Anti-TREM2 humanized antibody, antigen binding fragment thereof, and use thereof

Abstract

The present application relates to the technical field of biomedicines, and particularly to an anti-TREM2 antibody, an antigen binding fragment thereof, and a use thereof. The anti-TREM2 antibody or the antigen binding fragment thereof has relatively strong activity of inducing an ADCC effect, and can be used for enhancing an immune response and / or treating immune-related diseases, such as cancer, of an individual, including using the anti-TREM2 antibody or the antigen binding fragment thereof to kill non-irritating myeloid cells, thereby disabling or reducing the non-irritating myeloid cells.

Description

Anti-TREM2 humanized antibodies, antigen-binding fragments thereof, and uses thereof Technical Field

[0001] The present application relates to the field of biomedicine technology, and specifically to an anti-TREM2 antibody, an antigen-binding fragment thereof, and applications thereof, especially an anti-TREM2 humanized antibody, an antigen-binding fragment thereof, and applications thereof. Background Art

[0002] Triggering receptor 2 on myeloid cells (TREM2) belongs to the immunoglobulin superfamily and is a transmembrane receptor. The physiological functions of TREM2 include cell maturation, cell proliferation, cell survival, phagocytosis, and inflammation regulation. TREM2 is considered an important pathology-induced immune signaling hub and plays a crucial role in myeloid cell activation and survival. TREM2 has multiple ligands, primarily free negatively charged molecules bound to the plasma membrane, including bacterial products, DNA, lipoproteins, and phospholipids. After binding to ligands, TREM2 transmits signals into the cell via DNAX activating protein 10 (DAP10) and DNAX activating protein 12 (DAP12), subsequently activating multiple downstream signaling pathways and producing diverse effects. TREM2 is a marker of macrophage infiltration in tumors. TREM2 expression on the surface of tumor-associated macrophages (TAMs) has been found in various tumors and is negatively correlated with tumor survival. Binding of TREM2 to its ligands promotes high expression of CD163 by TAMs, amplifying inflammatory responses in the local tumor microenvironment and promoting tumor development and progression.

[0003] An increasing number of studies have found that TREM2-expressing TAMs accumulate in a variety of tumors and are associated with T cell exhaustion and resistance to immune checkpoint inhibitor therapy.

[0004] Therefore, TREM2 may be an ideal target for targeting tumor myeloid infiltration and enhancing the efficacy of immune checkpoint inhibitors.

[0005] Summary of the Invention

[0006] In response to the prior art, the present application provides an anti-TREM2 antibody, an antigen-binding fragment thereof, and uses thereof, wherein the anti-TREM2 antibody or its antigen-binding fragment comprises the heavy chain variable regions HCDR1, HCDR2, HCDR3 of the complementarity determining regions and / or the light chain variable regions LCDR1, LCDR2, LCDR3 of the complementarity determining regions; the anti-TREM2 antibody or its antigen-binding fragment has a strong activity of inducing ADCC effect, and can be used to enhance the immune response and / or for treating an individual's immune-related diseases such as cancer, including using the anti-TREM2 antibody or its antigen-binding fragment to kill non-stimulatory myeloid cells, thereby disabling the ability of non-stimulatory myeloid cells or reducing their number.

[0007] In a first aspect, the present application provides an anti-TREM2 antibody or an antigen-binding fragment thereof, comprising:

[0008] (a) a heavy chain variable region comprising the following complementarity determining regions:

[0009] a HCDR1 comprising the amino acid sequence of SEQ ID NO: 1, 7, 12, 16 or 42, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1, 7, 12, 16 or 42;

[0010] a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43;

[0011] a HCDR3 comprising the amino acid sequence of SEQ ID NO: 3, 9, 14, 18, 23 or 44, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 3, 9, 14, 18, 23 or 44; and / or

[0012] (b) a light chain variable region comprising the following complementarity determining regions:

[0013] LCDR1 comprising the amino acid sequence of SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54;

[0014] LCDR2 comprising the amino acid sequence of SEQ ID NO:5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52, or an amino acid sequence at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52;

[0015] LCDR3 comprising the amino acid sequence of SEQ ID NO: 6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53.

[0016] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0017] (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 4, 5 and 6;

[0018] (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 10, 11 and 6, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 10, 11 and 6, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 10, 11 and 6;

[0019] (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 12, 13 and 14, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 12, 13 and 14, respectively; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 10, 11 and 15, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 10, 11 and 15, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 10, 11 and 15;

[0020] (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 16, 17 and 18; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 19, 20 and 21;

[0021] (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 22 and 23, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 22 and 23; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 24, 25 and 26;

[0022] (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 27, 28 and 29;

[0023] (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 30, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences set forth in NOs: 4, 5 and 30;

[0024] (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 24, 25 and 26;

[0025] (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 31 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 31 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 32, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 31 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences set forth in NOs: 4, 5 and 32;

[0026] (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 22 and 23, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 22 and 23; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 33, 34 and 35, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 33, 34 and 35, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 33, 34 and 35;

[0027] (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 36, 37 and 30, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 36, 37 and 30, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 36, 37 and 30;

[0028] (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 38 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 39, 40 and 41, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 39, 40 and 41, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 39, 40 and 41;

[0029] (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 45, 46 and 47, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 45, 46 and 47;

[0030] (14) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 48, 49 and 29, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 48, 49 and 29;

[0031] (15) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 27, 5 and 26;

[0032] (16) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 50, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 27, 28 and 50, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 27, 28 and 50;

[0033] (17) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 38 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 51, 52 and 53, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 51, 5 and 26;

[0034] (18) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 36, 52 and 53, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in NOs: 36, 52 and 53; or

[0035] (19) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 54, 55 and 32, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively. The amino acid sequences shown in NOs: 54, 5 and 32 have amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0036] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0037] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, 58, 59 or 61, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 55, 58, 59 or 61; and / or

[0038] A light chain variable region comprising the amino acid sequence of SEQ ID NO: 56, 57, 60 or 62, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 56, 57, 60 or 62.

[0039] In some embodiments of the present application, the different amino acids between the amino acid sequence shown in SEQ ID NO: 55, 58, 59 or 61 and the amino acid sequence having at least 80% identity thereto are mainly or entirely located in the FR region of the heavy chain variable region; and / or the different amino acids between the amino acid sequence shown in SEQ ID NO: 56, 57, 60 or 62 and the amino acid sequence having at least 80% identity thereto are mainly or entirely located in the FR region of the light chain variable region.

[0040] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0041] (1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:56;

[0042] (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:57;

[0043] (3) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:58, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:58, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:57;

[0044] (4) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:60;

[0045] (5) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:61, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:62, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:62; or

[0046] (6) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:62, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62.

[0047] In some embodiments of the present application, the antibody is a mouse antibody, a monkey antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a fully human antibody; preferably, the antibody is a humanized antibody. In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof is selected from at least one of a monoclonal antibody, a polyclonal antibody, a neutralizing antibody, an antagonistic antibody, a fucosylated antibody, a monospecific antibody, a multispecific antibody, a nanobody, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb fragment, an isolated CDR region, and a scFv. In some embodiments of the present application, the anti-TREM2 antibody is a monoclonal antibody.

[0048] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof further comprises a constant region, which is a heavy chain constant region and / or a light chain constant region.

[0049] Preferably, the heavy chain constant region is the heavy chain constant region of IgG, IgA, IgM, IgE or IgD or a variant thereof; the heavy chain constant region is preferably the heavy chain constant region of IgG or a variant thereof, such as the constant region of IgG1, IgG2, IgG3 or IgG4 or a variant thereof; the heavy chain constant region is more preferably the heavy chain constant region of IgG1 or a variant thereof; for example, the heavy chain constant region of human IgG1, whose amino acid sequence is shown in SEQ ID NO: 75 or 76.

[0050] Preferably, the light chain constant region is a constant region of a κ chain or a λ chain or a variant thereof, preferably a constant region of a human κ chain, whose amino acid sequence is shown in SEQ ID NO: 77.

[0051] In some embodiments, the heavy chain constant region comprises a full-length heavy chain constant region or a fragment thereof, which can be selected from a CH1 region, an Fc region, or a CH3 region. In some embodiments, the heavy chain constant region or a variant thereof comprises an IgG1 Fc region having one or more mutations that enhance antibody-dependent cell-mediated cytotoxicity (ADCC).

[0052] In some embodiments, the heavy chain constant region or variant thereof comprises a mutation at position 234, 235, and 243, or a mutation at position 239, 330, and 332 of the IgG1 Fc region. In some embodiments, the IgG1 Fc region comprises a mutation at S239D, A330L, and I332E. In some embodiments, the heavy chain constant region or variant thereof comprises at least one mutation at position 234, 235, 243, 239, 330, or 332 of the IgG1 Fc region. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof further comprises an IgG1 Fc region comprising at least one mutation of S239D, A330L, and I332E.

[0053] In some embodiments, the Fc region binds an Fcγ receptor, e.g., FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb.

[0054] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0055] a heavy chain comprising the amino acid sequence of SEQ ID NO: 67, 69, 72, 63, 66 or 71, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 67, 69, 72, 63, 66 or 71; and / or

[0056] A light chain comprising the amino acid sequence of SEQ ID NO: 68, 70, 64 or 65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 68, 70, 64 or 65.

[0057] In some embodiments, the different amino acids between the amino acid sequence shown in SEQ ID NO: 67, 69, 72, 63, 66 or 71 and the amino acid sequence with at least 80% identity thereto are mainly or entirely located in the FR region and / or constant region of the heavy chain; and / or the different amino acids between the amino acid sequence shown in SEQ ID NO: 68, 70, 64 or 65 and the amino acid sequence with at least 80% identity thereto are mainly or entirely located in the FR region and / or constant region of the light chain.

[0058] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0059] (1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:67, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:67; and the light chain comprises the amino acid sequence of SEQ ID NO:68, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:68;

[0060] (2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:63, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:63; and the light chain comprises the amino acid sequence of SEQ ID NO:64, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:64;

[0061] (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:69, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:69; and the light chain comprises the amino acid sequence of SEQ ID NO:70, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:70;

[0062] (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:67, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:67; and the light chain comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:70;

[0063] (5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:72, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:72; and the light chain comprises the amino acid sequence of SEQ ID NO:68, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:68;

[0064] (6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:63, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:63; and the light chain comprises the amino acid sequence of SEQ ID NO:65, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids of SEQ ID NO:65;

[0065] (7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:66, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:66; and the light chain comprises the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65; or

[0066] (8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:71 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:71; and the light chain comprises the amino acid sequence of SEQ ID NO:64 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64.

[0067] In some embodiments, the antibody is a multispecific antibody that specifically binds to TREM2 and additionally specifically binds to one or more other targets. Preferably, the multispecific antibody, such as a bispecific antibody, further comprises at least one second antibody having a second binding specificity for a second target. Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. More preferably, the multispecific antibody is a bispecific antibody.

[0068] As non-limiting examples, the anti-TREM2 antibody or antigen-binding fragment thereof has one or more of the following properties:

[0069] (1) Ability to bind to human TREM2;

[0070] (2) able to bind to mouse TREM2;

[0071] (3) able to bind to cynomolgus monkey TREM2;

[0072] (4) competing with one or more TREM2 ligands for binding to TREM2;

[0073] (5) inhibiting and / or blocking the binding of TREM2 to ligands;

[0074] (6) inhibiting and / or blocking intracellular signal transduction mediated by TREM2 binding ligands;

[0075] (7) Induce cytokine or chemokine secretion;

[0076] (8) having at least one of antibody-dependent cell-mediated cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and antibody-mediated phagocytosis (ADCP) activity;

[0077] (9) Enhance immune response;

[0078] (10) Enhanced ADCC activity.

[0079] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof binds to human TREM2 at a K D Values ​​<5E-08M, <1E-09M, <1E-10M, <5E-10M, <1E-11M, or <1E-12M.

[0080] In some embodiments, the one or more TREM2 ligands are selected from Escherichia coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid-β peptide.

[0081] In some embodiments, the cytokine or chemokine is selected from IFN-γ, TNF-α, CXCL1, or CXCL10.

[0082] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof is capable of specifically killing, depleting, or disabling TREM2+ myeloid cells.

[0083] Optionally, the TREM2+ myeloid cells are non-stimulatory myeloid cells, such as CD45+, HLA-DR+, CD11c+, CD14+, and BDCA3- non-stimulatory myeloid cells. Optionally, the TREM2+ myeloid cells are intratumoral myeloid cells. Optionally, the TREM2+ cells are selected from dendritic cells, macrophages, monocytes, and neutrophils; the macrophages are preferably tumor-associated macrophages (TAMs).

[0084] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof has ADCC activity. ADCC can occur when the antibody binds to an antigen on the surface of a pathogenic or tumorigenic target cell.

[0085] The second aspect of the present application provides a nucleic acid molecule, which encodes the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application.

[0086] In some embodiments, the nucleic acid molecule includes a nucleic acid molecule encoding the heavy chain variable region and / or light chain variable region of the anti-TREM2 antibody or antigen-binding fragment thereof described herein, respectively.

[0087] The third aspect of the present application provides a recombinant vector comprising the nucleic acid molecule described in the second aspect of the present application.

[0088] The fourth aspect of the present application provides a host cell, which comprises the nucleic acid molecule described in the second aspect of the present application or the recombinant vector described in the third aspect of the present application.

[0089] In some embodiments, the vector is a cloning vector; in other embodiments, the vector is an expression vector. The expression vector can optionally be any expression vector capable of expressing the anti-TREM2 antibody or antigen-binding fragment thereof described herein, or a moiety thereof.

[0090] The fifth aspect of the present application provides a method for preparing an anti-TREM2 antibody or an antigen-binding fragment thereof, which comprises culturing the host cell described in the fourth aspect of the present application.

[0091] In some embodiments, the host cell is a prokaryotic cell. In other embodiments, the host cell is a eukaryotic cell.

[0092] In some embodiments, the host cell is selected from yeast cells, mammalian cells, or other cells suitable for preparing antibodies or antigen-binding fragments thereof, or moieties thereof. Mammalian cells are, for example, Chinese hamster ovary cells (CHO), human kidney epithelial cell lines 293 cells, or 293T cells. In some embodiments, the recombinant cell is a recombinant CHO cell. In some embodiments, the method further comprises isolating and purifying the expression product of the host cell, for example, by purification using a Protein A affinity column.

[0093] The use of the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of this application, the nucleic acid molecule described in the second aspect of this application, the recombinant vector described in the third aspect of this application, or the host cell described in the fourth aspect of this application in the preparation of drugs.

[0094] In some embodiments, the drug is a drug for preventing and / or treating a disease or condition associated with TREM2. In some embodiments, the disease or condition associated with TREM2 is cancer. In some embodiments, the disease or condition associated with TREM2 is a lipid-related disease or condition. In some embodiments, the disease or condition associated with TREM2 is a fibrotic disease or condition.

[0095] In some embodiments, the drug is a drug that modulates the subject's immune response. In some specific embodiments, the drug is a drug that increases the subject's anti-tumor immune response and / or induces a subject's memory immune response.

[0096] In some embodiments, the present application relates to the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application, the nucleic acid molecule described in the second aspect of the present application, the recombinant vector described in the third aspect of the present application, or the host cell described in the fourth aspect of the present application for preventing and / or treating a disease or condition related to TREM2, or regulating an immune response in a subject. Alternatively, the present application relates to a method for preventing and / or treating a disease or condition related to TREM2, or regulating an immune response in a subject, comprising administering to a subject in need thereof the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application, the nucleic acid molecule described in the second aspect of the present application, the recombinant vector described in the third aspect of the present application, or the host cell described in the fourth aspect of the present application.

[0097] The sixth aspect of the present application provides the use of the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect, the nucleic acid molecule described in the second aspect of the present application, the recombinant vector described in the third aspect of the present application, or the host cell described in the fourth aspect of the present application in the preparation of a reagent for diagnosing TREM2-related diseases or conditions.

[0098] In some embodiments, the TREM2-related disease or condition is cancer. In some embodiments, the TREM2-related disease or condition is a lipid-related disease or condition. In some embodiments, the TREM2-related disease or condition is a fibrotic disease or condition.

[0099] In some embodiments, the agent can modulate the subject's immune response. In some specific embodiments, the agent can increase the subject's anti-tumor immune response and / or induce a memory immune response in the subject.

[0100] The seventh aspect of the present application provides a kit for detecting TREM2, which comprises the anti-TREM2 antibody or its antigen-binding fragment described in the first aspect of the present application or the nucleic acid molecule described in the second aspect of the present application.

[0101] The eighth aspect of the present application provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application to the subject.

[0102] In some embodiments, the disease or condition is a TREM2-related disease or condition. In some embodiments, the TREM2-related disease or condition is cancer. In some embodiments, the TREM2-related disease or condition is a lipid-related disease or condition. In some embodiments, the TREM2-related disease or condition is a fibrotic disease or condition.

[0103] The ninth aspect of the present application provides a method for enhancing the immune response of a subject, comprising administering the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application to the subject.

[0104] Preferably, the enhancing the subject's immune response is increasing the subject's anti-tumor immune response and / or inducing the subject's memory immune response.

[0105] In some specific embodiments, the subject is a mammal, such as a human. In some embodiments, the immune response is an adaptive immune response. In some embodiments, the immune response is an innate immune response.

[0106] In some embodiments, the cancer is selected from melanoma, renal cancer, hepatobiliary cancer, head and neck squamous cell carcinoma (HNSC), pancreatic cancer, colorectal cancer, bladder cancer, glioblastoma, prostate cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, kidney cancer, leukemia, lymphoma or mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is breast cancer.

[0107] In some embodiments, the lipid-related disease or disorder is selected from obesity, fatty liver disease, heart disease, stroke, atherosclerosis, diabetes, osteoarthritis, gout, sleep apnea, or hypertension.

[0108] In some embodiments, the fibrotic disease or disorder is a liver disease. Optionally, the liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0109] Beneficial effects of this application:

[0110] The anti-TREM2 antibodies or antigen-binding fragments thereof of the present application have antibody-dependent cellular cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, antibody-mediated phagocytosis (ADCP) activity, and binding affinity, and in particular have a strong activity of inducing ADCC effects, and can be used to enhance immune responses and / or for treating individual immune-related diseases such as cancer, including using anti-TREM2 antibodies or antigen-binding fragments thereof to kill non-stimulatory myeloid cells, thereby disabling or eliminating non-stimulatory myeloid cells.

[0111] The monoclonal antibody targeting TREM2 in the present application blocks TREM2-mediated signal transduction or eliminates tumor-associated macrophages (TAMs) expressing TREM2 in the tumor microenvironment through at least one of the ADCC effect, CDC effect, and ADCP effect (especially through the ADCC effect), thereby helping to enhance the anti-tumor immune response.

[0112] The anti-TREM2 antibodies or antigen-binding fragments thereof of the present application can cross-bind to human, mouse, or monkey TREM2-overexpressing cell lines or cross-bind to human or monkey TREM2-overexpressing cell lines. BRIEF DESCRIPTION OF THE DRAWINGS

[0113] Figures 1-1 to 1-4 are graphs showing the binding detection results of the chimeric antibody and positive control antibody of Example 2 with human TREM2 overexpressing cell lines;

[0114] Figures 1-5 to 1-8 are graphs showing the binding test results of the chimeric antibody and positive control antibody of Example 2 with the mouse TREM2 overexpressing cell line;

[0115] Figures 1-9 and 1-10 are graphs showing the binding test results of the chimeric antibody and positive control antibody of Example 2 with the cynomolgus monkey TREM2 overexpressing cell line;

[0116] Figures 2-1 to 2-4 are graphs showing the binding test results of the humanized antibody and positive control antibody of Example 6 with human TREM2 overexpressing cell lines;

[0117] Figures 2-5 and 2-6 are graphs showing the binding test results of the humanized antibody and positive control antibody of Example 6 with the mouse TREM2 overexpressing cell line;

[0118] Figures 2-7 to 2-9 are graphs showing the binding test results of the humanized antibody and positive control antibody of Example 6 with the cynomolgus monkey TREM2 overexpressing cell line;

[0119] Figures 3-1 and 3-2 are diagrams showing the ADCC effect of the humanized antibody of Example 7;

[0120] Figure 4-1 is a graph showing the in vivo efficacy and tumor growth curve of the humanized antibody of the present invention;

[0121] Figure 4-2 is a graph showing the in vivo efficacy and body weight change trends of the humanized antibody of the present invention;

[0122] FIG5 is a graph showing the results of the mutation-enhanced ADCC effect of the humanized antibody of the present application. DETAILED DESCRIPTION

[0123] In order to make the present application easier to understand, the present application will be described in detail below with reference to embodiments. These embodiments are merely illustrative and do not limit the scope of application of the present application.

[0124] Unless otherwise indicated, the terms "comprise, comprise, and comprising" or their equivalents (contain, contains, containing, include, includes, including) used herein are open-ended expressions and mean that in addition to the listed elements, components, and steps, other unspecified elements, components, and steps may also be included.

[0125] Unless otherwise indicated, all numbers used herein expressing amounts of ingredients, measurements, or reaction conditions are to be understood as modified in all instances by the term "about." When used in conjunction with a percentage, the term "about" can mean, for example, ±1%, preferably ±0.5%, and more preferably ±0.1%.

[0126] Unless the context clearly indicates otherwise, singular terms herein encompass plural referents and vice versa. Similarly, the word "or" herein is intended to include "and" unless the context clearly indicates otherwise. Unless otherwise indicated, the terms "optional" or "optionally" as used herein indicate that the object or event it modifies exists or does not exist, or occurs or does not occur.

[0127] Unless otherwise indicated, the term "treat" as used herein means that after administration, the disease or its related symptoms can be inhibited, contained, alleviated, improved, slowed down, relieved or eliminated, the progression of the disease or its related symptoms can be delayed, postponed, slowed down, stopped or terminated, or the recurrence of the disease or its related symptoms can be prevented, controlled or reduced.

[0128] Unless otherwise indicated, the term "subject" as used herein encompasses any vertebrate, e.g., mammals and non-mammals, such as humans, non-human primates, sheep, dogs, cats, horses, cows, chickens, pigs, mice, etc. Preferably, the subject in this application is a human. The term "subject" as used herein can be used interchangeably with the term "patient."

[0129] The term "complementarity determining region" may refer to the portion of the variable region of an antibody that confers antigen binding specificity, and may refer to an amino acid sequence found in the hypervariable region of the heavy or light chain of an immunoglobulin. The heavy chain may include three complementary determining regions (CDRs) (HCDR1, HCDR2, and HCDR3; and the light chain may include three complementary determining regions (CDRs) (LCDR1, LCDR2, and LCDR3). The CDRs may provide contact residues that play an important role in the binding of an antibody to its antigen or antigenic epitope.

[0130] The term "humanized antibody" refers to a non-human antibody that has been genetically engineered and whose amino acid sequence has been modified to increase homology with the sequence of a human antibody. Generally speaking, all or part of the CDR region of a humanized antibody comes from a non-human antibody (donor antibody), and all or part of the non-CDR region (e.g., variable region FR and / or constant region) comes from a human immunoglobulin (recipient antibody). Humanized antibodies generally retain or partially retain the expected properties of the donor antibody, including but not limited to antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance immune response, etc.

[0131] The term "chimeric antibody" refers to an antibody whose variable region sequences are derived from one species and whose constant region sequences are derived from another species, for example, an antibody formed by fusing the variable region of a murine antibody with the constant region of a human antibody. When referring to an antibody, unless otherwise indicated, it is an isolated antibody. The term "isolated" herein means that the antibody is substantially free of other cellular components with which it is naturally associated. For example, an isolated antibody can be an antibody that has been removed from its native environment.

[0132] In this context, the percent identity (degree of homology) between sequences can be determined by comparing two sequences, for example, using freely available computer programs commonly used for this purpose on the World Wide Web (e.g. www.ncbi.nlm.nih.gov), such as BLASTp or BLASTn with default settings.

[0133] In a first aspect, the present application provides an anti-TREM2 antibody or an antigen-binding fragment thereof, comprising:

[0134] (a) a heavy chain variable region comprising the following complementarity determining regions:

[0135] HCDR1 (heavy chain CDR1) comprising the amino acid sequence of SEQ ID NO: 1, 7, 12, 16 or 42, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 1, 7, 12, 16 or 42;

[0136] HCDR2 (heavy chain CDR2) comprising the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43;

[0137] HCDR3 (heavy chain CDR3) comprising the amino acid sequence of SEQ ID NO: 3, 9, 14, 18, 23 or 44, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 3, 9, 14, 18, 23 or 44; and / or

[0138] (b) a light chain variable region comprising the following complementarity determining regions:

[0139] LCDR1 (light chain CDR1) comprising the amino acid sequence of SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54;

[0140] LCDR2 (light chain CDR2) comprising the amino acid sequence of SEQ ID NO: 5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52;

[0141] LCDR3 (light chain CDR3) comprising the amino acid sequence of SEQ ID NO: 6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53.

[0142] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0143] (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 6, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 4, 5 and 6;

[0144] (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 10, 11 and 6, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 10, 11 and 6, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 10, 11 and 6;

[0145] (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 12, 13 and 14, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 12, 13 and 14, respectively; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 10, 11 and 15, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 10, 11 and 15, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 10, 11 and 15;

[0146] (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 16, 17 and 18, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 16, 17 and 18; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 19, 20 and 21;

[0147] (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 22 and 23, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 22 and 23; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 24, 25 and 26;

[0148] (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 27, 28 and 29;

[0149] (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 30, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences set forth in NOs: 4, 5 and 30;

[0150] (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 24, 25 and 26, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 24, 25 and 26;

[0151] (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 31 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 31 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 4, 5 and 32, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 31 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences set forth in NOs: 4, 5 and 32;

[0152] (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 22 and 23, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 22 and 23; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 33, 34 and 35, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 33, 34 and 35, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 33, 34 and 35;

[0153] (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 36, 37 and 30, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 36, 37 and 30, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 36, 37 and 30;

[0154] (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 38 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 39, 40 and 41, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 39, 40 and 41, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 39, 40 and 41;

[0155] (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 45, 46 and 47, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 42, 43 and 44, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 45, 46 and 47;

[0156] (14) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 48, 49 and 29, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 48, 49 and 29;

[0157] (15) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively, or amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequences of SEQ ID NOs: 27, 28 and 29, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences set forth in NOs: 1, 2 and 3;

[0158] (16) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 7, 8 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 7, 8 and 9; and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 27, 28 and 50, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 27, 28 and 50, respectively. amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 27, 28 and 50;

[0159] (17) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 38 and 9; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 51, 52 and 53, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 38 and 9, respectively; amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity with the amino acid sequences set forth in NOs: 51, 5 and 26;

[0160] (18) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 36, 52 and 53, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively; an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in NOs: 36, 52 and 53; or

[0161] (19) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3; the LCDR1, LCDR2 and LCDR3 have the amino acid sequences of SEQ ID NOs: 54, 55 and 32, respectively, or amino acid sequences having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to the amino acid sequences of SEQ ID NOs: 1, 2 and 3, respectively. The amino acid sequences shown in NOs: 54, 5 and 32 have amino acid sequences that are at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical.

[0162] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0163] (1) HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 1, 2, and 3, respectively; and LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively;

[0164] (2) HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 7, 8, and 9, respectively; and LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 10, 11, and 6, respectively;

[0165] (3) HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NOs: 12, 13, and 14, respectively; and LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NOs: 10, 11, and 15, respectively;

[0166] (4) HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 16, 17 and 18, respectively; LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 19, 20 and 21, respectively.

[0167] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0168] (1) HCDR1, HCDR2, and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 1, 2, and 3, respectively; and LCDR1, LCDR2, and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 4, 5, and 6, respectively;

[0169] (2) HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively; LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 10, 11 and 6, respectively.

[0170] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0171] a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55, 58, 59 or 61, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 55, 58, 59 or 61; and / or

[0172] A light chain variable region comprising the amino acid sequence of SEQ ID NO: 56, 57, 60 or 62, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 56, 57, 60 or 62.

[0173] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0174] (1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56, or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:56;

[0175] (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:60;

[0176] (3) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:57;

[0177] (4) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:58, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:58, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:57;

[0178] (5) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:61, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:62, or a sequence of amino acids that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the sequence of amino acids set forth in SEQ ID NO:62; or

[0179] (6) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:62, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:62.

[0180] In some embodiments, the different amino acids between the amino acid sequence of SEQ ID NO: 55, 56, 57, 58, 59, 60, 61 or 62 and an amino acid sequence at least 80% identical thereto are all located in the FR region.

[0181] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0182] (1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 56;

[0183] (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 60;

[0184] (3) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 57;

[0185] (4) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 58, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 57; or

[0186] (5) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 62;

[0187] The different amino acids between the amino acid sequence of SEQ ID NO: 55, 56, 57, 58, 59, 60, 61 or 62 and an amino acid sequence having at least 80% identity thereto are all located in the FR region.

[0188] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0189] (1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 56; or

[0190] (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 60;

[0191] The different amino acids between the amino acid sequence of SEQ ID NO: 55, 56, 59 or 60 and an amino acid sequence having at least 80% identity therewith are all located in the FR region.

[0192] In some embodiments of the present application, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0193] (1) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 55 and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 56; or

[0194] (2) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 59, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 60.

[0195] The scope of the above-mentioned CDR has been defined according to the AbM numbering rules, but those skilled in the art will understand that CDR sequences numbered according to any one or more of the ImMunoGenTics (IMGT) numbering rules, the Kabat numbering rules, the Chothia numbering rules and the Contact numbering rules (based on analysis of available complex crystal structures) also fall within the scope of protection of this application.

[0196] In the present application, conservative modifications can also be made to anti-TREM2 antibodies or antigen-binding fragments thereof. Conservative modifications refer to amino acid modifications that do not significantly affect or change the binding properties of the antibody. For example, conservative amino acid substitutions can be made by replacing another amino acid of the same type (having similar chemical properties or functions). As an example, amino acids can be divided into the following categories based on their side chain properties: (1) non-polar amino acids: Ala (A), Val (V), Leu (L), Ile (I), Pro (P), Phe (F), Trp (W), Met (M); (2) uncharged polar amino acids: Gly (G), Ser (S), Thr (T), Cys (C), Tyr (Y), Asn (N), Gln (Q); (3) acidic amino acids: Asp (D), Glu (E); (4) basic amino acids: Lys (K), Arg (R), His (H). Alternatively, amino acids can be divided into the following categories based on common side chain properties: (1) hydrophobic amino acids: Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic amino acids: Cys, Ser, Thr, Asn, Gln; (3) acidic amino acids: Asp, Glu; (4) basic amino acids: His, Lys, Arg; (5) amino acids that affect chain orientation: Gly, Pro; (6) aromatic amino acids: Trp, Tyr, Phe.

[0197] The anti-TREM2 antibodies or antigen-binding fragments thereof and variants thereof described in the present application are all capable of specifically binding to TREM2.

[0198] The anti-TREM2 antibody or antigen-binding fragment thereof of the present application is an isolated anti-TREM2 antibody or antigen-binding fragment thereof.

[0199] In some embodiments, the antibody is a mouse antibody, a monkey antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a fully human antibody; preferably, the antibody is a humanized antibody.

[0200] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof is selected from at least one of a monoclonal antibody, a polyclonal antibody, a neutralizing antibody, an antagonistic antibody, a fucosylated antibody, a monospecific antibody, a multispecific antibody, a nanobody, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb fragment, an isolated CDR region, and a scFv.

[0201] In some embodiments, the anti-TREM2 antibody is a monoclonal antibody.

[0202] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof further comprises a heavy chain constant region and / or a light chain constant region.

[0203] Preferably, the heavy chain constant region is the heavy chain constant region of IgG, IgA, IgM, IgE or IgD or a variant thereof; the heavy chain constant region is preferably the heavy chain constant region of IgG or a variant thereof, such as the constant region of IgG1, IgG2, IgG3 or IgG4 or a variant thereof; the heavy chain constant region is more preferably the heavy chain constant region of IgG1 or a variant thereof.

[0204] Preferably, the light chain constant region is a constant region of a kappa chain or a lambda chain, or a variant thereof.

[0205] In some embodiments, the heavy chain constant region comprises a full-length heavy chain constant region or a fragment thereof, and the fragment can be selected from a CH1 region, an Fc region, or a CH3 region;

[0206] In some embodiments, the heavy chain constant region or variant thereof comprises an IgG1 Fc region having one or more mutations that enhance antibody-dependent cell-mediated cytotoxicity (ADCC).

[0207] In some embodiments, the heavy chain constant region or variant thereof comprises mutations at positions 234, 235, and 243 of the IgG1 Fc region, or mutations at positions 239, 330, and 332. In some embodiments, the IgG1 Fc region comprises mutations at positions S239D, A330L, and I332E.

[0208] In some embodiments, the Fc region binds an Fcγ receptor, e.g., FcγRI, FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa, or FcγRIIIb.

[0209] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises the heavy and light chain variable regions described above, and an IgG1 Fc region. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises the heavy and light chain variable regions described above, and an IgG1 Fc region and a constant region of a human kappa chain. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises the heavy and light chain variable regions described above, an IgG1 Fc region and a constant region of a human kappa chain. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises the heavy and light chain variable regions described above, an IgG1 heavy chain constant region, and a constant region of a human kappa chain and a constant region of a human lambda chain at a concentration ratio of 2:1. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises the heavy and light chain variable regions described above, and an IgG1 Fc region having at least one mutation of S239D, A330L, and I332E. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises: (1) the heavy chain variable region and light chain variable region described above, (2) an IgG1 Fc region having at least one mutation among S239D, A330L, and I332E; and (3) a constant region of a human kappa chain. In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises: (1) the heavy chain variable region and light chain variable region described above, (2) an IgG1 Fc region having at least one mutation among S239D, A330L, and I332E; and (3) a constant region of a human kappa chain and a constant region of a human lambda chain at a concentration ratio of 2:1.

[0210] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises: (1) a heavy chain comprising the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 67; and a light chain comprising the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0211] (2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 63; and the light chain comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 64;

[0212] (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 69; and the light chain comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 70;

[0213] (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 67; and the light chain comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 70;

[0214] (5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 72; and the light chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0215] (6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 63; and the light chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 65;

[0216] (7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 66; and the light chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 65; or

[0217] (8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 71; and the light chain comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 64.

[0218] In some embodiments, the different amino acids between the amino acid sequence shown in SEQ ID NO: 67, 68, 69, 70, 72, 63, 64, 65, 66 or 71 and an amino acid sequence with at least 80% identity thereto are mainly or entirely located in the FR region and / or the constant region; preferably, all located in the FR region and / or the constant region.

[0219] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0220] (1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 67; and the light chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0221] (2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 63; and the light chain comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 64;

[0222] (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 72; and the light chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0223] (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 71; and the light chain comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 64;

[0224] (5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 69; and the light chain comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 70;

[0225] (6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 63; and the light chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 65; or

[0226] (7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 66; and the light chain comprises the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 65.

[0227] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises:

[0228] (1) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 67; and the light chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0229] (2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 72; and the light chain comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 68;

[0230] (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 63; and the light chain comprises the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 64; or

[0231] (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 71 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 71; and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence set forth in SEQ ID NO: 64.

[0232] In some embodiments, the antibody is a multispecific antibody that specifically binds TREM2 and additionally specifically binds one or more other targets.

[0233] Preferably, the multispecific antibody further comprises at least one second antibody having a second binding specificity for a second target. Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. More preferably, the multispecific antibody is a bispecific antibody.

[0234] As non-limiting examples, the anti-TREM2 antibody or antigen-binding fragment thereof has one or more of the following properties:

[0235] (1) Ability to bind to human TREM2;

[0236] (2) able to bind to mouse TREM2;

[0237] (3) able to bind to cynomolgus monkey TREM2;

[0238] (4) competing with one or more TREM2 ligands for binding to TREM2;

[0239] (5) inhibiting and / or blocking the binding of TREM2 to ligands;

[0240] (6) inhibiting and / or blocking intracellular signal transduction mediated by TREM2 binding ligands;

[0241] (7) Induce cytokine or chemokine secretion;

[0242] (8) having at least one of antibody-dependent cell-mediated cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and antibody-mediated phagocytosis (ADCP) activity;

[0243] (9) Enhance immune response;

[0244] (10) Enhanced ADCC activity.

[0245] In some embodiments, the one or more TREM2 ligands are selected from Escherichia coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholine, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid-β peptide.

[0246] In some embodiments, the cytokine or chemokine is selected from IFN-γ, TNF-α, CXCL1, or CXCL10.

[0247] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof is capable of specifically killing, depleting, or disabling TREM2+ myeloid cells.

[0248] Optionally, the TREM2+ myeloid cells are non-stimulatory myeloid cells, for example, CD45+, HLA-DR+, CD11c+, CD14+, and BDCA3- non-stimulatory myeloid cells. Optionally, the TREM2+ myeloid cells are intratumoral myeloid cells. Optionally, the TREM2+ cells are selected from dendritic cells, macrophages, monocytes, and neutrophils; the macrophages are preferably tumor-associated macrophages (TAMs).

[0249] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof has ADCC activity. ADCC can occur when the antibody binds to an antigen on the surface of a pathogenic or tumorigenic target cell.

[0250] To assess the activity of the ADCC effect of the target molecule, an in vitro ADCC assay such as that described in U.S. Patent No. 5,500,362 or 5,821,337 can be performed. Effector cells that can be used for the assay include peripheral blood mononuclear cells (PBMC) and natural killer (NK) cells. Alternatively or additionally, the activity of the ADCC effect of the target molecule can be assessed in vivo, for example, in an animal model such as that disclosed in Clynes et al., Proc. Natl. Acad. Sci. (USA) 95: 652-656 (1998).

[0251] The second aspect of the present application provides a nucleic acid molecule, which encodes the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application.

[0252] In some embodiments, the nucleic acid molecule includes a nucleic acid molecule encoding the heavy chain variable region and / or light chain variable region of the anti-TREM2 antibody or antigen-binding fragment thereof described in the present application.

[0253] The third aspect of the present application provides a recombinant vector comprising the nucleic acid molecule described in the second aspect of the present application.

[0254] The term "vector" refers to a tool for expressing a target gene in a host cell, such as a plasmid vector, a cosmid vector, and a viral vector such as a phage vector, a lentiviral vector, an adenoviral vector, a retroviral vector, and an adeno-associated viral vector. Recombinant vectors can be constructed by or by manipulating plasmids (e.g., pSC101, pGV1106, pACYC177, ColE1, pKT230, pME290, pBR322, pUC8 / 9, pUC6, pBD9, pHC79, pIJ61, pLAFR1, pHV14, pGEX series, pET series, pUC19, etc.), phages (e.g., λgt4λB, λ-Charon, λΔz1, M13, etc.), or viral vectors (e.g., SV40, etc.), which are commonly used in the art.

[0255] In a recombinant vector, a nucleic acid molecule can be operably linked to a promoter. The term "operably linked" is intended to refer to a functional connection between a target nucleotide sequence and an expression control sequence (e.g., a promoter sequence). When "operably linked," a regulatory element can control the transcription and / or translation of the target polynucleotide.

[0256] In some embodiments, the vector is a cloning vector; in other embodiments, the vector is an expression vector. The expression vector can optionally be any expression vector capable of expressing the anti-TREM2 antibody or antigen-binding fragment thereof described herein.

[0257] In order to use in a host such as a prokaryotic or eukaryotic cell, a recombinant vector can be constructed accordingly. For example, when constructing a vector as an expression vector for a prokaryotic host, the vector generally includes a strong promoter for transcription (e.g., pLλ promoter, CMV promoter, trp promoter, lac promoter, tac promoter, T7 promoter, etc.), a ribosome binding site for initiating translation, and a transcription / translation termination sequence. On the other hand, expression vectors for eukaryotic hosts include replication origins that can be operated in eukaryotic cells, such as f1 replication origin, SV40 replication origin, pMB1 replication origin, adenovirus replication origin, AAV replication origin, and BBV replication origin, but are not limited thereto. In addition, expression vectors generally include promoters derived from mammalian cell genomes (e.g., metallothionein promoters) or promoters derived from mammalian viruses (e.g., adenovirus late promoter, vaccinia virus 7.5K promoter, SV40 promoter, cytomegalovirus promoter, tk promoter of HSV, etc.), and a polyadenylation sequence as a transcription termination sequence. Recombinant cells can be prepared by introducing the recombinant vector into a suitable host cell. Any host cell known in the art can be used in the present disclosure, as long as it allows the recombinant vector to be continuously cloned and expressed in a stable manner. Examples of prokaryotic host cells that can be used in the present disclosure can be selected from Escherichia coli (E. coli) such as E. coli JM109, E. coli BL21, E. coli RR1, E. coli LE392, E. coli B, E. coli X1776, E. coli W3110, Bacillus species such as Bacillus subtilis and Bacillus thuringiensis, and Enterobacteriaceae strains, such as Salmonella typhimurium, Serratia marcescens and various Pseudomonas species. Eukaryotic host cells that can be used for transformation can be selected from, but are not limited to, Saccharomyces cerevisiae, insect cells, and animal cells, such as Sp2 / 0, CHO (Chinese hamster ovary) K1, CHO DG44, CHO S, CHO DXB11, CHO GS-KO, PER.C6, W138, BHK, COS-7, 293, HepG2, Huh7, 3T3, RIN, MDCK, etc. Nucleic acid molecules or recombinant vectors carrying nucleic acid molecules can be introduced (transfected) into host cells using methods well known in the relevant art. For example, when the host cell is a prokaryotic cell, CaCl2 or electroporation can be used for such transfection. For eukaryotic host cells, gene introduction can be achieved using, but is not limited to, microinjection, calcium phosphate precipitation, electroporation, liposome-mediated transfection, or particle bombardment.

[0258] In order to select transformed host cells, the phenotype associated with the selection marker can be utilized according to methods well known in the art. For example, when the selection marker is a gene that confers resistance to certain antibiotics, the host cells can be grown in culture medium in the presence of antibiotics to select target transformants.

[0259] The fourth aspect of the present application provides a host cell, which comprises the nucleic acid molecule described in the second aspect of the present application or the recombinant vector described in the third aspect of the present application.

[0260] The host cell in the present application can be any suitable host cell for expressing an anti-TREM2 antibody or an antigen-binding fragment thereof, or a portion (moiety) thereof.

[0261] In some embodiments, the host cell is a prokaryotic cell. In other embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is selected from yeast cells, mammalian cells or other cells suitable for preparing antibodies or antigen-binding fragments thereof, or portions thereof. Mammalian cells are, for example, Chinese hamster ovary cells (CHO), human kidney epithelial cell line 293 cells or 293T cells. In some embodiments, the recombinant cell is a recombinant CHO cell.

[0262] In a fifth aspect, the present application provides a method for preparing an anti-TREM2 antibody or an antigen-binding fragment thereof, comprising culturing the host cell described in the fourth aspect of the present application. Preferably, the method further comprises isolating and purifying the expression product of the host cell.

[0263] The use of the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of this application, the nucleic acid molecule described in the second aspect of this application, the recombinant vector described in the third aspect of this application, or the host cell described in the fourth aspect of this application in the preparation of drugs.

[0264] In some embodiments, the drug is a drug for preventing and / or treating a disease or condition associated with TREM2. In some embodiments, the disease or condition associated with TREM2 is cancer. In some embodiments, the disease or condition associated with TREM2 is a lipid-related disease or condition. In some embodiments, the disease or condition associated with TREM2 is a fibrotic disease or condition.

[0265] In some embodiments, the drug is a drug that modulates the subject's immune response. In some specific embodiments, the drug is a drug that increases the subject's anti-tumor immune response and / or induces a subject's memory immune response.

[0266] The sixth aspect of the present application provides the use of the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect, the nucleic acid molecule described in the second aspect of the present application, the recombinant vector described in the third aspect of the present application, or the host cell described in the fourth aspect of the present application in the preparation of a reagent for diagnosing TREM2-related diseases or conditions.

[0267] In some embodiments, the TREM2-related disease or condition is cancer. In some embodiments, the TREM2-related disease or condition is a lipid-related disease or condition. In some embodiments, the TREM2-related disease or condition is a fibrotic disease or condition.

[0268] In some embodiments, the agent can modulate the subject's immune response. In some specific embodiments, the agent can increase the subject's anti-tumor immune response and / or induce a memory immune response in the subject.

[0269] The seventh aspect of the present application provides a kit for detecting TREM2, which comprises the anti-TREM2 antibody or its antigen-binding fragment described in the first aspect of the present application or the nucleic acid molecule described in the second aspect of the present application.

[0270] The eighth aspect of the present application provides a method for treating or preventing a disease or condition in a subject in need thereof, comprising administering the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application to the subject.

[0271] In some embodiments, the disease is a TREM2-related disease or condition. In some embodiments, the TREM2-related disease or condition is cancer. In some embodiments, the TREM2-related disease or condition is a lipid-related disease or condition. In some embodiments, the TREM2-related disease or condition is a fibrotic disease or condition.

[0272] The ninth aspect of the present application provides a method for enhancing the immune response of a subject, comprising administering the anti-TREM2 antibody or antigen-binding fragment thereof described in the first aspect of the present application to the subject.

[0273] Preferably, the enhancing the subject's immune response is increasing the subject's anti-tumor immune response and / or inducing the subject's memory immune response.

[0274] In some specific embodiments, the subject is a mammal, such as a human. In some embodiments, the immune response is an adaptive immune response. In some embodiments, the immune response is an innate immune response.

[0275] Cancer cells that can be killed by the anti-TREM2 antibodies or antigen-binding fragments thereof of the present application include, but are not limited to, cancer cells from the following: bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal tract, gums, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, pancreas, testicles, tongue, cervix or uterus.

[0276] In addition, the cancer may specifically be of the following histological types, although not limited thereto: tumor, malignant neoplastic disease. In some embodiments, the cancer is selected from melanoma, renal cancer, hepatobiliary cancer, head and neck squamous cell carcinoma (HNSC), pancreatic cancer, colorectal cancer, bladder cancer, glioblastoma, prostate cancer, lung cancer, breast cancer, ovarian cancer, gastric cancer, esophageal cancer, kidney cancer, leukemia, lymphoma or mesothelioma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is breast cancer.

[0277] In some embodiments, the lipid-related disease or disorder is selected from obesity, fatty liver disease, heart disease, stroke, atherosclerosis, diabetes, osteoarthritis, gout, sleep apnea, or hypertension.

[0278] In some embodiments, the fibrotic disease or disorder is a liver disease. Optionally, the liver disease is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

[0279] The appropriate dose of the anti-TREM2 antibodies or antigen-binding fragments thereof described herein can be determined by a clinician based on factors such as the age, weight, sex, general condition, and severity of the disease of the subject; they can be administered by any conventional route known in the art, such as parenteral, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal administration.

[0280] Those skilled in the art can adjust the dosage regimen to provide the optimal desired response (e.g., clinical response) based on common knowledge in the art. For example, a single large dose can be administered, multiple divided doses can be administered over time, or the single dose can be reduced or increased in proportion to the severity of the therapeutic situation. For example, when the antibody is administered as a sustained-release formulation, it can be administered at a reduced frequency. Example

[0281] The solution of the present application will be further described below with reference to embodiments. However, those skilled in the art will appreciate that the scope of protection of the present application is not limited to these embodiments.

[0282] Unless otherwise specified, the reagents, materials, or instruments involved in the following examples are commercially available.

[0283] Example 1: Expression of positive control antibody

[0284] Pionyr Immunotherapeutics' TREM2 antibody PY314 was used as a positive control antibody. The variable region amino acid sequence of PY314 is described in WO2019118513. It uses the IgG1 subtype and enhances its ADCC effect through the heavy chain constant region S239D / I332E / A330L mutations. Its sequence is shown below:

[0285] PY314 heavy chain sequence, SEQ NO ID: 73:

[0286] PY314 light chain sequence, SEQ NO ID: 74:

[0287] The light chain and heavy chain genes of PY314 were synthesized and subcloned into the pcDNA3.4 expression vector, respectively, and transfected into Expi CHO cells. After culture at 37°C and 5% CO2, the cell culture was collected, centrifuged, and purified using a Protein A affinity column to obtain the PY314 antibody.

[0288] Example 2: Construction and screening of mouse immune library

[0289] Balb / C and C57 mice were immunized five times, alternate weeks apart, with either a single human TREM2 protein (purchased from Klebsiella pneumoniae) or a cross-immunization of human and mouse TREM2 proteins (purchased from Klebsiella pneumoniae). The initial immunization used 100 μg of TREM2 protein emulsified with Freund's complete adjuvant (FAA). Subsequent immunizations used 50 μg of FAA with incomplete FAB adjuvant (FAA). Injections were intraperitoneal and subcutaneous at multiple sites. Mice with good immune titer detection were killed by cervical dislocation, and the spleen of the mice was obtained under sterile conditions. RNA was extracted from the spleen cells according to the instructions of the RNA extraction kit (purchased from Omega), and cDNA was obtained by reverse transcription according to the instructions of the reverse transcription kit (purchased from TaKaRa). The immunized mouse antibody Fab gene was amplified by PCR using universal degenerate primers (synthesized by Jin Weizhi), and the obtained PCR amplification product was subjected to 1% agarose gel electrophoresis. The obtained PCR amplification product was recovered using a DNA purification and recovery kit (purchased from Omega) according to the instructions. The antibody Fab gene was recombined by Hind III and Not I (purchased from TaKaRa) enzyme digestion and T4 DNA ligase in vitro ligation. The recombinant antibody Fab gene sequence was inserted into the M13 phage vector, and 1% agarose gel electrophoresis was performed. The correctly constructed recombinant vector was recovered using a DNA purification and recovery kit (purchased from Omega) according to the instructions. The obtained recombinant vector was then transformed into Escherichia coli competent cells, cultured in LB medium, centrifuged, and washed with 1×PBS to obtain a mouse immune antibody library.

[0290] The mouse immune antibody library was screened by solid phase and liquid phase cross-screening, and specific Fab antibodies against human, mouse, and crab-eating macaque TREM2 were enriched by trypsin elution.

[0291] Mouse immune antibody library screening (Kingfisher method):

[0292] (1) Background subtraction: The mouse immune antibody library phage suspension was diluted with 5% BSA and blocked, and incubated with Dynabeads (purchased from Invitrogen), and the phages after negative screening incubation were collected.

[0293] (2) Dynabeads blocking and coating: The magnetic beads were bound and washed using the Kingfisher magnetic bead screening system (purchased from Thermo scientific), and 5% BSA was incubated with the magnetic beads.

[0294] (3) Positive screening: The phage suspension collected after negative screening was incubated with Dynabeads coated and blocked with biotin-labeled TREM2 protein (purchased from Kaijia), and the binding and washing were performed using the Kingfisher magnetic bead screening system.

[0295] (4) Elution: Use Trypsin (purchased from Shanghai Biotechnology) to elute the phage.

[0296] (5) Infection of library plates: After elution, the phage solution was thoroughly mixed with logarithmic phase SS320 cells and incubated at 37°C for 30 min. The cells were then spread onto 2YT-Car+-Tet+ plates and cultured in a 37°C incubator overnight.

[0297] (6) Titer: The eluted phage solution was diluted 10-fold with logarithmic phase SS320 cells, incubated at 37°C for 30 min, mixed and dropped 2 μL onto a plate, and cultured in a 37°C incubator overnight.

[0298] (7) Statistics: Calculate phage input, output, etc., prepare the input phage by scraping and perform two rounds of screening. Each round of screening uses a 3-fold gradient antigen concentration reduction to obtain antibody clones with higher affinity.

[0299] Mouse immune antibody library screening (immunotube method):

[0300] (1) Background subtraction: The mouse immune library phage suspension was blocked with 5% PBSM.

[0301] (2) Immunotube coating and blocking: TREM2 protein (purchased from KaiXia) was coated with 5% PBSM for blocking.

[0302] (3) Positive screening: incubate the phage suspension with the protein-coated and sealed immunotubes, and perform binding and washing according to the immunotube screening system method.

[0303] (4) Elution: Use Trypsin (purchased from Shanghai Biotechnology) to elute the phage.

[0304] (5) Infection of library plates: After elution, the phage solution was thoroughly mixed with logarithmic phase SS320 cells and incubated at 37°C for 30 min. The cells were then spread onto 2YT-Car+-Tet+ plates and cultured in a 37°C incubator overnight.

[0305] (6) Titer: The eluted phage solution was diluted 10-fold with logarithmic phase SS320 cells, incubated at 37°C for 30 min, mixed and dropped 2 μL onto a plate, and cultured in a 37°C incubator overnight.

[0306] (7) Statistics: Calculate phage input, output, etc., prepare the input phage by scraping and perform three rounds of screening. Each round of screening uses a 3-fold gradient antigen concentration reduction to obtain antibody clones with higher affinity.

[0307] The enrichment of the above different output pools was tested by ELISA according to the following steps:

[0308] (1) Coating: 96-well plates were coated with 2 μg / mL human, mouse, or cynomolgus monkey TREM2 (all purchased from Kaijia), 30 μL per well, incubated overnight at 4°C, and washed three times with PBST.

[0309] (2) Blocking: Add 5% PBSM to each well for 1 hour at room temperature, and wash the plate three times with PBST.

[0310] (3) Primary antibody incubation: The Fab or phage expression supernatants of the above different output pools were diluted 5-fold with 5% PBSM, and the diluted supernatants were added at 30 μL / well. The plates were incubated at room temperature for 1 hour, and the plates were washed 3 times with PBST.

[0311] (4) Secondary antibody incubation: Add the secondary antibody Anti-mouse-Fab-HRP (purchased from Sino biological) diluted 1:5000 in PBS to the Fab supernatant, and add the secondary antibody Anti-M13-HRP (purchased from Sino biological) diluted 1:20000 in 5% PBSM to the phage supernatant, 30 μL / well, incubate at room temperature for 1 hour, and wash the plate 6 times with PBST.

[0312] (5) Termination: Add 30 μL / well of TMB (purchased from SurModics) to develop color at room temperature for 5-10 minutes, then add 30 μL / well of stop solution (2 M sulfuric acid) to terminate the reaction, and read the data using a microplate reader at OD 450.

[0313] Output sets that can cross-enrich with human, mouse, and cynomolgus monkey TREM2 (all purchased from Kaijia) at the Fab level or phage level, or can cross-enrich with human and cynomolgus monkey TREM2, were selected. Monoclonal clones from the output sets of the second and third rounds of screening were selected for primary phage ELISA screening against human, mouse, and cynomolgus monkey TREM2. A total of 786 clones were selected in the primary screening, from which 90 positive clones with human, mouse, and monkey cross-binding activity at the protein ELISA level were obtained, and 163 positive clones with human and monkey cross-binding activity were obtained, of which 65 were sequence-unique molecules. Full-length chimeric antibodies were constructed for 61 of these molecules using the human IgG1 subtype.

[0314] The chimeric antibody construction process is as follows: the genes of the 61 Fab molecules mentioned above and the genes of the heavy chain constant region and light chain constant region (κ chain) of human IgG1 are cloned into the pcDNA3.4 expression vector respectively, and the chimeric antibody expression plasmid with the correct sequence is obtained by sequencing analysis. TM The chimeric antibody expression plasmid was transfected into Expi CHO cells according to the instructions of CHO transfection reagent (purchased from Thermo). After incubation at 37°C and 5% CO2, the supernatant was collected by centrifugation and purified by Protein A affinity chromatography to obtain the chimeric antibody.

[0315] Example 3: FACS binding activity of chimeric antibodies

[0316] The binding activity of each chimeric antibody in Example 2 to CHO-K1 cells overexpressing human TREM2, mouse TREM2, and crab-eating macaque TREM2 (all purchased from Yoshiman Gene) was detected by flow cytometry, and the steps are as follows.

[0317] (1) According to 1×10 5 Cells were seeded at 100 μg / well, centrifuged and washed with FACS buffer.

[0318] (2) Add 100 μL of the chimeric antibody after concentration gradient dilution (initial concentration 50 μg / mL, 4-fold dilution with FACS buffer, FACS buffer is DPBS + 1% BSA) to the cells, incubate at 4°C for 60 min, and wash the cells twice with FACS buffer by centrifugation.

[0319] (3) Add 100 μL of PE-labeled anti-Human Fc (purchased from Abcam) to the cells and incubate at 4°C for 30 min.

[0320] (4) Resuspend the cells in FACS buffer and analyze them using a flow cytometer.

[0321] Figures 1-1 to 1-4 show the binding of chimeric antibodies to human TREM2-overexpressing cell lines, Figures 1-5 to 1-8 show the binding of chimeric antibodies to mouse TREM2-overexpressing cell lines, and Figures 1-9 to 1-10 show the binding of chimeric antibodies to cynomolgus monkey TREM2-overexpressing cell lines, with PY314 antibody used as a positive control. It can be seen that chimeric antibodies can cross-bind to human, mouse, and monkey TREM2-overexpressing cell lines, or to human and monkey TREM2-overexpressing cell lines.

[0322] Among them, chimeric antibodies constructed based on clones A48, A33, A37, B59, A21, A4, A18, A40, A82, A35, A22, A29, A44, A45, A53, A55, A80, A20, and A31 showed better binding activity. The CDR sequences of the chimeric antibodies are shown in Table 1.

[0323] Table 1 CDR sequences of chimeric antibodies

[0324] Example 4: Humanization of chimeric antibodies

[0325] The chimeric antibodies A33, A37, A48, and B59 constructed in Example 2 were humanized. Humanized design was performed based on the amino acid sequences of the chimeric antibody heavy and light chains. The CDR region sequences of the chimeric antibodies A33, A37, A48, and B59 remained unchanged. According to the results of germline alignment and the results of antibody structure simulation, different humanized antibody templates were selected for the heavy and light chains, respectively. After humanization, the framework regions were reverse mutated to design candidate humanized antibody sequences. 10, 8, 8, and 16 humanized antibody molecules were designed based on the chimeric antibody A33, A37, A48, and B59 antibody sequences, respectively. The heavy and light chains of the designed humanized antibodies were gene synthesized separately, the heavy chain was subcloned into the pcDNA3.4-hIgG1 expression vector, and the light chain was subcloned into the pcDNA3.4-hIgKc expression vector. After sequencing verification, the constructed vector was transiently expressed in Expi CHO cells and purified using Protein A affinity chromatography to obtain the humanized antibody. The heavy and light chain sequences of representative humanized antibodies are shown in Table 2.

[0326] Table 2 Humanized antibody heavy chain and light chain sequences

[0327] Example 5: ELISA binding activity of humanized antibodies

[0328] The binding activity of the humanized antibodies to human, mouse, and cynomolgus monkey TREM2 was tested by ELISA according to the following steps and compared with the parental chimeric antibodies (human-mouse chimeric antibodies A33, A37, A48, and B59):

[0329] (1) Coating: 96-well plates were coated with 2 μg / mL human, mouse, or cynomolgus monkey TREM2 (all purchased from Kaijia), 30 μL per well, incubated overnight at 4°C, and washed three times with PBST.

[0330] (2) Blocking: Add 5% PBSM to each well for 2 hours at room temperature, and wash the plate three times with PBST.

[0331] (3) Primary antibody incubation: dilute the antibody to be tested with 1% PBSM in a 3-fold gradient to a final concentration of 3, 0.333, 0.111, 0.037, 0.0123, 0.00412, 0, 00137, and 0.00045 μg / mL, respectively. Add 30 μL / well of the diluted antibody and incubate at room temperature for 1 hour. Wash the plate three times with PBST.

[0332] (4) Secondary antibody incubation: Add secondary antibody Anti-human-Fc-IgG-HRP (purchased from abcam) diluted 1:8000 with 1% milk, incubate at room temperature for 1 hour, and wash the plate 6 times with PBST.

[0333] (5) Termination: Add 30 μL / well of TMB (purchased from SurModics) to develop color at room temperature for 5-10 minutes, then add 30 μL / well of stop solution (2 M sulfuric acid) to terminate the reaction, and read the data using a microplate reader at OD 450.

[0334] Tables 3 to 6 show the binding of humanized antibodies A33, A37, A48, and B59 to human, mouse, and cynomolgus monkey TREM2 proteins, respectively. It can be seen that some humanized antibodies of A33, A37, A48, and B59 retain good binding activity compared to the parent chimeric antibody.

[0335] Table 3 EC binding of A33 humanized antibody by ELISA 50 Results Summary Table

[0336] Note: N means no binding activity or weak binding activity, EC cannot be calculated 50 .

[0337] Table 4 EC binding of A37 humanized antibody by ELISA 50 Results Summary Table

[0338] Table 5 EC binding of A48 humanized antibody by ELISA 50 Results Summary Table

[0339] Table 6 EC binding of B59 humanized antibody ELISA 50 Results Summary Table

[0340] Note: N means no binding activity or weak binding activity, EC cannot be calculated 50 .

[0341] Example 6: FACS binding activity of humanized antibodies

[0342] According to the steps described in Example 3, flow cytometry was used to detect the binding activity of humanized antibodies to CHO-K1 cells overexpressing human TREM2, mouse TREM2, and crab-eating macaque TREM2.

[0343] Figures 2-1 to 2-4 show the binding of representative humanized antibodies to human TREM2-overexpressing cell lines, Figures 2-5 to 2-6 show the binding of representative humanized antibodies to mouse TREM2-overexpressing cell lines, and Figures 2-7 to 2-9 show the binding of representative humanized antibodies to cynomolgus monkey TREM2-overexpressing cell lines, with PY314 antibody used as a positive control. It can be seen that the humanized antibodies A33, A37, A48, and B59 all retained good FACS binding activity compared to the parental chimeric antibodies (human-mouse chimeric antibodies A33, A37, A48, and B59).

[0344] Example 7: ADCC effect of humanized antibodies

[0345] The ability of humanized antibodies to mediate ADCC effects was detected using the following steps, with human PBMC cells as effector cells and CHO-K1 cells overexpressing human TREM2 (purchased from Yoshimitsu Gene) as target cells.

[0346] (1) According to 1×10 4 hu-TREM2-CHO-K1 cells were inoculated at 50 μL / well and incubated at 37°C for 30 min. At the same time, target cell plus effector cell wells (only target cells and effector cells were added), target cell non-lysis wells (only target cells were added), and target cell full lysis wells (only target cells were added) were set.

[0347] (2) The humanized antibody was serially diluted with 1840 medium containing 1% FBS and added to the cells at 50 μL / well to achieve final concentrations of 2, 0.2, 0.02, and 0.002 μg / mL, respectively. The cells were incubated at 37°C for 30 min.

[0348] (3) According to 5×10 5 cells / well, 100 μL / well PBMC cells (prepared by Sanyou Biotechnology) were added and incubated at 37°C for 4 h.

[0349] (4) Add 10 μL of 10% Triton X-100 to the target cell lysis well and incubate at 37°C for 30 min.

[0350] (5) After centrifugation, 60 μL of supernatant was taken from each well and mixed with LDH reagent in equal proportions. The mixture was incubated at room temperature for 30 min and the OD value was measured at 490 nm.

[0351] (6) Calculate the lysis rate according to the following formula: lysis rate = (OD value of sample well - OD value of target cell plus effector cell well) / (OD value of target cell fully lysed well - OD value of target cell non-lysed well)

[0352] Figures 3-1 and 3-2 show the ADCC effect results of humanized antibodies. It can be seen that humanized antibodies A33-H5-L1, A33-H4-L2, A33-H5-L2, A48-H4-L1, and A48-H2-L2 have strong activity in inducing ADCC effect.

[0353] Example 8: Affinity of humanized antibodies

[0354] The affinity of humanized antibodies A33-H5-L1 and A48-H2-L2 for human TREM2 was determined using a Biacore T200 (Cytiva) instrument. The test antibodies were diluted to 30 nM in 1× HBS-EP buffer (pH 7.4). Human TREM2 (purchased from Klein Biosciences) was diluted two-fold in 1× HBS-EP buffer (pH 7.4) to concentrations of 150, 75, 37.5, 18.75, 9.38, 4.69, 2.34, 1.17, and 0.58 nM, respectively. Protein A chips (purchased from Cytiva) were used for detection according to pre-set protocols. First, the chip captured the antibody to be tested for 120 seconds. After the capture was completed, it was equilibrated in 1×HBS-EP (pH 7.4) buffer for 30 seconds. Then, different concentrations of antigen dilutions were passed through the chip in sequence for antibody-antigen binding for 180 seconds, and then switched to 1×HBS-EP (pH 7.4) buffer for dissociation for 300 seconds. Finally, the K value was obtained by fitting the binding and dissociation data of different concentrations of antigen and antibody. D , K on and K off .

[0355] Table 7 shows the affinity test results of the humanized antibodies. It can be seen that the affinity of the humanized antibody A48-H2-L2 to human TREM2 is higher than that of PY314, and A33-H5-L1 is comparable to PY314.

[0356] Table 7 Affinity of humanized antibodies to human TREM2

[0357] Example 9: In vivo efficacy study of humanized antibodies

[0358] The humanized antibodies A33-H5-L1 and A48-H2-L2 were used to study the efficacy of the humanized antibodies in a mouse tumor model. To better simulate the efficacy in humans, TREM2 humanized C57BL / 6 mice (purchased from Shanghai Model Organisms) with the human TREM2 gene were used. Female TREM2 humanized mice were subcutaneously inoculated with MC38 mouse colon cancer cells at a dose of 2.5E6 per mouse to establish a subcutaneous tumor-bearing model. The tumors were grown to 100 mm. 3 Around 14:00, the mice were divided into groups and dosed according to the schedule shown in Table 8. During the study, the survival and general condition of the mice were observed every day, and the tumor volume and body weight were measured twice a week.

[0359] The tumor growth curve and body weight change trend graph up to the study endpoint are shown in Figure 4-1 and Figure 4-2, respectively. The tumor growth inhibition rate (TGI) is shown in Table 8. The research results show that humanized antibodies A33-H5-L1 and A48-H2-L2 both have significant tumor inhibitory effects, and their tumor inhibitory effects are significantly higher than those of PY314. There was no significant weight loss in the animals in each group during the experiment.

[0360] Table 8 In vivo efficacy study plan for humanized antibodies

[0361] Example 10: ADCC enhancement modification of humanized antibodies

[0362] To further enhance the ADCC effect of humanized antibodies A33-H5-L1 and A48-H2-L2, S239D / I332E / A330L point mutations were performed on their heavy chain constant regions. These mutations are represented by HC. A33-H5-L1-HC represents the A33-H5-L1 molecule after mutation, and A48-H2-L2-HC represents the A48-H2-L2 molecule after mutation. The sequences are shown in Table 9.

[0363] Table 9 ADCC-enhanced humanized antibody heavy and light chain sequences

[0364] Example 11: ADCC effect of humanized antibodies after mutation modification

[0365] The ability of the humanized antibodies A33-H5-L1-HC and A48-H2-L2-HC to mediate ADCC effects after mutation was detected using the steps described in Example 7, and the humanized antibodies A33-H5-L1 and A48-H2-L2 before mutation were used as controls. The final concentrations of A33-H5-L1-HC and A48-H2-L2-HC added to the cells were 5, 1.667, 0.556, 0.185, 0.0617, 0.0206, 0.0069, and 0.0023 nM, respectively, and the final concentrations of A33-H5-L1 and A48-H2-L2 added to the cells were 100, 20, 4, 0.8, 0.16, 0.032, 0.0064, and 0.0013 nM, respectively.

[0366] FIG5 shows the ADCC effect results of the humanized antibodies after mutation modification. It can be seen that the ADCC effect-inducing activity of the mutated A33-H5-L1-HC and A48-H2-L2-HC is significantly enhanced compared with that before mutation modification.

[0367] The sequences of the present application are listed in Table 10 below.

[0368] Table 10

[0369] For the purposes of description and disclosure, all patents, patent applications, and other publications are expressly incorporated herein by reference. These publications are provided solely because their disclosure predates the filing date of the present application. All statements regarding the dates of these documents or the representations of their contents are based on the information available to the applicant and do not constitute any admission as to the correctness of the dates of these documents or the contents of these documents. Furthermore, any citation of these publications herein does not constitute an admission that such publications become part of the common general knowledge in the art in any country.

[0370] Those skilled in the art will recognize that the scope of the present application is not limited to the various specific implementation modes and examples described above, but that various modifications, replacements, or recombinations can be made without departing from the spirit of the present application, which all fall within the scope of protection of the present application.

Claims

1. An anti-TREM2 antibody or an antigen-binding fragment thereof, comprising: (a) a heavy chain variable region comprising the following complementarity determining regions: HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 1, 7, 12, 16 or 42, or an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO: 1, 7, 12, 16 or 42; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43, or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO: 2, 8, 13, 17, 22, 31, 38 or 43; HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 3, 9, 14, 18, 23 or 44, or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 3, 9, 14, 18, 23 or 44; and / or (b) a light chain variable region comprising the following complementarity determining regions: LCDR1 comprising the amino acid sequence shown in SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54, or an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO:4, 10, 19, 24, 27, 33, 36, 39, 45, 48, 51 or 54; LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52, or an amino acid sequence having at least 80% identity to the amino acid sequence shown in SEQ ID NO: 5, 11, 20, 25, 28, 34, 37, 40, 46, 49 or 52; LCDR3, which comprises the amino acid sequence shown in SEQ ID NO:6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53, or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:6, 15, 21, 26, 29, 30, 32, 35, 41, 47, 50 or 53.

2. The anti-TREM2 antibody or antigen-binding fragment thereof according to claim 1, comprising: (1) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 4, 5 and 6, respectively; (2) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 10, 11 and 6, respectively; (3) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 12, 13 and 14, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 10, 11 and 15, respectively; (4) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 16, 17 and 18, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 19, 20 and 21, respectively; (5) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 22 and 23, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26, respectively; (6) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 27, 28 and 29, respectively; (7) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 4, 5 and 30, respectively; (8) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 24, 25 and 26, respectively; (9) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 31 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 4, 5 and 32, respectively; (10) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 22 and 23, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 33, 34 and 35, respectively; (11) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 36, 37 and 30, respectively; (12) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 38 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 39, 40 and 41, respectively; (13) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 42, 43 and 44, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 45, 46 and 47, respectively; (14) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 48, 49 and 29, respectively; (15) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 27, 5 and 26, respectively; (16) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 7, 8 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 27, 28 and 50, respectively; (17) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 38 and 9, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 51, 5 and 26, respectively; (18) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 36, 52 and 53, respectively; or (19) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein the HCDR1, HCDR2 and HCDR3 have the amino acid sequences shown in SEQ ID NOs: 1, 2 and 3, respectively, and the LCDR1, LCDR2 and LCDR3 have the amino acid sequences shown in SEQ ID NOs: 54, 5 and 32, respectively.

3. The anti-TREM2 antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising: A heavy chain variable region comprising an amino acid sequence as shown in SEQ ID NOs: 55, 58, 59 or 61, or an amino acid sequence having at least 80% identity with an amino acid sequence as shown in SEQ ID NOs: 55, 58, 59 or 61; and / or A light chain variable region comprising an amino acid sequence as shown in SEQ ID NOs: 56, 57, 60 or 62, or an amino acid sequence having at least 80% identity with the amino acid sequence as shown in SEQ ID NOs: 56, 57, 60 or 62.

4. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 3, comprising: (1) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:56 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:56; (2) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:55 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:55, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:57; (3) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:58 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:58, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:57 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:57; (4) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:59 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:59, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:60 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:60; (5) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:61 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:61, and a light chain variable region comprising the amino acid sequence of SEQ ID NO:62 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:62; or (6) a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 59 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 59, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 62 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

62.

5. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein The antibody is a mouse antibody, a monkey antibody, a rabbit antibody, a chimeric antibody, a humanized antibody, or a fully human antibody; the antibody is preferably a humanized antibody; and / or The anti-TREM2 antibody or its antigen-binding fragment is selected from at least one of a monoclonal antibody, a polyclonal antibody, a neutralizing antibody, an antagonistic antibody, a fucosylated antibody, a monospecific antibody, a multispecific antibody, a nanobody, a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fd fragment, a Fv fragment, a dAb fragment, an isolated CDR region, and a scFv; the anti-TREM2 antibody is preferably a monoclonal antibody or a multispecific Preferably, the multispecific antibody is a bispecific antibody, a trispecific antibody or a tetraspecific antibody; or preferably, the multispecific antibody further comprises at least one second antibody having a second binding specificity for a second target.

6. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, further comprising a heavy chain constant region and / or a light chain constant region; Preferably, the heavy chain constant region is the heavy chain constant region of IgG, IgA, IgM, IgE or IgD or a variant thereof; the heavy chain constant region is preferably the heavy chain constant region of IgG or a variant thereof; the heavy chain constant region is more preferably the heavy chain constant region of human IgG1 or a variant thereof; Preferably, the light chain constant region is a constant region of a human kappa chain or a lambda chain or a variant thereof; Preferably, the heavy chain constant region comprises the amino acid sequence shown in SEQ ID NO: 75 or 76; and / or the light chain constant region comprises the amino acid sequence shown in SEQ ID NO:

77.

7. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 6, comprising: A heavy chain comprising an amino acid sequence as set forth in SEQ ID NO: 67, 69, 72, 63, 66 or 71, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence as set forth in SEQ ID NO: 67, 69, 72, 63, 66 or 71; and / or a light chain comprising the amino acid sequence of SEQ ID NO:68, 70, 64 or 65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:68, 70, 64 or 65; Preferably, the anti-TREM2 antibody or antigen-binding fragment thereof comprises: (1) a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO:67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:67; the light chain comprising the amino acid sequence of SEQ ID NO:68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:68; (2) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:63, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63; and the light chain comprises the amino acid sequence of SEQ ID NO:64, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:64; (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:69; and the light chain comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:70; (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:67, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:67; and the light chain comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:70; (5) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:72, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:72; and the light chain comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:68; (6) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:63, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:63; and the light chain comprises the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65; (7) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:66, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:66; and the light chain comprises the amino acid sequence of SEQ ID NO:65, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:65; or (8) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:71 or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:71; and the light chain comprises the amino acid sequence of SEQ ID NO:64 a sequence, or an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO:64; 8. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, comprising: (1) a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO:67 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:67; the light chain comprising the amino acid sequence of SEQ ID NO:68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:68; (2) a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO:63 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:63; the light chain comprising the amino acid sequence of SEQ ID NO:64 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:64; (3) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence of SEQ ID NO:72 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:72; and the light chain comprises the amino acid sequence of SEQ ID NO:68 or an amino acid sequence that is at least 80% identical to the amino acid sequence of SEQ ID NO:68; or (4) a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 71 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO: 71; and the light chain comprises the amino acid sequence shown in SEQ ID NO: 64 or an amino acid sequence that is at least 80% identical to the amino acid sequence shown in SEQ ID NO:

64.

9. The anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, wherein The anti-TREM2 antibody or antigen-binding fragment thereof has one or more of the following characteristics: (1) Ability to bind to human TREM2; (2) able to bind to mouse TREM2; (3) able to bind to cynomolgus monkey TREM2; (4) Compete with one or more TREM2 ligands for binding to TREM2 (5) inhibiting and / or blocking the binding of TREM2 to ligands; (6) inhibiting and / or blocking intracellular signal transduction mediated by TREM2 binding ligand; (7) Induce cytokine or chemokine secretion; (8) having at least one of antibody-dependent cell-mediated cytotoxicity (ADCC) activity, complement-dependent cytotoxicity (CDC) activity, and antibody-mediated phagocytosis (ADCP) activity; (9) Enhance immune response; (10) Enhanced ADCC activity; (11) K binding to human TREM2 D Values ​​<5E-08M, <1E-09M, <1E-10M, <5E-10M, <1E-11M or <1E-12M.

10. A nucleic acid molecule encoding the anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1-9. A recombinant vector comprising the nucleic acid molecule according to claim 10 . 12 . A host cell comprising the nucleic acid molecule according to claim 10 or the recombinant vector according to claim 11 .

13. A method for preparing an anti-TREM2 antibody or an antigen-binding fragment thereof, comprising culturing the host cell of claim 12.

14. An anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1 to 9, a nucleic acid molecule according to claim 10, a recombinant vector according to claim 11, or a host cell according to claim 12 for use in diagnosing, preventing and / or treating a TREM2-related disease or condition, or modulating an immune response in a subject; Preferably, the disease is cancer, a lipid-related disease or disorder, or a fibrotic disease or disorder; Preferably, regulating the subject's immune response is increasing the subject's anti-tumor immune response and / or inducing the subject's memory immune response.

15. A kit for detecting TREM2, comprising the anti-TREM2 antibody or antigen-binding fragment thereof according to any one of claims 1-9 and the nucleic acid molecule according to claim 10.

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