO: 41, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-18 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-18 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-18. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-18 or with the amino acid sequence of SEQ ID NO: 41, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-18 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 41. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-18 or the amino acid sequence of SEQ ID NO: 41. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-18 or SEQ ID NO: 41, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-18 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-18 antibody, and (c) the HVR-H3 amino acid sequence AL2p-18 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-18 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-18 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the AL2p-18 antibody light chain variable domain amino acid sequence or SEQ ID amino acid sequence

- 64 044134

NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-18 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-18 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-18 antibody, and (c) the HVR-L3 amino acid sequence AL2p-18 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-19 or with the amino acid sequence of SEQ ID NO: 42; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-19 antibody or with the amino acid sequence of SEQ ID NO: 98. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-19 or with the amino acid sequence of SEQ ID NO: 42, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-19 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-19 or with the amino acid sequence of SEQ ID NO: 98, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-19. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-19 or with the amino acid sequence of SEQ ID NO: 42, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-19 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 42. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-19 or the amino acid sequence of SEQ ID NO: 42. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-19 or SEQ ID NO: 42, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-19 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-19 antibody, and (c) the HVR-H3 amino acid sequence AL2p-19 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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

- 65 044134 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 light chain variable domain of the antibody AL2p-19 or with the amino acid sequence of SEQ ID NO: 98, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence), but an anti-TREM2 antibody comprising such sequence, retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-19 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 98. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-19 antibody light chain variable domain or amino acid sequence SEQ ID NO: 98. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-19 or SEQ ID NO: 98, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-19 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-19 antibody, and (c) the HVR-L3 amino acid sequence AL2p-19 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-20 or with the amino acid sequence of SEQ ID NO: 42; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-20 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-20 or with the amino acid sequence of SEQ ID NO: 42, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-20. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-20 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-20. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-20 or with the amino acid sequence of SEQ ID NO: 42, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-20 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 42. In some embodiments, a total of 1 to 5 amino acids were replaced, inserted

- 66 044134 but and/or deleted in the amino acid sequence of the heavy chain variable domain of the AL2p-20 antibody or the amino acid sequence of SEQ ID NO: 42. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (i.e., on the FR- areas). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-20 or SEQ ID NO: 42, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-20 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-20 antibody, and (c) the HVR-H3 amino acid sequence AL2p-20 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-20 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-20 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-20 antibody light chain variable domain or amino acid sequence SEQ ID NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-20 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-20 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-20 antibody, and (c) the HVR-L3 amino acid sequence AL2p-20 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-21 or with the amino acid sequence of SEQ ID NO: 43; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-21 antibody or with the amino acid sequence of SEQ ID NO: 100. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-21 or with the amino acid sequence of SEQ ID NO: 43, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-21. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-21 or with the amino acid sequence of SEQ ID NO: 100, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-21. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%

- 67 044134 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 heavy chain variable domain of the antibody AL2p-21 or with the amino acid sequence of SEQ ID NO: 43, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody comprising such sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-21 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 43. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-21 or the amino acid sequence of SEQ ID NO: 43. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-21 or SEQ ID NO: 43, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-21 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-21 antibody, and (c) the HVR-H3 amino acid sequence AL2p-21 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-21 or with the amino acid sequence of SEQ ID NO: 100, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-21 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 100. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-21 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 100. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-21 or SEQ ID NO: 100, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-21 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-21 antibody, and (c) the HVR-L3 amino acid sequence AL2p-21 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-22 or with the amino acid sequence of SEQ ID NO: 44; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-22 antibody or with the amino acid sequence of SEQ ID NO: 101. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-22 or with the amino acid sequence of SEQ ID NO: 44, wherein variable

- 68 044134 the heavy chain domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-22 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-22 or with the amino acid sequence of SEQ ID NO: 101, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-22. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-22 or with the amino acid sequence of SEQ ID NO: 44, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-22 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 44. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-22 or the amino acid sequence of SEQ ID NO: 44. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-22 or SEQ ID NO: 44, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-22 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-22 antibody, and (c) the HVR-H3 amino acid sequence AL2p-22 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-22 or with the amino acid sequence of SEQ ID NO: 101, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-22 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 101. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-22 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 101. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-22 or SEQ ID NO: 101, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-22 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-22 antibody, and (c) the HVR-L3 amino acid sequence AL2p-22 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-23 or with the amino acid sequence of SEQ ID NO: 45; and/or the light chain variable domain contains an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%,

- 69 044134 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 light chain variable domain of the AL2p-23 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising the amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of the variable domain heavy chain of the AL2p-23 antibody or the amino acid sequence of SEQ ID NO: 45, wherein the heavy chain variable domain comprises the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-23 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of antibody AL2p-23 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVRL3 antibodies AL2p-23. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-23 or with the amino acid sequence of SEQ ID NO: 45, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-23 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 45. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-23 or the amino acid sequence of SEQ ID NO: 45. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-23 or SEQ ID NO: 45, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-23 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-23 antibody, and (c) the HVR-H3 amino acid sequence AL2p-23 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-23 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-23 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 up to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the AL2p-23 antibody light chain variable domain or amino acid sequence SEQ ID NO: 96. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (i.e. on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-23 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the amino acid sequence of the HVR-L1 antibody AL2p-23, (b) the amino acid sequence

- 70 044134 sequence of HVR-L2 antibody AL2p-23 and (c) amino acid sequence of HVR-L3 antibody AL2p-23.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-24 or with the amino acid sequence of SEQ ID NO: 46; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-24 antibody or with the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-24 or with the amino acid sequence of SEQ ID NO: 46, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-24. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-24 or with the amino acid sequence of SEQ ID NO: 99, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-24. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-24 or with the amino acid sequence of SEQ ID NO: 46, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-24 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 46. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-24 or the amino acid sequence of SEQ ID NO: 46. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-24 or SEQ ID NO: 46, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-24 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-24 antibody, and (c) the HVR-H3 amino acid sequence AL2p-24 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-24 or with the amino acid sequence of SEQ ID NO: 99, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence), but anti-TREM2 antibody,

- 71 044134 including such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-24 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 99. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-24 antibody light chain variable domain or amino acid sequence SEQ ID NO: 99. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-24 or SEQ ID NO: 99, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-24 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-24 antibody, and (c) the HVR-L3 amino acid sequence AL2p-24 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-25 or with the amino acid sequence of SEQ ID NO: 47; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-25 antibody or with the amino acid sequence of SEQ ID NO: 96. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-25 or with the amino acid sequence of SEQ ID NO: 47, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-25. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-25 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-25. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-25 or with the amino acid sequence of SEQ ID NO: 47, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-25 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 47. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-25 or the amino acid sequence of SEQ ID NO: 47. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-25 or SEQ ID NO: 47, including

- 72 044134 post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-25 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-25 antibody, and (c) the HVR-H3 amino acid sequence AL2p-25 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-25 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-25 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-25 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-25 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-25 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-25 antibody, and (c) the HVR-L3 amino acid sequence AL2p-25 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 48; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 48, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-26. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 95, wherein the light chain variable domain includes the amino acid sequences of HVRL1, HVR-L2 and HVR-L3 antibody AL2p-26. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 48, and

- 73 044134 containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-26 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 48. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-26 or the amino acid sequence of SEQ ID NO: 48. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-26 or SEQ ID NO: 48, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-26 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-26 antibody, and (c) the HVR-H3 amino acid sequence AL2p-26 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-26 or with the amino acid sequence of SEQ ID NO: 95, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody that includes such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-26 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 95. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-26 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 95. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-26 or SEQ ID NO: 95, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-26 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-26 antibody, and (c) the HVR-L3 amino acid sequence AL2p-26 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-27 or with the amino acid sequence of SEQ ID NO: 49; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-27 antibody or with the amino acid sequence of SEQ ID NO: 102. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-27 or with the amino acid sequence of SEQ ID NO: 49, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-27. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of at least 85%, at least 86%, at least 87%, at least 88%, at least 89% ,

- 74 044134 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 light chain variable domain of the antibody AL2p-27 or with the amino acid sequence of SEQ ID NO: 102, wherein the light chain variable domain includes the amino acid sequences of HVR-L1, HVR-L2 and HVR-L3 antibodies AL2p-27. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-27 or with the amino acid sequence of SEQ ID NO: 49, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-27 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 49. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-27 or the amino acid sequence of SEQ ID NO: 49. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-27 or SEQ ID NO: 49, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-27 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-27 antibody, and (c) the HVR-H3 amino acid sequence AL2p-27 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-27 or with the amino acid sequence of SEQ ID NO: 102, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-27 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 102. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-27 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 102. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-27 or SEQ ID NO: 102, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-27 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-27 antibody, and (c) the HVR-L3 amino acid sequence AL2p-27 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 50; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 96. In some embodiments

- 75 044134 embodiments of the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 50, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR- H2 and HVR-H3 antibodies AL2p-28. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 96, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-28. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 50, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-28 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 50. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-28 or the amino acid sequence of SEQ ID NO: 50. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-28 or SEQ ID NO: 50, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-28 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-28 antibody, and (c) the HVR-H3 amino acid sequence AL2p-28 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-28 or with the amino acid sequence of SEQ ID NO: 96, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-28 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 96. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-28 antibody light chain variable domain or amino acid sequence SEQ ID NO: 96. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-28 or SEQ ID NO: 96, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-28 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-28 antibody, and (c) the HVR-L3 amino acid sequence AL2p-28 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 85%

- 76 044134 at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, according to 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 heavy chain variable domain of the antibody AL2p-29, or with amino acid sequence SEQ ID NO: 51; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-29 antibody or with the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-29 or with the amino acid sequence of SEQ ID NO: 51, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-29. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-29 or with the amino acid sequence of SEQ ID NO: 99, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-29. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-29 or with the amino acid sequence of SEQ ID NO: 51, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-29 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 51. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-29 or the amino acid sequence of SEQ ID NO: 51. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-29 or SEQ ID NO: 51, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-29 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-29 antibody, and (c) the HVR-H3 amino acid sequence AL2p-29 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-29 or with the amino acid sequence of SEQ ID NO: 99, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-29 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 99. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the va amino acid sequence

- 77 044134 ryabelny domain of the light chain of the antibody AL2p-29 or the amino acid sequence of SEQ ID NO: 99. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-29 or SEQ ID NO: 99, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two, or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-29 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-29 antibody, and (c) the HVR-L3 amino acid sequence AL2p-29 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-30 or with the amino acid sequence of SEQ ID NO: 52; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-30 antibody or with the amino acid sequence of SEQ ID NO: 100. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-30 or with the amino acid sequence of SEQ ID NO: 52, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-30 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-30 or with the amino acid sequence of SEQ ID NO: 100, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-30. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-30 or with the amino acid sequence of SEQ ID NO: 52, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-30 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 52. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-30 or the amino acid sequence of SEQ ID NO: 52. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-30 or SEQ ID NO: 52, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-30 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-30 antibody, and (c) the HVR-H3 amino acid sequence AL2p-30 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) sequence having at least 85%, at least 86%, at least 87%, at least

- 78 044134

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 light chain variable domain of the antibody AL2p-30 or with the amino acid sequence of SEQ ID NO: 100, and containing substitutions (for example, conservative substitution, insertion or deletion compared to the reference sequence), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-30 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 100. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-30 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 100. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-30 or SEQ ID NO: 100, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-30 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-30 antibody, and (c) the HVR-L3 amino acid sequence AL2p-30 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-31 or with the amino acid sequence of SEQ ID NO: 53; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-31 antibody or with the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-31 or with the amino acid sequence of SEQ ID NO: 53, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-31. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-31 or with the amino acid sequence of SEQ ID NO: 97, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-31. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-31 or with the amino acid sequence of SEQ ID NO: 53, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-31 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 53. B

- 79 044134 in some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-31 or the amino acid sequence of SEQ ID NO: 53. In some embodiments, the substitution, insertion, or deletions are located in regions outside the HVR (i.e., FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-31 or SEQ ID NO: 53, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-31 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-31 antibody, and (c) the HVR-H3 amino acid sequence AL2p-31 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-31 or with the amino acid sequence of SEQ ID NO: 97, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-31 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 97. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-31 antibody light chain variable domain or amino acid sequence SEQ ID NO: 97. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-31 or SEQ ID NO: 97, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-31 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-31 antibody, and (c) the HVR-L3 amino acid sequence AL2p-31 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-32 or with the amino acid sequence of SEQ ID NO: 54; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-32 antibody or with the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-32 or with the amino acid sequence of SEQ ID NO: 54, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-32. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-32 or with the amino acid sequence of SEQ ID NO: 97, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and

- 80 044134

HVR-L3 antibody AL2p-32. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-32 or with the amino acid sequence of SEQ ID NO: 54, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-32 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 54. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-32 or the amino acid sequence of SEQ ID NO: 54. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-32 or SEQ ID NO: 54, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-32 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-32 antibody, and (c) the HVR-H3 amino acid sequence AL2p-32 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-32 or with the amino acid sequence of SEQ ID NO: 97, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-32 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 97. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-32 antibody light chain variable domain or amino acid sequence SEQ ID NO: 97. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-32 or SEQ ID NO: 97, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-32 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-32 antibody, and (c) the HVR-L3 amino acid sequence AL2p-32 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-33 or with the amino acid sequence of SEQ ID NO: 55; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-33 antibody or with the amino acid sequence of SEQ ID NO: 103. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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

- 81 044134 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 heavy chain variable domain of the antibody AL2p-33 or with the amino acid sequence of SEQ ID NO: 55, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-33 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-33 or with the amino acid sequence of SEQ ID NO: 103, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-33. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-33 or with the amino acid sequence of SEQ ID NO: 55, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-33 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 55. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-33 or the amino acid sequence of SEQ ID NO: 55. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-33 or SEQ ID NO: 55, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-33 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-33 antibody, and (c) the HVR-H3 amino acid sequence AL2p-33 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-33 or with the amino acid sequence of SEQ ID NO: 103, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-33 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 103. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-33 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 103. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-33 or SEQ ID NO: 103, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-33 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-33 antibody, and (c) the HVR-L3 amino acid sequence AL2p-33 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%

- 82 044134 or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-35 or with the amino acid sequence of SEQ ID NO: 57; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-35 antibody or with the amino acid sequence of SEQ ID NO: 104. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-35 or with the amino acid sequence of SEQ ID NO: 57, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-35. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-35 or with the amino acid sequence of SEQ ID NO: 104, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-35. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-35 or with the amino acid sequence of SEQ ID NO: 57, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-35 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 57. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-35 or the amino acid sequence of SEQ ID NO: 57. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-35 or SEQ ID NO: 57, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-35 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-35 antibody, and (c) the HVR-H3 amino acid sequence AL2p-35 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-35 or with the amino acid sequence of SEQ ID NO: 104, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-35 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 104. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-35 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 104. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments

- 83 044134 substitutions, insertions or deletions are located in FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-35 or SEQ ID NO: 104, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-35 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-35 antibody, and (c) the HVR-L3 amino acid sequence AL2p-35 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 58; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 104. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 58, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-36. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 104, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-36. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 58, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-36 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 58. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-36 or the amino acid sequence of SEQ ID NO: 58. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-36 or SEQ ID NO: 58, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-36 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-36 antibody, and (c) the HVR-H3 amino acid sequence AL2p-36 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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

- 84 044134 at least 96%, at least 97%, at least 98%, at least 99% or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-36 or with the amino acid sequence of SEQ ID NO: 104, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to a reference sequence), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-36 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 104. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-36 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 104. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-36 or SEQ ID NO: 104, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-36 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-36 antibody, and (c) the HVR-L3 amino acid sequence AL2p-36 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 59; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 104. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 59, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-37. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 104, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-37. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 59, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-37 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 59. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the anti heavy chain variable domain

- 85 044134 AL2p-37 body or amino acid sequence SEQ ID NO: 59. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-37 or SEQ ID NO: 59, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-37 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-37 antibody, and (c) the HVR-H3 amino acid sequence AL2p-37 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-37 or with the amino acid sequence of SEQ ID NO: 104, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-37 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 104. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-37 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 104. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-37 or SEQ ID NO: 104, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-37 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-37 antibody, and (c) the HVR-L3 amino acid sequence AL2p-37 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-38 or with the amino acid sequence of SEQ ID NO: 60; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-38 antibody or with the amino acid sequence of SEQ ID NO: 105. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-38 or with the amino acid sequence of SEQ ID NO: 60, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-38. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-38 or with the amino acid sequence of SEQ ID NO: 105, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-38. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) sequence having at least 85%

- 86 044134 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 heavy chain variable domain of the antibody AL2p-38 or with the amino acid sequence of SEQ ID NO: 60, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody comprising such sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-38 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 60. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-38 or the amino acid sequence of SEQ ID NO: 60. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-38 or SEQ ID NO: 60, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-38 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-38 antibody, and (c) the HVR-H3 amino acid sequence AL2p-38 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-38 or with the amino acid sequence of SEQ ID NO: 105, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-38 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 105. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-38 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 105. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-38 or SEQ ID NO: 105, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-38 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-38 antibody, and (c) the HVR-L3 amino acid sequence AL2p-38 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-39 or with the amino acid sequence of SEQ ID NO: 60; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-39 antibody or with the amino acid sequence of SEQ ID NO: 106. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain

- 87 044134 antibody AL2p-39 or with the amino acid sequence of SEQ ID NO: 60, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-39. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-39 or with the amino acid sequence of SEQ ID NO: 106, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-39. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-39 or with the amino acid sequence of SEQ ID NO: 60, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-39 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 60. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-39 or the amino acid sequence of SEQ ID NO: 60. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-39 or SEQ ID NO: 60, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-39 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-39 antibody, and (c) the HVR-H3 amino acid sequence AL2p-39 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-39 or with the amino acid sequence of SEQ ID NO: 106, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-39 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 106. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-39 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 106. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-39 or SEQ ID NO: 106, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-39 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-39 antibody, and (c) the HVR-L3 amino acid sequence AL2p-39 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-40 or with the amino acid sequence of SEQ ID NO: 60; and/or variable to

- 88 044134 light chain men contains an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of the light chain variable domain of the antibody AL2p-40 or to the amino acid sequence of SEQ ID NO: 107. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising the amino acid sequence with 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%, according to 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 heavy chain variable domain of the antibody AL2p-40, or with the amino acid sequence of SEQ ID NO: 60, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-40 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-40 or with the amino acid sequence of SEQ ID NO: 107, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-40. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-40 or with the amino acid sequence of SEQ ID NO: 60, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-40 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 60. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-40 or the amino acid sequence of SEQ ID NO: 60. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-40 or SEQ ID NO: 60, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-40 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-40 antibody, and (c) the HVR-H3 amino acid sequence AL2p-40 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-40 or with the amino acid sequence of SEQ ID NO: 107, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-40 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 107. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-40 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 107. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-40 or SEQ ID NO: 107, including post-translational

- 89 044134 modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-40 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-40 antibody, and (c) the HVR-L3 amino acid sequence AL2p-40 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-41 or with the amino acid sequence of SEQ ID NO: 61; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-41 antibody or with the amino acid sequence of SEQ ID NO: 106. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-41 or with the amino acid sequence of SEQ ID NO: 61, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-41. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-41 or with the amino acid sequence of SEQ ID NO: 106, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-41. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-41 or with the amino acid sequence of SEQ ID NO: 61, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-41 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 61. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-41 or the amino acid sequence of SEQ ID NO: 61. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-41 or SEQ ID NO: 61, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-41 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-41 antibody, and (c) the HVR-H3 amino acid sequence AL2p-41 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-41 or with amino acids

- 90 044134 with the amino acid sequence of SEQ ID NO: 106, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody comprising such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-41 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 106. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-41 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 106. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-41 or SEQ ID NO: 106, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-41 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-41 antibody, and (c) the HVR-L3 amino acid sequence AL2p-41 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-42 or with the amino acid sequence of SEQ ID NO: 61; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-42 antibody or with the amino acid sequence of SEQ ID NO: 107. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-42 or with the amino acid sequence of SEQ ID NO: 61, wherein the heavy chain variable domain comprises the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-42 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-42 or with the amino acid sequence of SEQ ID NO: 107, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-42. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-42 or with the amino acid sequence of SEQ ID NO: 61, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-42 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 61. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-42 or the amino acid sequence of SEQ ID NO: 61. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). Somehow

- 91 044134 In many embodiments, the substitutions, insertions or deletions are located at FR regions. Optionally, the anti-TIEM2 antibody contains the VH sequence of the antibody AL2p-42 or SEQ ID NO: 61, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-42 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-42 antibody, and (c) the HVR-H3 amino acid sequence AL2p-42 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-42 or with the amino acid sequence of SEQ ID NO: 107, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-42 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 107. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-42 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 107. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-42 or SEQ ID NO: 107, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-42 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-42 antibody, and (c) the HVR-L3 amino acid sequence AL2p-42 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-43 or with the amino acid sequence of SEQ ID NO: 62; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-43 or with the amino acid sequence of SEQ ID NO: 105. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-43 or with the amino acid sequence of SEQ ID NO: 62, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-43. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-43 or with the amino acid sequence of SEQ ID NO: 105, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-43. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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%,

- 92 044134 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 heavy chain variable domain of the antibody AL2p-43 or with the amino acid sequence sequence of SEQ ID NO: 62, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody comprising such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-43 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 62. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-43 or the amino acid sequence of SEQ ID NO: 62. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-43 or SEQ ID NO: 62, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-43 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-43 antibody, and (c) the HVR-H3 amino acid sequence AL2p-43 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-43 or with the amino acid sequence of SEQ ID NO: 105, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-43 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 105. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-43 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 105. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-43 or SEQ ID NO: 105, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-43 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-43 antibody, and (c) the HVR-L3 amino acid sequence AL2p-43 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-44 or with the amino acid sequence of SEQ ID NO: 62; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-44 antibody or with the amino acid sequence of SEQ ID NO: 107. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-44 or with the amino acid sequence of SEQ ID NO: 62, wherein the heavy chain variable domain includes the amino acid sequences of HVR-H1, HVR-H2 and HVR-H3 anti

- 93 044134 body AL2p-44. In some embodiments, the aHTu-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-44 or with the amino acid sequence of SEQ ID NO: 107, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-44. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-44 or with the amino acid sequence of SEQ ID NO: 62, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-44 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 62. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-44 or the amino acid sequence of SEQ ID NO: 62. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-44 or SEQ ID NO: 62, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-44 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-44 antibody, and (c) the HVR-H3 amino acid sequence AL2p-44 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-44 or with the amino acid sequence of SEQ ID NO: 107, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-44 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 107. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-44 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 107. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-44 or SEQ ID NO: 107, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-44 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-44 antibody, and (c) the HVR-L3 amino acid sequence AL2p-44 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-45 or with the amino acid sequence of SEQ ID NO: 63; and/or the light chain variable domain contains an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%,

- 94 044134 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 light chain variable domain of the AL2p-45 antibody or with the amino acid sequence of SEQ ID NO: 108. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising the amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of the variable domain heavy chain of the AL2p-45 antibody or the amino acid sequence of SEQ ID NO: 63, wherein the heavy chain variable domain comprises the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-45 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-45 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-45. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-45 or with the amino acid sequence of SEQ ID NO: 63, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-45 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 63. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-45 or the amino acid sequence of SEQ ID NO: 63. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-45 or SEQ ID NO: 63, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-45 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-45 antibody, and (c) the HVR-H3 amino acid sequence AL2p-45 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-45 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-45 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 108. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-45 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-45 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-45 antibody,

- 95 044134 (b) the HVR-L2 amino acid sequence of the AL2p-45 antibody and (c) the HVR-L3 amino acid sequence of the AL2p-45 antibody.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 63; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 63, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-46. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-46. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 63, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-46 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 63. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-46 or the amino acid sequence of SEQ ID NO: 63. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-46 or SEQ ID NO: 63, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-46 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-46 antibody, and (c) the HVR-H3 amino acid sequence AL2p-46 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-46 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence), but anti-TREM2 an

- 96 044134 a antibody comprising such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-46 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-46 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-46 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-46 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-46 antibody, and (c) the HVR-L3 amino acid sequence AL2p-46 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 64; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 108. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 64, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-47. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-47. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 64, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-47 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 64. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-47 or the amino acid sequence of SEQ ID NO: 64. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-47 or SEQ ID NO: 64, including

- 97 044134 post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-47 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-47 antibody, and (c) the HVR-H3 amino acid sequence AL2p-47 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-47 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-47 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 108. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-47 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-47 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-47 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-47 antibody, and (c) the HVR-L3 amino acid sequence AL2p-47 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-48 or with the amino acid sequence of SEQ ID NO: 64; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-48 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-48 or with the amino acid sequence of SEQ ID NO: 64, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-48. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-48 or with the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-48. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy variable domain

- 98 044134 of the AL2p-48 antibody chain or with the amino acid sequence of SEQ ID NO: 64, and containing substitutions (for example, conservative substitutions, insertions or deletions compared to the reference sequence), but an anti-TREM2 antibody including such a sequence retains the ability contact TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-48 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 64. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-48 or the amino acid sequence of SEQ ID NO: 64. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-48 or SEQ ID NO: 64, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-48 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-48 antibody, and (c) the HVR-H3 amino acid sequence AL2p-48 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-48 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-48 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-48 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-48 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-48 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-48 antibody, and (c) the HVR-L3 amino acid sequence AL2p-48 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-49 or with the amino acid sequence of SEQ ID NO: 65; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-49 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-49 or with the amino acid sequence of SEQ ID NO: 65, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-49. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising the amino acid sequence from to

- 99 044134 at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of the variable domain light chain of the AL2p-49 antibody or the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain comprises the amino acid sequences HVR-L1, HVR-L2 and HVR-L3 of the AL2p-49 antibody. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-49 or with the amino acid sequence of SEQ ID NO: 65, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-49 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 65. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-49 or the amino acid sequence of SEQ ID NO: 65. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-49 or SEQ ID NO: 65, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-49 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-49 antibody, and (c) the HVR-H3 amino acid sequence AL2p-49 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-49 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-49 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-49 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-49 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-49 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-49 antibody, and (c) the HVR-L3 amino acid sequence AL2p-49 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-50 or with the amino acid sequence of SEQ ID NO: 66; and/or the light chain variable domain contains an amino acid sequence with 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%

- 100 044134 or 100% identity with the amino acid sequence of the light chain variable domain of the AL2p-50 antibody or with the amino acid sequence of SEQ ID NO: 108. In some embodiments, the anti-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising the amino acid sequence from to 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 antibody heavy chain variable domain AL2p-50 or the amino acid sequence of SEQ ID NO: 66, wherein the heavy chain variable domain comprises the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-50 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-50 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-50. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-50 or with the amino acid sequence of SEQ ID NO: 66, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-50 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 66. In some embodiments, a total of 1 up to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the AL2p-50 antibody or the amino acid sequence of SEQ ID NO: 66. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-50 or SEQ ID NO: 66, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-50 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-50 antibody, and (c) the HVR-H3 amino acid sequence AL2p-50 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-50 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-50 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 108. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-50 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-50 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-50 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-50 antibody, and (c) the HVR-L3 amino acid sequence AL2p-50 antibodies.

- 101 044134

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-51 or with the amino acid sequence of SEQ ID NO: 66; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-51 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-51 or with the amino acid sequence of SEQ ID NO: 66, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-51. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-51 or with the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-51. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-51 or with the amino acid sequence of SEQ ID NO: 66, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-51 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 66. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-51 or the amino acid sequence of SEQ ID NO: 66. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-51 or SEQ ID NO: 66, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-51 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-51 antibody, and (c) the HVR-H3 amino acid sequence AL2p-51 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-51 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted

- 102 044134 and/or deleted in the amino acid sequence of the AL2p-51 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence the light chain variable domain of the antibody AL2p-51 or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-51 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-51 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-51 antibody, and (c) the HVR-L3 amino acid sequence AL2p-51 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-52 or with the amino acid sequence of SEQ ID NO: 67; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-52 antibody or with the amino acid sequence of SEQ ID NO: 108. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-52 or with the amino acid sequence of SEQ ID NO: 67, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-52. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-52 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-52. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-52 or with the amino acid sequence of SEQ ID NO: 67, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-52 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 67. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-52 or the amino acid sequence of SEQ ID NO: 67. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-52 or SEQ ID NO: 67, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the amino acid sequence of HVR-H1

- 103 044134 AL2p-52 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-52 antibody and (c) the HVR-H3 amino acid sequence of the AL2p-52 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-52 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-52 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 108. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-52 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-52 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-52 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-52 antibody, and (c) the HVR-L3 amino acid sequence AL2p-52 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-53 or with the amino acid sequence of SEQ ID NO: 67; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-53 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-53 or with the amino acid sequence of SEQ ID NO: 67, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-53. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of antibody AL2p-53 or with the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-53. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-53 or with the amino acid sequence of SEQ ID NO: 67, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference after

- 104 044134 consistency), but an aHTu-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-53 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 67. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-53 or the amino acid sequence of SEQ ID NO: 67. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-53 or SEQ ID NO: 67, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-53 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-53 antibody, and (c) the HVR-H3 amino acid sequence AL2p-53 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-53 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-53 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-53 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-53 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-53 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-53 antibody, and (c) the HVR-L3 amino acid sequence AL2p-53 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-54 or with the amino acid sequence of SEQ ID NO: 68; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-54 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-54 or with the amino acid sequence of SEQ ID NO: 68, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-54. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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

- 105 044134 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 light chain variable domain of the AL2p antibody -54 or the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR-L2 and HVR-L3 of the antibody AL2p-54. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-54 or with the amino acid sequence of SEQ ID NO: 68, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-54 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 68. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-54 or the amino acid sequence of SEQ ID NO: 68. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-54 or SEQ ID NO: 68, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-54 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-54 antibody, and (c) the HVR-H3 amino acid sequence AL2p-54 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-54 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-54 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-54 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-54 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-54 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-54 antibody, and (c) the HVR-L3 amino acid sequence AL2p-54 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 69; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 108. In some embodiments

- 106 044134 embodiments of the aHTu-TREM2 antibodies of the present invention contain a heavy chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 69, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR- H2 and HVR-H3 antibodies AL2p-55. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-55. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 69, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-55 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 69. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-55 or the amino acid sequence of SEQ ID NO: 69. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-55 or SEQ ID NO: 69, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-55 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-55 antibody, and (c) the HVR-H3 amino acid sequence AL2p-55 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-55 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-55 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 108. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-55 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-55 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-55 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-55 antibody, and (c) the HVR-L3 amino acid sequence AL2p-55 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein variable to

- 107 044134 heavy chain men contains an amino acid sequence with 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 heavy chain variable domain of the antibody AL2p-56 or with the amino acid sequence of SEQ ID NO: 69; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-56 antibody or with the amino acid sequence of SEQ ID NO: 108. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-56 or with the amino acid sequence of SEQ ID NO: 69, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-56. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-56 or with the amino acid sequence of SEQ ID NO: 108, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-56. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-56 or with the amino acid sequence of SEQ ID NO: 69, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-56 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 69. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-56 or the amino acid sequence of SEQ ID NO: 69. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-56 or SEQ ID NO: 69, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-56 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-56 antibody, and (c) the HVR-H3 amino acid sequence AL2p-56 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-56 or with the amino acid sequence of SEQ ID NO: 108, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-56 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments,

- 108 044134 a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-56 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 108. In some embodiments, the substitutions, insertions, or deletions are located in areas outside of HVR (i.e. FR areas). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-56 or SEQ ID NO: 108, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-56 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-56 antibody, and (c) the HVR-L3 amino acid sequence AL2p-56 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-57 or with the amino acid sequence of SEQ ID NO: 69; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-57 antibody or with the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-57 or with the amino acid sequence of SEQ ID NO: 69, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-57. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of antibody AL2p-57 or with the amino acid sequence of SEQ ID NO: 109, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-57. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-57 or with the amino acid sequence of SEQ ID NO: 69, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-57 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 69. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-57 or the amino acid sequence of SEQ ID NO: 69. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-57 or SEQ ID NO: 69, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-57 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-57 antibody, and (c) the HVR-H3 amino acid sequence AL2p-57 antibodies. In some embodiments, implementation

- 109 044134 aHTu-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-57 or with the amino acid sequence of SEQ ID NO: 109, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-57 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 109. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-57 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 109. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-57 or SEQ ID NO: 109, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-57 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-57 antibody, and (c) the HVR-L3 amino acid sequence AL2p-57 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-58 or with the amino acid sequence of SEQ ID NO: 59; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-58 antibody or with the amino acid sequence of SEQ ID NO: 112. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-58 or with the amino acid sequence of SEQ ID NO: 59, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-58. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-58 or with the amino acid sequence of SEQ ID NO: 112, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-58. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-58 or with the amino acid sequence of SEQ ID NO: 59, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 ami

- 110 044134 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the AL2p-58 antibody heavy chain variable domain or amino acid sequence SEQ ID NO: 59. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted. or deleted from the amino acid sequence of the heavy chain variable domain of the AL2p-58 antibody or the amino acid sequence of SEQ ID NO: 59. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-58 or SEQ ID NO: 59, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-58 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-58 antibody, and (c) the HVR-H3 amino acid sequence AL2p-58 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-58 or with the amino acid sequence of SEQ ID NO: 112, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-58 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 112. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-58 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 112. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-58 or SEQ ID NO: 112, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-58 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-58 antibody, and (c) the HVR-L3 amino acid sequence AL2p-58 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-59 or with the amino acid sequence of SEQ ID NO: 91; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-59 antibody or with the amino acid sequence of SEQ ID NO: 118. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-59 or with the amino acid sequence of SEQ ID NO: 91, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-59. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99% or 100% identity with the amino acid sequence variable to

- 111 044134 exchanges the light chain of the AL2p-59 antibody or with the amino acid sequence of SEQ ID NO: 118, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR-L2 and HVR-L3 of the AL2p-59 antibody. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-59 or with the amino acid sequence of SEQ ID NO: 91, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-59 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 91. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-59 or the amino acid sequence of SEQ ID NO: 91. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-59 or SEQ ID NO: 91, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-59 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-59 antibody, and (c) the HVR-H3 amino acid sequence AL2p-59 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-59 or with the amino acid sequence of SEQ ID NO: 118, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-59 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 118. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-59 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 118. In some embodiments, the substitutions, insertions, or deletions are located in regions outside of the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-59 or SEQ ID NO: 118, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-59 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-59 antibody, and (c) the HVR-L3 amino acid sequence AL2p-59 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-60 or with the amino acid sequence of SEQ ID NO: 53; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-60 antibody or with the amino acid sequence of SEQ ID NO: 113. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of at least 85 % at least

- 112 044134

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 heavy chain variable domain of the antibody AL2p-60 or with the amino acid sequence of SEQ ID NO: 53, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the AL2p-60 antibody. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-60 or with the amino acid sequence of SEQ ID NO: 113, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-60. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-60 or with the amino acid sequence of SEQ ID NO: 53, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-60 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 53. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-60 or the amino acid sequence of SEQ ID NO: 53. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-60 or SEQ ID NO: 53, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-60 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-60 antibody, and (c) the HVR-H3 amino acid sequence AL2p-60 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-60 or with the amino acid sequence of SEQ ID NO: 113, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-60 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 113. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-60 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 113. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-60 or SEQ ID NO: 113, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-60 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-60 antibody, and (c) the HVR-L3 amino acid sequence AL2p-60 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%,

- 113 044134 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 heavy chain variable domain of the antibody AL2p-61 or with the amino acid sequence of SEQ ID NO: 70; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-61 antibody or with the amino acid sequence of SEQ ID NO: 110. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-61 or with the amino acid sequence of SEQ ID NO: 70, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-61. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-61 or with the amino acid sequence of SEQ ID NO: 110, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-61. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-61 or with the amino acid sequence of SEQ ID NO: 70, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-61 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 70. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-61 or the amino acid sequence of SEQ ID NO: 70. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (i.e. on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-61 or SEQ ID NO: 70, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-61 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-61 antibody, and (c) the HVR-H3 amino acid sequence AL2p-61 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) 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 light chain variable domain of the antibody AL2p-61 or with the amino acid sequence of SEQ ID NO: 110, and containing substitutions (for example, conservative substitutions, insertions or deletions compared with a reference sequence), but an anti-TREM2 antibody containing such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-61 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 110. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted and/or deleted in the amino acid sequence of the AL2p-61 antibody light chain variable domain or amino acids

- 114 044134 No. SEQ ID NO: 110. In some embodiments, the substitutions, insertions or deletions are located in regions outside the HVR (ie, FR regions). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-61 or SEQ ID NO: 110, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-61 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-61 antibody, and (c) the HVR-L3 amino acid sequence AL2p-61 antibodies.

In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain and a heavy chain variable domain, wherein the heavy chain variable domain comprises an amino acid sequence with 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 at least 96%, at least 97%, at least 98%, at least 99%, or 100% identity with the amino acid sequence of the heavy chain variable domain of the antibody AL2p-62 or with the amino acid sequence of SEQ ID NO: 71; and/or the light chain variable domain contains an amino acid sequence with 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 light chain variable domain of the AL2p-62 antibody or with the amino acid sequence of SEQ ID NO: 111. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a heavy chain variable domain comprising an amino acid sequence of 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 heavy chain variable domain of the antibody AL2p-62 or with the amino acid sequence of SEQ ID NO: 71, wherein the heavy chain variable domain includes the amino acid sequences HVR-H1, HVR-H2 and HVR-H3 of the antibody AL2p-62. In some embodiments, the anti-TREM2 antibodies of the present invention comprise a light chain variable domain comprising an amino acid sequence of 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%, according to at least 98%, at least 99%, or 100% identity with the amino acid sequence of the light chain variable domain of the antibody AL2p-62 or with the amino acid sequence of SEQ ID NO: 111, wherein the light chain variable domain includes the amino acid sequences HVR-L1, HVR- L2 and HVR-L3 antibodies AL2p-62. In some embodiments, the anti-TREM2 antibody comprises a heavy chain variable domain (VH) 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 heavy chain variable domain of the antibody AL2p-62 or with the amino acid sequence of SEQ ID NO: 71, and containing substitutions (e.g., conservative substitutions, insertions or deletions compared with the reference sequence ), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind to TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-62 antibody heavy chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 71. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the heavy chain variable domain of the antibody AL2p-62 or the amino acid sequence of SEQ ID NO: 71. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VH sequence of the antibody AL2p-62 or SEQ ID NO: 71, including post-translational modifications of this sequence. In a specific embodiment, the VH contains one, two or three HVRs selected from (a) the HVR-H1 amino acid sequence of the AL2p-62 antibody, (b) the HVR-H2 amino acid sequence of the AL2p-62 antibody, and (c) the HVR-H3 amino acid sequence AL2p-62 antibodies. In some embodiments, the anti-TREM2 antibodies of the present invention include a light chain variable domain (VL) sequence having at least 85%, at least 86%, at least

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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 light chain variable domain of the antibody AL2p-62 or with the amino acid sequence of SEQ ID NO: 111, and containing substitutions (eg, conservative substitutions, insertions or deletions compared to a reference sequence), but an anti-TREM2 antibody incorporating such a sequence retains the ability to bind TREM2. In some embodiments, a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in the AL2p-62 antibody light chain variable domain amino acid sequence or amino acid sequence SEQ ID NO: 111. In some embodiments, a total of 1 to 5 amino acids have been substituted, inserted, and/or deleted in the amino acid sequence of the AL2p-62 antibody light chain variable domain or the amino acid sequence of SEQ ID NO: 111. In some embodiments, the substitutions, insertions, or deletions are located in regions outside the HVR (i.e., on FR sections). In some embodiments, the substitutions, insertions, or deletions are located at FR regions. Optionally, the anti-TREM2 antibody contains the VL sequence of the antibody AL2p-62 or SEQ ID NO: 111, including post-translational modifications of this sequence. In a specific embodiment, the VL contains one, two or three HVRs selected from (a) the HVR-L1 amino acid sequence of the AL2p-62 antibody, (b) the HVR-L2 amino acid sequence of the AL2p-62 antibody, and (c) the HVR-L1 amino acid sequence L3 antibody AL2p-62.

In some embodiments, an anti-TREM2 antibody is provided, wherein the antibody comprises VH as in any of the embodiments above and VL as in any of the embodiments above. In some embodiments, anti-TREM2 antibodies are provided herein, wherein the antibody comprises VH as in any of the embodiments above and VL as in any of the embodiments above. In one embodiment, the antibody contains the VH and VL sequences set forth in SEQ ID NOs: 27-71 and 91 and SEQ ID NOs: 92-113 and 118, respectively, including post-translational modifications of these sequences.

In some embodiments, the antibody contains a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53, and/or a light chain variable region containing the amino acid sequence of SEQ ID NO: 97. In some embodiments, the antibody contains a heavy chain variable region containing the amino acid sequence sequence SEQ ID NO: 59; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 64; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 70; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 110. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 71; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 111. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 112. In some embodiments, the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53; and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113.

Any of the antibodies of the present invention can be produced by a cell line. In some embodiments, the cell line may be a mammalian cell line. In some embodiments, the cell line may be a hybridoma cell line. In other embodiments, the cell line may be a yeast cell line. Any cell line known to those skilled in the art suitable for antibody production can be used to produce the antibody of the present invention. Typical examples of cell lines for antibody production are described in the present invention.

In some embodiments, the anti-TREM2 antibody is an anti-TREM2 monoclonal 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,

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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 aHTu-TREM2 antibody is the aHTu-TREM2 monoclonal antibody AL2p-31. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to substantially the same epitope of TREM2 as AL2p-31. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-31. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-31. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-31 .

In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody AL2p-37. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to substantially the same epitope of TREM2 as AL2p-37. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-37. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-37. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-37 .

In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody AL2p-47. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to substantially the same epitope of TREM2 as AL2p-47. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-47. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-47. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-47 .

In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody AL2p-58. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to substantially the same TREM2 epitope as AL2p-58. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-58. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-58. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-58 .

In some embodiments, the anti-TREM2 antibody is an anti-TREM2 monoclonal antibody AL2p-60. In some embodiments, an anti-TREM2 antibody is an isolated antibody that binds to substantially the same TREM2 epitope as AL2p-60. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-60. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-60. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-60 .

In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody AL2p-61. In some embodiments, the anti-TREM2 antibody is an isolated antibody that binds to substantially the same epitope of TREM2 as AL2p-61. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising an HVR-H1, HVR-H2, and HVR-H3 heavy chain variable domain monoclonal

- 117 044134 new antibody AL2p-61. In some embodiments, the aHTu-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-61. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-61 .

In some embodiments, the anti-TREM2 antibody is the anti-TREM2 monoclonal antibody AL2p-62. In some embodiments, an anti-TREM2 antibody is an isolated antibody that binds to substantially the same TREM2 epitope as AL2p-62. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising HVR-H1, HVR-H2, and HVR-H3 of the heavy chain variable domain of the monoclonal antibody AL2p-62. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the HVR-L1, HVR-L2, and HVR-L3 light chain variable domain of the monoclonal antibody AL2p-62. In some embodiments, the anti-TREM2 antibody is an isolated antibody comprising the heavy chain variable domain HVR-H1, HVR-H2, and HVR-H3 and the light chain variable domain HVR-L1, HVR-L2, and HVR-L3 of the monoclonal antibody AL2p-62 .

In some embodiments, the anti-TREM2 antibodies of the present invention do not compete with one or more TREM2 ligands for binding to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention are capable of binding TREM2 without simultaneously blocking the binding of one or more TREM2 ligands to TREM2. In some embodiments, the anti-TREM2 antibodies of the present invention are capable of additive and/or synergistic functional interactions with one or more TREM2 ligands. In some embodiments, the anti-TREM2 antibodies of the present invention increase the maximum activity of TREM2 when exposed to saturating concentrations of one or more TREM2 ligands. In some embodiments, the anti-TREM2 antibodies of the present invention increase the TREM2 activity achieved at any concentration of one or more TREM2 ligands.

Binding affinity of anti-TREM2 antibody.

The dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 and cynomolgus TREM2 can be at least 1-fold lower, at least 2-fold lower, at least 3-fold lower, at least 4-fold lower , at least 5 times lower, at least 6 times lower, at least 7 times lower, at least 8 times lower, at least 9 times lower, at least 10 times lower, according to at least 11 times lower, at least 12 times lower, at least 13 times lower, at least 14 times lower, at least 15 times lower, at least 16 times lower, at least 17 times lower, at least 18 times lower, at least 19 times lower, at least 20 times lower, or even lower than an anti-TREM2 antibody selected from an anti-TREM2 antibody containing a variable region a heavy chain containing the amino acid sequence of SEQ ID NO: 27, and containing a light chain variable region containing the amino acid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 91 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 may range from about 300 nM to about 100 pM, from about 200 nM to about 100 pM, from about 100 nM to about 100 pM, from about 90 nM to about 100 pM, about 80 nM to about 100 pM, about 70 nM to about 100 pM, about 60 nM to about 100 pM, about 50 nM to about 100 pM, about 40 nM to about 100 pM, from about 30 nM to about 100 pM, from about 20 nM to about 100 pM, from about 10 nM to about 100 pM, from about 9 nM to about 100 pM, from about 8 nM to about 100 pM, from about 7 nM to about 100 pM, about 6 nM to about 100 pM, about 5 nM to about 100 pM, about 4 nM to about 100 pM, about 3 nM to about 100 pM, about 2 nM to about 100 pM, from about 1 nM to about 100 pM, from 900 pM to about 100 pM, from about 800 pM to about 100 pM, from 700 pM to about 100 pM, from 600 pM to about 500 pM, from 400 pM to about 100 pM, from 300 pM to about 100 pM, from 200 pM to about 100 pM, from 900 pM to about 100 pM, or less than 100 pM. In some embodiments, implementation

- 118 044134 dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 may range from about 300 nM to about 90 pM, from about 300 nM to about 80 pM, from about 300 nM to about 70 pM, from about 300 nM to about 60 pM, about 300 nM to about 50 pM, about 300 nM to about 40 pM, about 300 nM to about 30 pM, about 300 nM to about 20 pM, about 300 nM to about 10 pM, from about 300 nM to about 9 pM, from about 300 nM to about 8 pM, from about 300 nM to about 7 pM, from about 300 nM to about 6 pM, from about 300 nM to about 5 pM, from about 300 nM to about 4 pM, about 300 nM to about 3 pM, about 300 nM to about 2 pM, about 300 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 200 nM to about 90 pM, from about 200 nM to about 80 pM, from about 200 nM to about 70 pM, from about 200 nM to about 60 pM, about 200 nM to about 50 pM, about 200 nM to about 40 pM, about 200 nM to about 30 pM, about 200 nM to about 20 pM, about 200 nM to about 10 pM, from about 200 nM to about 9 pM, about 200 nM to about 8 pM, about 200 nM to about 7 pM, about 200 nM to about 4 pM, about 200 nM to about 5 pM, about 200 nM to about 4 pM pM, from about 200 nM to about 3 pM, from about 200 nM to about 2 pM, from about 200 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 100 nM to about 90 pM, from about 100 nM to about 80 pM, from about 100 nM to about 70 pM, from about 100 nM to about 60 pM, about 100 nM to about 50 pM, about 100 nM to about 40 pM, about 100 nM to about 30 pM, about 100 nM to about 20 pM, about 100 nM to about 10 pM, from about 100 nM to about 9 pM, about 100 nM to about 8 pM, about 100 nM to about 7 pM, about 100 nM to about 6 pM, about 100 nM to about 5 pM, about 100 nM to about 4 pM, about 100 nM to about 3 pM, about 100 nM to about 2 pM, about 100 nM to about 1 pM, or less than 1 pM. Dissociation constants (KD) of anti-TREM2 antibodies with human TREM2 can range from about 90 nM to about 90 pM, from about 90 nM to about 80 pM, from about 90 nM to about 70 pM, from about 90 nM to about 60 pM , from about 90 nM to about 50 pM, from about 90 nM to about 40 pM, from about 90 nM to about 30 pM, from about 90 nM to about 20 pM, from about 90 nM to about 10 pM, from about 90 nM to about 9 pM, from about 90 nM to about 8 pM, from about 90 nM to about 7 pM, from about 90 nM to about 6 pM, from about 90 nM to about 5 pM, from about 90 nM to about 4 pM, from about 90 nM to about 3 pM, from about 90 nM to about 2 pM, from about 90 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 80 nM to about 90 pM, from about 80 nM to about 80 pM, from about 80 nM to about 70 pM, from about 80 nM to about 60 pM, about 80 nM to about 50 pM, about 80 nM to about 40 pM, about 80 nM to about 30 pM, about 80 nM to about 20 pM, about 80 nM to about 10 pM, from about 80 nM to about 9 pM, about 80 nM to about 8 pM, about 80 nM to about 7 pM, about 80 nM to about 6 pM, about 80 nM to about 5 pM, about 80 nM to about 4 pM, about 80 nM to about 3 pM, about 80 nM to about 2 pM, about 80 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 70 nM to about 90 pM, from about 70 nM to about 80 pM, from about 70 nM to about 70 pM, from about 70 nM to about 60 pM, about 70 nM to about 50 pM, about 70 nM to about 40 pM, about 70 nM to about 30 pM, about 70 nM to about 20 pM, about 70 nM to about 10 pM, from about 70 nM to about 9 pM, about 70 nM to about 8 pM, about 70 nM to about 7 pM, about 70 nM to about 6 pM, about 70 nM to about 5 pM, about 70 nM to about 4 pM, about 70 nM to about 3 pM, about 70 nM to about 2 pM, about 70 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 60 nM to about 90 pM, from about 60 nM to about 80 pM, from about 60 nM to about 70 pM, from about 60 nM to about 60 pM, about 60 nM to about 50 pM, about 60 nM to about 40 pM, about 60 nM to about 30 pM, about 60 nM to about 20 pM, about 60 nM to about 10 pM, from about 60 nM to about 9 pM, from about 60 nM to about 8 pM, from about 60 nM to at

- 119 044134 approximately 7 pM, from about 60 nM to about 6 pM, from about 60 nM to about 5 pM, from about 60 nM to about 4 pM, from about 60 nM to about 3 pM, from about 60 nM to about 2 pM, from about 60 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 50 nM to about 90 pM, from about 50 nM to about 80 pM, from about 50 nM to about 70 pM, from about 50 nM to about 60 pM, about 50 nM to about 50 pM, about 50 nM to about 40 pM, about 50 nM to about 30 pM, about 50 nM to about 20 pM, about 50 nM to about 10 pM, from about 50 nM to about 9 pM, about 50 nM to about 8 pM, about 50 nM to about 7 pM, about 50 nM to about 6 pM, about 50 nM to about 5 pM, about 50 nM to about 4 pM, about 50 nM to about 3 pM, about 50 nM to about 2 pM, about 50 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 40 nM to about 90 pM, from about 40 nM to about 80 pM, from about 40 nM to about 70 pM, from about 40 nM to about 60 pM, about 40 nM to about 50 pM, about 40 nM to about 40 pM, about 40 nM to about 30 pM, about 40 nM to about 20 pM, about 40 nM to about 10 pM, from about 40 nM to about 9 pM, about 40 nM to about 8 pM, about 40 nM to about 7 pM, about 40 nM to about 6 pM, about 40 nM to about 5 pM, about 40 nM to about 4 pM, about 40 nM to about 3 pM, about 40 nM to about 2 pM, about 40 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 30 nM to about 90 pM, from about 30 nM to about 80 pM, from about 30 nM to about 70 pM, from about 30 nM to about 60 pM, about 30 nM to about 50 pM, about 30 nM to about 40 pM, about 30 nM to about 30 pM, about 30 nM to about 20 pM, about 30 nM to about 10 pM, from about 30 nM to about 9 pM, about 30 nM to about 8 pM, about 30 nM to about 7 pM, about 30 nM to about 6 pM, about 30 nM to about 5 pM, about 30 nM to about 4 pM, about 30 nM to about 3 pM, about 30 nM to about 2 pM, about 30 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 20 nM to about 90 pM, from about 20 nM to about 80 pM, from about 20 nM to about 70 pM, from about 20 nM to about 60 pM, about 20 nM to about 50 pM, about 20 nM to about 40 pM, about 20 nM to about 30 pM, about 20 nM to about 20 pM, about 20 nM to about 10 pM, from about 20 nM to about 9 pM, about 20 nM to about 8 pM, about 20 nM to about 7 pM, about 20 nM to about 6 pM, about 20 nM to about 5 pM, about 20 nM to about 4 pM, about 20 nM to about 3 pM, about 20 nM to about 2 pM, about 20 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 10 nM to about 90 pM, from about 10 nM to about 80 pM, from about 10 nM to about 70 pM, from about 10 nM to about 60 pM, about 10 nM to about 50 pM, about 10 nM to about 40 pM, about 10 nM to about 30 pM, about 10 nM to about 20 pM, about 10 nM to about 10 pM, from about 10 nM to about 9 pM, about 10 nM to about 8 pM, about 10 nM to about 7 pM, about 10 nM to about 6 pM, about 10 nM to about 5 pM, about 10 nM to about 4 pM, about 10 nM to about 3 pM, about 10 nM to about 2 pM, about 10 nM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 5 nM to about 90 pM, from about 5 nM to about 80 pM, from about 5 nM to about 70 pM, from about 5 nM to about 60 pM, about 5 nM to about 50 pM, about 5 nM to about 40 pM, about 5 nM to about 30 pM, about 5 nM to about 20 pM, about 5 nM to about 10 pM, from about 5 nM to about 9 pM, about 5 nM to about 8 pM, about 5 nM to about 7 pM, about 5 nM to about 6 pM, about 5 nM to about 5 pM, about 5 nM to about 4 pM, about 5 nM to about 3 pM, about 5 nM to about 2 pM, about 5 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 1 nM to about 90 pM, from about 1 nM to about 80 pM, from about 1 nM to about 70 pM, from about 1 nM to about 60 pM, about 1 nM to about 50 pM, about 1 nM to about 40 pM, about 1 nM to about 30 pM, about 1 nM to about 20 pM, about 1 nM to about 10 pM, from about 1 nM to about 9 pM, about 1 nM to about 8 pM, about 1 nM to about 7 pM, about 1 nM to about 6 pM, about 1 nM to about 5 pM, about 1 nM to about 4 pM, about 1 nM to about 3 pM, about 1 nM to about 2 pM, about 1 nM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 500 pM to about 90 pM, from about 500 pM to about 80 pM, from about 500 pM to about 70 pM, from about 500 pM to approximately

- 120 044134 pM, from about 500 pM to about 50 pM, from about 500 pM to about 40 pM, from about 500 pM to about 30 pM, from about 500 pM to about 20 pM, from about 500 pM to about 10 pM, from about 500 pM to about 9 pM, from about 500 pM to about 8 pM, from about 500 pM to about 7 pM, from about 500 pM to about 6 pM, from about 500 pM to about 5 pM, from about 500 pM to about 4 pM, about 500 pM to about 3 pM, about 500 pM to about 2 pM, about 500 pM to about 1 pM, or less than 1 pM. Dissociation constants (K _D ) of anti-TREM2 antibodies with human TREM2 can range from about 250 pM to about 90 pM, from about 250 pM to about 80 pM, from about 250 pM to about 70 pM, from about 250 pM to about 60 pM, about 250 pM to about 50 pM, about 250 pM to about 40 pM, about 250 pM to about 30 pM, about 250 pM to about 20 pM, about 250 pM to about 10 pM, from about 250 pM to about 9 pM, about 250 pM to about 8 pM, about 250 pM to about 7 pM, about 250 pM to about 4 pM, about 250 pM to about 5 pM, about 250 pM to about 4 pM pM, from about 250 pM to about 3 pM, from about 250 pM to about 2 pM, from about 250 pM to about 1 pM, or less than 1 pM. Dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 can range from about 100 pM to about 90 pM, from about 100 pM to about 80 pM, from about 100 pM to about 70 pM, from about 100 pM to about 60 pM, about 100 pM to about 50 pM, about 100 pM to about 40 pM, about 100 pM to about 30 pM, about 100 pM to about 20 pM, about 100 pM to about 10 pM, from about 100 pM to about 9 pM, about 100 pM to about 8 pM, about 100 pM to about 7 pM, about 100 pM to about 6 pM, about 100 pM to about 5 pM, about 100 pM to about 4 pM, about 100 pM to about 3 pM, about 100 pM to about 2 pM, about 100 pM to about 1 pM, or less than 1 pM. In some embodiments, the dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with human TREM2 may be less than 260 nM, may be less than 225 nM, may be less than 200 nM, may be less than 150 nM, may be less than 135 nM, may be less than 125 nM, may be less than 100 nM, may be less than 95 nM, may be less than 90 nM, may be less than 85 nM, may be less than 80 nM, may be less than 75 nM, may be less than 70 nM, may be less than 65 nM , may be less than 60 nM, may be less than 55 nM, may be less than 50 nM, may be less than 45 nM, may be less than 40 nM, may be less than 36 nM, may be less than 35 nM, may be less than 30 nM, may may be less than 29 nM, may be less than 28 nM, may be less than 27 nM, may be less than 26 nM, may be less than 25 nM, may be less than 24 nM, may be less than 23 nM, may be less than 22 nM, may be less 21 nM, may be less than 20 nM, may be less than 19 nM, may be less than 18.5 nM, may be less than 18 nM, may be less than 15 nM, may be less than 14 nM, may be less than 13 nM, may be less 12 nM, may be less than 11 nM, may be less than 10 nM, may be less than 9.5 nM, may be less than 9 nM, may be less than 8.5 nM, may be less than 8 nM, may be less than 7.5 nM , may be less than 7 nM, may be less than 6.5 nM, may be less than 6 nM, may be less than 5.5 nM, may be less than 5 nM, may be less than 4.5 nM, may be less than 4 nM, may may be less than 3.5 nM, may be less than 3 nM, may be less than 2.5 nM, may be less than 2 nM, may be less than 1.5 nM, may be less than 1 nM, may be less than 950 pM, may be less 900 pM, may be less than 850 pM, may be less than 830 pM, may be less than 800 pM, may be less than 750 pM, may be less than 730 pM, may be less than 700 pM, may be less than 650 pM, may be less than 630 pM , may be less than 600 pM, may be less than 550 pM, may be less than 500 pM, may be less than 450 pM, may be less than 415 pM, may be less than 400 pM, may be less than 350 pM, may be less than 300 pM, may may be less than 250 pM, may be less than 200 pM, may be less than 150 pM, may be less than 100 pM, may be less than 95 pM, may be less than 90 pM, may be less than 85 pM, may be less than 80 pM, may be less 75 pM, may be less than 70 pM, may be less than 65 pM, may be less than 60 pM, may be less than 55 pM, may be less than 50 pM, may be less than 45 pM, may be less than 40 pM, may be less than 35 pM, may be less than 30 pM, may be less than 25 pM, may be less than 20 pM, may be less than 15 pM, may be less than 10 pM, may be less than 9 pM, may be less than 8 pM, may be less than 7 pM, may be less than 6 pM, may be less than 5 pM, may composition

- 121 044134 be less than 4 pM, may be less than 3 pM, may be less than 2 pM, or may be less than 1 pM. In some embodiments, the dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 10 μM to about 100 pM, from about 200 nM to about 100 pM, from about 100 nM to about 100 pM, from about 90 nM to about 100 pM, from about 80 nM to about 100 pM, from about 70 nM to about 100 pM, from about 60 nM to about 100 pM, from about 50 nM to about 100 pM, from about 40 nM to about 100 pM, about 30 nM to about 100 pM, about 20 nM to about 100 pM, about 10 nM to about 100 pM, about 9 nM to about 100 pM, about 8 nM to about 100 pM, from about 7 nM to about 100 pM, about 6 nM to about 100 pM, about 5 nM to about 100 pM, about 4 nM to about 100 pM, about 3 nM to about 100 pM, about 2 nM to about 100 pM, about 1 nM to about 100 pM, 900 pM to about 100 pM, about 800 pM to about 100 pM, 700 pM to about 100 pM, 600 pM to about 500 pM, 400 pM to about 100 pM, 300 pM to about 100 pM, 200 pM to about 100 pM, 900 pM to about 100 pM, or less than 100 pM. In some embodiments, the dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, KD is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 10 μM to about 900 pM, from about 10 μM to about 800 pM, from about 10 μM to about 700 pM, from about 10 μM to about 600 pM, from about 10 μM to about 500 pM, from about 10 μM to about 400 pM, from about 10 μM to about 300 pM, from about 10 μM to about 200 pM, from about 10 μM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 5 μM to about 900 pM, from about 5 μM to about 800 pM, from about 5 μM to about 700 pM, from about 5 μM to about 600 pM, from about 5 μM to about 500 pM, from about 5 μM to about 400 pM, from about 5 μM to about 300 pM, from about 5 μM to about 200 pM, from about 5 μM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 1 μM to about 900 pM, from about 1 μM to about 800 pM, from about 1 μM to about 700 pM, from about 1 μM to about 600 pM, from about 1 μM to about 500 pM, from about 1 μM to about 400 pM, from about 1 μM to about 300 pM, from about 1 μM to about 200 pM, from about 1 μM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 900 nM to about 900 pM, from about 900 nM to about 800 pM, from about 900 nM to about 700 pM, from about 900 nM to about 600 pM, from about 900 nM to about 500 pM, from about 900 nM to about 400 pM, from about 900 nM to about 300 pM, from about 900 nM to about 200 pM, from about 900 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 800 nM to about 900 pM, from about 800 nM to about 800 pM, from about 800 nM to about 700 pM, from about 800 nM to about 600 pM, from about 800 nM to about 500 pM, from about 800 nM to about 400 pM, from about 800 nM to about 300 pM, from about 800 nM to about 200 pM, from about 800 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 700 nM to about 900 pM, from about 700 nM to about 800 pM, from about 700 nM to about 700 pM, from about 700 nM to about 600 pM, from about 700 nM to about 500 pM, from about 700 nM to about 400 pM, from about 700 nM to about 300 pM, from about 700 nM to about 200 pM, from about 700 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants (K _D ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 600 nM to about 900 pM, from about 600 nM to about 800 pM, from about 600 nM to about 700 pM , from about 600 nM to about 600 pM, from about 600 nM to about 500 pM, from about 600 nM to about 400 pM, from about 600 nM to about 300 pM, from about 600 nM to about 200 pM, from about 600 nM to about 100 pM or less

- 122 044134

100 pM. In some embodiments, the dissociation constants ( _KD ) of aHTu-TREM2 antibodies with cynomolgus TREM2 may range from about 500 nM to about 900 pM, from about 500 nM to about 800 pM, from about 500 nM to about 700 pM, from about 500 nM to about 600 pM, from about 500 nM to about 500 pM, from about 500 nM to about 400 pM, from about 500 nM to about 300 pM, from about 500 nM to about 200 pM, from about 500 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 400 nM to about 900 pM, from about 400 nM to about 800 pM, from about 400 nM to about 700 pM, from about 400 nM to about 600 pM, from about 400 nM to about 500 pM, from about 400 nM to about 400 pM, from about 400 nM to about 300 pM, from about 400 nM to about 200 pM, from about 400 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 300 nM to about 900 pM, from about 300 nM to about 800 pM, from about 300 nM to about 700 pM, from about 300 nM to about 600 pM, from about 300 nM to about 500 pM, from about 300 nM to about 400 pM, from about 300 nM to about 300 pM, from about 300 nM to about 200 pM, from about 300 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 200 nM to about 900 pM, from about 200 nM to about 800 pM, from about 200 nM to about 700 pM, from about 200 nM to about 600 pM, from about 200 nM to about 500 pM, from about 200 nM to about 400 pM, from about 200 nM to about 300 pM, from about 200 nM to about 200 pM, from about 200 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 100 nM to about 900 pM, from about 100 nM to about 800 pM, from about 100 nM to about 700 pM, from about 100 nM to about 600 pM, from about 100 nM to about 500 pM, from about 100 nM to about 400 pM, from about 100 nM to about 300 pM, from about 100 nM to about 200 pM, from about 100 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 90 nM to about 900 pM, from about 90 nM to about 800 pM, from about 90 nM to about 700 pM, from about 90 nM to about 600 pM, from about 90 nM to about 500 pM, from about 90 nM to about 400 pM, from about 90 nM to about 300 pM, from about 90 nM to about 200 pM, from about 90 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 80 nM to about 900 pM, from about 80 nM to about 800 pM, from about 80 nM to about 700 pM, from about 80 nM to about 600 pM, from about 80 nM to about 500 pM, from about 80 nM to about 400 pM, from about 80 nM to about 300 pM, from about 80 nM to about 200 pM, from about 80 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants (K _D ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 70 nM to about 900 pM, from about 70 nM to about 800 pM, from about 70 nM to about 700 pM, from about 70 nM to about 600 pM, about 70 nM to about 500 pM, about 70 nM to about 400 pM, about 70 nM to about 300 pM, about 70 nM to about 200 pM, about 70 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 60 nM to about 900 pM, from about 60 nM to about 800 pM, from about 60 nM to about 700 pM, from about 60 nM to about 600 pM, from about 60 nM to about 500 pM, from about 60 nM to about 400 pM, from about 60 nM to about 300 pM, from about 60 nM to about 200 pM, from about 60 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 50 nM to about 900 pM, from about 50 nM to about 800 pM, from about 50 nM to about 700 pM, from about 50 nM to about 600 pM, from about 50 nM to about 500 pM, from about 50 nM to about 400 pM, from about 50 nM to about 300 pM, from about 50 nM to about 200 pM, from about 50 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants (KD) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 40 nM to about 900 pM, from about 40 nM to about 800 pM, from about 40 nM to about 700 pM, from about 40 nM to about 600 pM, about 40 nM to about 500 pM, about 40 nM to about 400 pM, about 40 nM to about 300 pM, about 40 nM to about 200 pM, about 40 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 30 nM to about 900 pM, from about 30 nM to about 800 pM, from example

- 123 044134 but 30 nM to about 700 pM, from about 30 nM to about 600 pM, from about 30 nM to about 500 pM, from about 30 nM to about 400 pM, from about 30 nM to about 300 pM, from about 30 nM to about 200 pM, from about 30 nM to about 100 pM or less than 100 pM, from about 20 nM to about 900 pM, from about 20 nM to about 800 pM, from about 20 nM to about 700 pM, from about 20 nM to about 600 pM, from about 20 nM to about 500 pM, from about 20 nM to about 400 pM, from about 20 nM to about 300 pM, from about 20 nM to about 200 pM, from about 20 nM to about 100 pM, or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 10 nM to about 900 pM, from about 10 nM to about 800 pM, from about 10 nM to about 700 pM, from about 10 nM to about 600 pM, from about 10 nM to about 500 pM, from about 10 nM to about 400 pM, from about 10 nM to about 300 pM, from about 10 nM to about 200 pM, from about 10 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 9 nM to about 900 pM, from about 9 nM to about 800 pM, from about 9 nM to about 700 pM, from about 9 nM to about 600 pM, from about 9 nM to about 500 pM, from about 9 nM to about 400 pM, from about 9 nM to about 300 pM, from about 9 nM to about 200 pM, from about 9 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 8 nM to about 900 pM, from about 8 nM to about 800 pM, from about 8 nM to about 700 pM, from about 8 nM to about 600 pM, from about 8 nM to about 500 pM, from about 8 nM to about 400 pM, from about 8 nM to about 300 pM, from about 8 nM to about 200 pM, from about 8 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 7 nM to about 900 pM, from about 7 nM to about 800 pM, from about 7 nM to about 700 pM, from about 7 nM to about 600 pM, from about 7 nM to about 500 pM, from about 7 nM to about 400 pM, from about 7 nM to about 300 pM, from about 7 nM to about 200 pM, from about 7 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 6 nM to about 900 pM, from about 6 nM to about 800 pM, from about 6 nM to about 700 pM, from about 6 nM to about 600 pM, from about 6 nM to about 500 pM, from about 6 nM to about 400 pM, from about 6 nM to about 300 pM, from about 6 nM to about 200 pM, from about 6 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants (KD) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 5 nM to about 900 pM, from about 5 nM to about 800 pM, from about 5 nM to about 700 pM, from about 5 nM to about 600 pM, about 5 nM to about 500 pM, about 5 nM to about 400 pM, about 5 nM to about 300 pM, about 5 nM to about 200 pM, about 5 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 4 nM to about 900 pM, from about 4 nM to about 800 pM, from about 4 nM to about 700 pM, from about 4 nM to about 600 pM, from about 4 nM to about 500 pM, from about 4 nM to about 400 pM, from about 4 nM to about 300 pM, from about 4 nM to about 200 pM, from about 4 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 3 nM to about 900 pM, from about 3 nM to about 800 pM, from about 3 nM to about 700 pM, from about 3 nM to about 600 pM, from about 3 nM to about 500 pM, from about 3 nM to about 400 pM, from about 3 nM to about 300 pM, from about 3 nM to about 200 pM, from about 3 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 2 nM to about 900 pM, from about 2 nM to about 800 pM, from about 2 nM to about 700 pM, from about 2 nM to about 600 pM, from about 2 nM to about 500 pM, from about 2 nM to about 400 pM, from about 2 nM to about 300 pM, from about 2 nM to about 200 pM, from about 2 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may range from about 1 nM to about 900 pM, from about 1 nM to about 800 pM, from about 1 nM to about 700 pM, from about 1 nM to about 600 pM, from about 1 nM to about 500 pM, from about 1 nM to about 400 pM, from about 1 nM to about 300 pM, from about 1 nM to about 200 pM, from about 1 nM to about 100 pM or less than 100 pM. In some embodiments, the dissociation constant (K _D ) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or

- 124 044134 full-length antibodies in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

In some embodiments, the dissociation constants ( _KD ) of anti-TREM2 antibodies with cynomolgus TREM2 may be less than 6 μM, may be less than 5 μM, may be less than 4.6 μM, may be less than 4 μM, may be less than 3 μM, may be less than 2 µM, may be less than 1.5 µM, may be less than 1 µM, may be less than 900 nM, may be less than 800 nM, may be less than 700 nM, may be less than 600 nM, may be less than 500 nM, may be less than 400 nM, may be less than 300 nM, may be less than 200 nM, may be less than 100 nM, may be less than 95 nM, may be less than 90 nM, may be less than 85 nM, may be less than 80 nM, may be less than 75 nM, may be less than 70 nM, may be less than 65 nM, may be less than 60 nM, may be less than 55 nM, may be less than 50 nM, may be less than 45 nM, may be less than 40 nM, may be less than 36 nM, may be less than 35 nM, may be less than 31 nM, may be less than 30 nM, may be less than 29 nM, may be less than 28 nM, may be less than 27 nM, may be less than 26 nM, may be less than 25 nM, may be less than 24 nM, may be less than 23 nM, may be less than 22 nM, may be less than 21 nM, may be less than 20 nM, may be less than 19 nM, may be less than 18.5 nM, may be less than 18 nM, may be less than 17 nM, may be less than 16.5 nM, may be less than 16 nM, may be less than 15.5 nM, may be less than 15 nM, may be less than 14.5 nM, may be less than 14 nM, may be less than 13 nM, may be less than 12 nM, may be less than 11 nM, may be less than 10 nM, may be less than 9.5 nM, may be less than 9 nM, may be less than 8.5 nM, may be less than 8 nM, may be less than 7.5 nM, may be less than 7 nM, may be less than 6.5 nM, may be less than 6 nM, may be less than 5.5 nM, may be less than 5 nM, may be less than 4.5 nM, may be less than 4 nM, may be less than 3.5 nM, may be less than 3 nM, may be less than 2.5 nM, may be less than 2 nM, may be less than 1.5 nM, may be less than 1 nM, may be less than 950 pM, may be less than 900 pM, may be less than 890 pM, may be less than 850 pM, may be less than 800 pM, may be less than 750 pM, may be less than 700 pM, may be less than 650 pM, may be less than 600 pM, may be less than 550 pM, may be less than 500 pM, may be less than 450 pM, may be less than 400 pM, may be less than 375 pM, may be less than 350 pM, may be less than 325 pM, may be less than 300 pM, may be less than 270 pM, may be less than 250 pM, may be less than 225 pM, may be less than 200 pM, may be less than 150 pM, or may be less than 100 pM. In some embodiments, the dissociation constant (KD) is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody in monovalent form. Methods for generating and selecting antibodies that interact and/or specifically bind to TREM2 are described herein (eg, see Examples 1 and 2).

Dissociation constants can be determined by any analytical technique, including any biochemical or biophysical technique such as ELISA, surface plasmon resonance (SPR), biolayer interferometry (see, for example, ForteBio's Octet System), isothermal titration calorimetry (ITC) ), differential scanning calorimetry (DSC), circular dichroism (CD), stopped-flow analysis, and colorimetric or fluorescent protein melting assays. In some embodiments, the dissociation constant (K _D ) of TREM2 is determined at a temperature of approximately 25°C. In some embodiments, the K _D is determined using a monovalent antibody (eg, Fab) or a full-length antibody. In some embodiments, KD is determined using a full-length antibody in monovalent form. Using, for example, any assay described herein (see, for example, Examples 1 and 2).

Additional anti-TREM2 antibodies, for example, antibodies that specifically bind to the TREM2 protein of the present invention, can be identified, screened, and/or characterized by determining their physical/chemical properties and/or biological activities using various assays known in the art. .

Bispecific antibodies.

Certain aspects of the present invention relate to bispecific antibodies that bind to the TREM2 protein of the present invention and a second antigen. Methods for producing bispecific antibodies are well known in the art and are described herein. In some embodiments, the bispecific antibodies of the present invention bind to one or more amino acid residues of human TREM2 (SEQ ID NO: 1), or amino acid residues of the TREM2 protein corresponding to the amino acid residues of SEQ ID NO: 1. In other embodiments, the bispecific antibodies of the present invention the invention also linking

- 125 044134 are combined with one or more amino acid residues of human DAP12.

In some embodiments, the bispecific antibodies of the present invention recognize a first antigen and a second antigen. In some embodiments, the first antigen is human TREM2 or a natural variant thereof, or human DAP12 or a natural variant thereof. In some embodiments, the second antigen is (a) an antigen that facilitates transport across the blood-brain barrier;

(b) an antigen that facilitates transport across the blood-brain barrier selected from transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2) , diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopep peptide and ANG1005;

(c) a pathogenic protein selected from beta-amyloid, oligomeric beta-amyloid, beta-amyloid plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alphasynuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72) , c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI , serum amyloid A, medina, prolactin, transthyretin, lysozyme, beta-2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, non-ATG repeat-associated (RAN) translation products, peptides with dipeptide repeat peptides (DPR), glycine-alanine repeat peptides (GA), glycine-proline repeat peptides (GP), glycine-arginine repeat peptides (GR), proline-alanine repeat peptides (PA), ubiquitin, and peptides with proline-arginine repeats (PR); and (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or proteins are selected from CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3 and phosphatidylserine; and (e) a protein, lipid, polysaccharide or glycolipid expressed on one or more tumor cells, and any combination thereof.

Antibody fragments.

Certain aspects of the present invention relate to antibody fragments that bind to one or more human TREM2, a natural variant of human TREM2, and a disease variant of human TREM2. In some embodiments, the antibody fragment is a Fab, Fab', Fab'-SH, F(ab')2, Fv, or scFv fragment. In some embodiments, the antibody fragment is used in combination with one or more antibodies that specifically bind a pathogenic protein selected from (a) an antigen that facilitates transport across the blood-brain barrier;

(b) an antigen that facilitates transport across the blood-brain barrier selected from transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2) , diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopep peptide and ANG1005;

(c) a pathogenic protein selected from beta-amyloid, oligomeric beta-amyloid, beta-amyloid plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alphasynuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72) , c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI , serum amyloid A, medina, prolactin, transthyretin, lysozyme, beta-2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, non-ATG repeat-associated (RAN) translation products, peptides with dipeptide repeat peptides (DPR), glycine-alanine repeat peptides (GA), glycine-proline repeat peptides (GP), glycine-arginine repeat peptides (GR), proline-alanine repeat peptides (PA), ubiquitin, and peptides with proline-arginine repeats (PR); and (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or proteins are selected from CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3 and phosphatidylserine; and (e) a protein, lipid, polysaccharide or glycolipid expressed on one or more tumor cells, and any combination thereof.

Antibody scaffolds.

Any antibodies described herein further include a framework. In some embodiments, the scaffold is a human immunoglobulin scaffold. For example, in some embodiments, an antibody (e.g., an anti-TREM2 antibody) comprises

- 126 044134

The HVR is as in any of the above-described embodiments and further comprises a human acceptor scaffold, such as a human immunoglobulin scaffold or a human consensus scaffold. Human immunoglobulin frameworks may be part of a human antibody, or a non-human antibody may be humanized by replacing one or more endogenous frameworks with human ones. Human frameworks that can be used for humanization include, but are not limited to: frameworks selected using the best fit method (see, for example, Sims et al., J. Immunol., 151:2296 (1993)); framework regions derived from the consensus sequence of a particular subset of human antibody light or heavy chain variable regions (see, for example, Carter et al., Proc. Natl. Acad. Sci., USA, 89:4285 (1992); and Presta et al. ., J. Immunol., 151:2623 (1993)); human mature (somatically mutated) frameworks or human germline frameworks (see, for example, Almagro and Fransson, Front. Biosci., 13:1619-1633 (2008)); and framework regions obtained by screening FR libraries (see, for example, Vasa et al., J. Biol. Chem., 272:10678-10684 (1997); and Rosok et al., J. Biol. Chem., 271 :22611-22618 (1996)).

In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2 and HVR-H3 of the present invention and one, two, three or four heavy chain framework regions as set forth in Table. 4A-4D. In some embodiments, the antibody comprises a light chain variable region comprising HVR-L1, HVR-L2 and HVR-L3 of the present invention and one, two, three or four light chain framework regions as set forth in Table. 5A-5D. In some embodiments, the antibody comprises a heavy chain variable region comprising HVR-H1, HVR-H2 and HVR-H3 of the present invention, and one, two, three or four heavy chain framework regions as set forth in Table. 4A-4D, and further contains a light chain variable region containing HVR-L1, HVR-L2 and HVR-L3 of the present invention, and one, two, three or four light chain framework regions, as indicated in table. 5A-5D.

Modulated expression of proinflammatory mediators.

In some embodiments, anti-TREM2 antibodies of the present invention can modulate (eg, increase or decrease) the expression of pro-inflammatory mediators upon binding to TREM2 protein expressed in a cell.

As used herein, proinflammatory mediators are proteins involved, directly or indirectly (eg, through proinflammatory signaling pathways) in a mechanism that induces, activates, promotes, or otherwise enhances the inflammatory response. Any method known to those skilled in the art for identifying and characterizing proinflammatory mediators can be used. Examples of pro-inflammatory mediators include, but are not limited to, cytokines such as IFN-β, IL-1a, TYp, TNF-a, IL-6, IL-8, CRP, CD86, MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18 and IL-23.

In some embodiments, the anti-TREM2 antibodies of the present invention can modulate the functional expression and/or secretion of pro-inflammatory mediators, such as FN-β, IL-1a, IL-1P, CD86, TNF-a, IL-6, IL-8, CRP, MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF1, OPN, CD11c, GM- CSF, IL-11, IL-12, IL-17, IL-18 and IL-23. In some embodiments, modulated expression of proinflammatory mediators occurs in macrophages, dendritic cells, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglial cells. Modulated expression may include, but is not limited to, modulated gene expression, modulated transcriptional expression, or modulated protein expression. Any method known to those skilled in the art for determining the expression of a gene, transcript (eg, mRNA) and/or protein can be used. For example, Northern blotting can be used to determine gene expression levels of a pro-inflammatory mediator, RT-PCR can be used to determine the level of transcription of a pro-inflammatory mediator, and Western blotting can be used to determine protein levels of a pro-inflammatory mediator.

In some embodiments, pro-inflammatory mediators include inflammatory cytokines. Accordingly, in some embodiments, the anti-TREM2 antibodies of the present invention can modulate the secretion of one or more inflammatory cytokines. Examples of inflammatory cytokines whose secretion can be reduced by the anti-TREM2 antibodies of the present invention include, but are not limited to, FN-β, IL-1a, IL-1p, CD86, TNF-a, IL-6, IL-8, CRP, MCP- 1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF1, OPN, CD11c, GM-CSF, IL- 11, IL-12, IL-17, IL-18 and IL-23.

In some embodiments, pro-inflammatory mediators include inflammatory receptors. Accordingly, in some embodiments, the anti-TREM2 antibodies of the present invention may modulate the expression of one or more inflammatory receptors. Examples of inflammatory receptors whose expression can be reduced by anti-TREM2 antibodies by

- 127 044134 of the present invention include, without limitation, CD86.

As used herein, a pro-inflammatory mediator may have modulated expression if its expression in one or more cells of a subject receiving an anti-TREM2 antibody of the present invention is modulated (e.g., increased or decreased) relative to the expression of the same pro-inflammatory mediator , expressed in one or more cells of the corresponding subject not receiving the anti-TREM2 antibody. In some embodiments, an anti-TREM2 antibody of the present invention may modulate the expression of a pro-inflammatory mediator in one or more cells of a subject by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% , at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, according at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, for example, compared to the expression of a proinflammatory mediator in one or more cells of a corresponding subject not receiving an anti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody may modulate the expression of a pro-inflammatory mediator in one or more cells of the subject by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.0-fold. 8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times , at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, according to at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9, 0-fold, at least 9.5-fold, or at least 10-fold, for example, compared with the expression of a proinflammatory mediator in one or more cells of a corresponding subject not receiving an anti-TREM2 antibody.

In some embodiments, anti-TREM2 antibodies of the present invention may be useful for preventing, reducing the risk of, or treating conditions and/or diseases associated with abnormal levels of one or more proinflammatory mediators, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia , mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathic disease, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis , rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, ocular infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrous disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza), comprising administering to the individual a therapeutically effective amount of an agent which does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of at least one TREM2 ligand. Other aspects of the present invention provide an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of at least one TREM2 ligand, for use in preventing, reducing the risk of, or treating a disease, race

- 128 044134 structure or lesion selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, diseases from the group of tauopathies, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus , Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury brain, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, TREM2-expressing tumors, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection , HIV type I and Pfeiffer bacillus (Haemophilus influenza).

Phosphorylation of Syk.

In some embodiments, the anti-TREM2 antibodies of the present invention can induce phosphorylation of spleen tyrosine kinase (Syk) upon binding to the TREM2 protein expressed in the cell.

Spleen tyrosine kinase (Syk) is an intracellular signaling molecule that functions downstream of TREM2 by phosphorylating multiple substrates, thereby promoting the formation of a signaling complex leading to cellular activation and inflammatory processes.

In some embodiments, anti-TREM2 antibodies of the present invention may be useful for preventing, reducing the risk of, or treating conditions and/or diseases associated with reduced levels of Syk phosphorylation, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia , Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathic disease, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis , wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, ShyDrager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infections, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza), comprising administering to the individual a therapeutically effective amount of an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or increases one or more

- 129 044134 how many activities of at least one TREM2 ligand. Other aspects of the present invention provide an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of at least one TREM2 ligand, for use in preventing, reducing the risk of, or treating a disease, disorder, or lesion selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, diseases from the tauopathies group, NasuHakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors, TREM2 expressing, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza)..

DAP12 binding and phosphorylation.

In some embodiments, anti-TREM2 antibodies of the present invention can induce binding of TREM2 to DAP12. In other embodiments, anti-TREM2 antibodies of the present invention can induce phosphorylation of DAP12 upon binding to TREM2 protein expressed in the cell. In other embodiments, TREM2-mediated phosphorylation of DAP12 is induced by one or more SRC family tyrosine kinases. Examples of Src family tyrosine kinases include, but are not limited to, Src, Syk, Yes, Fyn, Fgr, Lck, Hck, Blk, Lyn, and Frk.

DAP12 is variously called TYRO protein tyrosine kinase binding protein, TYROBP, KARAP, and PLOSL. DAP12 is a transmembrane signaling protein that contains an immunoreceptor tyrosine-activated motif (ITAM) in its cytoplasmic domain. In some embodiments, an anti-TREM2 antibody may induce phosphorylation of DAP12 at its ITAM motif. Any method known to those skilled in the art for determining protein phosphorylation, such as DAP12 phosphorylation, can be used.

In some embodiments, DAP12 is phosphorylated by SRC family kinases, resulting in the recruitment and activation of Syk kinase, ZAP70 kinase, or both, to the DAP12/TREM2 complex. Thus, in some embodiments, the anti-TREM2 antibodies of the present invention may recruit Syk, ZAP70, or both to the DAP12/TREM2 complex. Without wishing to be bound by theory, the anti-TREM2 antibodies of the present invention are believed to be useful for preventing, reducing the risk of, or treating conditions and/or diseases associated with decreased levels of DAP12 activity, DAP12 phosphorylation, or recruitment of Syk, ZAP70, or both , in the DAP12/TREM2 complex, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathic disease, Nasu-Hakola disease, stroke , acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury , age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis

- 130 044134 roses, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, infection Leishmania donovani, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza), comprising administering to the individual a therapeutically effective amount of an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or increases one or more activities of one or more TREM2 ligands. Other aspects of the present invention relate to the use of an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or increases one or more activities of one or more TREM2 ligands. in the prevention, risk reduction, or treatment of a disease, disorder or lesion selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, diseases from the group of tauopathies, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor , lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal injury brain, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter infection jejuni, Neisseria meningiditis infections, HIV type I, and Pfeiffer bacillus (Haemophilus influenza).

Proliferation, Survival, and Functionality of TREM2-Expressing Cells In some embodiments, the anti-TREM2 antibodies of the present invention can increase the proliferation, survival, and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and microglial cells (microglia ) after binding to the TREM2 protein expressed in the cell. In some embodiments, the anti-TREM2 antibodies of the present invention do not inhibit the growth (eg, proliferation and/or survival) of one or more natural immune cells.

Microglial cells are a type of glial cell that are resident macrophages of the brain and spinal cord and thus act as the first and foremost form of active immune defense in the central nervous system (CNS). Microglial cells make up 20% of the total glial cell population in the brain. Microglial cells continually clear the CNS of plaque, damaged neurons, and infectious agents. The brain and spinal cord are considered immune-privileged organs because they are separated from the rest of the body by a series of endothelial cells known as the blood-brain barrier, which prevents most infections from entering vulnerable nerve tissue. When infectious agents are introduced directly into the brain or cross the blood-brain barrier, microglial cells must respond quickly to reduce inflammation and destroy the infectious agents before they damage sensitive nerve tissue. Due to the unavailability of antibodies from other parts of the body (few antibodies are small enough to cross the blood-brain

- 131 044134 th barrier), microglia must be able to recognize foreign bodies, absorb them, and act as antigen-presenting cells that activate T cells. Because this process must occur quickly to prevent potentially fatal damage, microglial cells are extremely sensitive to even minor pathological changes in the central nervous system. This sensitivity is achieved in part due to unique potassium channels that respond to even minor changes in extracellular potassium.

As used herein, macrophages of the present invention include, without limitation, M1 macrophages, activated M1 macrophages, and M2 macrophages. As used herein, microglial cells of the present invention include, without limitation, M1 microglial cells, activated M1 microglial cells, and M2 microglial cells. In some embodiments, anti-TREM2 antibodies of the present invention may be useful for reducing the risk of, or treating, conditions and/or diseases associated with decreased proliferation or survival of immune cells, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathic disease, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, ShyDrager syndrome, progressive supranuclear palsy, corticobasal ganglionic degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection , lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer , renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, myeloid-derived tumors, TREM2-expressing tumors, thyroid cancer, infections, central nervous system herpes, parasitic infections, trypanosomal infection , Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza), comprising administering to the individual a therapeutically effective amount of an agent that does not inhibit interaction between TREM2 and one or more TREM2 ligands, and/or increases one or more activities of one or more TREM2 ligands. Other aspects of the present invention provide an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of one or more TREM2 ligands for use in preventing, reducing the risk of, or treating a disease, disorder, or lesion selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, diseases from the tauopathies group, NasuHakol's disease, stroke, acute injury, chronic injury, cognitive impairment abilities, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with corpuscles Lewy syndrome, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa , retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer gland cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL ), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple

- 132 044134 myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, central nervous system herpes, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection , Pseudomonas aeruginosa infections, Leishmania donovani infections, group B Streptococcus infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type I, and Pfeiffer bacillus (Haemophilus influenza).

In some embodiments, the anti-TREM2 antibodies of the present invention can increase the expression of CD83 and/or CD86 on dendritic cells, monocytes and/or macrophages.

As used herein, measures of proliferation, survival and/or function of macrophages, dendritic cells, monocytes and/or microglia may include increased expression if measures of proliferation, survival and/or function of dendritic cells, macrophages, monocytes, osteoclasts, Langerans cells skin, Kupffer cells, and/or microglia in a subject treated with an anti-TREM2 antibody of the present invention, exceeds the proliferation, survival, and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia in a matched subject not receiving anti-TREM2 antibody treatment. In some embodiments, an anti-TREM2 antibody of the present invention can increase rates of proliferation, survival, and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia in a subject by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95 %, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, for example, compared to proliferation rates , survival and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia in a corresponding subject not receiving anti-TREM2 antibody treatment. In other embodiments, an anti-TREM2 antibody of the present invention may increase rates of proliferation, survival, and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia in a subject by at least 1. 5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times , at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2.3 times, at least 2.35 times, at least 2.4 times, according to at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7, 5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times, or at least 10 times, for example, compared to proliferation rates, survival and/or function of dendritic cells, macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, and/or microglia in a corresponding subject not receiving anti-TREM2 antibody treatment.

In some embodiments, anti-TREM2 antibodies of the present invention may be useful for preventing, reducing the risk of, or treating conditions and/or diseases associated with decreased function of dendritic cells, macrophages, monocytes, osteoclasts, cutaneous Langerans cells, Kupffer cells, and/or microglia, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathies, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease , dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer brain, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer,

- 133 044134 melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, infection Leishmania donovani, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza), comprising administering to the individual a therapeutically effective amount of an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or increases one or more activities of at least one TREM2 ligand. Other aspects of the present invention provide an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of at least one TREM2 ligand for use in preventing, reducing the risk of, or treating a disease, disorder, or lesion. selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathies, Nasu-Hakola disease, stroke, acute trauma, chronic trauma , cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma , retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer , breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors , TREM2-expressing, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and bacilli Pfeiffer (Haemophilus influenza).

TREM2-dependent gene expression.

In some embodiments, the anti-TREM2 antibodies of the present invention can increase the activity and/or expression of TREM2-dependent genes, such as one or more transcription factors of the nuclear factor of activated T cell (NFAT) family of transcription factors.

In some embodiments, anti-TREM2 antibodies of the present invention may be useful for preventing, reducing the risk of, or treating conditions and/or diseases associated with decreased levels of TREM2-related genes, including dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathic disease, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, ShyDrager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer

- 134 044134 colon, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL) , acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influ enza ), comprising administering to an individual a therapeutically effective amount of an agent that does not inhibit the interaction between TREM2 and one or more TREM2 ligands, and/or enhances one or more activities of at least one TREM2 ligand. Other aspects of the present invention relate to an agent that does not inhibit the interaction between TREM2 and one or more CD33 ligands, for use in the prevention, risk reduction or treatment of a disease, disorder or lesion selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia , mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, diseases from the tauopathy group, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis , rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, ocular infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrous disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I, and Pfeiffer bacillus (Haemophilus influenza).

Obtaining an antibody.

Ahtu-TREM2 antibodies of the present invention may include polyclonal antibodies, monoclonal antibodies, humanized and chimeric antibodies, human antibodies, antibody fragments (eg, Fab, Fab'-SH, Fv, scFv and F(ab') ₂ ), bispecific and polyspecific antibodies, multivalent antibodies, antibodies derived from libraries, antibodies having modified effector functions, fusion proteins containing an antibody region, and any other modified configuration of an immunoglobulin molecule that includes an antigen recognition site, such as an epitope having the amino acid residues of the TREM2 protein herein the invention, including antibody glycosylation variants, antibody amino acid sequence variants and covalently modified antibodies. Ahtu-TREM2 antibodies may be human, murine, rat, or of any other origin (including chimeric or humanized antibodies).

(1) Polyclonal antibodies.

Polyclonal antibodies, such as anti-TREM2 polyclonal antibodies, are typically produced by animals through repeated subcutaneous (sc) or intraperitoneal (ip) injections of the relevant antigen and adjuvant. It may be useful to conjugate a relevant antigen (eg, purified or recombinant TREM2 protein of the present invention) to a protein that is immunogenic for the species being immunized, for example, fissureella hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor, using bifunctional or derivatizing agent, for example, maleimidobenzoylsulfosuccinimide ester (conjugation via cysteine residues), N-hydroxysuccinimide (via lysine residues), glutaraldehyde, succinic anhydride, SOCl ₂ or R1N=C=NR, where R and R ¹ independently represent lower alkyl groups . Examples of adjuvants that may be used include complete

- 135 044134 Freund's adjuvant and MPL-TDM adjuvant (monophosphoryl lipid A, synthetic trehalose dicorynomycolate). The immunization protocol can be selected by one skilled in the art without undue experimentation.

Animals are immunized with the desired antigen, immunogenic conjugate, or derivative by combining, for example, 100 μg (for rabbits) or 5 μg (for mice) of the protein or conjugate with 3 volumes of Freund's complete adjuvant and injecting the solution intradermally at several sites, after a month, the animals are given booster injection of 1/5 to 1/10 of the initial amount of peptide or conjugate in Freund's complete adjuvant by subcutaneous injection at several sites. After seven to fourteen days, blood is drawn from the animals and the serum is analyzed for antibody titer. Animals are given booster injections until a stable titer is achieved. Conjugates can also be produced in recombinant cell culture as protein fusion products. Also, aggregating agents such as alum are useful for enhancing the immune response.

(2) Monoclonal antibodies.

Monoclonal antibodies, such as anti-TREM2 monoclonal antibodies, are obtained from a population of essentially homogeneous antibodies, i.e. The individual antibodies making up the population are identical, except for possible natural mutations and/or post-translational modifications (eg, isomerization, amidation) that may be present in minor quantities. Thus, the definition of monoclonal indicates that the nature of the antibodies is not a mixture of individual antibodies.

For example, anti-TREM2 monoclonal antibodies can be produced using the hybridoma method first described by Kohler et al., Nature, 256:495 (1975), or can be produced by recombinant DNA methods (US Pat. No. 4,816,567).

In the hybridoma method, a mouse or other suitable host animal, such as a hamster, is immunized as described above to obtain lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization (eg, purified or recombinant TREM2 protein according to the present invention). Alternatively, lymphocytes can be immunized in vitro. The lymphocytes are then fused with the myeloma cells using a suitable fusion agent such as polyethylene glycol to form a hybridoma cell (Goding, Monoclonal Antibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).

The immunizing agent will typically include an antigenic protein (eg, a purified or recombinant TREM2 protein of the present invention) or a fusion variant thereof. Typically, peripheral blood lymphocytes (PBL) are used if cells of human origin are desired, while spleen or lymph node cells are used if non-human mammalian sources are desired. Lymphocytes are then fused to the immortalized cell line using a suitable cell fusion agent such as polyethylene glycol to form hybridoma cells. Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), p. 59-103.

Immortalized cell lines are typically transformed mammalian cells, particularly myeloma cells of rodent, bovine or human origin. Typically, rat or mouse myeloma cell lines are used. The hybridoma cells thus obtained are seeded and grown in a suitable culture medium which preferably contains one or more substances that inhibit the growth or survival of the unfused parental myeloma cells. For example, if the parent myeloma cells lack the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT), the hybridoma culture medium will typically include hypoxanthine, aminopterin, and thymidine (HAT medium), which are substances that inhibit the growth of HGPRT-deficient cells.

Preferred immortalized myeloma cells efficiently fuse, support stable production of high levels of antibodies by the selected antibody-producing cells, and are sensitive to media such as HAT media. Of these, preferred are murine myeloma lines such as murine tumor-derived MOPC-21 and MPC-11 (available from Salk Institute Cell Distribution Center, San Diego, California USA), as well as SP-2 cells and derivatives thereof (eg, X63 -Ag8-653) (available from the American Type Culture Collection, Manassas, Virginia USA). The use of human myeloma and heteromyeloma mouse-human cell lines for the production of human monoclonal antibodies has also been described (Kozbor, J. Immunol, 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 ( Marcel Dekker, Inc., New York, 1987)).

The culture medium in which the hybridoma cells are grown is assayed for the production of monoclonal antibodies directed against the antigen (eg, the TREM2 protein of the present invention). Preferably, the binding specificity of monoclonal antibodies produced by hybridoma cells is determined by immunoprecipitation or an in vitro binding assay such as a radioimmunoassay (RIA) or an enzyme-linked immunosorbent assay (ELISA).

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The culture medium in which the hybridoma cells are cultured can be analyzed for the presence of monoclonal antibodies directed against the desired antigen (eg, the TREM2 protein of the present invention). Preferably, the binding affinity and specificity of a monoclonal antibody can be determined by immunoprecipitation or by an in vitro binding assay such as a radioimmunoassay (RIA) or an enzyme-linked immunosorbent assay (ELISA). Such techniques and analyzes are known to those skilled in the art. For example, binding affinity can be determined using the Scatchard assay according to Munson et al., Anal. Biochem., 107:220 (1980).

After identifying hybridoma cells that produce antibodies of the desired specificity, affinity, and/or activity, clones can be subcloned using limiting dilution procedures and grown by standard methods (Goding, supra). Suitable culture media for this purpose include, for example, D-MEM or RPMI-1640 media. In addition, hybridoma cells can be grown in vivo, like tumors in a mammal.

Monoclonal antibodies secreted by the subclones are appropriately separated from the culture medium, ascitic fluid or serum using conventional immunoglobulin purification procedures, such as, for example, protein A-Sepharose chromatography, hydroxyapatite chromatography, gel electrophoresis, dialysis, affinity chromatography and others. methods as described above.

Ahtu-TREM2 monoclonal antibodies can also be produced by recombinant DNA methods, such as those disclosed in US Pat. No. 4,816,567 and as described above. DNA encoding monoclonal antibodies can be easily isolated and sequenced using conventional procedures (eg, by using oligonucleotide probes that specifically bind to the genes encoding the heavy and light chains of murine antibodies). Preferably, the source of such DNA is hybridoma cells. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells, such as E. coli cells, monkey COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin protein, to synthesis of monoclonal antibodies in such recombinant host cells. Review articles on recombinant bacterial expression of antibody-encoding DNA include Skerra et al., Curr. Opin. Immunol., 5:256-262 (1993); and Pluckthun, Immunol. Rev., 130:151-188 (1992).

In some embodiments, anti-TREM2 antibodies can be isolated from phage antibody libraries generated using techniques described in McCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature, 352:624-628 (1991); and Marks et al., J. Mol. Biol., 222:581-597 (1991) described the isolation of mouse and human antibodies, respectively, from phage libraries. Subsequent publications describe the production of high-affinity (in the nanomolar (nM) range) human antibodies by chain shuffling (Marks et al., Bio/Technology, 10:779-783 (1992)), as well as combinatorial infection and in vivo recombination as a strategy for constructing very large phage libraries (Waterhouse et al., Nucl. Acids Res., 21:2265-2266 (1993)). Thus, these techniques are viable alternatives to traditional monoclonal antibody hybridoma methods for isolating monoclonal antibodies of desired specificity (eg, those binding the TREM2 protein of the present invention).

The DNA encoding antibodies or fragments thereof may also be modified, for example, by replacing the coding sequence with human heavy and light chain constant domains instead of homologous murine sequences (US Pat. No. 4,816,567; Morrison et al., Proc. Natl Acad. Sci., USA, 81:6851 (1984)), or by covalently attaching to the immunoglobulin coding sequence all or part of the coding sequence of a non-immunoglobulin polypeptide. Typically, such non-immunoglobulin polypeptides replace the constant domains of an antibody or replace the variable domains of one antigen binding site of an antibody to create a chimeric bivalent antibody comprising one antigen binding site having specificity for an antigen and another antigen binding site having specificity for a different antigen.

Monoclonal antibodies described herein (eg, anti-TREM2 antibodies of the present invention or fragments thereof) may be monovalent, the preparation of which is well known in the art. For example, one method involves recombinant expression of an immunoglobulin light chain and a modified heavy chain. The heavy chain is typically shortened at any point in the Fc region to prevent cross-linking of the heavy chain. Alternatively, the corresponding cysteine residues may be replaced by another amino acid residue or deleted to prevent cross-linking. In vitro methods are also suitable for the production of monovalent antibodies. Hydrolysis of antibodies to obtain fragments, in particular Fab fragments, can be carried out using conventional methods known to those skilled in the art.

Chimeric or hybrid anti-TREM2 antibodies can also be produced in vitro using known methods of chemical protein synthesis, including the use of cross-linking agents. For example, immunotoxins can be constructed using a disulfide exchange reaction or through the formation of a thioester bond. Examples of suitable reagents for this purpose include iminothiolate and methyl 4-mercaptobutyrimidate.

- 137 044134 (3) Humanized antibodies.

Ahtu-TREM2 antibodies of the present invention or antibody fragments may further include humanized or human antibodies. Humanized forms of non-human (eg, murine) antibodies are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fab, Fab'-SH, Fv, scFv, F(ab') ₂ or other antigen-binding antibody subsequences) that contain a minimal sequence , derived from non-human immunoglobulin. Humanized antibodies include human immunoglobulins (recipient antibody) in which residues from the complementarity determining region (CDR) of the recipient are replaced with residues from the CDR of a non-human species (donor antibody), such as mouse, rat or rabbit, having the desired specificity, affinity and functional abilities. In some cases, human immunoglobulin Fv framework residues are replaced with corresponding non-human residues. Humanized antibodies may also contain residues not present in either the recipient antibody or the imported CDR or framework sequences. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions represent a consensus sequence of a human immunoglobulin. The humanized antibody will optimally also contain at least a portion of an immunoglobulin constant region (Fc), typically a human immunoglobulin. Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-329 (1988); and Presta, Curr. Opin. Struct. Biol., 2:593-596 (1992).

Methods for humanizing non-human anti-TREM2 antibodies are well known in the art. Typically, a humanized antibody has one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often referred to as imported residues, which are typically taken from an imported variable domain. Humanization can be carried out substantially in accordance with the method of Winter and associates, Jones et al., Nature, 321:522-525 (1986); Riechmann et al., Nature, 332:323-327 (1988); Verhoeyen et al., Science, 239:1534-1536 (1988), or by replacing the rodent CDRs or CDR sequences with the corresponding human antibody sequences. Accordingly, such humanized antibodies are chimeric antibodies (US Pat. No. 4,816,567) in which substantially less than the intact human variable domain has been replaced by the corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some of the CDR residues, and possibly some of the FR residues, are replaced with residues from the analogous sites of rodent antibodies.

The selection of human variable domains, both light and heavy, for use in the production of humanized antibodies is very important to reduce antigenicity. According to the so-called best-fit method, the variable domain sequence of a rodent antibody is screened against a complete library of known human variable domain sequences. The human sequence closest to the rodent sequence is then taken as the human framework (FR) for the humanized antibody. Sims et al., J. Immunol, 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901 (1987). Another method uses a specific scaffold derived from the consensus sequence of all human antibodies of a particular subset of light or heavy chains. The same framework can be used for several different humanized antibodies. Carter et al., Proc. Nat'l Acad. Sci., USA, 89:4285 (1992); Presta et al., J. Immunol., 151:2623 (1993).

In addition, it is important that the antibodies are humanized to retain high affinity for the antigen and other favorable biological properties. To achieve this goal, in accordance with the preferred method, humanized antibodies are obtained by analyzing the parent sequences and various conceptual humanized products using three-dimensional models of the parent and humanized sequences. Three-dimensional immunoglobulin models are publicly available and familiar to those skilled in the art. Computer programs are available to illustrate and display possible three-dimensional conformational structures of selected candidate immunoglobulin sequences. Examination of such images allows analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e. analysis of residues that affect the ability of a candidate immunoglobulin to bind to its antigen. Thus, the FR residues of the recipient sequence and the import sequence can be selected and combined to achieve a desired antibody characteristic, such as increased affinity for the target antigen or antigens (eg, the TREM2 proteins of the present invention). In general, CDR residues directly and most significantly influence antigen binding.

Various forms of humanized anti-TREM2 antibody are provided. For example, a humanized anti-TREM2 antibody may be an antibody fragment, such as a Fab, that is optionally conjugated to one or more TREM2 ligands, such as HSP60. Alternatively

- 138 044134 the humanized aHTu-TREM2 antibody may be an intact antibody, such as an intact IgGl antibody.

(4) Antibody fragments.

In some embodiments, there are advantages to using fragments of anti-TREM2 antibodies rather than whole anti-TREM2 antibodies. In some embodiments, smaller fragment sizes allow for faster clearance and better penetration into the brain.

Various techniques have been developed for the production of antibody fragments. Traditionally, such fragments have been prepared by proteolytic digestion of intact antibodies (see, for example, Morimoto et al., J. Biochem. Biophys. Method., 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, such fragments can now be produced directly using recombinant host cells, for example, using nucleic acids encoding the anti-TREM2 antibodies of the present invention. Fab, Fv and scFv antibody fragments can all be expressed in and secreted from E. coli, thereby allowing the direct production of large quantities of these fragments. Anti-TREM2 antibody fragments can also be isolated from a phage antibody library as described above. Alternatively, Fab'-SH fragments can be directly isolated from E. coli and chemically coupled to form F(ab')2 fragments (Carter et al., Bio/Technology, 10:163-167 (1992)). In another approach, F(ab')2 fragments can be isolated directly from recombinant host cell cultures. The production of Fab fragments and F(ab')2 antibodies with increased half-lives in vivo is described in US Pat. No. 5,869,046. In other embodiments, the preferred antibody is a single chain Fv fragment (scFv). See WO 93/16185; US Patent No. 5571894; and US Pat. No. 5,587,458. The anti-TREM2 antibody fragment may also be a linear antibody, for example, as described in US Pat. No. 5,641,870. Such linear antibody fragments may be monospecific or bispecific.

(5) Bispecific and polyspecific antibodies.

Bispecific antibodies (BsAbs) are antibodies that bind specifically to at least two different epitopes, including those located on the same or different proteins (eg, one or more TREM2 proteins of the present invention). Alternatively, one portion of the BsAb may be capable of binding to the TREM2 target antigen, and the other may be associated with an arm that binds to a second protein. Such antibodies can be obtained from full-length antibodies or antibody fragments (eg, F(ab') ₂ bispecific antibodies).

Methods for producing bispecific antibodies are known to those skilled in the art. Traditional production of full-length bispecific antibodies is based on the coexpression of two immunoglobulin heavy chain/light chain pairs, the two chains having different specificities. Millstein et al., Nature, 305:537-539 (1983). Due to the random nature of the immunoglobulin heavy and light chain sorting, such hybridomas (quadromas) yield potentially a mixture of 10 different antibody molecules, of which only one has the correct bispecific structure. Purification of the correct molecule, which is usually carried out stepwise by affinity chromatography, is quite labor intensive and the product yield is low. Similar procedures are disclosed in WO 93/08829; and in Traunecker et al., EMBO J., 10:3655-3659 (1991).

In another approach, antibody variable domains with desired binding specificities (antibody-antigen binding sites) are fused to immunoglobulin constant domain sequences. The fusion is preferably carried out with an immunoglobulin heavy chain constant domain containing at least part of the hinge, _CH 2 and _CH 3 regions. Preferably, the first heavy chain constant region (CH1) contains a site required for light chain binding present in at least one of the fusion products. DNAs encoding the heavy chains of the immunoglobulin fusion products and, if necessary, the light chain of the immunoglobulin are inserted into separate expression vectors and co-transfected into a suitable host organism. This provides greater flexibility in adjusting the relative proportions between the three polypeptide fragments in those embodiments where optimal yield is achieved with unequal ratios of the three polypeptide chains used. However, it is possible to insert the coding sequences of two or all three polypeptide chains into a single expression vector when expressing at least two polypeptide chains in equal ratios results in high yield or when the ratios are not particularly significant.

In a preferred embodiment of this approach, the bispecific antibodies consist of a hybrid immunoglobulin heavy chain with a first binding specificity in one arm, and a hybrid immunoglobulin heavy chain-light chain pair (providing a second binding specificity) in the other arm. This asymmetric structure has been found to facilitate the separation of the desired bispecific compound from undesired combinations of immunoglobulin chains, since the presence of the immunoglobulin light chain in only half of the bispecific molecule allows for a simple separation method. This approach is disclosed in WO 94/04690. Further details of the preparation of bispecific antibodies are given, for example, in Suresh et al.

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Methods in Enzymology, 121:210 (1986); and Garber, Nature Reviews Drug Discovery, 13, 799-801 (2014).

In another approach, as described in WO 96/27011 or US Pat. No. 5,731,168, the interface between a pair of antibody molecules can be modified to maximize the percentage of heterodimers recovered from the recombinant cell culture. A preferred interface includes at least a portion of the CH3 region of the antibody constant domain. In this method, one or more small amino acid side chains from the interface of the first antibody molecule are replaced with larger side chains (eg, tyrosine or tryptophan). At the interface of the second antibody molecule, the large side chains create compensating cavities of identical or similar size by replacing large amino acid side chains with smaller ones (for example, alanine or threonine). This provides a mechanism for increasing heterodimer yield compared to other undesirable end products such as homodimers.

Methods for producing bispecific antibodies from antibody fragments have been described in the literature. For example, bispecific antibodies can be produced using chemical bonding. Brennan et al., Science, 229:81 (1985) describe a procedure in which intact antibodies are subjected to proteolytic hydrolysis to produce F(ab') ₂ fragments. These moieties are reduced in the presence of the dithiol complexing agent sodium arsenite to stabilize the vicinal dithiols and prevent the formation of intermolecular disulfide bonds. The resulting Fab fragments are then converted into thionitrobenzoate (TNB) derivatives. One of the Fab'-TNB derivatives is then reconverted to the Fab'-TNB derivative to form a bispecific antibody. The resulting bispecific antibodies can be used as agents for the selective immobilization of enzymes.

Fab' fragments can be isolated directly from E. coli and chemically coupled to form bispecific antibodies. Shalaby et al., J. Exp. Med., 175:217-225 (1992) describes the production of a fully humanized F(ab') ₂ bispecific antibody molecule. Each Fab' fragment was separately secreted from E. coli and subjected to targeted chemical coupling in vitro to form a bispecific antibody. The bispecific antibody thus obtained was able to bind to cells overexpressing the ErbB2 receptor and normal human T cells, and to initiate the lytic activity of human cytotoxic lymphocytes against human breast tumor targets.

Various methods for obtaining and isolating bivalent antibody fragments directly from recombinant cell cultures have also been described. For example, bivalent heterodimers have been prepared using leucine zippers. Kostelny et al., J. Immunol, 148(5):1547-1553 (1992). Leucine zipper peptides from the Fos and Jun proteins were linked to the Fab' regions of two different antibodies by gene fusion. Antibody homodimers were reduced at the hinge region to form monomers and then reoxidized to form antibody heterodimers. Diabody technology described by Hollinger et al., Proc. Nat'l Acad. Sci., USA, 90:6444-6448 (1993), provided an alternative mechanism for the production of bispecific/bivalent antibody fragments. The fragments contain a heavy chain variable domain (V _H ) connected to a light chain variable domain (V _L ) by a linker too short to allow pairing between two domains of the same chain. Accordingly, the V _H and V _L domains of one fragment are forced to pair with the complementary V _L and V _H domains of another fragment, thereby forming two antigen-binding sites. Another strategy for producing bispecific/bivalent antibody fragments using single-chain Fv (sFv) dimers has also been described. See Gruber et al., J. Immunol, 152:5368 (1994).

Another method for producing bispecific antibodies is called controlled Fab fragment exchange (cFAE) and is a convenient way to generate bispecific IgG1 (bsIgG1). The protocol provides for the following stages:

(i) separate expression of two parental IgG1 containing matched single point mutations in the CH3 domain;

(ii) mixing the original IgG1 under permissive redox conditions in vitro to allow recombination of the hemimolecules;

(iii) removing the reducing agent to allow reoxidation of the interchain disulfide bonds; and (iv) analysis of exchange efficiency and finished product using chromatography or mass spectrometry (PC)-based methods.

The protocol allows the generation of bispecific antibodies (bsAbs) with regular IgG architecture, characteristics and quality characteristics, both at benchtop scale (micrograms to milligrams) and at mini-bioreactor scale (milligrams to grams) designed to simulate large-scale production ( kilograms). When using good quality purified proteins as starting materials, >95% exchange efficiency can be obtained within 2-3 days (including quality control). See Labrijn et al., Natur Protocols, 9, 2450-2463 (2014); and Garber, Nature Reviews Drug Discovery, 13, 799-801 (2014).

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Antibodies with more than two valencies are also contemplated. For example, trispecific antibodies can be prepared. Tutt et al., J. Immunol., 147:60 (1991).

Exemplary examples of bispecific antibodies may bind to two different epitopes of a given molecule (eg, the TREM2 protein of the present invention). In some embodiments, the bispecific antibody binds to a first antigen, such as TREM2 or the DAP12 protein of the present invention, and a second antigen that facilitates transport across the blood-brain barrier. Those skilled in the art are aware of numerous antigens that facilitate transport across the blood-brain barrier (see, for example, Gabathuler R., Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases, Neurobiol. Dis., 37 (2010) 48-57) . Such second antigens include, but are not limited to, transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, including CRM197 (non-toxic mutant of diphtheria toxin), single domain llama antibodies such as TMEM 30(A) (flippase), protein transduction domains such as TAT, Syn-B, or penetratin, polyarginine or generally positively charged peptides, Angiopep peptides such as ANG1005 (see, e.g., Gabathuler, 2010), and other cell surface proteins that have increased concentration on endothelial cells of the blood-brain barrier (see, e.g., Daneman et al., PLoS One., 2010 Oct 29, 5(10):e13741 ). In some embodiments, the second antigens of the anti-TREM2 antibody may include, without limitation, the DAP12 antigen of the present invention. In other embodiments, bispecific antibodies that bind to both TREM2 and DAP12 can promote and enhance one or more activities of TREM2. In other embodiments, the second anti-TREM2 antibody antigens may include, without limitation, an A-beta peptide antigen, or an alpha-synuclein protein antigen, or a tau protein antigen, or a TDP-43 protein antigen, or a prion protein antigen, or a protein antigen. huntingtin, or RAN, antigen of translation products, including dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA) or prolinearginine (PR ).

(6) Polyvalent antibodies.

A multivalent antibody can be internalized (and/or catabolized) by a cell expressing the antigen to which the antibody binds more quickly than a bivalent antibody. The Ahtu-TREM2 antibodies of the present invention or antibody fragments may be multivalent antibodies (other than those belonging to the IgM class) with three or more antigen binding sites (eg, tetravalent antibodies), which can be readily produced by recombinant expression of nucleic acid encoding the polypeptide chains of the antibody . A multivalent antibody may contain a dimerization domain and three or more antigen binding sites. The preferred dimerization domain includes the Fc region or hinge region. In this scenario, the antibody will contain an Fc region and three or more antigen binding sites at the amino terminus of the Fc region. The preferred multivalent antibody herein contains from three to about eight, but preferably four, antigen binding sites. A multivalent antibody contains at least one polypeptide chain (and preferably two polypeptide chains), wherein the polypeptide chain or chains contain two or more variable domains. For example, the polypeptide chain or chains may comprise VD1-(X1)n-VD2-(X2)n-Fc, where VD1 is the first variable domain, VD2 is the second variable domain, Fc is one polypeptide chain of the Fc region, X1 and X2 is an amino acid or a polypeptide and n is 0 or 1. Likewise, the polypeptide chain or chains may comprise a V _H -Cn1 flexible linker chain-V _H -Cn1-Fc region; or V _H C _H 1-V _H -C _H 1-Fc chain. The multivalent antibody herein preferably further comprises at least two (and preferably four) light chain variable domain polypeptides. A multivalent antibody herein may, for example, comprise from about two to about eight light chain variable domain polypeptides. The light chain variable domain polypeptides provided herein contain a light chain variable domain and optionally further contain a CL domain. Multivalent antibodies may recognize TREM2 antigen as well as, without limitation, additional A-beta peptide antigens, alpha-synuclein protein antigen, or tau protein antigen, or TDP-43 protein antigen, or prion protein antigen, or huntingtin protein antigen, or RAN , antigen of translation products including dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA) or proline-arginine (PR), insulin receptor , insulin-like growth factor receptor, transferrin receptor, or any other antigen that facilitates the movement of antibody across the blood-brain barrier.

(7) Effector function construction.

It may also be desirable to modify the anti-TREM2 antibody of the present invention to modify effector function and/or increase the serum half-life of the antibody. For example, the Fc receptor binding site in the constant region may be modified or mutated to eliminate or reduce binding affinity to certain receptors

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Fc, such as FcyRI, FcyRII, and/or FcyRIII, to reduce antibody-dependent cell-mediated cytotoxicity. In some embodiments, effector function is disrupted by removing N-glycosylation of the Fc region (eg, in the CH2 domain of an IgG) of the antibody. In some embodiments, effector function is disrupted by modifying regions such as 233-236, 297 and/or 327-331 of human IgG, as described in PCT WO 99/58572; and Armor et al., Molecular Immunology 40:585-593 (2003); Reddy et al., J. Immunology, 164:1925-1933 (2000). In other embodiments, it may also be desirable to modify the anti-TREM2 antibody of the present invention to modify effector function to increase selectivity for detection of ITIM-containing FcgRIIb (CD32b) to enhance clustering of the TREM2 antibody on adjacent cells without activating humoral responses, including antibody-dependent cell-mediated mediated cytotoxicity and antibody-dependent cellular phagocytosis.

To increase the half-life of serum antibodies, a salvage receptor binding epitope can be incorporated into the antibody (especially an antibody fragment), for example, as described in US Pat. No. 5,739,277. As used herein, the term salvage receptor binding epitope refers to an epitope of the Fc region of an IgG molecule. (eg, IgG1, _IgG2 , _IgG3 , or _IgG4 ) responsible for increasing the in vivo serum half-life of the IgG molecule.

(8) Other amino acid sequence modifications.

Modifications to the amino acid sequence of the anti-TREM2 antibodies of the present invention, or antibody fragments, are also contemplated. For example, it may be desirable to improve the binding affinity and/or other biological properties of antibodies or antibody fragments. Variants of the amino acid sequences of antibodies or antibody fragments are obtained by introducing appropriate nucleotide changes into the nucleic acid encoding the antibodies or antibody fragments, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into, and/or substitutions of residues in the amino acid sequences of the antibody. Any combination of deletions, insertions and substitutions is performed to produce a finished construct, provided that the finished construct has the desired characteristics (ie, the ability to bind or physically interact with the TREM2 protein of the present invention). Amino acid changes can also affect post-translational processes of the antibody, such as changes in the number or position of glycosylation sites.

An effective method for identifying specific residues or regions of an anti-TREM2 antibody that are preferred positions for mutagenesis is called alanine scanning mutagenesis, as described by Cunningham and Wells, Science, 244:1081-1085 (1989). In this case, the target residue or group of residues is identified (e.g., charged residues such as arg, asp, his, lys, and glu) and replaced with a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to influence the amino acid interaction with the target antigen. Such amino acid positions that demonstrate functional sensitivity to substitution are then refined by introducing additional or different variants at or for the substitution sites. Thus, although the site of introduction of a change in the amino acid sequence is predetermined, the nature of the mutation per se is not necessarily predetermined. For example, to analyze the functional characteristics of a mutation at a given site, alanine scanning or non-specific mutagenesis of the target codon or region is performed and variants of the expressed antibody are screened for the desired activity.

Amino acid sequence insertions include amino (N) and/or carboxy (C) terminal fusions ranging in length from one residue to polypeptides containing one hundred or more residues, as well as intrachain insertions of one or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue or an antibody fused to a cytotoxic polypeptide. Other insertional variants of the antibody molecule include fusion of the N- or C-terminus of the antibody to an enzyme or polypeptide that increases the half-life of serum antibodies.

Another type of variant is an amino acid substitution variant. Such variants have at least one amino acid residue replaced by another residue in the antibody molecule. Sites of greatest interest for replacement mutagenesis include hypervariable regions, but FR changes are also contemplated. Conservative substitutions are given in table. Below under the heading Preferred Substitutions. If such substitutions lead to a change in biological activity, then more significant substitutions named in table can be introduced. In Typical examples of substitutions or further described below with reference to amino acid classes, and product screening was carried out.

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Table B

Amino acid substitutions

Original balance Typical examples of substitutions Preferred Substitutions Ala (A) val; leu; ile val Arg(R) lys; gin; asn lys Asn(N) gin; his; asp, lys; arg gin Asp (D) glu; asn glu Cys(C) ser; ala ser Gin (Q) asn; glu asn Glu(E) asp; gin asp Gly (G) ala ala His(H) asn; gin; lys; arg arg He(I) leu; val; met; ala; phe; norleucine leu Leu (L) norleucine; ile; val; met; ala; phe ile Lys(K) arg; gin; asn arg Met(M) leu; phe; ile leu Phe(F) leu; val; ile; ala; tyr tyr Pro (P) ala ala Ser(S) thr thr Thr (T) ser ser Trp(W) tyr; phe tyr Tyr(Y) trp; phe; thr; ser phe Val(V) ile; leu; met; phe; ala; norleucine leu

Significant modifications of the biological properties of an antibody are accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone at the substitution site, such as a sheet or helix conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) side chain volume. Natural residues are divided into the following groups based on the general properties of the side chains:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gln, his, lys, arg;

(5) residues affecting chain orientation: gly, pro; and (6) aromatic: trp, tyr, phe.

Non-conservative substitutions involve replacing a member of one of these classes with another class.

Any cysteine residue not involved in maintaining proper antibody conformation can also be replaced, typically with serine, to improve the oxidative stability of the molecule and prevent aberrant cross-linking. Conversely, cysteine linkage(s) may be added to the antibody to increase its stability (particularly in cases where the antibody is an antibody fragment, such as an Fv fragment).

A particularly preferred type of substitution variant involves replacing one or more hypervariable region residues of a parent antibody (eg, a humanized or human anti-TREM2 antibody). Typically, the resulting variant(s) selected for further development will have improved biological properties compared to the parent antibody from which it is derived. A convenient method for producing such substituted variants involves affinity maturation using phage display. Briefly, several hypervariable region sites (eg, 6-7 sites) are mutated to obtain all possible amino acid substitutions at each site. The antibody variants thus obtained are displayed monovalently on filamentous phage particles as hybrids with the M13 gene III product packaged within each particle. The phage displayed variants are then screened for their biological activity (eg, binding affinity) as disclosed herein. To identify candidate hypervariable region sites for modification, alanine scanning muta may be performed.

- 143 044134 genesis in order to determine the hypervariable region residues that make a significant contribution to antigen binding. Alternatively or additionally, it may be useful to analyze the crystal structure of the antigen-antibody complex to determine the points of contact between the antibody and the antigen (eg, the TREM2 protein of the present invention). Such contact residues and adjacent residues are candidates for replacement according to the methods developed herein. Once such variants are obtained, the panel of variants is screened as described herein, and antibodies with improved properties as determined by one or more appropriate assays can be selected for subsequent development. Affinity maturation can also be carried out by using yeast presentation technology, such as disclosed, for example, in WO 2009/036379A2; WO 2010105256; WO 2012009568; and Xu et al., Protein Eng. Des. Sel., 26(10):663-70 (2013).

Another type of amino acid variant of an antibody changes the original glycosylation pattern of the antibody. By modification is meant the deletion of one or more carbohydrate moieties present in the antibody and/or the addition of one or more glycosylation sites not present in the antibody.

Glycosylation of antibodies is usually N-linked or O-linked. N-linking refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for the enzymatic attachment of a carbohydrate moiety to the asparagine side chain. Thus, the presence of any of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the addition of one of the sugars N-acetylgalactosamine, galactose or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine can also be used.

The addition of glycosylation sites to an antibody is conveniently accomplished by altering the amino acid sequence so that it contains one or more of the tripeptide sequences described above (for N-linked glycosylation sites). Changes can also be made by adding, or replacing, one or more serine or threonine residues to the sequence of the original antibody (for O-linked glycosylation sites).

Nucleic acid molecules encoding variants of the amino acid sequences of anti-IgE antibodies are produced by various methods known to those skilled in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring variants of amino acid sequences) or production by oligonucleotide-mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of a previously obtained variant or invariant version of antibodies (for example, anti-TREM2 antibodies of the present invention) or antibody fragments.

(9) Other modifications of antibodies.

The Ahtu-TREM2 antibodies of the present invention or antibody fragments may be further modified to contain non-protein fragments known to those skilled in the art and readily available, or to contain various types of drug conjugates known to those skilled in the art and readily available. Preferably, the fragments suitable for antibody derivatization are water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol/propylene glycol copolymers, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-dioxolane, poly-1,3,6-trioxane, ethylene/maleic anhydride copolymer, polyamino acids (homopolymers or random copolymers), and dextran or poly(vinylpyrrolidone)polyethylene glycol, polypropylene glycol homopolymers, polypropylene oxide/ethylene oxide copolymers, polyoxyethylated polyols (eg glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol propionaldehyde may have a manufacturing advantage due to its stability in water. The polymer can have any molecular weight and can be branched or unbranched. The number of polymers attached to the antibody may vary, and if more than one polymer is attached, they may be the same or different molecules. In general, the number and/or type of polymers used for derivatization may be determined based on considerations including, but not limited to, the specific properties or functions of the antibody that are to be improved, whether the antibody derivative will be used in therapy under certain conditions, etc. Such techniques and other suitable formulations are disclosed in Remington: The Science and Practice of Pharmacy, 20th ed., Alfonso Gennaro, ed., Philadelphia College of Pharmacy and Science (2000).

Drug conjugation involves combining a biologically active cytotoxic (anti-cancer) payload or drug with an antibody that specifically targets a specific tumor marker (eg, a protein that is ideally present only in or on tumor cells). Antibodies find these proteins in the body and attach to the surface of cancer cells. Biochemical reaction between an antibody and a target protein (antigen)

- 144 044134 initiates a signal in the tumor cell, which then absorbs or internalizes the antibody along with the cytotoxin. Once the ADC (antibody-drug conjugate) is internalized, the cytotoxic drug is released and kills the cancer. Thanks to this targeting, the drug ideally has lower side effects and creates a wider therapeutic window than other chemotherapy agents. The technical basis of antibody conjugation is disclosed and known to those skilled in the art (see, for example, Jane de Lartigue, OncLive July 5, 2012; ADC Review on antibody-drug conjugates; and Ducry et al. (2010), Bioconjugate Chemistry, 21(1):5 -13).

Binding and other assays.

The Ahtu-TREM2 antibodies of the present invention can be tested for antigen binding activity, for example, by known methods such as ELISA, Western blotting, etc.

In some embodiments, competition assays can be used to identify an antibody that competes with any of the antibodies listed in table. 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6A, 6B, 7A and 7B or 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, for binding to TREM2. In some embodiments, such a competing antibody binds to the same epitope (eg, a linear or conformational epitope) that binds any of the antibodies listed in Table 1. 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6A, 6B, 7A and 7B or 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. For a detailed description of typical methods for mapping the epitope to which an antibody binds, see Morris (1996), Epitope Mapping Protocols, in Methods in Molecular Biology, vol. 66 (Humana Press, Totowa, NJ).

In a typical example of a competition assay, immobilized TREM2 or cells expressing TREM2 on the cell surface are incubated in a solution containing a first labeled antibody that binds to TREM2 (e.g., human or non-human primate) and a second unlabeled antibody that is tested for its ability to compete with the first antibody for binding to TREM2. The second antibody may be present in the supernatant of the hybridoma. As a control, immobilized TREM2 or cells expressing TREM2 were incubated in a solution containing the first labeled antibody but not the second unlabeled antibody. After incubation under conditions permissive for binding of the first antibody to TREM2, excess unbound antibody is removed and the amount of label bound to immobilized TREM2 or TREM2-expressing cells is measured. If the amount of label associated with immobilized TREM2 or cells expressing TREM2 is significantly reduced in the test sample compared to the control sample, then this indicates that the second antibody is competing with the first antibody for binding to TREM2. See Harlow and Lane (1988), Antibodies: A Laboratory Manual, ch. 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY).

Nucleic acids, vectors and host cells.

The Ahtu-TREM2 antibodies of the present invention can be produced using recombinant methods and compositions, for example, as described in US Pat. No. 4,816,567. In some embodiments, isolated nucleic acids are provided having a nucleotide sequence encoding any of the anti-TREM2 antibodies of the present invention . Such nucleic acids may encode an amino acid sequence comprising the VL and/or an amino acid sequence containing the VH of an anti-TREM2 antibody (eg, the light and/or heavy chains of the antibody). In some embodiments, one or more vectors (eg, expression vectors) containing such nucleic acids are provided. In some embodiments, a host cell containing such a nucleic acid is also provided. In some embodiments, the host cell contains (eg, has been transduced) (1) a vector containing a nucleic acid that encodes an amino acid sequence containing a VL antibody and an amino acid sequence containing a VH antibody; or

- 145 044134 (2) a first vector containing a nucleic acid that encodes an amino acid sequence containing a VL antibody, and a second vector containing a nucleic acid that encodes an amino acid sequence containing a VH antibody.

In some embodiments, the host cell is a eukaryotic, such as a Chinese hamster ovary (CHO) cell, or a lymphoid cell (eg, a Y0, NS0, Sp20 cell). The host cells of the present invention also include, but are not limited to, isolated cells, in vitro cultured cells, and ex vivo cultured cells.

Methods for producing the anti-TREM2 antibody of the present invention are provided. In some embodiments, the method comprises culturing a host cell of the present invention containing a nucleic acid encoding an anti-TREM2 antibody under conditions suitable for expressing the antibody. In some embodiments, the antibody is then isolated from the host cell (or host cell culture medium).

To recombinantly produce an anti-TREM2 antibody of the present invention, a nucleic acid encoding an anti-TREM2 antibody is isolated and inserted into one or more vectors for further cloning and/or expression in a host cell. Such nucleic acids can be easily isolated and sequenced using conventional procedures (eg, by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody).

Suitable vectors containing a nucleic acid sequence encoding any of the anti-TREM2 antibodies of the present invention, or fragment polypeptides thereof (including antibodies) described herein include, but are not limited to, cloning vectors and expression vectors. Suitable cloning vectors can be constructed according to standard techniques, or can be selected from the large number of cloning vectors known in the art. Although the cloning vector selected may vary depending on the host cell to be used, suitable cloning vectors generally have the ability to self-replicate, may have a single target for a particular restriction endonuclease, and/or may carry marker genes that can be used in the selection clones containing the vector. Suitable examples include plasmids and bacterial viruses, eg pUC18, pUC19, Bluescript (eg pBS SK+) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColE1, pCR1, RP4, phage DNA, and shuttle vectors such as pSA3 and pAT28. These and many other cloning vectors are available from commercial suppliers such as BioRad, Strategene, and Invitrogen.

Expression vectors are typically replicable polynucleotide constructs that contain the nucleic acid of the present invention. The expression vector can replicate in host cells as episomes or as an integral part of chromosomal DNA. Suitable expression vectors include, but are not limited to, plasmids, viral vectors including adenoviruses, adeno-associated viruses, retroviruses, cosmids, and the expression vector(s) disclosed in PCT Publication No. WO 87/04462. The vector components may generally include, without limitation, one or more of the following: a signal sequence; origin of replication; one or more marker genes; suitable transcription control elements (such as promoters, enhancers and terminator). Expression (i.e., translation) also typically requires one or more translation control elements, such as ribosome binding sites, translation initiation sites, and stop codons.

Vectors containing nucleic acids of interest can be introduced into a host cell by any of a number of suitable means, including electroporation, transfection using calcium chloride, rubidium chloride, calcium phosphate, DEAE-dextran, or other substances; microparticle bombardment; lipofection; and infection (eg, in cases where the vector is an infectious agent such as vaccinia virus). The choice of introduction vectors or polynucleotides will often depend on the characteristics of the host cell. In some embodiments, the vector contains a nucleic acid comprising one or more amino acid sequences encoding an anti-TREM2 antibody of the present invention.

Suitable host cells for cloning or expressing antibody-encoding vectors include prokaryotic or eukaryotic cells. For example, the anti-TREM2 antibodies of the present invention can be produced in bacteria, particularly when glycosylation and Fc effector function are not required. For the expression of antibody fragments and polypeptides in bacteria (e.g., U.S. Patent Nos. 5,648,237, 5,789,199, and 5,840,523; and Charlton, Methods in Molecular Biology, vol. 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ, 2003), p. 245-254, describing the expression of antibody fragments in E. coli). Once expressed, the antibody can be isolated from the bacterial cell paste in the soluble fraction and can be further purified.

In addition to prokaryotes, eukaryotic microorganisms such as filamentous fungi or yeast are also suitable hosts for cloning or expressing antibody-encoding vectors, including fungal and yeast strains with humanized glycosylation pathways resulting in the production of an antibody with partially or fully human glycosylation

- 146 044134 lation (eg, Gerngross, Nat. Biotech., 22:1409-1414 (2004); and Li et al., Nat. Biotech., 24:210-215 (2006)).

Suitable host cells for expression of the glycosylated antibody can also be obtained from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Numerous baculovirus strains have been identified that can be used in combination with insect cells, particularly for transfection of Spodoptera frugiperda cells. Plant cell cultures can also be used as hosts (eg, US Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978, and 6,417,429, which describe PLANTIBODIES™ technology for producing antibodies in transgenic plants).

Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted for suspension growth may be suitable. Other examples of useful mammalian host cell lines include the monkey kidney line CV1 transformed with SV40 (COS-7); human embryonic kidney line (293 or 293 cells as described, for example, in Graham et al., J. Gen. Virol., 36:59 (1977)); baby hamster kidney (BHK) cells; mouse Sertoli cells (TM4 cells, as described, for example, in Mather, Biol. Reprod., 23:243-251 (1980)); monkey kidney cells (CV1); African green monkey kidney cells (VERO-76); human cervical carcinoma (HELA) cells; dog kidney cells (MDCK; buffalo rat liver cells (BRL 3A); human lung cells (W138); human liver cells (Hep G2); mouse mammary tumor (MMT 060562); TRI cells as described, e.g. , in Mather et al., Annals N.Y. Acad. Sci., 383:44-68 (1982); MRC 5 cells; and FS4 cells. Other suitable mammalian host cell lines include Chinese hamster ovary (CHO) cells, including DHFR cells -CHO (Urlaub et al., Proc. Natl. Acad. Sci., USA, 77:4216 (1980)); and myeloma cell lines such as Y0, NS0 and Sp2/0. Review of some mammalian host cell lines, suitable for antibody production is given, for example, by Yazaki and Wu, Methods in Molecular Biology, vol 248 (B.K.C. Lo, ed., Humana Press, Totowa, NJ), pp. 255-268 (2003).

Pharmaceutical compositions.

The Ahtu-TREM2 antibodies of the present invention can be formulated in various formulations for therapeutic administration by combining the antibodies with suitable pharmaceutically acceptable carriers or diluents, and can be formulated in solid, semi-solid, liquid or gaseous form. Examples of such compositions include, but are not limited to, tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Pharmaceutical compositions may include, depending on the desired formulation, pharmaceutically acceptable non-toxic carriers or diluents, which are media commonly used in the formulation of pharmaceutical compositions for administration to animals or humans. The diluent is chosen so as not to affect the biological activity of the combination. Examples of such diluents include, but are not limited to, distilled water, buffered water, saline, PBS (phosphate buffered saline), Ringer's solution, dextrose solution, and Hanks solution. The pharmaceutical composition or formulation of the present invention may further include other carriers, adjuvants, or non-toxic, non-therapeutic, non-immunogenic stabilizers, excipients and the like. The compositions may also include additional substances to approximate physiological conditions, such as pH adjusters and buffering agents, toxicity adjusters, wetting agents and detergents.

The pharmaceutical composition of the present invention may also include any of various stabilizing agents, such as an antioxidant, for example. In cases where the pharmaceutical composition includes a polypeptide, the polypeptide may be complexed with various well-known compounds that increase the in vivo stability of the polypeptide, or otherwise improve its pharmacological properties (for example, increase the half-life of the polypeptide, reduce its toxicity, and increase solubility or absorption ). Examples of such modifications or complexing agents include, but are not limited to, sulfate, gluconate, citrate and phosphate. The polypeptides of the composition can also be complexed with molecules that enhance their in vivo performance. Such molecules include, but are not limited to, carbohydrates, polyamines, amino acids, other peptides, ions (eg, sodium, potassium, calcium, magnesium, manganese) and lipids.

Additional examples of compositions suitable for various types of administration are provided in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985). A brief review of drug delivery methods is given in Langer, Science, 249:1527-1533 (1990).

For oral administration, the active ingredient may be administered in solid dosage forms such as capsules, tablets and powders, or in liquid dosage forms such as elixirs, syrups and suspensions. The active ingredient(s) may be encapsulated in gelatin capsules together with inactive ingredients and powdered carriers such as glucose, lactose, sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesium stearate, stearic acid, sodium saccharin, talc, magnesium carbonate. Examples of additional inactive ingredients that may be added to provide desired color, flavor, stability, buffering capacity

- 147 044134 properties, dispersibility or other known desirable characteristics are red iron oxide, silica gel, sodium lauryl sulfate, titanium dioxide, and food-grade white paint. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the drug over several hours. Compressed tablets may have a sugar coating or a film coating to mask any unpleasant taste and protect the tablet from the atmosphere, or an enteric coating for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

Compositions suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injectable solutions, which may contain antioxidants, buffers, bacteriostats, and solutes to ensure that the composition is isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions, which may include suspending agents. agents, solubilizers, thickeners, stabilizers and preservatives.

Ingredients used to formulate pharmaceutical compositions are preferably of high purity and substantially free of potentially harmful contaminants (e.g., qualified to at least National Food (NF), typically qualified to at least Part No. d.a. and more typically are qualified for at least pharmaceutical products). In addition, compositions intended for use in vivo are generally sterile. To the extent that a given compound must be synthesized prior to use, the resulting product is typically substantially free of any potentially toxic agents, in particular any endotoxins, that may be present during the synthesis or purification process. Compositions for parenteral administration are also sterile, substantially isotonic and manufactured under good manufacturing practice (GMP) conditions.

The compositions may be optimized for retention and stabilization in the brain or central nervous system. In cases where an agent is administered to a cranial compartment, it is desirable that the agent is retained in the compartment and does not diffuse or otherwise move across the blood-brain barrier. Stabilization methods include cross-linking, multimerization or binding to groups such as polyethylene glycol, polyacrylamide, neutral protein carriers, etc. to ensure an increase in molecular weight.

Other strategies to increase retention include entrapment of an antibody, such as the anti-TREM2 antibody of the present invention, in a biodegradable or bioerodible implant. The rate of release of the therapeutically active agent is controlled by the rate of transport through the polymer matrix, and biodegradation of the implant. Transport of the drug through the polymer barrier will also depend on the solubility of the compound, the hydrophilicity of the polymer, the degree of cross-linking of the polymer, the expansion of the polymer upon absorption of water to increase the permeability of the polymer barrier to the drug, the geometry of the implant, etc. The implants are sized to match the size and shape of the area chosen for implantation. Implants can be particles, sheets, patches, patches, fibers, microcapsules, and the like. and may be of any size or shape compatible with the chosen injection site.

Implants can be monolithic, i.e. having a homogeneous distribution of the active agent in the polymer matrix, or encapsulated, when the reservoir of the active agent is encapsulated by the polymer matrix. The choice of polymer composition used will vary depending on the site of administration, the desired period of treatment, patient tolerance, the nature of the disease being treated, and the like. Characteristics of polymers will include biodegradability at the site of implantation, compatibility with the agent of interest, ease of encapsulation, half-life in a physiological environment.

Biodegradable polymer compositions suitable for use may be organic esters or ethers which, when degraded, provide physiologically acceptable degradation products, including monomers. Anhydrides, amides, orthoesters, etc., alone or in combination with other monomers, may find use. The polymers will be condensation polymers. Polymers can be cross-linked or non-cross-linked. Of particular interest are polymers of hydroxyaliphatic carboxylic acids, whether homo- or copolymers, and polysaccharides. Polyesters of interest include polymers of D-lactic acid, L-lactic acid, racemic lactic acid, glycolic acid, polycaprolactone, and combinations thereof. When using L-lactate or D-lactate, a slowly biodegradable polymer is obtained, whereas for the racemate, degradation is significantly enhanced. Copolymers of glycolic and lactic acids are of particular interest, with the rate of biodegradation controlled by the ratio of glycolic and lactic acids. The most rapidly degrading copolymer contains approximately equal amounts of glycolic and lactic acids, while either homopolymer is more resistant to degradation. The ratio of glycolic acid to lactic acid will also affect the fragility of it.

- 148 044134 plant, while a more flexible implant is desirable for large geometric dimensions. Polysaccharides of interest are calcium alginate and functionalized celluloses, in particular carboxymethylcellulose esters, characterized by water insolubility, with a molecular weight of from about 5 to 500 kDa, etc. Biodegradable hydrogels can also be used in the implants of the present invention. Hydrogels are typically a copolymer material characterized by the ability to absorb liquid. Typical examples of biodegradable hydrogels that can be used are described by Heller in Hydrogels in Medicine and Pharmacy, N.A. Peppes ed., vol. III, CRC Press, Boca Raton, Fla., 1987, p. 137-149.

Pharmaceutical dosages.

The pharmaceutical compositions of the present invention containing the anti-TREM2 antibody of the present invention can be administered to an individual in need of treatment with an anti-TREM2 antibody, preferably a human, according to known methods, such as intravenous administration as a bolus or by continuous infusion over over a period of time, intramuscular, intraperitoneal, intracerebrospinal, intracranial, intraspinal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, local routes or inhalation.

The dosages and desired concentrations of drugs in the pharmaceutical compositions of the present invention may vary depending on the specific intended use. Determining the appropriate dosage or route of administration is within the skill level of the ordinary practitioner. Animal experiments provide reliable guidance for determining effective doses for human treatment. Interspecies effective dose conversion factors can be applied according to the principles described in Mordenti, J. and Chappell, W. The Use of Interspecies Scaling in Toxicokinetics, in Toxicokinetics and New Drug Development, Yacobi et al., eds, Pergamon Press, New York, 1989, p. 42-46.

For in vivo administration of any anti-TREM2 antibodies of the present invention, normal dosage levels may range from about 10 ng/kg to about 100 mg/kg of an individual's body weight or more per day, preferably from about 1 to 10 mg/kg/day. depending on the route of administration. For repeated administration over several days or longer, depending on the severity of the disease, disorder or condition requiring treatment, treatment is continued until the desired suppression of symptoms is achieved.

A typical dosage regimen may include an initial dose of about 2 mg/kg anti-TREM2 antibody, followed by a weekly maintenance dose of about 1 mg/kg every two weeks. Other dosage regimens may be suitable depending on the nature of the attenuation of the pharmacokinetic effect that the physician considers desirable to achieve. For example, the present document provides for the administration of one to twenty-one doses per week to an individual. In some embodiments, dosages ranging from about 3 μg/kg to about 2 mg/kg (such as about 3 μg/kg, about 10 μg/kg, about 30 μg/kg, about 100 μg/kg, approximately 300 mcg/kg, approximately 1 mg/kg and approximately 2/ mg/kg). In some embodiments, the dosing frequency is three times a day, twice a day, once a day, every two days, once a week, every two weeks, every four weeks, every five weeks, every six weeks , once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, or once a month, once every two months, once every three months or more. The progress of therapy is easily monitored using conventional methods and tests. The dosing schedule, including the anti-TREM2 antibody administered, may vary over time regardless of the dose used.

Dosages for a particular anti-TREM2 antibody can be determined empirically in individuals who receive one or more administrations of the anti-TREM2 antibody. Individuals receive increasing doses of anti-TREM2 antibody. To assess the effectiveness of the anti-TREM2 antibody, any clinical symptom of any of the diseases, disorders or conditions of the present invention (eg, dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease and multiple sclerosis) may be monitored.

Administration of the anti-TREM2 antibody of the present invention may be continuous or intermittent depending, for example, on the physiological state of the recipient, whether the purpose of administration is therapeutic or prophylactic, and other factors known to those skilled in the art. Administration of the anti-TREM2 antibody may be substantially continuous over a preselected period of time or may be a series of doses administered at intervals.

Recommendations regarding specific dosages and delivery methods are available in the literature; see, for example, US Pat. No. 4,657,760; 5206344; or 5,225,212. The present invention contemplates that different compositions will be effective for different treatments and different disorders, and that an administration intended to treat a particular organ or tissue may require delivery in a manner different from that used for another organ or tissue. In addition, dosages may be administered through one or more separate administrations, or by continuous infusion. For repeated administration over several days or a longer period of time

- 149 044134 or, depending on the condition, treatment is carried out until the desired suppression of the symptoms of the disease is achieved. However, other administration schedules may be useful. The progress of such therapy is easily monitored by conventional methods and tests.

Therapeutic use.

As disclosed herein, the anti-TREM2 antibodies of the present invention can be used to prevent, reduce the risk of, or treat dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, tauopathies, Nasu-Hakol disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis , obesity, malaria, essential tremor, lupus of the central nervous system, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorder, sarcoidosis, diseases aging, seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera , essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovani infection, group B Streptococcus infections, Campylobacter jejuni infections, Neisseria meningiditis infections, HIV type I, and/or Pfeiffer bacillus (Haemophilus influenza). In some embodiments, the anti-TREM2 antibodies are agonistic antibodies.

In some embodiments, the present invention provides methods for preventing, reducing the risk of, or treating an individual with dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, Huntington's disease, a disease from the group tauopathy, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitive impairment, memory loss, lupus, acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, central nervous system lupus, Behçet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticobasal ganglion degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, epileptic seizures, spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis disease, osteitis deformans, cancer, bladder cancer, brain cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer, kidney cancer, renal cell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma, polycythemia vera, essential thrombocytosis, primary or idiopathic myelofibrosis, primary or idiopathic myelosclerosis, tumors of myeloid origin, tumors expressing TREM2, thyroid cancer, infections, herpes central nervous system, parasitic infections, trypanosomal infection, Trypanosoma cruzi infection, Pseudomonas aeruginosa infection, Leishmania donov infection ani, group B Streptococcus infection, Campylobacter jejuni infection, Neisseria meningiditis infection, HIV type I and Pfeiffer's bacillus (Haemophilus influenza), by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention. In some embodiments, the method further includes administering to the individual at least one antibody that specifically

- 150 044134 digitally binds to a checkpoint inhibitory molecule and/or other standard or investigational anticancer therapy. In some embodiments, an antibody that specifically binds to a checkpoint inhibitory molecule is administered in combination with an isolated antibody. In some embodiments, the at least one antibody that specifically binds to a checkpoint inhibitory molecule is selected from an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody, anti-B7-H3 antibodies, anti-B7-H4 antibodies, and anti-HVEM antibodies, anti-B and T lymphocyte attenuator antibodies (BTLA), anti-killer inhibitory receptor (KIR) antibodies, anti-GAL9 antibodies, anti-TIM3 antibodies, anti-A2AR antibody, anti-LAG-3 antibody, antiphosphatidylserine antibody, anti-CD27 antibody, and any combination thereof. In some embodiments, the standard or investigational anticancer therapy is one or more therapies selected from radiation therapy, cytotoxic chemotherapy, targeted therapy, hormonal therapy, imatinib (Gleevec®), trastuzumab (Herceptin®), bevacizumab ( Avastin®), ofatumumab (Arzerra®), rituximab (Rituxan®, (MabThera®), Zytux®), cryotherapy, ablation, radiofrequency ablation, adoptive cell transfer (ACT), transfer chimeric antigen receptor T cells (CAR-T), vaccine therapy, and cytokine therapy. In some embodiments, the method further includes administering to the individual at least one antibody that specifically binds to an inhibitory cytokine. In some embodiments, at least one antibody that specifically binds to an inhibitory cytokine, is administered in combination with an isolated antibody.In some embodiments, at least one antibody that specifically binds to an inhibitory cytokine is selected from an anti-CCL2 antibody, an anti-CSF-1 antibody, an anti-IL-2 antibody and any combination thereof. In some embodiments, the method further comprises administering to the individual at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein. In some embodiments, at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with an isolated antibody. In some embodiments, the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is selected from an agonistic anti-CD40 antibody, an agonistic anti-OX40 antibody, an agonistic anti-ICOS antibody, an agonistic anti-CD28 antibody, an agonistic anti-CD137 antibody /4-1BB antibody, agonistic anti-CD27 antibody, agonistic antibody against glucocorticoid-induced TNFR-related protein GITR, and any combination thereof. In some embodiments, the method further includes administering to the individual at least one stimulatory cytokine. In some embodiments, at least one stimulatory cytokine is administered in combination with an isolated antibody. In some embodiments, the at least one stimulatory cytokine is selected from TNF-α, IL-10, IL-6, IL-8, CRP, TGF-beta chemokine protein family member, IL20 family member, IL-33, LIF, OSM, CNTF, TGF-beta, IL-11, IL-12, IL-17, IL-8, IL-23, IFN-α, IFN-β, IL-2, IL-18, GM-CSF, G-CSF and any combination of them.

In some embodiments, the present invention provides methods for preventing, reducing the risk of, or treating an individual with Alzheimer's disease by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention. In some embodiments, the anti-TREM2 antibody increases the expression of one or more inflammatory mediators, such as IL-1e, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof. In some embodiments, the anti-TREM2 antibody reduces the expression of one or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof. In some embodiments, the anti-TREM2 antibody reduces levels of Abeta peptide in an individual (eg, in the individual's brain). In some embodiments, the anti-TREM2 antibody increases the number of CD11b ⁺ microglial cells in the brain of an individual. In some embodiments, the anti-TREM2 antibody enhances memory in an individual. In some embodiments, the anti-TREM2 antibody reduces cognitive impairment in an individual. In some embodiments, the anti-TREM2 antibody increases motor coordination in an individual.

In some embodiments, the present invention provides methods for enhancing memory, reducing cognitive impairment, or both, in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the present invention provides methods for increasing motor coordination in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the present invention provides methods for reducing levels of Abeta peptide in an individual in need thereof by administering to the individual a therapeutic agent.

- 151 044134 highly effective amount of the aHTu-TREM2 antibody of the present invention.

In some embodiments, the present invention provides methods for increasing the number of CD11b ⁺ microglial cells in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the present invention provides methods for increasing the levels of one or more of FLT1, OPNCSF1, CD11c, and AXL in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the anti-TREM2 antibody of the present invention may increase the expression of one or more inflammatory mediators, such as IL-1e, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof, in one or more cells of an individual in at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80 %, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least at least 190%, or at least 200%, for example, compared to the expression of one or more inflammatory mediators such as IL1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc and any combination thereof, in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody of the present invention increases the expression of one or more inflammatory mediators, such as ΓΕ-1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof, in one or more cells of an individual, at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3.0 times, at least at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6 ,5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times or at least 10 times, for example, compared with the expression of one or more inflammatory mediators such as ]Σ-1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc and any combination thereof, in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present invention may reduce the expression of one or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof, in one or more cells of an individual by at least 10% , at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, according to at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140% , at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, for example, compared to expression one or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof, in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody of the present invention reduces the expression of one or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof, in one or more cells of an individual in at least 1 ,5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7 .5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times, or at least 10 times, for example, compared to

- 152 044134 expression of one or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof, in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present invention may modulate the expression of one or more stage 2 microglia associated with neurodegenerative disease markers (DAMs), such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax , Clec7a, Lilrb4, Timp2, and any combination thereof, in one or more cells of an individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, by at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120% , at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, according at least 180%, at least 190%, or at least 200%, for example, compared to the expression of one or more DAM markers such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and any combination thereof, in one or more cells of a corresponding individual not receiving anti-TREM2 antibody. See Keren-Shaul et al., Cell, 169:1276–1290 (2017), which is incorporated herein by reference in its entirety. In other embodiments, the anti-TREM2 antibody of the present invention modulates the expression of one or more DAM markers, such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and any combination thereof , in one or more cells of an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2.3 times, at least 2 ,35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times, or at least 10-fold, for example, compared to the expression of one or more DAM markers, such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and any combination thereof, in one or multiple cells from a corresponding individual not receiving anti-TREM2 antibody. In some embodiments, the DAM marker is Cst7. In some embodiments, the DAM marker is Ccl6. In some embodiments, the DAM marker is Itgax. In some embodiments, the modulation is increased expression.

Further provided herein are methods for determining whether an individual is a responder or non-responder to treatment with an anti-TREM2 antibody, which comprises the steps of (a) measuring the levels of one or more stage 2 type microglia associated with neurodegenerative disease markers (DAMs), such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and any combination thereof, in a sample from an individual taken from said individual before treatment;

(b) measuring the level of one or more Stage 2 microglia associated with neurodegenerative disease markers (DAMs) such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2 and any combination thereof, in a sample from an individual taken from said individual at a time point after the first treatment; and (c) comparing the levels measured in stage ii) with the levels measured in stage i), the difference between said levels demonstrating whether the individual is a responder or a non-responder.

In some embodiments, the difference between the specified levels represents an increase and demonstrates that the specified individual is a responder. In some embodiments, the difference between the specified levels represents a decrease or no change and demonstrates that the specified individual is a non-responder. In some embodiments, the DAM marker is Cst7. In some embodiments, the DAM marker is Ccl6. In some embodiments, the DAM marker is Itgax.

In some embodiments, an anti-TREM2 antibody of the present invention may reduce levels of Abeta peptide in one or more cells of an individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70% , at least 75%, at least

- 153 044134 at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, according at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, for example, compared to the levels of Abeta peptide in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody of the present invention reduces the levels of Abeta peptide in one or more cells of an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8 times, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2, 25 times, at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times , at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, according to at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0-fold, at least 9.5-fold, or at least 10-fold, for example, compared to the levels of Abeta peptide in one or more cells of a corresponding individual not receiving an anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present invention may enhance an individual's memory by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35 %, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120%, at least at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, at least 180 %, at least 190%, or at least 200%, for example, compared to the memory of a corresponding individual not receiving an anti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody of the present invention increases an individual's memory by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2 ,3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9 .5 times, or at least 10 times, for example, compared to the memory of a corresponding individual not receiving anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present invention may reduce cognitive impairment in an individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, at least 110%, at least 115%, at least 120% , at least 125%, at least 130%, at least 135%, at least 140%, at least 145%, at least 150%, at least 160%, at least 170%, according at least 180%, at least 190%, or at least 200%, for example, compared to cognitive impairment in a corresponding individual not receiving anti-TREM2 antibody treatment. In other embodiments, the anti-TREM2 antibody of the present invention reduces the cognitive impairment of an individual by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3 ,0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times, at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, at least 9.5 times or at least 10 times, for example, compared with the cognitive impairment in a corresponding individual not receiving anti-TREM2 antibody treatment.

In some embodiments, an anti-TREM2 antibody of the present invention may increase motor coordination in an individual by at least 10%, at least 15%, by

- 154 044134 at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least at least 100%, at least 110%, at least 115%, at least 120%, at least 125%, at least 130%, at least 135%, at least 140%, at least 145 %, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%, for example, compared to motor coordination in the corresponding individual, not receiving anti-TREM2 antibody treatment. In other embodiments, the anti-TREM2 antibody of the present invention increases an individual's motor coordination by at least 1.5-fold, at least 1.6-fold, at least 1.7-fold, at least 1.8-fold, at least 1.9 times, at least 2.0 times, at least 2.1 times, at least 2.15 times, at least 2.2 times, at least 2.25 times, at least 2.3 times, at least 2.35 times, at least 2.4 times, at least 2.45 times, at least 2.5 times, at least 2.55 times, at least 3, 0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, at least 5.5 times, at least 6.0 times , at least 6.5 times, at least 7.0 times, at least 7.5 times, at least 8.0 times, at least 8.5 times, at least 9.0 times, according to at least 9.5 times, or at least 10 times, for example, compared to motor coordination in a corresponding individual not receiving anti-TREM2 antibody treatment.

Other aspects of the present invention relate to methods of increasing one or more TREM2 activities induced by binding of one or more TREM2 ligands to TREM2 protein in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention. Other aspects of the present invention relate to methods of inducing one or more TREM2 activities in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention. Any suitable method for measuring TREM2 activity can be used, such as the in vitro cell assays or in vivo models of the present invention. Representative examples of TREM2 activity include, but are not limited to, TREM2 binding to DAP12; phosphorylation of TREM2; phosphorylation of DAP12; activation of one or more tyrosine kinases, wherein optionally one or more tyrosine kinases include Syk kinase, ZAP70 kinase, or both; activation of phosphatidylinositol 3-kinase (PI3K); activation of protein kinase B (Akt); recruitment of phospholipase C-gamma (PLC-gamma) to the cell plasma membrane, activation of PLC-gamma, or both; recruitment of TEC family dVav kinase to the cell plasma membrane; activation of nuclear factor-rB (NF-rB); inhibition of MAPK signaling; phosphorylation of linker activation of T cells (LAT), linker activation of B cells (LAB), or both; activation of IL-2-inducible tyrosine kinase (Itk); transient activation followed by inhibition of one or more proinflammatory mediators selected from IFN-a4, IFN-b, IL-1e, TNF-α, IL-10, IL-6, IL-8, CRP, members of the TGF-beta chemokine protein families , family members IL-20, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL-18, IL-23, CXCL10 , VEGF, CCL4 and MCP-1, wherein optionally transient activation followed by inhibition occurs in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, cutaneous Langerans cells, Kupffer cells cells, and microglial cells; phosphorylation of extracellular signal-regulated kinase (ERK); increased expression of C-C chemokine receptor 7 (CCR7) in one or more cells selected from macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, dendritic cells, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, microglia, M1 microglia, activated microglia M1, and microglia M2, and any combination thereof; induction of chemotaxis of microglial cells towards cells expressing CCL19 and CCL21; normalization of impaired TREM2/DAP12-dependent gene expression; recruitment of Syk, ZAP70, or both to the DAP12/TREM2 complex; increasing the activity of one or more TREM2-dependent genes, wherein optionally one or more TREM2-dependent genes include nuclear factor of activated T cells (NFAT) transcription factors; increased maturation of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof; increased ability of dendritic cells, monocytes, microglia, M1 microglia, activated M1 microglia and M2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, or any combination thereof, to induce T cell proliferation; increased ability, normalized ability, or both, of bone marrow-derived dendritic cells to induce proliferation of antigen-specific T cells; induction of osteoclast production, increased rate of osteoclastogenesis, or both; increased survival of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, skin Langerans cells, Kupffer cells, microglia,

- 155 044134 M1 microglia, activated M1 microglia, and M2 microglia, or any combination thereof; increased function of dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, microglia, M1 microglia, activated M1 microglia and M2 microglia, or any combination thereof; modulating phagocytosis by dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, microglia, M1 microglia, activated M1 microglia and M2 microglia, or any combination thereof; inducing one or more types of clearance selected from the clearance of apoptotic neurons, the clearance of neural tissue debris, the clearance of non-neural tissue debris, the clearance of bacteria or other foreign bodies, the clearance of pathogenic agents, the clearance of tumor cells, or any combination thereof, not necessarily pathogenic the agent is selected from amyloid beta or fragments thereof, tau protein (Tau), IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, SIBM protein, and translation products associated with non-ATG repeats ( RAN), including dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR), antisense RNA with GGCCCC repeat expansion (G2C4); inducing phagocytosis of one or more of apoptotic neurons, neural debris, non-neural tissue debris, bacteria, other foreign bodies, pathogenic agents, tumor cells, or any combination thereof, wherein the pathogenic agent is optionally selected from beta-amyloid or fragments thereof, tau protein (Tau), IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta-2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, and translation products associated with non-ATG repeats (RAN) , including dipeptide repeats (DPR peptides) consisting of glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR), antisense RNA with expansion of GGCCCC repeats (G2C4); increased expression of one or more stimulatory molecules selected from CD83, CD86 MHC class II, CD40, and any combination thereof, wherein optionally CD40 is expressed on dendritic cells, monocytes, macrophages, or any combination thereof, and optionally dendritic cells include dendritic cells bone marrow origin; decreased secretion of one or more inflammatory mediators, wherein optionally one or more inflammatory mediators are selected from CD86, IFN-a4, IFN-b, ΓΕ-1β, TNF-α, IL-10, IL-6, IL-8, CRP , TGF-beta chemokine protein family members, IL-20, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL family members -18, IL-23, CXCL10, VEGF, CCL4 and MCP-1 and any combination thereof; increased memory; and reduced cognitive impairment.

As disclosed herein, the anti-TREM2 antibodies of the present invention can be used to reduce cellular levels of TREM2 on one or more cells, including, but not limited to, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, natural killer cells, osteoclasts, skin Langerans cells and Kupffer cells and/or cell lines. In some embodiments, the present invention provides methods for reducing cellular levels of TREM2 on one or more cells in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention. In some embodiments, the one or more cells are selected from dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, macrophages, neutrophils, natural killer cells, osteoclasts, skin Langerans cells and Kupffer cells, and any combination thereof. Cellular levels of TREM2 may refer to, but are not limited to, cell surface TREM2 levels, intracellular TREM2 levels, and total TREM2 levels. In some embodiments, reducing cellular levels of TREM2 includes reducing levels of cell surface TREM2. As used herein, cell surface levels of TREM2 can be measured by any of the in vitro cell assays or suitable in vivo model described herein or known to those skilled in the art. In some embodiments, the reduction in cellular levels of TREM2 includes a reduction in intracellular levels of TREM2. As used herein, intracellular levels of TREM2 can be measured by any of the in vitro cellular assays or suitable in vivo model described herein or known to those skilled in the art. In some embodiments, the reduction in cellular levels of TREM2 includes a reduction in overall levels of TREM2. As used herein, total TREM2 levels can be measured by any of the in vitro cell assays or suitable in vivo model described herein or known to those skilled in the art. In some embodiments, anti-TREM2 antibodies induce TREM2 degradation, TREM2 cleavage, TREM2 internalization, shedding

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TREM2, and/or decreased expression of TREM2. In some embodiments, cellular levels of TREM2 are measured on primary cells (eg, dendritic cells, bone marrow-derived dendritic cells, monocytes, microglia, and macrophages) or on cell lines using an in vitro cell-based assay.

As disclosed herein, the anti-TREM2 antibodies of the present invention may also be used to enhance memory and/or reduce cognitive impairment. In some embodiments, the present invention provides methods for enhancing memory and/or reducing cognitive impairment in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the individual has a heterozygous variant allele of TREM2 with a glutamic acid change to a stop codon in the nucleic acid sequence encoding amino acid residue 14 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with a glutamine stop codon substitution in the nucleic acid sequence encoding amino acid residue 33 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with a stop codon substitution of tryptophan in the nucleic acid sequence encoding amino acid residue 44 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with an arginine to histidine amino acid substitution at amino acid residue 47 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with a stop codon substitution of tryptophan in the nucleic acid sequence encoding amino acid residue 78 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with a valine to glycine amino acid substitution at the amino acid position corresponding to amino acid residue 126 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with an amino acid substitution from aspartic acid to glycine at the amino acid position corresponding to amino acid residue 134 of the human TREM2 protein (SEQ ID NO: 1). In some embodiments, the individual has a heterozygous TREM2 variant allele with a lysine to asparagine amino acid substitution at the amino acid position corresponding to amino acid residue 186 of the human TREM2 protein (SEQ ID NO: 1).

In some embodiments, the individual has a heterozygous TREM2 variant allele with a deletion of a guanine nucleotide at the nucleotide position corresponding to nucleotide residue G313 of the nucleic acid sequence encoding SEQ ID NO: 1; deletion of a guanine nucleotide at a nucleotide position corresponding to nucleotide residue G267 of the nucleic acid sequence encoding SEQ ID NO: 1; amino acid replacement of threonine with methionine at the amino acid position corresponding to amino acid residue Thr66 SEQ ID NO: 1; and/or an amino acid substitution of serine for cysteine at the amino acid position corresponding to the amino acid residue Ser116 of SEQ ID NO: 1.

As disclosed herein, the anti-TREM2 antibodies of the present invention can also be used to induce and/or promote the natural survival of immune cells. In some embodiments, the present invention provides methods for inducing or promoting the natural survival of immune cells in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

As disclosed herein, the anti-TREM2 antibodies of the present invention can also be used to induce and/or promote wound healing, such as following trauma. In some embodiments, the wound healing may be the healing of rectal wounds following trauma. In some embodiments, the present invention provides methods for inducing or promoting wound healing in an individual in need thereof by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the methods of the present invention may include co-administration of anti-TREM2 antibodies, or bispecific antibodies, with TLR antagonists or TLR agonist neutralizing agents (eg, cytokine or interleukin neutralizing antibodies).

In some embodiments, the methods of the present invention may include administration of chimeric constructs, including an anti-TREM2 antibody of the present invention in combination with a TREM2 ligand, such as HSP60.

In some embodiments, the anti-TREM2 antibodies of the present invention do not inhibit the growth of one or more natural immune cells. In some embodiments, the anti-TREM2 antibodies of the present invention bind to one or more

- 157 044134 immune cells with K _D less than 50 nM, less than 45 nM, less than 40 nM, less than 35 nM, less than 30 nM, less than 25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 9 nM, less 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, less than 4 nM, less than 3 nM, less than 2 nM or less than 1 nM. In some embodiments, the anti-TREM2 antibody of the present invention accumulates in the brain, or cerebrospinal fluid (CSF), or both, in an amount of 1% or more, 2% or more, 3% or more, 4% or more, 5% or more, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more of the antibody concentration in the blood.

In some embodiments, the subject or individual is a mammal. Mammals include, but are not limited to, domesticated animals (eg, cows, sheep, cats, dogs and horses), primates (eg, humans and non-human primates such as monkeys), rabbits and rodents (eg, mice and rats). In some embodiments, the subject or individual is a human.

Dementia.

Dementia is a nonspecific syndrome (i.e., a set of signs and symptoms) that manifests itself as a severe loss of general cognitive abilities in a previously unaffected individual, beyond what is expected with normal aging. Dementia may be static, resulting from a unique global brain injury. Alternatively, dementia may be progressive, resulting in long-term deterioration due to physical impairment or disease. Although dementia is significantly more common in the geriatric population, it can also occur in people under 65 years of age. Cognitive areas affected in dementia include, but are not limited to, memory, attention span, language, and problem solving. Typically, symptoms must have been present for at least six months before an individual is diagnosed with dementia.

Common examples of forms of dementia include, but are not limited to, frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, and dementia with Lewy bodies.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat dementia. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with dementia (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Frontotemporal dementia.

Frontotemporal dementia (FTD) is a condition resulting from progressive degeneration of the frontal lobe of the brain. Over time, degeneration may affect the temporal lobe. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of cases of presenile dementia. Clinical features of FTD include memory deficits, behavioral abnormalities, personality changes, and language impairment (Cruts, M. & Van Broeckhoven, C, Trends Genet., 24:186-194 (2008); Neary, D. et al., Neurology, 51 :1546-1554 (1998); Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, J.R., Neurology, 58:1615-1621 (2002)).

A significant proportion of cases of FTD are inherited in an autosomal dominant manner, but even within a single family, symptoms can span the spectrum from FTD with behavioral disturbances to primary progressive aphasia to corticobasal ganglion degeneration. FTD, like most neurodegenerative diseases, can be characterized by the abnormal presence of specific protein aggregates in the affected brain. Historically, early descriptions of FTD noted the presence of intraneuronal accumulations of hyperphosphorylated tau protein in neurofibrillary tangles or Pick bodies. The causative role of microtubule-associated protein tau has been confirmed by the identification of mutations in the gene encoding tau protein in several families (Hutton, M. et al., Nature, 393:702-705 (1998). However, in most brains affected by FTD , no accumulation of hyperphosphorylated tau protein was detected, and immunoreactivity for ubiquitin (Ub) and TAR DNA binding protein (TDP43) was demonstrated (Neumann, M. et al., Arch. Neurol., 64:1388-1394 (2007)). The majority of these cases of FTD with Ub inclusions (FTD-U) have been shown to carry mutations in the progranulin gene.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat FTD. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with FTD (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia. There is no cure for the disease, which worsens as it progresses and gradually leads to death. AD is most often diagnosed in people over the age of 65. However, a less common form of Alzheimer's disease with early onset may appear much earlier.

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Common symptoms of Alzheimer's disease include behavioral symptoms such as difficulty remembering recent events; cognitive symptoms, confusion, irritability and aggression, emotional lability, language problems, and long-term memory loss. As the disease progresses, bodily functions are lost, ultimately leading to death. Alzheimer's disease develops over an unknown and variable period of time before becoming fully manifest and can progress while remaining undiagnosed for years.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat Alzheimer's disease. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with Alzheimer's disease (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Nasu-Hakola disease.

Nasu-Hakola disease (NHD), which may alternatively be called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare hereditary leukodystrophy characterized by progressive presenile dementia associated with recurrent bone fractures due to polycystic bone lesions of the lower and upper extremities. The course of NHD disease is generally divided into four stages: latent, skeletal, early neurological, and late neurological. After normal development during childhood (latent stage), manifestations of NHD begin to appear in adolescence or early adulthood (typical age of onset 20–30 years) with pain in the arms, wrists, ankles and feet. Patients then begin to suffer from recurrent bone fractures due to polycystic bone lesions and osteoporotic lesions in the bones of the extremities (osseous stage). During the third or fourth decade of life (early neurological stage), patients exhibit significant personality changes (eg, euphoria, lack of concentration, loss of judgment, and social inhibition) characteristic of frontal lobe syndrome. Patients also typically suffer from progressive memory impairment. Epileptic seizures are also common. Eventually (late neurological stage), patients progress to profound dementia, unable to speak or move, and usually die by age 50.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat Nasu-Hakola disease (NHD). In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with NHD (eg, phosphorylation of DAP12, activation of PI3K, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Parkinson's disease.

Parkinson's disease, which may be called idiopathic or primary parkinsonism, hypokinetic rigid syndrome (HRS), or shaking palsy, is a neurodegenerative disorder of the brain that affects motor control. The progressive death of dopamine-producing brain cells leads to significant symptoms of Parkinson's disease. Parkinson's disease is most often diagnosed in people over 50 years of age. Parkinson's disease is idiopathic (no known cause) in most people. However, genetic factors also play a role in the disease.

Symptoms of Parkinson's disease include, but are not limited to, tremors of the hands, arms, legs, jaw and face, stiffness in the muscles of the limbs and trunk, slow movements (bradykinesia), postural instability, difficulty walking, neuropsychiatric problems, changes in speech or behavior, depression, anxiety, pain, psychosis, dementia, hallucinations and sleep problems.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat Parkinson's disease. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with Parkinson's disease (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Amyotrophic lateral sclerosis.

As used herein, amyotrophic lateral sclerosis (ALS) or motor neurone disease or Lou Gehrig's disease are used interchangeably and refer to a debilitating disease of varying etiologies characterized by rapidly progressive weakness, muscle wasting and fascicular tremor, muscle spasticity, difficulty speaking ( dysarthria), difficulty swallowing (dysphagia), and difficulty breathing (dyspnea).

Progranulin has been shown to play a role in ALS (Schymick, J.C. et al. (2007), J. Neurol. Neurosurg. Psychiatry., 78:754-6) and protects against damage caused by ALS-causing agents.

- 159 044134 proteins such as TDP-43 (Laird, A.S. et al. (2010), PLoS ONE, 5:e13368). It has also been demonstrated that pro-NGF induces p75-mediated death of oligodendrocytes and corticospinal neurons after spinal cord injury (Beatty et al., Neuron (2002), 36, p. 375-386; Giehl et al., Proc. Natl. Acad. Sci., USA (2004), 101, pp. 6226-30).

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat ALS. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with ALS (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Huntington's disease.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an autosomal dominant mutation in the huntingtin gene (HTT). Expansion of the cytokine-adenine-guanine (CAG) triplet repeat in the huntingtin gene results in the production of a mutant form of the huntingtin (Htt) protein encoded by the gene. This mutant huntingtin protein (mHtt) is toxic and contributes to neuronal death. Symptoms of Huntington's disease most often appear between the ages of 35 and 44, although they can appear at any age.

Symptoms of Huntington's disease include, but are not limited to, motor control problems, jerky, erratic movements (chorea), abnormal eye movements, poor balance, seizures, difficulty chewing, difficulty swallowing, cognitive problems, altered speech, memory deficits, difficulty thinking, insomnia, fatigue, dementia, personality changes, depression, anxiety and compulsive behavior.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat Huntington's disease (HD). In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with HD (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more pro-inflammatory mediators).

Tauopathy.

Tauopathies are a class of neurodegenerative diseases caused by the aggregation of microtubule-associated protein tau in the brain.

Alzheimer's disease (AD) is the best known of the tauopathies and involves the accumulation of tau protein in neurons in the form of insoluble neurofibrillary tangles (NFTs). Other tauopathies and disorders include progressive supranuclear palsy, boxer's dementia (chronic traumatic encephalopathy), frontotemporal dementia and parkinsonism associated with chromosome 17, Lytico-Bodig disease (Parkinsonism-dementia complex in Guam), tangle-predominant dementia, ganglioglioma and gangliocytoma , meningoangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Pick's disease, corticobasal degeneration, argyrophilic granule disease (AGD), Huntington's disease, frontotemporal dementia and frontotemporal lobar degeneration.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat a tauopathic disorder. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with a tauopathic disorder (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, or decreased expression of one or more proinflammatory mediators).

Multiple sclerosis.

Multiple sclerosis (MS) may also be called disseminated sclerosis or disseminated encephalomyelitis. MS is an inflammatory disease that damages the fatty myelin sheaths around axons in the brain and spinal cord, leading to demyelination and scarring and a wide range of signs and symptoms. PC affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve cells communicate by sending electrical signals called action potentials along long fibers called axons that are surrounded by an insulating substance called myelin. In MS, the body's own immune system attacks and damages myelin. When myelin is lost, axons lose their ability to conduct signals effectively. The onset of PC usually occurs in young people and is more common in women.

Symptoms of PC include, but are not limited to, changes in sensation such as loss of sensation or tingling; stabbing pain or numbness such as hypoesthesia and paresthesia; muscle weakness; clonus; muscle spasms; difficulty moving; complications with coordination and balance such as ataxia; problems with speech, such as dysarthria, or swallowing, such as dysphagia; vision problems such as nystagmus, retrobulbar neuritis including phosphenes, and diplopia; fatigue; ost

- 160 044134 paradise or chronic pain; and problems with the bladder and intestines; cognitive impairment of varying degrees; emotional symptoms of depression or unstable mood; Uchtoff's phenomenon, which is an exacerbation of existing symptoms when exposed to temperatures above normal ambient temperatures; and Lhermitte's sign, which is an electrical sensation running down the back when the neck is flexed.

In some embodiments, administration of an anti-TREM2 antibody of the present invention can prevent, reduce the risk of, and/or treat multiple sclerosis. In some embodiments, administration of an anti-TREM2 antibody may induce one or more TREM2 activities in an individual with multiple sclerosis (eg, DAP12 phosphorylation, PI3K activation, increased expression of one or more anti-inflammatory mediators, and decreased expression of one or more proinflammatory mediators).

Cancer.

Additional aspects of the present invention provide methods for preventing, reducing the risk of, or treating an individual with cancer, comprising administering to the individual a therapeutically effective amount of an isolated anti-TREM2 antibody of the present invention. Any of the isolated antibodies of the present invention can be used in such methods.

As described above, the tumor microenvironment is known to contain a heterogeneous immune infiltrate that contains T lymphocytes, macrophages, and cells of myeloid/granulocyte origin. In particular, the presence of M2 macrophages in tumors is associated with poor prognosis. Therapies that reduce the number of such cells in tumors, such as agents that block CSF-1R, show beneficial effects in preclinical models and early-stage clinical trials. It has been shown that TREM2 acts synergistically with CSF-1 to promote macrophage survival in vitro, and that this effect is particularly pronounced in M2 macrophages compared to other phagocytic cell types. Pivotal preclinical studies have also demonstrated synergism between drugs targeting tumor-associated macrophages (eg, CSF-1/CSF-1R blocking antibodies) and checkpoint blocking antibodies that target T cells, indicating that manipulation with both cell types demonstrates effectiveness in tumor models for which individual therapies are ineffective (Zhu Y., Cancer Res., 2014 Sep 15, 74(18):5057-69). Therefore, without wishing to be bound by theory, it is believed that blocking TREM2 signaling in tumor-associated macrophages can inhibit suppression of the immune response in the tumor microenvironment, leading to a therapeutic antitumor immune response.

Due to the synergy between TREM2 and CSF-1 and between targeting tumor-associated macrophages and targeting T cells, in some embodiments, methods of preventing, reducing the risk of, or treating an individual with cancer further comprises administering to the individual at least one antibody that specifically binds to the molecule , inhibiting the checkpoint. Examples of antibodies that specifically bind to a checkpoint inhibitory molecule include, but are not limited to, anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PDL2 antibody, anti-PD-1 antibody, anti-B7-H3 antibody, anti- B7-H4 antibody, and anti-HVEM antibody, anti-BTLA antibody, anti-GAL9 antibody, anti-TIM3 antibody, anti-A2AR antibody, anti-LAG-3 antibody, antiphosphatidylserine antibody, and any combination thereof. In some embodiments, at least one antibody that specifically binds to a checkpoint inhibitory molecule is administered in combination with an anti-TREM2 antibody of the present invention.

In some embodiments, the cancers to be prevented or treated by the methods of the present invention include, but are not limited to, squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and squamous cell lung cancer. peritoneal, hepatocellular cancer, gastric or gastric cancer, including gastrointestinal cancer and gastrointestinal stromal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urinary tract cancer, hepatoma , breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal cancer, penile cancer, melanoma, superficial melanoma, lentigo maligna melanoma, acral lentiginous melanomas, nodular melanomas, multiple myeloma and B-cell lymphoma; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative syndrome (PTLS), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as associated with brain tumors), Meigs syndrome, cancer of the brain, as well as head and neck cancer), and associated metastases. In some embodiments, said cancer is colorectal cancer. In some embodiments, the cancer is selected from non-small cell lung cancer, glioblastoma, neuroblastoma, renal cell cancer, bladder cancer, ovarian cancer, melanoma, breast cancer, gastric cancer, and liver cancer

- 161 044134 cell cancer. In some embodiments, said cancer is triple negative breast cancer. In some embodiments, the cancer may be an early stage cancer or a late stage cancer. In some embodiments, the cancer may be a primary tumor. In some embodiments, the cancer may be a metastatic tumor in a second site derived from any of the above types of cancer.

In some embodiments, the anti-TREM2 antibodies of the present invention can be used to prevent, reduce the risk of, or treat cancer, including, without limitation, bladder cancer, breast cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell cancer, cancer renal pelvis, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma and thyroid cancer.

In some embodiments, the present invention provides methods for preventing, reducing the risk of, or treating an individual with cancer by administering to the individual a therapeutically effective amount of an anti-TREM2 antibody of the present invention.

In some embodiments, the method further comprises administering to the individual at least one antibody that specifically binds to a checkpoint inhibitory molecule and/or other standard or investigational anticancer therapy. In some embodiments, at least one antibody that specifically binds to a checkpoint inhibitory molecule is administered in combination with an isolated antibody. In some embodiments, the at least one antibody that specifically binds to a checkpoint inhibitory molecule is selected from an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody, an -B7-H3 antibodies, anti-B7-H4 antibodies and anti-HVEM antibodies, anti-B and T lymphocyte attenuator antibodies (BTLA), anti-killer inhibitory receptor (KIR) antibodies, anti-GAL9 antibodies, anti-TIM3 antibodies, anti-A2AR antibodies, anti-LAG-3 antibodies, antiphosphatidylserine antibodies, anti-CD27 antibodies, and any combination thereof. In some embodiments, the standard or investigational anticancer therapy is one or more therapies selected from radiation therapy, cytotoxic chemotherapy, targeted therapy, imatinib (Gleevec®), trastuzumab (Herceptin®), adoptive cell transfer (ACT) , chimeric antigen receptor T-cell transfer (CAR-T), vaccine therapy, hormonal therapy, bevacizumab (Avastin®), ofatumumab (Arzerra®), rituximab (Rituxan®), MabThera®, Zytux ®), cryotherapy, ablation, radiofrequency ablation and cytokine therapy.

In some embodiments, the method further includes administering to the individual at least one antibody that specifically binds to the inhibitory cytokine. In some embodiments, at least one antibody that specifically binds to an inhibitory cytokine is administered in combination with an isolated antibody. In some embodiments, the at least one antibody that specifically binds to an inhibitory cytokine is selected from an anti-CCL2 antibody, an anti-CSF-1 antibody, an anti-IL-2 antibody, and any combination thereof.

In some embodiments, the method further comprises administering to the individual at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein. In some embodiments, at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is administered in combination with an isolated antibody. In some embodiments, the at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein is selected from an agonistic anti-CD40 antibody, an agonistic anti-OX40 antibody, an agonistic anti-ICOS antibody, an agonistic anti-CD28 antibody, an agonistic anti-CD137/4 antibody -1BB antibody, anti-CD27 agonist antibody, anti-glucocorticoid-induced TNFR-related protein GITR agonist antibody, and any combination thereof.

In some embodiments, the method further includes administering to the individual at least one stimulatory cytokine. In some embodiments, at least one stimulatory cytokine is administered in combination with an isolated antibody. In some embodiments, the at least one stimulatory cytokine is selected from TNF-α, IL-1o, IL-1β, IL-10, IL-6, IL-8, CRP, TGF-beta chemokine protein family members, IL family members -20, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, IL-11, IL-12, IL-17, IL-8, CRP, IFN-α, IFN-β, IL-2 , IL-18, IL-23, CXCL10, CCL4, MCP-1, VEGF, GM-CSF, G-CSF and any combination thereof.

Sets/products.

The present invention also provides kits containing an isolated antibody of the present invention (eg, the anti-TREM2 antibody described herein) or a functional fragment thereof. Kits of the present invention may include one or more containers containing a purified antibody of the present invention. In some variants

- 162 044134 implementation kits further include instructions for use in accordance with the methods of the present invention. In some embodiments, such instructions include a description of administering an isolated antibody of the present invention (e.g., an anti-TREM2 antibody described herein) to prevent, reduce the risk of, or treat an individual with a disease, disorder, or lesion selected from dementia, frontotemporal dementia , Alzheimer's disease, Nasu-Hakola disease, multiple sclerosis and cancer, in accordance with any methods of the present invention.

In some embodiments, the instructions include a description of how TREM2 is to be detected, for example, in an individual, in a tissue sample, or in a cell. The kit may further comprise a description of selecting an individual suitable for treatment based on determining whether the individual has a disease and the stage of the disease.

In some embodiments, the kits may further include another antibody of the present invention (e.g., at least one antibody that specifically binds to a checkpoint inhibitory molecule, at least one antibody that specifically binds to an inhibitory cytokine, and/or at least at least one agonistic antibody that specifically binds to a stimulatory checkpoint protein) and/or at least one stimulatory cytokine. In some embodiments, the kits may further include instructions for using an antibody and/or stimulatory cytokine in combination with an isolated antibody of the present invention (e.g., an anti-TREM2 antibody described herein), instructions for using an isolated antibody of the present invention in combination with antibody and/or stimulatory cytokine, or instructions for using an isolated antibody of the present invention and an antibody and/or stimulatory cytokine, in accordance with any methods of the present invention.

The instructions typically include information regarding the dosage, dosage regimen, and route of administration of the intended treatment. Containers may be unit doses, lot packs (eg, multi-dose packs), or smaller doses. The instructions included in the kits of the present invention are typically written instructions on a label or package insert (e.g., a sheet of paper included in the kit), but machine readable instructions (e.g., instructions on a magnetic or optical storage device) are also acceptable. disk).

The label or package insert indicates that the composition is used to treat, for example, a disease of the present invention. Instructions may be provided for performing any of the methods described herein.

The kits of the present invention are provided in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (eg, sealed Mylar or plastic bags), and the like. Also provided are packages for use in combination with a specific device, such as an inhaler, a nasal delivery device (eg, a nebulizer), or an infusion device, such as a mini-pump. The kit may have a sterile entry port (eg, the container may be an intravenous solution bag or a vial with a stopper pierced by a hypodermic needle). The container may also have a sterile entry channel (eg, the container may be a bag of intravenous solution or a vial with a stopper pierced by a hypodermic needle). At least one active agent in the composition is an isolated antibody of the present invention (eg, the anti-TREM2 antibody described herein). The container may further contain a second pharmaceutically active agent.

The kits may optionally provide additional components such as buffers and explanatory information. Typically, the kit includes a container and a label or packaging insert(s) on or associated with the container.

Diagnostic application.

Isolated antibodies of the present invention (eg, anti-TREM2 antibodies described herein) are also suitable for diagnostic use. This disclosure therefore provides methods for using an antibody according to this disclosure, or functional fragments thereof, for diagnostic purposes, such as detecting TREM2 in an individual or in tissue samples obtained from an individual.

In some embodiments, the individual is a human. In some embodiments, the individual is a person suffering from or at risk of developing cancer. In some embodiments, the diagnostic methods include detecting TREM2 in a biological sample, such as a biopsy sample, tissue, or cell. An isolated antibody of the present invention (eg, an anti-TREM2 antibody described herein) is contacted with a biological sample and antigen-bound antibody is detected. For example, a tumor sample (eg, a biopsy sample) can be stained with an anti-TREM2 antibody described herein in order to detect and/or quantify the association

- 163 044134 tumor-associated macrophages (for example, M2 type macrophages). The detection method may include quantifying an antibody bound to an antigen. Detection of antibodies in biological samples can be performed by any method known in the art, including immunofluorescence microscopy, immunocytochemistry, immunohistochemistry, ELISA, FACS (fluorescence activated cell sorting) analysis, immunoprecipitation, or micro-positron emission tomography. In some embodiments, the antibody is labeled with a radioactive isotope, such as ¹⁸ F, and then detected using micro-positron emission tomography analysis. Antibody binding can also be quantified in a patient by non-invasive techniques such as positron emission tomography (PET), X-ray computed tomography, single photon emission computed tomography (SPECT), computed tomography (CT), and axial computed tomography (ACT).

In other embodiments, an isolated antibody of the present invention (e.g., an anti-TREM2 antibody described herein) can be used to detect and/or quantify, for example, microglia in a brain sample taken from a preclinical disease model (e.g. non-human model of disease). As such, an isolated antibody of the present invention (e.g., the anti-TREM2 antibody described herein) may be useful for assessing therapeutic response after treatment in a model of a disease or disorder of the nervous system, such as dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease or multiple sclerosis compared with controls.

Antibodies with modified constant regions.

Other aspects of the present invention relate to antibodies having modified constant regions (ie, Fc regions). In some embodiments, the modified Fc regions contain two or more amino acid substitutions that increase the clustering of the antibody without activating complement compared to a corresponding antibody having an Fc region that does not contain two or more amino acid substitutions. Accordingly, in some embodiments, the antibody is an antibody comprising an Fc region, wherein the antibody contains an amino acid substitution at position E430G and one or more amino acid substitutions at the Fc region at a residue position selected from L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, and any combination thereof, with the remainder numbering following the EU or Kabat numbering schemes. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, L243A, L235A, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G and K322A, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, A330S, and P331S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and A330S, wherein the residue position numbering follows the EU numbering scheme. In some embodiments, the Fc region contains amino acid substitutions at positions E430G, K322A, and P331S, wherein the residue position numbering follows the EU numbering scheme.

In some embodiments, the Fc region increases clustering without activating complement compared to a corresponding antibody comprising an Fc region that does not contain amino acid substitutions. In some embodiments, the antibody induces one or more activities of a target specifically bound by the antibody. In some embodiments, the antibody binds to TREM2.

The present invention will be better understood with reference to the following examples. However, they should not be construed as limiting the scope of the present invention. All references in this specification are hereby expressly incorporated herein by reference.

Examples

Example 1 Humanized AL2p antibodies retain affinity and function.

The mouse anti-TREM2 antibody AL2p is also described as 9F5 and 9F5a in WO 2017/062672 (PCT/US2016/055828).

Ways.

Humanized variants of the mouse anti-TREM2 antibody AL2p were generated by combining 21 human IgG1 VH variants with 6 human IgG1 VK variants, each containing 0 to 11 framework residue mutations. These variants were tested by ForteBio for affinity with the TREM2 antigen, and 94 variants were selected for further in vitro analysis.

The affinity of TREM2 antibodies was determined by measuring their _KD and association and dissociation rates (on- and off-rates) using ForteBio OctetRed, as previously described by Estep et al., Mabs, 2013.

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5(2):270-278. Briefly, IgG was loaded online onto AHQ probes (anti-human IgG quantification probes). The sensors were equilibrated offline in assay buffer for 30 min and then monitored online for 60 s to establish a baseline. To measure binding avidity, IgG-loaded sensors are treated with 100 nM antigen (containing a human TREM2 Fc fusion using the entire ECD (extracellular domain) of TREM2; only one Fc arm fused to TREM2) for 3 min, then transferred to assay buffer for flow 3 min to measure the dissociation rate. Monovalent binding measurements were performed by loading human TREM2 Fc fusion antigens onto the AHQ sensor followed by exposure to ca. 100 nM TREM2 Fab antibody. Kinetic data were fitted using a 1:1 binding model in a data analysis application provided by ForteBio. The analysis was carried out at room temperature (25°C).

To analyze the binding of cells to anti-TREM2 antibodies, human TREM2-expressing recombinant BW5147.G.1.4 cells (ATCC® TIB48™) stably expressing murine TREM2 or human TREM2 together with Dap12 were generated by viral infection. Cells were collected by scraping, washed in PBS (phosphate-buffered saline), counted and seeded into 96-well U-bottom plates at 1x105 cells/well. The plates were centrifuged at 1400 rpm for 3 min and primary anti-TREM2 or control antibodies were added in FACS buffer (PBS + 2% FBS and incubated on ice for 1 h. Cells were then centrifuged as described previously and washed three times with FACS buffer. Cells were then incubated with anti-human phycoerythrin (PE)-conjugated secondary antibody (BD Biosciences) in FACS buffer for 30 min on ice. Cells were washed again three times with FACS buffer and analyzed using a BD FACS Canto. measured as the average fluorescence intensity in the APC (allophycocyanin) channel.

The ability of plate-immobilized full-length anti-TREM2 antibody to activate human TREM2-dependent genes was assessed using a luciferase reporter gene under the control of the NFAT (nuclear factor of activated T cells) promoter. The BW5147.G.1.4 cell line, derived from mouse thymic lymphoma T lymphocytes, was infected with human TREM2/DAP12 fusion protein and Cignal Lenti NFAT-Luciferase virus (Qiagen). To test antibodies in solution, they were added to culture plates along with cells and incubated for 4-6 hours at 37°C. Luciferase activity was measured by adding OneGlo Reagent (Promega) to each well and incubating for 3 min at room temperature on a plate shaker. Luciferase signal was measured using a BioTek plate reader.

Results.

Humanized variants of the anti-TREM2 antibody AL2p were generated by combining 21 human IgG1 VH variants with 6 human IgG1 VK variants, each containing 0 to 11 framework residue mutations. The sequences of the heavy chain and light chain variable regions of 26 humanized anti-TREM2 antibodies are presented in table. 6A, 6B, 7A and 7B.

Clones were tested for affinity for human TREM2 using ForteBio Octet Red (Table 1). Most humanized AL2p variants retained similar affinity to the original human-mouse AL2p chimeric antibody (which has a mouse antibody variable region and a human Fc region). In addition, the humanized variants retained the ability to bind to human TREM2 expressed on BW cells, and some even showed increased affinity compared to the parent antibody (Table 1). In addition, the humanized variants retained the ability to induce TREM2 signaling in a heterologous NFAT:luciferase signaling assay (Table 1). Two variants (AL2p-h50 and AL2p-h77) were selected for further affinity maturation studies because they both retained the affinity and function of the parent antibody while having minor changes compared to the human germline, indicating low immunogenicity.

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Table 1

Characterization of humanized variants of the aHmu-TREM2 antibody AL2p

Antibody K _D Fab TREM2 human-Fc (M) monovalent TREM2 binding person/OAR12 s BWZ cells (FOB) Activation by soluble luciferase at 10 μg/ml, fold compared to control AL2p l,02E-07 79 3.55 AL2p-hl9 l,93E-07 87 4.97 AL2p-h21 l,37E-07 76 6.28 AL2p-h22 3.25E-07 61 5.00 AL2p-h23 3.34E-07 76 5.38 AL2p-h24 1D5E-06 69 4.36 AL2p-h25 l,53E-07 90 7.45 AL2p-h26 9.53E-08 78 7.25 AL2p-h27 l,20E-07 78 7.23 AL2p-h28 H.C. 79 5.59 AL2p-h29 H.C. 82 5.80 AL2p-h30 l,81E-07 88 6.01 AL2p-h31 1D6E-07 83 5.04 AL2p-h32 l,44E-07 81 5.60 AL2p-h33 2.25E-07 74 6.21 AL2p-h34 l,42E-07 84 6.92 AL2p-h35 l,27E-07 69 6.81 AL2p-h36 H.C. 85 4.13 AL2p-h42 l,41E-07 79 9.29 AL2p-h43 l,34E-07 91 8.65 AL2p-h44 l,80E-07 80 7.29 AL2p-h47 l,61E-07 93 9.28 AL2p-h50 l,80E-07 78 6.36 AL2p-h59 l,30E-07 69 7.06 AL2p-h76 8.30E-08 86 6.52 AL2p-h77 9.39E-08 83 7.14 AL2p-h90 6.12E-08 126 4.35

In table 1 N.S. represents the absence of binding; and FOB denotes fold over background.

Example 2 Affinity Mature AL2p Antibodies Show Highly Increased Affinity.

Ways.

Affinity maturation of the AL2p-h50 and AL2p-h77 variants of humanized AL2p was performed. Briefly, key amino acid residues of the heavy or light chains were selectively mutated and mutants with improved binding were selected through additional rounds of screening. This process simultaneously improves specificity, species cross-reactivity and manifestation profiles, allowing precise adjustment of properties critical to the desired mechanism of action, activity in bioassays, and preclinical modeling. Delivery characterization included Forte Bio and MSD affinity measurements, cell binding, and several manifestation assays. After the first round of affinity maturation, antibodies with increased affinity also showed increased polyspecific reactivity (PSR), which is used to determine nonspecific antibody binding. Therefore, a second round of affinity maturation was performed to improve affinity without increasing PSR.

The affinity of affinity matured anti-TREM2 antibodies was determined by measuring their _KD and association and dissociation rates using ForteBio OctetRed as previously described by Estep et al., Mabs, 2013, 5(2):270-278. Briefly, IgG was loaded online onto AHQ sensors. Level sensors

- 166 044134 were suspended offline in assay buffer for 30 min and then monitored online for 60 s to establish a baseline. To measure binding avidity, IgG-loaded probes were treated with 100 nM antigen (containing a human or cynomolgus Fc fusion of TREM2 using the entire extracellular domain (ECD) of TREM2; only one Fc arm fused to TREM2) for 3 min, after which they were transferred to assay buffer for 3 min to measure dissociation rate. Monovalent binding measurements were performed by loading human TREM2 Fc fusion antigens onto the AHQ probe followed by treatment with ca. 100 nM TREM2 Fab antibody. Kinetic data were fitted using a 1:1 binding model in a data analysis application provided by ForteBio. The analysis was carried out at room temperature (25°C).

For cell binding studies of affinity matured anti-TREM2 antibodies, both dendritic cells derived from primary human monocytes and recombinant cells expressing human TREM2 were used. In the latter case, BW5147.G.1.4 (ATCC® TIB48™) and HEK293T cells stably expressing human TREM2 along with Dap12 were developed using viral infection. For dendritic cells derived from primary human monocytes, human monocytes were isolated from whole blood using RosetteSep Human Monocyte Enrichment Cocktail (Stemcell Technologies) and Ficoll centrifugation according to the manufacturer's protocols. After lysis of red blood cells with ASA lysis buffer, monocytes were resuspended in complete medium (RPMI, 10% FBS, penicillin/streptomycin (Pen/Strep), L-glutamine, HEPES, nonessential amino acids, sodium pyruvate) with 100 ng/ml human GM -CSF (granulocyte-macrophage colony-stimulating factor) (hu-GMCSF) and human IL-4 (hu-IL-4) for dendritic cell differentiation for 6 days.

Cells were collected by trypsinization (Hek293T) or scraping (BW and dendritic cells), washed with PBS, counted, and seeded into 96-well U-bottom plates at 1 x 105 cells/well. The plates were centrifuged at 1400 rpm for 3 min and primary TREM2 or control antibodies in FACS buffer (PBS+2% FBS) were added and incubated on ice for 1 h. Cells were then centrifuged as described previously and washed three times with buffer for FACS. Cells were then incubated with anti-human phycoerythrin-conjugated secondary antibody (BD Biosciences) in FACS buffer for 30 min on ice.

Cells were washed again three times with FACS buffer and analyzed using a BD FACS Canto or an Intellicyt Flow Cytometer. Binding was measured as the average fluorescence intensity in the APC channel.

Results.

Two rounds of affinity maturation were performed for AL2p-h50 and AL2p-h77 AL2p variants. A total of 57 affinity matured clones were selected from the AL2p-h50 progeny and 4 clones from the AL2p-h77 progeny. The HVR sequences of the variable region of the heavy chain of antibodies are presented in table. 2A-2C. The HVR sequences of the variable region of the light chain of antibodies are presented in table. 3A-3C. The framework regions of the heavy chain of antibodies are presented in table. 4A-4D. The framework regions of the light chain of antibodies are presented in table. 5A-5D. The sequences of the variable region of the heavy chain of antibodies are presented in table. 6A. The heavy chain sequences of AL2p antibody variants are presented in Table. 6B. The sequences of the variable region of the light chain of antibodies are presented in table. 7A. The light chain sequences of AL2p antibody variants are presented in Table. 7B.

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Table 2A

H1 HVR heavy chain sequences of aHmu-TREM2 antibodies

Antibody (AB) Hl HVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-33, AL2ph77, and AL2p-36 YAFSSSWMN 124 AL2p-29, AL2p-30, AL2p-31, AL2p37, AL2p-58, AL2p-60, AL2p-61, and AL2p-62 YAFSSQWMN 132 AL2p-10, AL2p-ll, AL2p-45, AL2p46, AL2p-47, AL2p-48, and AL2p-49 YAFSSDWMN 136 AL2p-7 and AL2p-8 YAFSLSWMN 157 AL2p-9 YAFSRSWMN 158 AL2p-12, AL2p-13, AL2p-14, AL2p15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p22, AL2p-23, AL2p-24, AL2p- 25, AL2p-26, AL2p-27, AL2p-28, AL2p38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p57, and AL2p-59 YAFSSHWMN 159 AL2p-32 YAFSSEWMN 160 AL2p-35 YAFWSSWMN 161 Formula I YAFX^XsWMN Xx is S or W Xr is S, L or R X ₃ is S, D, H, Q or E 121

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Table 2B

H2 HVR heavy chain sequences of aHmu-TREM2 antibodies

Antibody (AB) H2 HVR SEQ ID NO: AL2p-h50, AL2p-5, AL2p-6, AL2p-9, AL2p-10, AL2p-14, AL2p-15, AL2p-29, AL2p-32, AL2p-33, AL2p-h77, and AL2p-35 RIYPGDGDTNYAQKFQG 125 AL2p-31 and AL2p-60 RIYPGGGDTNYARKFQG 133 AL2p-37 and AL2p-58 RIYPGGGDTNYAGKFQG 135 AL2p-47, AL2p-48, AL2p-49 RIYPGEGDTNYARKFHG 137 AL2p-45, AL2p-46, and AL2p-61 RIYPGEGDTNYARKFQG 141 AL2p-62 RIYPGEGDTNYAGKFQG 143 AL2p-2 and AL2p-24 RIYPGGGDTNYAQKFQG 162 AL2p—3 RIYPGEGDTNYAQKFQG 163 AL2p-4 and AL2p-27 RIYPGQGDTNYAQKFQG 164 AL2p-7 and AL2p-16 RIYPGDGDTNYAQKFRG 165 AL2p-8, AL2p-ll, AL2p-19, AL2p-20, and AL2p-36 RIYPGDGDTNYARKFQG 166 AL2p-12 RIYPGDGDTNYAHKFQG 167 AL2p-13 RIYPGDGDTNYAQKFKG 168 AL2p-17 RIYPGDGDTNYAQKRQG 169 AL2p-18 RIYPGDGDTNYAQKWQG 170 AL2p-21 nAL2p-30 RIYPGDGDTNYAWKFQG 171 AL2p-22 RIYPGDGDTNYAYKFQG 172 AL2p-23 RIYPGDGQTNYAQKRQG 173 AL2p-25, AL2p-38, AL2p-39, and AL2p-40 RIYPGGGDTNYAQKFRG 174 AL2p-26 RIYPGGGDTNYAQKRQG 175 AL2p-28 RIYPGVGDTNYAQKFQG 176 AL2p-41 and AL2p-42 RIYPGEGDTNYAQKFRG 177 AL2p-43 and AL2p-44 RIYPGGGDTNYARKFRG 178 AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, and AL2p-57 RIYPGEGDTNYAQKFHG 179 AL2p-59 RIYPGEGQTNYAQKRQG 180 Formula II RIYPGX ₁ GX2TNYAX ₃ KX ₄ X5 G Xi is D, G, E, Q or V Xg is D or Q X ₃ is Q, R, H, W, Y or G X ₄ is F, R or W X ₅ represents Q, R, K or H 122

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Table 2C

H3 HVR heavy chain sequences of aHmu-TREM2 antibodies

Antibody (AB) H3 HVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p5, AL2p-6, AL2p-7, AL2p-10, AL2p-ll, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-17, 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-37, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-58, AL2p-59, AL2p-60, AL2p-61, and AL2p-62 ARLLRNQPGESYAMDY 126 AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-54, AL2p-55, AL2p-56, and AL2p-57 ARLLRNKPGESYAMDY 138 AL2p-8 and AL2p-18 ARLLRNQPGS S YA MD Y 181 AL2p-9, AL2p-16, AL2p-36, AL2p-38, ARLLRNQPGASYAMDY 182 AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, and AL2p-44 AL2p-35 ARLLRNQPGESYAHDY 183 Formula III ARLLRNX ₁ PGX2SYAX ₃ DY Xi is Q or K X ₂ is E, S, or A X ₃ is M or H 123

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Table FOR

LI HVR light chain sequences of anti-TREM2 antibodies

Antibody (AB) LI HVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-10, AL2p-12, AL2p-31, AL2p-32, AL2p-h77, AL2p-35, AL2p-36, and AL2p-37 RSSQSLVHSNGYTYLH 130 AL2p-45, AL2p-47, AL2p-50, AL2p-52, AL2p-55, and AL2p-56 RTSQSLVHSNAYTYLH 139 AL2p-61 and AL2p-62 RSSQSLVHSNQYTYLH 142 AL2p-5, AL2p-58, and AL2p-60 RSSQSLVHSNRYTYLH 144 AL2p-6 RSSQSLVHSNWYTYLH 184 AL2p-7, AL2p-8, AL2p-13, and AL2p-26 RSSQSLIHSNGYTYLH 185 AL2p-9, AL2p-16, AL2p-18, AL2p-20, AL2p-23, AL2p-25, AL2p-28, and AL2p-33 RTSQSLVHSNGYTYLH 186 AL2p-ll, AL2p-14, AL2p-17, AL2p-19, AL2p-22, AL2p-24, AL2p-27, and AL2p-29 RSSRSLVHSNGYTYLH 187 AL2p-15, AL2p-21, and AL2p-30 RSSSSLVHSNGYTYLH 188 AL2p-38 and AL2p-43 RS SRSLVHSNRYTYLH 189 AL2p-39 and AL2p-41 RS SRSLVHSNQ YTYLH 190 AL2p-40, AL2p-42, and AL2p-44 RT SRSLVHSNRYTYLH 191 AL2p-46, AL2p-48, AL2p-49, AL2p-51, AL2p-53, AL2p-54, AL2p-57, and AL2p-59 RTSQSLVHSNQ YTYLH 192 Formula IV RX ₁ SX ₂ SLX ₃ HSNX ₄ YTYLH 127 Xi is S or T X ₂ is Q, R or S X ₃ is V or I X ₄ is G, R, W, Q or A

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Table 3 B

L2 HVR light chain sequences of anti-TREM2 antibodies

Antibody (AB) L2 HVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p6, AL2p-14, AL2p-24, AL2p-29, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-58, and AL2p-62 KVSNRFS 131 AL2p-7, AL2p-8, AL2p-10, AL2p-12, AL2p-13, AL2p-22, AL2p-26, AL2p-31, AL2p-32, AL2p-38, AL2p-39, AL2p-40, AL2p- 41, AL2p-42, AL2p-43, AL2p-44, AL2p-60, and AL2p-61 KVSNRRS 134 AL2p-9, AL2p-ll, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-23, AL2p-25, AL2p-27, AL2p-28, AL2p-33, 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, and AL2p-59 KVSNRVS 140 AL2p-15, AL2p-21, and AL2p-30 KVSNRKS 193 Formula V KVSNRXiS Xi represents F, R, V or K 128

Table 3C

L3 HVR light chain sequences of anti-TREM2 antibodies____

Antibody (Ab) L3 HVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-l 1, AL2p-12, AL2p -13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, SQSTRVPYT 129 AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p40, 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, AL2p54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, and AL2p-62

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Table 4A

Sequences of framework region 1 of the aHmu-TREM2 antibody heavy chain

AB (Antibody) VHFR1 SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, 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-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-50, AL2p-51, AL2p-54, AL2p-59, AL2p-60, and AL2p-61 QVQLVQSGAEVKKPGSSVKVSCKAS G 9 AL2p-33, AL2p-49, AL2p-52, AL2p-53, AL2p-55, AL2p-56, and AL2p-57 EVQLVQSGAEVKKPGSSVKVSCKAS G 10 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-58, and AL2p-62 QVQLVQSGAEVKKPGASVKVSCKAS G eleven

Table 4B

Anti-TREM2 antibody heavy chain framework region 2 sequences

Antibody (Ab) FR2 VH SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, AL2p-12, AL2p- 13, AL2p-14, AL2p15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p55, AL2p-56, AL2p- 57, AL2p-59, AL2p-60, and AL2p-61 WVRQAPGQGLEWM G 12 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p58, and AL2p-62 WVRQAPGQRLEWIG 13

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Table 4C

Heavy chain framework region 3 sequences of aHmu-TREM2 antibodies

Antibody (AB) FR3 VH SEQ ID NO: AL2p-h50, AL2p-2, AL2p3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, AL2p12, AL2p-13, AL2p- 14, AL2p-15, AL2p-16, AL2p17, AL2p-18, AL2p-19, AL2p-20, AL2p21, AL2p-22, AL2p-23, AL2p24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p30, AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p- RVTITADESTSTAYMELSSLRSEDTAVYY C 14 39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p56, AL2p-57, AL2p-59, AL2p-60, and AL2p-61 AL2p-h77, AL2p-35, AL2p36, AL2p-37, AL2p-58, and AL2p-62 RVTITADTSASTAYMELSSLRSEDTAVYY C 15

Table 4D

Anti-TREM2 antibody heavy chain framework region 4 sequences

Antibody (Ab) FR4 VH SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, AL2p12, 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, and AL2p-62 WGQGTLVTVS S 16

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Table 5A

Sequences of framework region 1 of aHmu-TREM2 antibody light chain

Antibody (AB) FR1 VL SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-l 1, AL2p-17, DVVMTQTPLSLSVTPGQPASISC 17 AL2p-19, AL2p-45, AL2p-46, AL2p47, AL2p-48, AL2p-49, AL2p-50, AL2p51, AL2p-52, AL2p-53, AL2p-54, AL2p55, AL2p-56, and AL2p-57 AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-12, AL2p-13, AL2p-14, AL2p15, AL2p-16, AL2p-18, AL2p-20, AL2p21, AL2p-22, AL2p-23, AL2p-24, AL2p25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p38, AL2p-39, AL2p-40, AL2p-41, AL2p42, AL2p-43, AL2p-44, AL2p-59, AL2p60, and AL2p-61 GVVMTQTPLSLSVTPGQPASISC 18 AL2p-33 GVVMAQTPLSLSVTPGQPASISC 19 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-58, and AL2p-62 DVVMTQSPDSLAVSLGERATIN C 20

Table 5 B

Anti-TREM2 antibody light chain framework region 2 sequences

Antibody (Ab) FR2 VL SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, AL2p-12, AL2p- 13, AL2p-14, AL2p15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p30, WYLQKPGQSPQLLIY 21

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AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p54, AL2p-55, AL2p-56, AL2p-57, AL2p-59, AL2p60, and AL2p-61 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-58, and AL2p-62 WYQQKPGQSPKLLIY 22

Table 5C

Anti-TIEM2 antibody light chain framework region 3 sequences

Antibody (Ab) FR3 VL SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p10, AL2p-ll, 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, GVPDRFSGSGSGTDFTLKISRVEAEDVGVYY C 23 AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, and AL2p-61 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, and AL2p-62 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYY C 24

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Table 5D

AHTu-TREM2 antibody light chain framework region 4 sequences

Antibody (AB) FR4 VL SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-ll, 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, and AL2p-61 FGQGTKLEIK 25 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, and AL2p62 FGGGTKVEIK 26

Table 6A

Anti-TREM2 antibody heavy chain variable region sequences

Antibody (Ab) HCVR SEQ ID NO: AL2ph50, AL2p-5, and Q VQL VQ SGAEVKKPGS SVK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 27 AL2p-6 AL2p-2 Q VQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWMGRIYPGGGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 28 AL2p-3 Q VQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWMGRIYPGEGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 29 AL2p-4 Q VQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWMGRIYPGQGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS thirty AL2p-7 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSLSWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 31 AL2p-8 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSLSWMNWVRQAP GQGLEWMGRIYPGDGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGSSYAMD YWGQGTL VTVSS 32 AL2p-9 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSRSWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMD YWGQGTL VTVSS 33

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AL2p-10 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 34 AL2p-l 1 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGDGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 35 AL2p-12 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAHKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 36 AL2p-13 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFKGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 37 AL2p-14 and AL2p15 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 38 AL2p-16 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMD YWGQGTL VTVSS 39 AL2p-17 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKRQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 40 AL2p-18 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKWQGRVTITADESTSTAYME LS SLRSEDT AVYYC ARLLRNQPGS S YAMD YWGQGTL VT VS S 41 AL2p-19 and AL2p20 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 42 AL2p-21 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAWKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 43 AL2p-22 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGDTNYAYKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 44 AL2p-23 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGDGQTNYAQKRQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 45 AL2p-24 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 46 AL2p-25 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 47 AL2p-26 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKRQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 48 AL2p-27 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGQGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMD YWGQGTL VTVSS 49 AL2p-28 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP 50

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GQGLEWMGRIYPGVGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS AL2p-29 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 51 AL2p-30 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGDGDTNYAWKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 52 AL2p-31, AL2p-60, and AL2p- h31 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGGGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 53 AL2p-32 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSEWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 54 AL2p-33 EVQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 55 AL2ph77, AL2ph26, and AL2p-h90 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQRLEWIGRIYPGDGDTNYAQKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 56 AL2p-35 QVQLVQSGAEVKKPGASVKVSCKASGYAFWSSWMNWVRQA PGQRLEWIGRIYPGDGDTNYAQKFQGRVTITADTSASTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAHDYWGQGTLVTVSS 57 AL2p-36 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQRLEWIGRIYPGDGDTNYARKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSS 58 AL2p-37 and AL2p58 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP GQRLEWIGRIYPGGGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 59 AL2p-38, AL2p-39, QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKFRGRVTITADESTSTAYMEL 60

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and AL2p- 40 SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSS AL2p-41 and AL2p42 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSS 61 AL2p-43 and AL2p44 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYARKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSS 62 AL2p-45 and AL2p46 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSS 63 AL2p-47 and AL2p48 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSS 64 AL2p-49 EVQLVQ SGAEVKKPGS SVK VSCKASGYAF S SD WMNW VRQ AP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSS 65 AL2p-50 and AL2p51 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGDTNYAQKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 66 AL2p-52 and AL2p53 EVQL VQSGAEVKKPGS SVK VSCKASGYAF S SH WMNW VRQ AP GQGLEWMGRIYPGEGDTNYAQKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 67 AL2p-54 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGDTNYAQKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSS 68 AL2p-55, AL2p-56, and AL2p57 EVQL VQSGAEVKKPGS SVK VSCKASGYAF S SH WMNW VRQ AP GQGLEWMGRIYPGEGDTNYAQKFHGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSS 69 AL2p-61 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 70 AL2p-62 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP 71

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GQRLEWIGRIYPGEGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS AL2p-hl9 and AL2ph35 Q VQL VQ SGAEVKKPGS S VK VSCK ASGY A F S S S WMNWVRQ AP GQGLEWMGRIYPGDGDTNYAQKFQGRATITADTSSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 72 AL2p-h21 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTMTRDTSTSTVYME LSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 73 AL2p-h22 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWIGRIYPGDGDTNYAQKFQGRVTMTADTSTSTVYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 74 AL2p-h23 QVQLVQSGAEVKKPGASLKISCKASGYAFSSSWMNWVRQAPG QGLEWIGRIYPGDGDTNYAQKFQGRATLTTADTSTSTAYMELSS LRSEDTAVYYC ARLLRNQPGES YAMDYWGQGALVTVS S 75 AL2p-h24 QVQLVQSGAEVVKPGASLKISCKASGYAFSSSWMNWVRQAPG QGLEWIGRIYPGDGDTNYNQKFQGRATLTTADTSTSTAYMELSSS LRSEDTAVYFCARLLRNQPGESYAMDYWGQGALVTVSS 76 AL2p-h25 QVQLVQSGAEVKKPGASLKISCKASGYAFSSSWMNWVRQAPG QGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSTSTAYMELSS LRSEDTAVYYC ARLLRNQPGES YAMDYWGQGALVTVS S 77 AL2p-h27 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSSTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 78 AL2p-h28 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWIGRIYPGDGDTNYAQKFQGRATLTTADTSTSTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 79 AL2p-h29 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWIGRIYPGDGDTNYAQKFQGRATMTADTSTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 80 AL2p-h30 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWMGRIYPGDGDTNYAQKFQGRVTMTTADTSTSTAYME LS SLRSEDTAVYYC ARLLRNQPGES YAMDYWGQGTLVT VS S 81 AL2p-h32 Q VQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNWVRQ AP GQGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSTTTAYMELS 82

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SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS AL2p-h33 Q VQL VQ SGAEVKKPGS SVK VSCK ASGYAF S S S WMNW VRQ AP GQGLEWIGRIYPGDGDTNYAQKFQGRATLTADTSTTTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 83 AL2p-h34 Q VQL VQ SGAEVKKPGS S VK VSCK ASGYAF S S S WMNW VRQ AP GQGLEWIGRIYPGDGDTNYAQKFQGRATITADTSSTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 84 AL2p-h36 EVQLLESGGGL VQPGGSLRLSC AASGYAF S S SWMNWVRQ APG KGLEWIGRIYPGDGDTNYAQKFQGRATISADTSKNTAYLQMNS LRAEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 85 AL2p-h42 and AL2ph59 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQRLEWMGRIYPGDGDTNYAQKFQGRVTITRDTSASTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 86 AL2p-h43 Q VQLVQSGAEVKKPGASLKVSCKASGYAF S S S WMNW VRQ AP GQRLEWIGRIYPGDGDTNYNGEFRVRATLTADTSASTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 87 AL2p-h44 Q VQLVQSGAEVKKPGASLKVSCKASGYAF S S SWMNWVRQ AP GQRLEWIGRIYPGDGDTNYAQKFQGRATLTADTSASTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 88 AL2p-h47 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSWMNWVRQAP GQGLEWMGRIYPGDGDTNYNGEFRVRVTMTRDTSTSTVYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 89 AL2p-h76 Q VQL VQ SGAEVKKPGASVK VSCK ASGYAF S S SWMNWVRQ AP GQRLEWIGRIYPGDGDTNYAQKFQGRATITADTSASTAYMELS SLRSEDTAVYFCARLLRNQPGESYAMDYWGQGTLVTVSS 90 AL2p-59 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGQTNYAQKRQGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS 91

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Table 6B

Anti-TREM2 antibody heavy chain sequences

Antibody (AB) HC SEQ ID NO: AL2p-58 huIgGl QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP GQRLEWIGRIYPGGGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST 198 KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFP AVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTV LHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK AL2p-58 huIgGl QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP GQRLEWIGRIYPGGGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFP AVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGF YPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG 199 AL2p-58 huIgGl PSEG QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP GQRLEWIGRIYPGGGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFP AVLQ S SGL YSLS S VVT VP S S SLGTQT YICNVNHKP SN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTIS KAKGQPREPQVYTLPPSRDELTKN QVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHGALHNHYTQKSLSLSPGK 200 AL2p-58 huIgGl PSEG QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQWMNWVRQAP GQRLEWIGRIYPGGGDTNYAGKFQGRVTITADTSASTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFP AVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSN 201

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TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNY KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHGALHNHYTQKSLSLSPG AL2p-47 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 202 AL2p-47 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG 203 AL2p-47 huIgGl PSEG QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE 204

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QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHGALHNHYTQKSLSLSPGK AL2p-47 huIgGl PSEG QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPS DIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHGALHNHYTQKSLSLSPG 205 AL2p-61 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFQGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 206 AL2p-61 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQWMNWVRQAP GQGLEWMGRIYPGEGDTNYARKFQGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVE 207

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WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG AL2p-40 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFP AVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTC LVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 208 AL2p-40 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYAQKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFP A VLQ S SGL YSL S S V VTVP S S SLGTQT YICNVNHKP S NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG 209 AL2p-44 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYARKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFP AVLQSSGLYSLSSVVTVP SSSLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 210

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AL2p-44 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGGGDTNYARKFRGRVTITADESTSTAYMEL SSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPS NTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTL MISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPRE EQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTI SKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVK GFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG 211 AL2p-41 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGDTNYAQKFRGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK 212 AL2p-41 huIgGl QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWMNWVRQAP GQGLEWMGRIYPGEGDTNYAQKFRGRVTITADESTSTAYMELS SLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSN TKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLM ISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFY PSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPG 213

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Table 7A

Sequences of the variable region of the light chain of aHmu-TREM2 antibodies

Antibody (AB) LCVR SEQ ID NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-h42, AL2p-h43, AL2p-h44, and AL2p-h47 DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTYLHW YLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 92 AL2p-5 DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNRYTYLHWY LQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 93 AL2p-6 DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNWYTYLHW YLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 94 AL2p-7, AL2p-8, AL2p-13, and AL2p-26 GVVMTQTPLSLSVTPGQPASISCRSSQSLIHSNGYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 95 AL2p-9, AL2p-16, AL2p-18, AL2p-20, AL2p-23, AL2p-25, and AL2p-28 GVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNGYTYLHW YLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 96 AL2p-10, AL2p-12, AL2p-31, and AL2p-32 GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTYLHW YLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 97 AL2p-ll, AL2p-17, and AL2p-19 DVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTYLHWY LQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 98

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AL2p-14, AL2p-24, and AL2p-29 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTYLHWY LQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 99 AL2p-15, AL2p-21, and AL2p-30 GVVMTQTPL SL S VTPGQP ASISCRS S S SL VHSNGYT YLHW Y LQKPGQSPQLLIYKVSNRKSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 100 AL2p-22 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 101 AL2p-27 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTYLHWY LQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 102 AL2p-33 GVVMAQTPLSLSVTPGQPASISCRTSQSLVHSNGYTYLHW YLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 103 AL2p-h77, AL2p-35, AL2p-36, AL2p-37, and AL2p-h76 D V VMTQ SPD SL A VSLGERATINCRSSQSL VHSNGYT YLHW YQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISS LQAEDVAVYYCSQSTRVPYTFGGGTKVEIK 104 AL2p-38 and AL2p-43 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNRYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 105 AL2p-39 and AL2p-41 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNQYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 106 AL2p-40, AL2p-42, and AL2p-44 GVVMTQTPLSLSVTPGQPASISCRTSRSLVHSNRYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 107 AL2p-45, AL2p-47, AL2p-50, AL2p-52, AL2p-55, and DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNAYTYLHW YLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 108

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AL2p-56 AL2p-46, AL2p-48, AL2p-49, AL2p-51, AL2p-53, AL2p-54, and AL2p-57 DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNQYTYLHW YLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 109 AL2p-61 GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNQYTYLHW YLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 110 AL2p-62 DVVMTQSPDSLAVSLGERATFNCRSSQSLVHSNQYTYLHW YQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISS LQAEDVAVYYCSQSTRVPYTFGGGTKVEIK 111 AL2p-58 DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNRYTYLHW YQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 112 AL2p-60 GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNRYTYLHWY LQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 113 AL2p-hl9 DIVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTYLHWY LQKPGQ SPQLLIYKVSNRF SGVPDRF SSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGQGTKLEIK 114 AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTYLHW YLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISR VEAEDLGVYFC SQ STRVP YTFGQGTKLEIK 115 AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36 AL2p-h59 DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGYTYLHWY LQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCSQSTRVPYTFGGGTKVEIK 116 AL2p-h90 DVQMTQSPSSSLSASVGDRVTITCRSSQSLVHSNGYTYLHW YQQKPGKSPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISS LQPEDFATYYCSQSTRVPYTFGGGTKVEIK 117 AL2p-59 GVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNQYTYLHW YLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISR VEAEDVGVYYCSQSTRVPYTFGQGTKLEIK 118

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Table 7B

aHmu-TREM2 antibody light chain sequences

Antibody o (AB) L.C. SEQ ID NO: AL2p-58 huIgGl, and AL2p58 huIgGl PSEG DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNRYTYLHWYQQ KPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDV GVYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSG TASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214 AL2p-47 huIgGl, and AL2p47 huIgGl PSEG DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNAYTYLHWYLQK PGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQD SKD S TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 215 AL2p-61 huIgGl GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNQYTYLHWYLQK PGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNF YPREAKVQWKVDNALQSGNSQES VTEQD SKD S TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 216 AL2p-41 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNQYTYLHWYLQK 217 huIgGl PGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQD SKD S TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC AL2p-40 huIgGl, and AL2p44 huIgGl GVVMTQTPLSLSVTPGQPASISCRTSRSLVHSNRYTYLHWYLQK PGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVG VYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGT AS VVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQD SKD S TYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 218

Clones were tested for affinity using OctetRed and a strong increase in monovalent affinity was observed (Table 8). In addition, the clones were tested for binding to cynomolgus TREM2 and all clones were able to bind monovalently (Table 8). The clones were tested for binding to TREM2-expressing human BW cells and increased affinity was also observed under these conditions (Table 8). In addition, the antibodies showed increased binding to primary human dendritic cells that endogenously express human TREM2 (Table 8).

The original AL2p antibody contains two residues that may be subject to deamidation: DG in VH-CDR2 and NG in VL-CDR1. When testing affinity matured AL2p antibody variants, five clones were obtained with amino acid substitutions at the following positions: AL2p-2 (DG to GG), AL2p-3 (DG to EG), AL2p-4 (DG to QG), AL2p-5 ( NG to NR), AL2p-6 (NG to NW). These variants were confirmed to retain the same affinity as the parent AL2p-h50 antibody (Table 8). Additionally, variants AL2p-38 to AL2p-57 already included amino acid substitutions at these positions, which are DG to GG or EG in VH-CDR2, together with NG to NR or NQ or NA in VL-CDR1. These clones exhibit increased affinity and function compared to the parent clone, suggesting that the combination of amino acid substitutions at these positions does not affect function.

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Table 8

Summary of AL2p Antibody Variant Binding Experiments

Antibody K _D Fab ForteBio huTREM2-Fc (M) monovalent K _D IgG ForteBio huTREMlFc (M) note K _D Fab ForteBio TRE M2 cynomolgus-Fc (M) monovalent K _D bind huT2 to BW cells (nM) MFI communication with huDC AL2ph50 1.12E-07 1.19E-09 7.70E-06 3.7 26 AL2ph77 1.02E-07 1.17E-09 1.84E-07 3.9 162 AL2p-2 6.33E-08 8.37E-10 1.40E-06 2.2 AL2p-3 1.00E-07 1.19E-09 4.58E-06 2.3 AL2p-4 1.32E-07 8.17E-10 P.F. 2.1 AL2p-5 9.92E-08 1.00E-09 4.63E-06 2.0 AL2p-6 2.59E-07 1.06E-09 E15E-06 4.2 AL2p-7 8.38E-09 4.27E-10 8.95E-09 1.6 AL2p-8 4.01E-09 3.00E-10 3.10E-09 1.2 310 AL2p-9 6.44E-09 3.49E-10 5.63E-09 1.1 322 AL2p-10 1.85E-08 8.35E-10 2.77E-08 3.1 AL2p-l 1 9.83E-09 5.36E-10 E02E-08 2.4 AL2p-12 5.86E-09 5.14E-10 5.25E-09 1.8 AL2p-13 4.80E-09 3.40E-10 4.93E-09 1.5 AL2p-14 4.74E-09 3.15E-10 4.66E-09 2.1 AL2p-15 8.85E-09 5.38E-10 8.76E-09 2.2 262 AL2p-16 1.83E-09 2.22E-10 E36E-09 1.2 327 AL2p-17 4.83E-09 2.55E-10 4.62E-09 1.4 AL2p-18 3.17E-09 2.29E-10 2.73E-09 1.3 AL2p-19 4.02E-09 3.03E-10 4.01E-09 1.4 AL2p-20 4.73E-09 3.50E-10 4.72E-09 1.2 AL2p-21 4.15E-09 3.99E-10 3.84E-09 1.5 AL2p-22 1.58E-09 2.19E-10 E28E-09 1.5 AL2p-23 4.35E-09 3.34E-10 4.16E-09 1.2 AL2p-24 2.10E-09 2.33E-10 E63E-09 1.7 AL2p-25 2.34E-09 2.20E-10 E76E-09 1.7 AL2p-26 3.15E-09 2.01E-10 2.69E-09 1.1 296 AL2p-27 1.99E-09 2.74E-10 1.82E-09 1.5 AL2p-28 7.60E-09 4.17E-10 7.91E-09 2.2 AL2p-29 6.38E-09 4.03E-10 6.47E-09 1.3 AL2p-30 6.50E-09 3.77E-10 5.66E-09 1.2 AL2p-31 4.03E-09 3.17E-10 3.44E-09 1.0 288

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AL2p-32 3.60E-08 1.12E-09 3.48E-08 2.8 AL2p-33 1.03E-08 8.89E-10 8.84E-10 4.5 AL2p-35 2.84E-08 1.85E-09 2.46E-08 3.6 130 AL2p-36 1.21E-08 4.95E-10 7.38E-09 1.7 240 AL2p-37 2.38E-08 7.79E-10 1.61E-08 2.9 194 AL2p-38 6.23E-10 3.70E-10 4.79 499 AL2p-39 6.31E-10 3.46E-10 1.53 590 AL2p-40 6.02E-10 3.70E-10 2.27 547 AL2p-41 7.24E-10 3.52E-10 1.31 534 AL2p-42 8.29E-10 3.12E-10 1.91 662 AL2p-43 4.93E-10 3.60E-10 5.01 1035 AL2p-44 4.10E-10 2.71E-10 4.18 1467 AL2p-45 1.78E-08 2.09E-08 1.54 318 AL2p-46 1.30E-08 1.61E-08 1.33 187 AL2p-47 E48E-08 1.63E-08 1.09 372 AL2p-48 1.12E-08 1.49E-08 1.40 408 AL2p-49 1.16E-08 1.41E-08 1.15 413 AL2p-50 2.39E-08 3.61E-08 1.80 235 AL2p-51 2.12E-08 2.72E-08 1.92 195 AL2p-52 2.70E-08 2.80E-08 2.42 224 AL2p-53 2.11E-08 3.13E-08 1.72 159 AL2p-54 1.39E-08 1.68E-08 2.30 235 AL2p-55 1.85E-08 2.26E-08 2.05 141 AL2p-56 1.87E-08 1.88E-08 2.01 155 AL2p-57 E78E-08 1.76E-08 1.83 152 AL2p-59 3.85E-09 3.95E-09 AL2p-61 3.73E-06 3.84E-09 AL2p-62 2.11E-08 1.94E-08 AL2p-58 1.33E-08 1.24E-08 0.51

In table 8 experiments for clones AL2p-2 to AL2p-37 were performed separately from experiments characterizing AL2p-38 to AL2p-57. Binding to human dendritic cells (DCs) was performed with different donors for these two sets of antibodies, and because there is large variability between donors in TREM2 expression, MFI values between donors cannot be directly compared. P.F.=poor fit; MFI=mean fluorescence intensity.

Example 3 Affinity mature AL2p antibodies show greatly improved function. Ways.

The ability of full-length anti-TREM2 antibodies immobilized on a plate to activate human TREM2-dependent genes was assessed using a luciferase reporter gene under the control of the NFAT (nuclear factor of activated T cells) promoter. The BW5147.G.1.4 cell line, derived from mouse thymic lymphoma T lymphocytes, was infected with human TREM2/DAP12 fusion protein and Cignal Lenti NFAT-luciferase virus (Qiagen). For antibody testing, plate-immobilized anti-TREM2 and isotype control antibodies were dissolved in PBS, plated on tissue culture plates at a concentration of 10 μg/ml, and incubated overnight at 4°C to allow absorption of antibodies to the plate. After washing the plates, the cells were plated on antibodies immobilized on the plate and incubated for 4-6 hours at 37°C. To test antibodies in solution, they were added to culture plates along with cells and incubated for 4-6 hours at 37°C. Luciferase activity was measured by adding OneGlo Reagent (Promega) to each well and incubating for 3 min at room temperature on a plate shaker. Luciferase signal was measured using a BioTek plate reader.

The ability of soluble full-length anti-TREM2 antibodies to alter the activity of natural human TREM2 ligands was also assessed using a luciferase reporter gene assay. Cells were incubated for 4-6 hours, along with soluble anti-TREM2 and isotype control antibodies, on phosphatidylserine (or

- 193 044134 pid was dissolved and titrated in methanol, added to the plates and the methanol was allowed to evaporate overnight). Cells were lysed and luciferase activity was measured by adding OneGlo Reagent (Promega) to each well and incubating for 3 min at room temperature on a plate shaker. Luciferase signal was measured using a BioTek plate reader.

To assess the viability of human dendritic cells and macrophages, human monocytes were isolated from whole blood using RosetteSep Human Monocyte Enrichment Cocktail (Stemcell Technologies) and Ficoll centrifugation according to the manufacturer's protocols. After lysis of red blood cells with ACK lysis buffer, monocytes were resuspended in complete medium (RPMI, 10% FBS, penicillin/streptomycin (Pen/Strep), L-glutamine, HEPES, nonessential amino acid, sodium pyruate) with 100 ng/ml human GM -CSF (hu-GMCSF) and human IL-4 (hu-IL-4) for dendritic cell differentiation for 6 days. Macrophages were differentiated for 5-6 days in complete medium (RPMI, 10% FBS, penicillin/streptomycin (Pen/Strep), L-glutamine, HEPES, nonessential amino acid, sodium pyruvate) with 100 ng/ml human hu-MCSF (colony stimulating agent). macrophage factor).

Ahtu-TREM2 antibody or control antibody was added to a 96-well plate and left at 4°C overnight. The next day, the plate was washed twice with PBS. Cells were seeded at 25,000 cells/well and cultured for 2 days. Cells were then quantified using the CellTiter-Glo Luminescent Cell Viability Kit (Promega) according to the manufacturer's protocol and luminescence was determined as a measure of cell viability.

Results.

To test whether increased affinity correlates with gain of function, affinity-matured anti-TREM2 antibodies were tested first for their ability to initiate TREM2 signaling when added in solution or plate-immobilized to BW cells expressing human TREM2/Dap12 and the NFAT:luciferase reporter. The parent AL2p antibody can cluster and activate TREM2 signaling when added to cells in solution or when bound to a plate. Consistent with their increased affinity, affinity-matured AL2p antibody variants exhibited increased ability to cluster and activated TREM2 in both plate-immobilized and soluble formats (Table 9A). Specifically, in plate-immobilized format, affinity-matured antibodies strongly increased NFAT:luciferase signaling compared to the original humanized clones (Table 9A).

Fig. 3A and 3B show the results of functional analysis of affinity matured AL2p antibodies AL2p-58, AL2p-59, AL2p-60, AL2p-62, AL2p-47 and an isotype control IgG antibody. As (indicated) in table. 10A, antibodies were tested for their ability to induce TREM2 signaling in BW cells expressing NFAT:luciferase when added soluble or immobilized on a plate. The AL2p-58 antibody is an affinity matured antibody derived from the AL2p-62 clone but incorporating the light chain framework regions of two different germ lines (ie, clones of the original humanized anti-TREM2 antibodies). Specifically, antibody AL2p-58 has light chain framework regions 1 and 2 (FR1 and FR2) from the germline AL2p-h77 and light chain framework regions 3 and 4 (FR3 and FR4) from the germline AL2p-h50. In contrast, all four light chain framework regions of the AL2p-62 antibody belong to the AL2ph77 germline. The results demonstrate that the AL2p-58 antibody has unexpectedly good TREM2 signaling-induced activity, particularly compared to the AL2p-62 antibody, despite both antibodies sharing common CDR variable regions, with the exception of CDR-H2 and CDR-L1 ( Fig. 3A and 3B). However, the CDR-H2 and CDR-L1 sequence differences in AL2p-58 and AL2p-62 are caused by different hotfixes not associated with a positive or negative effect on antibody affinity or function (Table 9A). The results also demonstrate that although AL2p-58 has the same heavy chain variable region sequence as AL2p-37, AL2p-58 exhibits an unexpectedly significant increase in functional properties compared to AL2-p37.

Results in table. 10A also demonstrate that AL2p-47 exhibited unexpectedly better functional properties as well as higher affinity for cell-expressed TREM2 compared to antibodies AL2p-45, AL2p-55, and AL2p-56, which all have the same light chain variable domain sequences and very similar heavy chain variable domain. In particular, the only difference between the sequences of AL2p-47 and AL2p-45 is in HVR-H2, where AL2p-47 has an H at position 16 and AL2p-45 has a Q (Table 2B). The differences between the sequences of AL2-47 and AL2p-55 and AL2p-56 consist of one amino acid difference in HVR-H1 (Table 2A), one amino acid difference in the FR1 heavy chain (Table 4A), and one amino acid difference in HVR-H2 , where AL2p-47 has an R in the 13th position, and both AL2p-55 and AL2p-56 have a Q (Table 2B). From these results, it appears that the combination of R at position 13 of the HVR-H2 sequence and H at position 16 of the HVR-H2 sequence of antibody AL2p-47 exhibits an unexpected effect compared to R at position 13 alone (as in AL2-p45) or with only an H at position 16 (as in the case of AL2p-55 and AL2p-56), especially since AL2p-47 has affinity for human

- 194 044134 protein TREM2, close to AL2p-45, AL2p-55 and AL2p-56.

Fig. 3C demonstrates the ability of plate-immobilized affinity matured antibody variants to induce TREM2 signaling as measured by an NFAT:luciferase reporter assay. The results demonstrate a dramatic (up to 4-fold) increase in the potency of the affinity-matured antibodies compared to the corresponding parent humanized AL2p antibody (h50 or h77) or the parent mouse IgG1 antibody (AL2p).

TREM2 has been shown to influence the survival of primary murine macrophages and microglia in vitro, where TREM2 knockout cells show reduced viability (Wang et al., Cell, 2015, 160(6):1061-1071). To test the functionality of AL2p antibody variants in primary cells, human monocyte-derived macrophages or dendritic cells are stimulated with plate-immobilized AL2p antibody variants and cell viability is measured after 2 days. The parent antibody immobilized on the AL2p plate was found to increase viability in a dose-dependent manner. Compared to the parent clone, affinity matured variants of AL2p antibodies increased viability even more (Tables 9A and 10A).

Clones AL2p-23, AL2p-31 and AL2p-37 were produced in CHO cells containing the following variants: DG to EG and NG to NQ. These clones retain the affinity of the original clones (Table 9B).

Table 9A Functional analysis of affinity matured antibodies

Antibody Luciferase activation soluble IgG 10 nM, FOC Activation of luciferase immobilized on a plate IgG 33 nM, FOC Survival of huDC immobilized on an IgG plate, PPC AL2p-h50 1.26 6.83 337353 AL2p-h77 1.47 6.77 380527 AL2p-2 1.70 7.36 461171 AL2p-3 1.29 6.03 363252 AL2p-4 1.45 7.42 495712 AL2p-5 1.27 9.99 709979 AL2p-6 1.20 5.39 546995 AL2p-7 2.35 18.87 But. AL2p-8 2.78 n.d. 1088000 AL2p-9 2.62 15.21 976481 AL2p-10 1.60 4.63 But. AL2p-l 1 1.71 23.64 But. AL2p-12 1.96 15.80 But. AL2p-13 2.17 16.53 But. AL2p-14 1.79 22.07 But. AL2p-15 1.80 7.54 487849 AL2p-16 2.60 16.87 880480 AL2p-17 2.13 23.83 But. AL2p-18 2.06 8.46 But. AL2p-19 2.06 25.85 But. AL2p-20 2.12 22.45 But. AL2p-21 1.83 13.05 But. AL2p-22 1.75 24.86 But. AL2p-23 2.53 29.75 1108000 AL2p-24 2.12 24.13 But. AL2p-25 2.35 22.28 But. AL2p-26 2.59 25.91 1113000 AL2p-27 2.06 24.39 But.

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AL2p-28 2.14 9.27 H.O. AL2p-29 2.17 26.64 1113000 AL2p-30 2.31 15.78 H.O. AL2p-31 2.83 28.25 1209000 AL2p-32 1.47 4.90 H.O. AL2p-33 1.72 3.21 H.O. AL2p-35 2.05 5.15 453094 AL2p-36 2.64 22.70 1143000 AL2p-37 2.16 9.42 679678

In table Figure 9A shows functional analysis of a set of affinity matured AL2p antibodies compared to the parent antibodies AL2p-h50 and AL2p-h77. In the table no=not defined; AUC=area under the curve; FOC=fold over control, where control is an isotype control antibody. Clones AL2p-2 to AL2p-6 are variants of the parent antibody AL2p-h50 that include edits to remove the deamidation site.

Table 9B

Testing HVR variants for anti-TREM2 antibodies

Antibody Variants VH-HVR2 Options VLII\R1 Binding to K _D huT2 BW (M) cells Luciferase activation, soluble IgG, EC ₅₀ (M) AL2p-h50 No No 3.7E-01 6.31E-08 AL2p-h77 No No 3.90E-01 2.01E-08 AL2p-2 DG to GG No 2.2E-01 2.30E-08 AL2p-3 DG to EG No 2.3E-09 5.00E-08 AL2p-4 DG to QG No 2DE-09 6.62E-08 AL2p-5 No NG to NR 2.0E-09 3.81E-08 AL2p-6 No NG to NW 4.2E-09 3.86E-08 AL2p-59 DG to EG NG to NQ l,24E-09 l,12E-08 AL2p-60 GG to EG NG to NQ l,12E-09 l,03E-08 AL2p-62 DG to EG NG to NQ 2.63E-09 2.51E-08 AL2p-31 DG to GG No l,23E-09 6.92E-09

In table 9B, the values in the cells with a gray background were obtained in a different experiment than the other values in the same column.

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Table 10A

Functional analysis of affinity matured AL2p antibodies that include amino acid substitutions at positions susceptible to deamidation

Antibody Luciferase (Luc) assay with BW cells immobilized on a plate IgG 7.3 nM, FOC Luciferase assay with BW cells soluble IgG 7.3 nM, FOC Viable presence of dendritic cells (DC) Macrophage viability (Mac) (AUC) AL2p-31 7.49 4.48 860213 83712 AL2p-38 4.47 4.98 785505 39036 AL2p-39 8.12 3.81 850801 66855 AL2p-40 8.49 9.92 824725 63235 AL2p-41 7.61 2.92 859989 80670 AL2p-42 6.52 5.95 780879 57916 AL2p-43 5.41 8.84 But. But. AL2p-44 7.17 11.50 750071 74651 AL2p-45 2.29 2.38 543378 3676 AL2p-46 1.64 2.98 596898 6044 AL2p-47 3.54 3.48 771393 22055 AL2p-48 3.25 3.65 769717 23589 AL2p-49 3.12 3.28 753554 15109 AL2p-50 1.19 2.07 286306 -10420 AL2p-51 1.22 2.30 259485 -11153 AL2p-52 1.30 1.75 283169 -13548 AL2p-53 1.45 2.32 234316 -10245 AL2p-54 1.53 2.17 569761 -7639 AL2p-55 1.49 2.08 630883 -5284 AL2p-56 1.51 2.02 643293 -7621 AL2p-57 1.41 2.03 505964 -3564

In table 10A shows functional analysis of affinity-matured AL2p antibodies after a second round of affinity maturation. Antibodies were tested for their ability to induce TREM2 signaling in BW cells expressing NFAT:luciferase when added in soluble or plate-immobilized format, and for their ability to enhance macrophage or dendritic cell viability in plate-immobilized format. In table 10A n.a. = not determined; AUC=area under the curve. DC=primary human dendritic cells; Mac=primary human macrophages; FOC=fold over control.

Table 10B

Functional Analysis of Affinity Mature AL2p Antibody Variants

Antibody Luciferase activation, soluble IgG, EC ₅₀ (nM) Luciferase activation, plate-immobilized IgG, EC ₅₀ (nM) AL2p 19.3 But. AL2p-31 1.14 Yu, 1 AL2p-47 104 206 AL2p-58 14 36

In table 10B and in Fig. 4A and 4B show the results of functional analysis of the original mouse AL2p antibody, affinity matured antibodies AL2p-31, AL2p-47, AL2p-58 and a control antibody. For antibodies AL2p-31 and AL2p-58, antibodies were generated using the human IgG constant region (huFC) or the mouse IgG constant region (msFc) or both. Antibodies were tested for their ability to induce TREM2 signaling in BW cells expressing

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NFAT:luciferase, when added in soluble or plate-immobilized format, and their ability to enhance macrophage or dendritic cell viability in plate-immobilized format. In table 10V no = not defined. The results demonstrate that the affinity matured antibodies have better TREM2 signaling inducing activity and lower _EC50 than the parent AL2p mouse antibody (Table 10B and FIGS. 4A and 4B).

In table 10C shows a comparison of antibody performance between the affinity matured antibodies AL2p-31, AL2p-47 and AL2p-58, and the parent mouse AL2p antibody.

Table 10C

Comparison of affinity matured antibodies with the parent mouse antibody

Characteristic AL2p AL2p-47 AL2p-31 AL2p-58 Germline Mouse VH1-69; CK2D-29 VH1-69; CK2D-29 VH1-69; VK41/VK2D-29 K _D for Fab (nM) with recombinant hTREM2 1.12χ10- ⁷ 1.27x10' ⁸ 3.73x10' ⁹ 1,ЗЗх10- ⁸ k _on Fab (M) with recombinant 1.94x105 2.67x105 3.35x105 3.26x105 hTREM2 k _off Fab (M) with recombinant hTREM2 3.4χ10- ³ 3.40x10' ³ 1.26x10' ³ 4.33 HYu' ³ K _D of binding to a cell line expressing hTREM2 (nM) 3.04 1.22 0.56 0.51 Reporter assay immobilized on an IgG plate (EC ₅₀ , nM) short 206.3 Yu, 1 36.1 Reporter assay, soluble IgG (EC ₅₀ , nM) 19 104.7 I,4 14.0 Viability dendritic cells (1) + (2) ++(3) ++(3)

Example 4: PK/PD (pharmacokinetic/pharmacodynamic) analysis of affinity matured AL2p antibodies.

Ways.

Transgenic (Tg) mice with human TREM2, as well as wild-type (WT) littermate controls expressing only mouse TREM2, were used in pharmacokinetic/pharmacodynamic (PK/PD) studies to test the half-life of different affinity-matured AL2p antibody variants in the presence of or the absence of a binding target, as well as the effect of the AL2p antibody on soluble TREM2 in the plasma of TREM2 Tg mice.

Human TREM2 transgenic mice were given intraperitoneal injections on day 0 of 15 mg/kg of HEK- or CHO-produced AL2p variants AL2p-31-HF as wild type (WT) and PSEG huIgG1, AL2p-23-HF, AL2p-37-HF, AL2p -58-HF, AL2p-40, AL2p-41, AL2p-47, all in the huIgG1 backbone, as well as control huIgG1 (n=2-3 mice/group). Human TREM2 transgenic mice were treated on day 0 with an intraperitoneal injection of 15 mg/kg HEK- or CHO-produced AL2p variants AL2p-60 as PSEG huIgG1, AL2p-47 as huIgG1, AL2p-58 as huIgG1, and control huIgG1 (n= 2-3 mice/group). Blood was collected by puncture from the tail vein at the following time points: 4 hours after injection, days 1, 3, 6, 10 and 14. To isolate plasma, blood was collected in heparinized tubes and centrifuged at 10,000xg for 10 minutes at 4°C. The plasma supernatant was collected and stored at -80°C.

Human IgG1 antibody levels in plasma were determined using a standard available MSD assay (MesoScale Discovery). Briefly on 96-well multi-array plates

- 198 044134 (MesoScale Discovery) coat overnight at 4°C with 50 μl of 1 μg/ml goat anti-human IgG-specific Fab fragment (Jackson Immuno Research) on a plate shaker at 500 rpm. Plates were washed three times with 150 µl wash buffer (PBS+0.05% Tween) and blocked in binding buffer (PBS+1% BSA) for 1 h at room temperature (RT) on a plate shaker at 500 rpm. Plasma was diluted 1:200 and 1:10,000 with binding buffer and added to blocked plates and incubated for 1 h at 37°C. The huIgG1 control was used as a standard. The plates were then washed three times in 150 μl of wash buffer and incubated with 1 μg/ml goat anti-human sulfo-label-conjugated secondary antibody (MesoScale Discovery) in binding buffer for 1 h at room temperature. The plates were then washed three times in 150 μl of wash buffer and 150 μl of 1x reading buffer was added to each well and the plates were imaged using a Sector Imager (MesoScale Discovery) and data analyzed using GraphPad Prism.

For human TREM2-specific ELISA, immobilized T2KO8F11 antibody was applied to the plate at a concentration of 2 μg/ml in PBS overnight at 4°C (100 μl per well on high-binding ELISA plates). The plates were washed three times using a plate washer and 300 μl PBS+0.05% Triton per well. 15610000 pg/ml human TREM2-Fc (R&D Systems) was added to the plates as a standard, as were diluted plasma samples in binding buffer (PBS+1% BSA). The plates containing the samples and standard were incubated at room temperature for 1 hour. The plates were washed three times using a plate washer and 300 μl PBS+0.05% Triton per well. Biotinylated goat anti-human TREM2 polyclonal antibody (R&D Systems) was added at a 1:2000 dilution in binding buffer and incubated for 1 h at room temperature. The plates were washed three times using a plate washer and 300 μl PBS+0.05% Triton per well. Streptavidin-HRP (horseradish peroxidase) (1:200 in binding buffer, R&D Systems) was added to the plates and incubated for 20-30 min at room temperature. The plates were washed three times using a plate washer and 300 μl PBS+0.05% Triton per well. 100 μl of TMB (tetramethylbenzidine) substrate solution was added and incubated until color appeared. The reaction was stopped by adding 50 μl of 2 N sulfuric acid and the plate was read in a Synergy H1 plate reader at 450 and 630 nm. Data were analyzed using GraphPad Prism.

Results.

The half-life of AL2p antibody variants in human TREM2 transgenic mice was measured (Table 11). Following injection of the AL2p variant antibody, sTREM2 levels were significantly reduced to 65% of control levels and remained low for at least 6 days (Table 11). The reason for this decline is unclear. It may be caused by either AL2p blocking shedding of sTREM2 or AL2p-induced internalization of TREM2 after inducing clustering. Additionally, these data suggest that sTREM2 levels in plasma or CSF may be used as in vivo indicators of target binding in the periphery or brain of patients.

Table 11

Parameters measured in vivo in human TREM2 transgenic mice for control huIgG1 and affinity matured AL2p antibody variants

Antibody Estimated half-life (days) Plasma sTREM2 as % of baseline on day 6 Control huIgGl 14.6 99.97 AL2p-60 huIgGl PSEG 1.5 51.75 AL2p-47 huIgGl 2.8 73.37 AL2p-58 huIgGl 4.6 43.70

Example 5: Production and testing of Fc mutant variants of TREM-2 agonist antibodies.

Materials and methods.

Production of Fc-mutant antibodies.

Fc mutant antibodies were produced recombinantly by transient transfection of HEK cells and purification by protein A affinity capture and size exclusion chromatography (SEC) polishing.

BWZ reporter analysis.

In addition to the BWZ reporter assays described in Examples 2 and 3, reporter cell assays for Fc mutants were also performed in coculture with various expression agents.

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FcgR cell lines such as THP-1 or Raji. In this case, the assay was modified to include 105 each reporter cell line as well as the FcgR expressing line in the same final volume of media (100 μl per well). The two cell types were counted on a Vi-CELL XR (Beckman Coulter) and mixed in reporter cell medium (DMEM+10% FBS) immediately before aliquoting into 96-well plates and adding antibody. The assay was then performed as described previously (6 h incubation with antibody at 37°C followed by luciferase detection using the ONE-GLO reagent (Promega) and a BioTek plate reader).

Complement deposition assay (CDA).

The ability of anti-TREM2 antibodies to induce complement deposition was measured in a stable HEK cell line overexpressing human TREM2 and DAP12, as well as in primary cells (dendritic cells (DC) from monocytes). TREM2-expressing cells were diluted to 105 cells per 70 μl of medium (DMEM+10% FBS for HEK, RPMI for dendritic cells) and aliquots of 70 μl of cells per well were dispensed into round-bottomed 96-well plates (Falcon #351177). 10 μl of 10x antibody diluted in the same medium was added to these cells. Cells+antibody were incubated at 37°C for 30 min, then 20 μl per well of human serum pooled complement (Innovative Research, IPLA-CSER) was added as a complement source and the plates were incubated for an additional 2 h at 37°C. After this, the cells were washed 2x with FACS buffer (PBS + 2% FBS + 1 mM EDTA), 100 μl per well of a 1:50 diluted anti-C3b-APC antibody (Biolegend 846106) was added and incubated on ice for 30 min. Cells were then washed with 2x FACS buffer and resuspended in 50 μl/well FACS buffer + 0.25 μl/well propidium iodide (Fischer Scientific, BD 556463) before analysis on an iQue flow cytometer (IntelliCyt).

Preparation of reagents for detecting the Fc-gamma receptor.

Human and mouse FcgR detection reagents were constructed by fusing the extracellular domain of each FcgR with the C-terminal addition of an AVI/His tag to facilitate site-specific biotinylation and purification (Boesch et al., 2014). AVI-His FcgR was produced by transient transfection of HEK cells and purified by immobilized metal ion affinity chromatography (IMAC) capture followed by fine purification by size exclusion chromatography (SEC). Purified FcgRs were biotinylated according to the conditions specified in the BirA Biotin Protein Ligase Bulk Solution Reaction Kit (Avidity). Tetrameric FcgR reagents were prepared immediately before use by mixing 1 μg/ml FcgR with 1/4 molar amount of streptavidin-APC (eBioscience 17-4317-82) in FACS buffer and incubating for 10 min with rotation.

Fc-gamma receptor binding assay.

The ability of an antigen-bound antibody to bind Fc receptors is measured in a stable TREM2/DAP12 expressing HEK cell line. Briefly, TREM2-expressing cells are diluted to 100k cells per 90 μl of medium (DMEM+10% FBS for HEK) and aliquoted at 90 μl of cells per well into round-bottomed 96-well plates (Falcon). 10 μl of 10x antibody diluted in the same medium was added to these cells. Cells + antibody were incubated at 37°C for 1 h to opsonize target cells, then cells were washed 2x in FACS buffer, and 100 μl per well of tetrameric FcgR detection reagent in FACS buffer was added. Opsonized cells were incubated with FcgR tetramers for 1 h at 4°C and cells were washed with 2× FACS buffer and resuspended in FACS buffer before analysis on an iQue flow cytometer (IntelliCyt).

Results.

In the following example, the FC1 sequence (human IgG1 Glm 17.1) was used as the Fc of the original human IgG1, and the FC10 sequence was used as the Fc of the original human IgG2 for all further modifications.

Self-clustering Fc mutants that induce strong complement responses can also induce an agonistic response by inducing clustering (eg, by inducing antibody multimerization), which can activate receptors; however, such mutants may also target the complement system to the very target cells that stimulate beneficial activity. Therefore, combinations of Fc mutants were tested for their ability to retain beneficial clustering effects (eg, hexamer-forming mutants) while reducing complement-dependent cytotoxicity (CDC), for example, by reducing monomeric affinity for C1q.

Combinations of E430G with Fc mutants (eg K322A, A330S and P331S) capable of reducing complement activation; as well as other Fc mutants (e.g., combinations L234A, L234F, L235A, L235E, and A330L) that reduce binding to activating Fc-gamma receptors (Armour et al., 2003; Idusogie et al., 2001) were tested in the context of anti-gamma binding -TREM2 antibodies.

BWZ reporter analysis.

The agonistic capacity of the resulting antibodies was assessed using a reporter cell assay, as well as their ability to induce complement activation through CDC and C3b deposition assays. E430G variants of Fc-anti-TREM2 antibodies significantly enhanced the agonistic activity

- 200 044134 ity, even in the presence of compensatory mutations to eliminate C1q binding, such as P331S (Fig. 1A). To further probe these results, the ability of anti-TREM2 antibodies to activate TREM2 in the presence of cell types bearing Fc receptor gamma was tested. Fc-gamma receptor-dependent clustering may be an important mechanism for the activity of these antibodies in vivo, and as such should be preserved whenever possible. In a coculture system with THP-1 cells (ATCC® TIB-202™), which is a monocytic leukemia cell line expressing multiple Fc-gamma receptors, increased TREM2 signaling activity was observed for the humanized IgG1 variant (Figure 1B). The addition of the E430G mutation further increased activity, suggesting that the two mechanisms may be additive or synergistic. However, the addition of compensatory mutations to completely remove Fc receptor binding, such as LALAPS (L234A, L235A, P331S), also removed much of the beneficial effect of E430G in this system.

Complement deposition assay (CDA).

The E430G mutant can cause a strong increase in the deposition of C3b and CDC compared to the parent IgG1. This increase can be reduced after the addition of compensatory mutations such as LALAPS (Fig. 2A). Different combinations of Fc mutants K322A, A330S and P331S, together with E430G, were tested for their ability to retain agonist functionality (including FcgR-based mechanisms) while reducing complement activation. Incorporation of P331S alone with E430G (PSEG) was sufficient to reduce complement activation below the level induced by parental IgG1 in a single affinity-matured AL2p variant ( Fig. 2B ), whereas K322A and A330S had limited effect even in combination with P331S.

Fc-gamma receptor binding assay.

Fc mutant variants of AL2p leads were also tested for their ability to bind to Fc gamma receptors. In this assay, TREM-2-expressing cells were opsonized with anti-TREM2 antibodies and then a tetramerized FcgR/streptavidin-APC probe was used to assess their ability to bind to FcgR. Both mouse and human FcgRs were tested.

Example 6: Enhanced Affinity Mature TREM2 Antibody Binding to BW Cells Expressing Human TREM2.

Materials and methods.

Binding assay. FACS-based cell binding assay was performed as described in Example 2.

Results.

A direct comparison was made between the binding of the chimeric parent antibody AL2p as huIgG1 and its various humanized and affinity matured variants to huIgG1 or huIgG1 PSEG Fc. AL2p-58 and AL2p-61 showed a 2- to 3.6-fold increase in apparent affinity, while no significant improvement in affinity was observed for AL2p-37 and AL2p-47 with cell-expressed TREM2, although both antibodies showed increased affinity for recombinant TREM2 (Table 12).

Table 12

Cellular analysis of high-affinity binding of affinity-matured 9F5 variants

Antibody ID Isotype Fc Kd (nM) Bmax (MFI) AL2p huIgGl 1.32 199026 AL2p-58 huIgGl 0.63 196455 AL2p-58 huIgGl PSEG 0.36 140225 AL2p-37 huIgGl 1.17 216292 AL2p-47 huIgGl 1.20 226371 AL2p-61 huIgGl 0.42 210636

Example 7: Increased activation of soluble and plate-immobilized TREM2 signaling following affinity maturation of AL2p.

Materials and methods.

Luciferase assay. The ability of plate-coated or soluble full-length anti-TREM2 antibodies to activate human TREM2-dependent genes was assessed using a luciferase reporter assay as described in Example 3.

Results.

The ability of AL2p antibody variants to activate TREM2-mediated signaling was tested in a heterologous NFAT:luciferase system. BW cells express a human TREM2/DAP12 chimera as well as an NFAT:luciferase reporter gene that is activated upon TREM2 clustering by natural ligands or TREM2 antibodies. Compared to AL2p, which has unknown

- 201 044134 significant stimulatory activity when immobilized on the plate, all affinity matured AL2p progeny, with the exception of AL2p-37, demonstrated a dramatic increase in signal activation in the plate immobilized format, up to 10-fold compared to AL2p for AL2p-58 huIgG1 PSEG (Table 13). A similar increase was observed for soluble IgG signaling activation, where all affinity matured antibodies tested activated signaling with reduced EC 50 and increased signaling levels compared to AL2p.

Table 13

Activation of TREM2 signaling in BW cells expressing NFAT:luciferase

Antibody Isotype Fc IgG immobilized on the plate, fold compared to unstimulated control (25 nM IgG) Soluble IgG, EC50 (nM) Soluble IgG, fold compared to control IgG (17 nM IgG) AL2p huIgGl 1.29 14.59 4.51 AL2p-58 huIgGl 9.88 4.83 9.97 AL2p-58 huIgGl PSEG 12.91 2.99 12.11 AL2p-37 huIgGl 1.56 9.41 7.63 AL2p-47 huIgGl 3.94 6.50 8.77 AL2p-61 huIgGl 8.97 5.24 10.75

Example 8 AL2p variants block sTREM2 production by primary human dendritic cells in vitro.

Materials and methods.

Preparation of human dendritic cells and treatment with TREM2 antibodies. Human monocytes were isolated from whole blood using RosetteSep Human Monocyte Enrichment Cocktail (Stemcell Technologies) and Ficoll centrifugation according to the manufacturer's protocols. After lysis of red blood cells with ASA lysis buffer, monocytes were resuspended in complete medium (RPMI, 10% FBS, penicillin/streptomycin (Pen/Strep), L-glutamine, HEPES, nonessential amino acid, sodium pyruvate) with 100 ng/ml human GM -CSF (hu-GMCSF) and human IL-4 (hu-IL-4) for dendritic cell differentiation for 6 days.

All suspended dendritic cells were collected and tested for CD11c expression by FACS staining. Briefly, cells were washed in FACS buffer (PBS+2% FBS) and incubated with a 1:5 dilution of anti-human CD11c-FITC or isotype control-FITC (BD Biosciences) for 1 h on ice. The cells were washed with 2 ml of FACS buffer, the pellet was collected by centrifugation and 250 μl of FACS buffer was added and the cells were analyzed using a BD FACS Canto. For both donors tested, >90% of the cells were CD 11c positive and thus differentiated into human dendritic cells.

Collected dendritic cells were washed with PBS to remove cytokines, counted, and seeded at 100,000 cells/well in complete RPMI medium in 96-well plates in 50 μl. Cells were incubated at 37°C for 1 h to allow them to settle and the plate was blocked with serum albumin. After this, 50 μl of 2x titrated antibodies in RPMI was added to the plates. Cells were incubated for 48 hours.

Cell supernatant was collected for sTREM2 measurement. PBS+3 mM EDTA was added to the plates. The plates were incubated at 37 C for 5-10 min until the cells began to go into suspension when pipetting. Cells were transferred to 96-well U-bottom plates, pelleted by centrifugation and resuspended in 45 μL FACS buffer and analyzed by iQE. Relative cell abundance was measured by counting the number of cells in a fixed volume of FACS buffer. Data were analyzed using Microsoft Excel and GraphPad Prism.

TREM2 MSD analysis. An MSD assay specific for human TREM2 was developed. Immobilized anti-TREM2 antibody T2KO811 was applied to the plate at 1 μg/ml in PBS overnight at 4°C (25 μl per well in MSD single spot plates, Meso Scale Discovery). The plates were washed three times using a plate washer and 150 μl PBS+0.05% Triton per well. 1000.02 ng/ml human TREM2-Fc (R&D Systems) was added to the plates as a standard, as well as cell supernatant diluted in binding buffer (PBS+1% BSA), all at 50 μl per well. The plates containing the samples and standard were incubated at room temperature for 1 hour. The plates were washed three times using a plate washer and 150 μl PBS+0.05% Triton per well. Biotinylated goat anti-human TREM2 polyclonal antibody (R&D Systems) was added at a 1:2000 dilution in binding buffer and incubated for 1 h at room temperature.

- 202 044134 at natural temperature.

The plates were washed three times using a plate washer and 150 μl PBS+0.05% Triton per well. 25 μl of sulfo-labeled streptavidin (0.2 μg/ml in binding buffer, MesoScale Discovery) was added to the plates and incubated for 20 min at room temperature. The plates were washed three times using a plate washer and 150 μl PBS+0.05% Triton per well. 150 μl of 1x reading buffer (MesoScale Discovery) was added to each well and the plates were read using a Sector Imager (MesoScale Discovery). Data were analyzed in Excel and Graph Pad Prism. We tested whether AL2p antibodies would interfere with the assay by spiking the MSD plate with different concentrations of AL2p antibody variants. This had no effect on measured signal levels, suggesting no influence of AL2p antibody variants.

Results.

TREM2 is produced as a cell surface receptor that can be cleaved to release an extracellular domain. A rare TREM2 mutation in humans (H157Y) causes increased production of sTREM2 and increases the risk of developing late-onset Alzheimer's disease (Thornton et al., EMBO Mol. Med., 2017, 9(10):1366-78).

To test whether TREM2 antibodies block receptor shedding, sTREM2 secreted into the medium by primary human dendritic cells over 48 hours was measured by ELISA. Dendritic cells derived from monocytes from two human blood donors, donors 534 and 535, were tested. The average concentration of sTREM2 for donor 534 was 97.0 ng/ml and for donor 535-72.5 ng/ml. After addition of TREM2 antibody, sTREM2 secretion decreased with increasing antibody concentration (Figures 5A and 5B). The weakest effect was observed for the parent AL2p antibody in the huIgG1 chimera, although it significantly reduced sTREM2 levels at higher antibody concentrations in both donors. The affinity-matured humanized variant of AL20-58, either wild-type (WT) or PSEG huIgG1, showed the strongest reduction at the lowest antibody concentration. Both donors showed similar results.

To test whether the reduction in sTREM2 was caused by cell death and consequent reduction in cell abundance, cell density was measured after incubation with the antibody using an iQE FACS assay. Cell numbers did not change after treatment of dendritic cells with TREM2 antibodies in both donors (Figures 6A and 6B)

Example 9 TREM2 agonist antibodies enhance the viability of primary human macrophages and dendritic cells.

Ways.

Human monocytes from three different donors were isolated from whole blood using RosetteSep Human Monocyte Enrichment Cocktail (Stemcell Technologies) and Ficoll centrifugation according to the manufacturer's protocols. After lysis of red blood cells with ACK lysis buffer, monocytes were resuspended in complete medium (RPMI, 10% FBS, penicillin/streptomycin (Pen/Strep), L-glutamine, HEPES, nonessential amino acid, sodium pyruvate). For dendritic cell differentiation, 100 ng/ml human GM-CSF (hu-GMCSF) and human IL-4 (hu-IL-4) were added to the monocyte culture for six days. For macrophage differentiation, 100 ng/ml human M-CSF (huM-CSF) was used instead.

For plate-immobilized antibodies, 10 μg/ml anti-TREM2 or control antibodies were added to a 96-well plate the day before and left at 4°C overnight. The next day, the plate was washed twice with PBS. Cells were seeded at 25,000 cells/well without additional cytokines for human dendritic cells and macrophages, and cultured for 2 days. For experiments with soluble antibodies, antibodies were added to the medium when cells were seeded. Cell viability was quantified using a CellTiter-Glo Luminescent Cell Viability Kit (Promega) according to the manufacturer's protocol, and luminescence was measured using a Biotek Synergy HI plate reader. Data were analyzed using Microsoft Excel and GraphPad Prism.

Results.

Both the original AL2p antibody and its affinity-matured progeny were tested for their ability to promote the survival of primary human dendritic cells and macrophages. Cells were added to plates containing titrated plate-immobilized antibodies, incubated for 48 h, and viability was assessed by measuring cell ATP content using CellTiterGlo (Promega).

Compared with an isotype control antibody, stimulation of cells with TREM2 antibodies increased the viability of both primary human macrophages and dendritic cells in a dose-dependent manner (Fig. 8A and 8B). Compared to the parent AL2p antibody, all affinity matured variants demonstrated up to several hundred-fold increases in potency, as indicated by reduced half-maximal activity (see EC50 values in Table 14 (EC50 values (nM) for different TREM2 antibodies in promoting the viability of primary human macrophages or dendritic cells from three different donors (D558-560). P.F. is an unsatisfactory fitting curve. All antibodies were tested in huIgG1 format, where AL1p-58 was also tested in huIgG1 PSEG format)). The parent AL2p antibody exhibits a dose-dependent increase in viability, however, affinity matured antibody variants, particularly AL2p-58 (both as huIgG1 and huIgG1 PSEG), AL2p-47 and AL2p-60, exhibit several hundred times lower EC50 values. suggesting significantly higher activity. AL2p-37 still shows reduced EC50s compared to parental IgG, but with lower activity than other antibodies.

In addition, the ability of the AL2p-58 antibody to enhance viability in a soluble format was assessed in a similar assay, but the antibody was added to the medium when cells were seeded. Compared with the isotype control antibody, AL2p-58 was able to increase the viability of both primary human macrophages and dendritic cells (Fig. 8C-8P). These results suggest that the AL2p-58 antibody will be functionally active in vivo.

Table 14

Macrophages Dendritic cells Antibody D558 D559 D560 D558 D559 D560 AL2p 12,267 146,067 128,667 95,733 41,180 55.120 AL2p-58 0.005 0.359 0.469 0.288 0.341 0.271 AL2p-58 PSEG 0.001 0.322 0.426 0.206 0.276 0.206 AL2p-47 0.013 1.557 1.247 1.017 1.131 0.672 AL2p-60 PF. 0.194 0.154 0.152 0.244 0.178 AL2p-37 1.235 18,313 31,827 4,187 6,155 4,472

Example 10 AL2p variants reduce plasma sTREM2 levels in vivo.

Ways.

In vivo procedures. Human TREM2 BAC transgenic (Tg) mice were housed in groups in polycarbonate cages and acclimatized for at least 5 days before studies began. Animals were maintained on a 12-h light/dark cycle with room temperature maintained at ca. 22+2°C and approximately 50% humidity, and received food and water ad libitum. For Experiments I-III, animals were given intraperitoneal (I.P.) or intravenous (IV.) injections of AL2p-47 huIgG1, AL2p-47 huIgG1 ASPSEG, AL2p-58 huIgG1, AL2p-58 huIgG1 PSEG, AL2p-61 huIgG1 PSEG, or control huIgG1 per day 0 and blood for plasma were collected in heparinized tubes 2-4 days before the start of the study and on days 0 (4 hours after injection), 1, 3, 6, 10 and 14. For Experiment IV, AL2p msIgG1, T-21- 9 msIgG1 or control msIgG1 was administered at 20 mg/kg by intraperitoneal (I.P.) injection on day 0 and plasma was collected on days 0 (4 hours after injection), 2, 5, 8, and 14. Plasma was isolated by centrifuging blood samples for 5 min at 5000 rpm and then the supernatant was collected. A total of four in vivo experiments were carried out: experiment I: n=3 animals/group; experiment II: n=10 animals/group; experiment III: n=4 animals/group; experiment IV: n=4 animals/group.

Human TREM2 MSD Assay: Plasma sTREM2 is measured by the MSD method as described in Example 8.

Results.

Affinity mature AL2p variants were tested for their ability to reduce sTREM2 levels based on the in vitro experiments described in Example 8, which suggest that AL2p antibodies block TREM2 shedding either directly by blocking ADAM sheddase binding or indirectly by inducing TREM2 signaling activation and endocytosis. Transgenic BAC mice expressing human TREM2 were injected with 15 mg/kg IgG on day 0 and sTREM2 levels were monitored for 14 days until they returned to normal pre-experimental values. In table Figure 15 shows the % reduction in plasma sTREM2 observed after administration of different AL2p variants, and FIG. 7A-7C are graphs showing the decrease in sTREM2 following administration of affinity matured AL2p variants to human BAC Tg mice. In contrast, the parent AL2p had no significant effect on plasma sTREM2 levels (Fig. 7D), whereas another TREM2 antibody that binds the Ig domain of the protein (T21-9) caused a several-fold increase in plasma sTREM2, likely due to protein stabilization. All variants induced a decrease in sTREM2 for several days after administration. AL2p-58 huIgG1 PSEG induced the strongest and longest-lasting decrease in sTREM2 expression. These data suggest that sTREM2 in both plasma and CSF can be used as a marker of target binding in vivo in humans.

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Table 15

Reduction of plasma sTREM2 after administration of AL2p antibody variants

Antibody huIgGl Exp. # 4 4, day 0 Day 1 Day 3 Day 6 Day 10 Day 14 AL2p47 DT I 102.9 88.3 74.6* 73.4** 87.7** 82.3 III 89.7 92.9 83.6* 91.5** 111.5 133.0 AL2p47 ASPSE G III 103.1 107.5 93.5 97.5* 127.7 150.8 AL2p58 DT I 86.3 62.3*** * 45 Q**** 42 γ**** 67.7*** * 93.2 II 85.0* 56.7**** 54 q**** 94.8 100.9 III 98.5 85.8* 58.0**** 59 4**** 79 9*** * 131.9 AL2p58 PSEG II 62.8*** * 46 2**** 46 2**** 90.2* 113.2 AL2p61 PSEG I 74.2 57.8*** * 47 4**** 51.8**** 98.2 88.2

The % sTREM2 determined in the plasma of transgenic BAC mice with human TREM2 that received different variants of TREM2 antibodies in the form of huIgG1 WT or huIgG1 PSEG or huIgG1 ASPSEG are indicated. Asterisks indicate values that are significantly lower compared to mice injected with control huIgG1 (* p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001 ) using two-way ANOVA and post hoc test for pairwise comparisons.

Example 11 AL2p Variants in Vivo.

Ways.

C57BL/6 (WT) or Bac-TG-hTREM2 mice were treated with an intraperitoneal (ip) injection of 3 ml of 3% thioglycolate at 8 weeks of age. After 3 days, when the peritoneal cavity was enriched with peritoneal macrophages (CD11b ⁺ F4/80 ⁺ expressing TREM2), mice were injected with huIgG1 or TREM2-specific antibodies AL2p-58 huIgG1 or AL2p-58 huIgG1 (40 mg/kg). Peritoneal cells were collected. hour later and immediately lysed in lysis buffer (n-dodecyl-beta-maltoside 1%, 50 mM Tris-HCl (pH 8.0), 150 mM NaCl, 1 mM EDTA, 1.5 mM MgCl ₂ 10% glycerol, plus protease and phosphatase inhibitors), digested after lysis and immunoprecipitated with rat anti-human/mouse (anti-h/m) TREM2 antibody (RD, clone 237920) or isotype control. Precipitated proteins were fractionated by SDS-PAGE (in non-reducing conditions), transferred to nitrocellulose membranes and probed with anti-phosphotyrosine antibody (Millipore, 4G10).To ensure that each cell lysate used for TREM2 immunoprecipitation contained equal amounts of proteins, equal amounts of lysates were taken and fractionated by SDS prior to immunoprecipitation. PAAG (under reducing conditions). Immunoblots were probed with antibodies directed against human TREM2 (R&D, no. AF1828).

Results.

TREM2 ligand binding induces receptor clustering, which initiates phosphorylation of its adapter protein Dap12 and an intracellular signaling cascade. To test whether AL2p antibody variants induce activation of TREM2 signaling in vivo, transgenic WT or human TREM2-expressing Bac mice were injected with thioglycolate to recruit macrophages to the peritoneum. Three days later, mice are injected with anti-TREM2 or control huIgG1 antibodies, and peritoneal macrophages are then collected, lysed, and probed for phosphorylation of TREM2-associated Dap12 as a measure of activation of TREM2 signaling.

Administration of transgenic Bac mice with AL2p-58 huIgG1 or AL2p huIgG1 PSEG caused a strong increase in Dap12 phosphorylation compared with control huIgG1 (Fig. 9). In contrast, TREM2 antibodies showed no effect on Dap12 in wild-type mice because these antibodies are not cross-reactive in mice. These results demonstrate that AL2p-58 antibodies can cluster and activate the TREM2 receptor in vivo.

Example 12. Nonspecific reactivity of AL2p variants.

Ways.

FACS-based analysis to measure polyspecific reactivity (PSR) was performed as described by Xu et al., Protein Engineering, Design and Selection, 2013, 26(10), 663-70.

Results.

Although the original humanized variants of AL2p (AL2p-h50, AL2p-h77) had low polysp

- 205 044134 digital reactivity (PSR), indicating the absence of nonspecific binding to non-TREM2 targets, after increasing affinity for TREM2 through affinity maturation, AL2p antibody variants showed increased PSR values (Table 16). PSR is positively correlated with affinity and higher nonspecific binding, which may result in faster clearance of circulating antibody from the body and thus a shorter half-life. Results in table. 16, when considered together with those given in table. 9A, 9B, 10A-10C, 11, 13 and 14 demonstrate that the high PSR variants of the AL2p antibodies have too short a half-life, and the variants of the low PSR AL2p antibodies do not exhibit sufficient functionality. However, AL2p antibody variants with intermediate PSR values exhibit both low nonspecific binding and better functionality than AL2p antibody variants with low PSR values (Tables 9A, 9B, 10A-10C, 13 and 14).

Table 16

Summary of polyspecific reactivity (PSR) of AL2p antibody variants

Antibody PSR value PSR Value Range AL2p-h50 0.01 Short AL2p-h77 0.09 Short AL2p-2 0.10 Short AL2p—3 0.05 Short AL2p-4 0.10 Short AL2p-5 0.15 Short AL2p-6 0.10 Short AL2p-7 0.74 High AL2p-8 0.82 High AL2p-9 0.80 High AL2p-10 0.14 Short AL2p-l 1 0.68 High AL2p-12 0.57 Average AL2p-13 0.71 High AL2p-14 0.80 High

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AL2p-15 0.34 Average AL2p-16 0.84 High AL2p-17 0.77 High AL2p-18 0.72 High AL2p-19 0.84 High AL2p-20 0.74 High AL2p-21 0.75 High AL2p-22 0.88 High AL2p-23 0.70 High AL2p-24 0.85 High AL2p-25 0.80 High AL2p-26 0.80 High AL2p-27 0.87 High AL2p-28 0.52 Average AL2p-29 0.72 High AL2p-30 0.70 High AL2p-31 0.85 High AL2p-32 0.10 Short AL2p-33 0.05 Short AL2p-35 0.10 Short AL2p-36 0.82 High AL2p-37 0.15 Short AL2p-38 0.73 High AL2p-39 0.66 High AL2p-40 0.69 High AL2p-41 0.77 High AL2p-42 0.76 High AL2p-43 0.70 High AL2p-44 0.67 High AL2p-45 0.33 Average AL2p-46 0.44 Average AL2p-47 0.48 Average AL2p-48 0.55 Average AL2p-49 0.54 Average AL2p-50 0.16 Short AL2p-51 0.20 Short AL2p-52 0.14 Short AL2p-53 0.22 Short AL2p-54 0.38 Average AL2p-55 0.37 Average AL2p-56 0.37 Average AL2p-57 0.42 Average AL2p-59 H.O. AL2p-61 0.74 High AL2p-62 0.19 Short AL2p-58 0.59 Average

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Sequences

Human TREM2 protein (SEQ III NO: 1)

MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQ LGEKGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQS LHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPP TSILLLLACIFLIKILAASALWAAA WHGQKPGTHPPSELDCGHDPGYQLQTLPGLRDT

Mouse TREM2 protein (SEQ ID NO: 2)

MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQ LGEEGPCQRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQ SLRGREAEVLQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHSTSRNQETSFPPT SILLLLACVLLSKFLAASILWAV ARGRQKPGTPVVRGLDCGQDAGHQLQILTGPGGT

Rat TREM2 protein (SEQ ID NO: 3)

MEPLHVFVLLLVTELSQALNTTVLQGVAGQSLRVSCTYDALRHWGRRKAWCR QLAEEGPCQRVVSTHGVWLLAFLRKQNGSTVITDDTLAGTVTITLRNLQAGDAGLYQC QSLRGREAEVLQKVVVEVLEDPLDDQDAGDLWVPEESESFEGAQVEHSTSSQVSSCGSP LTYHLPPKEPIRKDLLPTHFHS SPPGLCPPEQASYSQHPLGCGQGQAEAGDTCGQWARL

Rhesus monkey TREM2 protein (SEQ ID NO: 4)

MPDPLFSAVQGKDKILHKALCICPWPGKGGMEPLRLLILLFATELSGAHNTTVFQ GVEGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRRNGST AITDDTLGGTLTITLRNLQPHDAGFYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDL WVPGESESFEDAHVEHSISRSLLE GEIPFPPTSVLLLLACIFLIKILAASALWAAAWHGQK PGTHPPSEPDCGHDPGHQLQTLPGLRDT

Cynomolgus TREM2 protein (SEQ ID NO: 5)

MEPLRLLILLFATELSGAHNTTVFQGVEGQSLQVSCPYDSMKHWGRRKAWCRQ LGEKGPCQRVVSTHNLWLLSFLRRRNGSTAITDDTLGGTLTITLRNLQPHDAGFYQCQS LHGSEADTLRKVLVEVLADPLDHRDAGDLWVPGESESFEDAHVEHSISRSLLEGEIPFPP TSVLLLLACIFLIKILAASALWAAAWH GQKPGTHPPSEPDCGHDPGHQLQTLPGLRDT

Horse TREM2 protein (SEQ ID NO: 6)

MEPLPLLILLSVAELSRGHNTTVFQGTAGRSLKVSCPYNSLMHWGRRKAWCRQL GEDGPCQQVVSTHSLWLLSFLKRRNGSTVITDDALGGILTITLRNLQAHDAGFYQCQSL HGGEADTLRKVLVEVLADPLDHQEPGDLWIPKESESFEDAQVEHSISRSLVEEEIPSLPTS ILLLLACIFLSKLLAASAIWAAAWH GQKQETPPASEPDRGHDPGYQLHTLTGERDT

Porcine TREM2 protein (SEQ ID NO: 7)

METLGLLLLLWVAELSRAHNTSVFQGTAGQSLRVSCSYNSLKHWGRRKAWCR QLSEEGLCQHVVSTHPTWLLSFLKRRNGSTAITDDALGGTLTITLRNLQAHDAGLYQCQ SLHGSEADTLKKVLVEVLADPLESQSKSFQDVQMEHSISRNLSEESLFPPTSTLFLLACVF LSKLLVASALWAAAWHGHKQRTSP AGGLDCGRDPGDQDQTLTDELGESSDQDQTLTE LRDT

Canine TREM2 protein (SEQ ID NO: 8)

MEPLWLLILLAVTELSGAHNTTVFQGMAGRSLQVSCPYNSLKHWGRRKAWCRQ VDKEGPCQRVVSTHRSWLLSFLKRWNGSTAIVDDALGGTLTITLRNLQAHDAGLYQCQ SLYGDEADTLRKVLVEVLADPLDHLDPGDLWIPEESKGFEDAHVEPSVSRSLSEEEIPFPP TSILFLLACIFLSKFLAASALWAAAW RGQKLGTPQASELDCSCDPGYQLQTLTEPRDM

Original mouse AL2p heavy chain variable region (SEQ ID NO: 119)

QVQLQQSGPELVKPGASLKISCKASGYAFSSSWMNWVKQRPGKGLEWIGRIYPG DGDTNYNGEFRVRATLTADTSSTTAYMQLSSLTSEDSAVYFCARLLRNQPGESYAMDY WGQGASVTVSS

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Original mouse AL2p light chain variable region (SEQ ID NO: 120)

DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGYTYLHWYLQKPGQSPKLLIYK VSNRFSGVPDRFSGSGSGTDFTLKISRVEADDLGVYFCSQSTRVPYTFGGGTKLEIK

FC1 (wild type human IgGl) (SEQ ID NO: 146)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

FC2 (IgGl E430G) (SEQ ID NO: 147)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC3 (IgGl L234A, L235A, P331S: LALAPS) (SEQ ID NO: 148)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

YTLPP SRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

FC4 (IgGl L234A, L235A, P331S, E430G: LALAPSEG) (SEQ ID NO: 149)

PREEQ TVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQV YTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC5 (IgGl K322A, E430G: KAEG) (SEQ ID NO: 150)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSV LTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC6 (IgGl P331S, E430G: PSEG) (SEQ ID NO: 151)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC7 (IgGl A33OS, P331S, E430G: ASPSEG) (SEQ ID NO: 152)

ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSV LTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYT LPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKL T VDKSRWQQGNVF SC S VMHGALHNHYTQKSLSLSPGK

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FC8 (IgGl K322A, P331S, E430G: KAPSEG) (SEQ ID NO: 153) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

VLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAP ELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP REEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPASIEKTISKAKGQPREPQVY TLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC9 (human IgG2 wild type) (SEQ ID NO: 154)

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

SREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

FC 10 (IgG2 E430G) (SEQ ID NO: 155)

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA

SREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTV DKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

FC11 (IgG2 A330S P331S E430G: ASPSEG) (SEQ ID NO: 156)

ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPA VLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPV AGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREE QFNSTFRVVSVLTVVHQ DWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPS REEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVD KSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

Claims (40)

1. An antibody that binds to the TREM2 protein, where the antibody contains a heavy chain variable region containing HVR-H1, HVR-H2 and HVR-H3, and a light chain variable region containing HVR-L1, HVR-L2 and HVR-L3, where (a) HVR-H1 contains the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFHG (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); or (b) 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). 2. Antibody according to claim 1, where HVR-H1 contains the amino acid sequence YAFSSDWMN (SEQ ID NO: 136); HVR-H2 contains the amino acid sequence RIYPGEGDTNYARKFHG (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). 3. Antibody according to claim 1, where 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 - 210 044134 HVR-L3 contains the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). 4. An antibody according to any one of claims 1 to 3, wherein the heavy chain variable region comprises one, two, three or four framework regions selected from VH FR1, VH FR2, VH FR3 and VH FR4, wherein VH FR1 contains a sequence selected from the group consisting of SEQ ID NO: 9-11, VH FR2 contains a sequence selected from the group consisting of SEQ ID NO: 12 and 13, VH FR3 contains a sequence selected from the group consisting of SEQ ID NO: 14 and 15, and VH FR4 contains the sequence SEQ ID NO: 16; and/or the light chain variable region comprises one, two, three or four framework regions selected from VL FR1, VL FR2, VL FR3 and VL FR4, where VL FR1 contains a sequence selected from the group consisting of SEQ ID NO: 17-20, VL FR2 contains a sequence selected from the group consisting of SEQ ID NOs: 21 and 22, VL FR3 contains a sequence selected from the group consisting of SEQ ID NOs: 23 and 24, and VL FR4 contains a sequence selected from the group consisting of SEQ ID NOs: 25 and 26. 5. The antibody according to claim 1, where (a) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 64 and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 108; or (b) the heavy chain variable region contains the amino acid sequence of SEQ ID NO: 59, and/or the light chain variable region contains the amino acid sequence of SEQ ID NO: 112. 6. The antibody according to claim 5, where the variable region of the heavy chain contains the amino acid sequence SEQ ID NO: 64; and the light chain variable region contains the amino acid sequence of SEQ ID NO: 108. 7. The antibody according to claim 5, where the variable region of the heavy chain contains the amino acid sequence SEQ ID NO: 59; and the light chain variable region contains the amino acid sequence of SEQ ID NO: 112. 8. An antibody according to any one of claims 1 to 7, wherein the antibody belongs to the IgG class, the IgM class or the IgA class. 9. The antibody according to claim 8, where the antibody belongs to the IgG class and has an isotype of IgG1, IgG2, IgG3 or IgG4. 10. The antibody of claim 9, wherein the antibody contains one or more amino acid substitutions in the Fc region 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, where the residue numbering follows the EU or Kabat numbering scheme. 11. The antibody according to claim 10, where (a) the Fc region contains amino acid substitutions at positions E430G, L234A, L235A and P331S, where the numbering of the residue positions corresponds to the EU numbering scheme; (b) the Fc region contains amino acid substitutions at positions E430G and P331S, where the residue position numbering follows the EU numbering scheme; (c) the Fc region contains amino acid substitutions at positions E430G and K322A, where the residue position numbering follows the EU numbering scheme; (d) the Fc region contains amino acid substitutions at positions E430G, A330S and P331S, where the residue position numbering follows the EU numbering scheme; (e) the Fc region contains amino acid substitutions at positions E430G, K322A, A330S and P331S, where the residue position numbering follows the EU numbering scheme; (f) the Fc region contains amino acid substitutions at positions E430G, K322A and A330S, where the residue position numbering follows the EU numbering scheme; (g) the Fc region contains amino acid substitutions at positions E430G, K322A and P331S, where the residue position numbering follows the EU numbering scheme; (h) the Fc region contains amino acid substitutions at positions S267E and L328F, where the residue position numbering follows the EU numbering scheme; (i) the Fc region contains an amino acid substitution at position C127S, where the residue position numbering follows the EU numbering scheme; (j) the Fc region contains amino acid substitutions at positions E345R, E430G and S440Y, where the residue position numbering follows the EU numbering scheme; or (k) the Fc region contains an amino acid sequence selected from the group consisting of SEQ ID NO: 146-156. 12. The antibody according to claim 11, wherein the Fc region contains an amino acid substitution at positions E430G and P331S, where the numbering of the residue positions corresponds to the EU numbering scheme. 13. An antibody according to any one of claims 1 to 12, wherein the TREM2 protein is a human protein. 14. The antibody of claim 13, wherein the TREM2 protein is a wild type protein. 15. The antibody of claim 13, wherein the TREM2 protein is a natural variant. 16. An antibody according to any one of claims 1 to 15, where the antibody is an antibody fragment that binds to one or more - 211 044134 human proteins selected from the group consisting of human TREM2, a natural variant of human TREM2 and a variant of human TREM2 that occurs in diseases; and optionally, the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, a natural variant of human TREM2, and a variant of human TREM2 that occurs in diseases. 17. The antibody of claim 16, wherein the antibody fragment is a Fab-, Fab'-, Fab'-SH-, F(ab')2-, Fv-, or scFv-fragment. 18. An antibody according to any one of claims 1 to 17, wherein the antibody is a monoclonal antibody. 19. An antibody according to any one of claims 1 to 18, wherein the antibody is a humanized antibody. 20. A bispecific antibody, characterized in that it contains the antibody according to claim 1 and a second antigen, where the second antigen is (a) an antigen that facilitates transport across the blood-brain barrier; (b) an antigen that facilitates transport across the blood-brain barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor-related proteins 1 and 2 (LPR- 1 and 2), diphtheria toxin receptor, CRM197, llama single domain antibody, TMEM 30(A), protein transduction domain, TAT, Syn-B, penetratin, polyarginine peptide, angiopeptide and ANG1005; (c) a pathogenic agent selected from the group consisting of pathogenic peptides or proteins, or pathogenic nucleic acids, where the pathogenic nucleic acids are GGCCCC (G2C4) repeat expansion antisense RNAs, the pathogenic proteins are selected from the group consisting of beta-amyloid, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, tau protein (Tau), IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein , prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy bodies, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medina, prolactin, transthyretin, lysozyme, beta-2-microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, non-ATG repeat-associated (RAN) translation products, dipeptide repeat peptides (DPR) ), glycine-alanine repeat peptides (GA), glycine-proline repeat peptides (GP), glycine-arginine repeat peptides (GR), proline-alanine repeat peptides (PA), ubiquitin and proline-arginine repeat peptides (PR ); (d) ligands and/or proteins expressed on immune cells, where 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) a protein, lipid, polysaccharide or glycolipid expressed on one or more tumor cells. 21. An antibody according to any one of the preceding claims, wherein the antibody specifically binds to both human TREM2 and cynomolgus TREM2. 22. The antibody of claim 21, wherein the antibody has a dissociation constant (KD) with cynomolgus TREM2 that ranges from about 50 nM to about 100 pM or less than 100 pM, where the KD is determined at a temperature of about 25°C. 23. An antibody according to any one of the preceding claims, wherein the antibody binds to primary human immune cells with an affinity that is at least 10 times higher than that of an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 27, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 92; or at least 10 times higher than the value for an anti-TREM2 antibody comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 56 and a light chain variable region containing the amino acid sequence of SEQ ID NO: 104. 24. An antibody according to any of the preceding claims, wherein the antibody clusters and activates the TREM2 signaling pathway in an amount that is greater than that of the control human IgG1 antibody. 25. An antibody according to any one of the preceding claims, wherein the antibody enhances the survival of immune cells in vitro to a greater extent than a human IgG1 control antibody. 26. An antibody according to any one of the preceding claims, wherein the antibody has an in vivo half-life that is less than that of the control human IgG1 antibody. 27. An antibody according to any one of the preceding claims, wherein the antibody reduces plasma levels of soluble TREM2 in vivo by at least 25% compared to a control human IgG1 antibody. 28. The antibody of claim 27, wherein the antibody reduces plasma levels of soluble TREM2 in vivo by blocking cleavage and/or by inducing internalization. 29. An antibody according to claim 1, containing a heavy chain and a light chain, where - 212 044134 (a) the heavy chain contains the amino acid sequence of SEQ ID NO: 198 and the light chain contains the amino acid sequence of SEQ ID NO: 214; (b) the heavy chain contains the amino acid sequence of SEQ ID NO: 199 and the light chain contains the amino acid sequence of SEQ ID NO: 214; (c) the heavy chain contains the amino acid sequence of SEQ ID NO: 200 and the light chain contains the amino acid sequence of SEQ ID NO: 214; (d) the heavy chain contains the amino acid sequence of SEQ ID NO: 201 and the light chain contains the amino acid sequence of SEQ ID NO: 214; (e) the heavy chain contains the amino acid sequence of SEQ ID NO: 202 and the light chain contains the amino acid sequence of SEQ ID NO: 215; (f) the heavy chain contains the amino acid sequence of SEQ ID NO:203 and the light chain contains the amino acid sequence of SEQ ID NO:215; (g) the heavy chain contains the amino acid sequence of SEQ ID NO: 204 and the light chain contains the amino acid sequence of SEQ ID NO: 215; or (h) the heavy chain contains the amino acid sequence of SEQ ID NO: 205 and the light chain contains the amino acid sequence of SEQ ID NO: 215. 30. The antibody according to claim 1, where the heavy chain contains the amino acid sequence of SEQ ID NO: 198 and the light chain contains the amino acid sequence of SEQ ID NO: 214; or the heavy chain contains the amino acid sequence of SEQ ID NO: 199 and the light chain contains the amino acid sequence of SEQ ID NO: 214. 31. The antibody according to claim 1, where the heavy chain contains the amino acid sequence of SEQ ID NO: 200 and the light chain contains the amino acid sequence of SEQ ID NO: 214; or the heavy chain contains the amino acid sequence of SEQ ID NO: 201 and the light chain contains the amino acid sequence of SEQ ID NO: 214. 32. The antibody according to claim 1, where the heavy chain contains the amino acid sequence of SEQ ID NO: 204 and the light chain contains the amino acid sequence of SEQ ID NO: 215; or the heavy chain contains the amino acid sequence of SEQ ID NO: 205 and the light chain contains the amino acid sequence of SEQ ID NO: 215. 33. An isolated nucleic acid containing a nucleic acid sequence encoding an antibody according to any of the preceding claims. 34. An expression vector containing the nucleic acid according to claim 33. 35. An isolated host cell containing the vector of claim 34. 36. A method of producing an antibody that binds to TREM2, comprising culturing the cell of claim 35 so that the antibody is produced, further comprising isolating the antibody produced by the cell. 37. An isolated antibody that binds to TREM2, obtained by the method of claim 36. 38. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 32 and a pharmaceutically acceptable carrier. 39. Use of an antibody according to any one of claims 1 to 32 in a method of preventing, reducing the risk of or treating an individual with a disease, disorder or lesion selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, disorder cognition, memory loss, spinal cord injury, traumatic brain injury, multiple sclerosis, chronic colitis and ulcerative colitis. 40. Use according to claim 39, wherein the disease, disorder or lesion is Alzheimer's disease.