Anti-lilrb1 and / or anti-lilrb2 antibodies and uses thereof

Abstract

In certain aspects, provided herein are antibodies that bind to LILRB1 and uses thereof. In certain aspects, provided herein are also antibodies that bind to LILRB2 and uses thereof. In certain aspects, provided herein are also multispecific antibodies that bind to LILRB1 and LILRB2 and uses thereof.

Description

[0001] Case Analysis This application is a divisional application of application number 202480023784.1, filed on February 1, 2024, entitled "Anti-LILRB1 and / or anti-LILRB2 antibodies and their uses". Cross-references to related applications

[0002] This application claims priority to International Patent Application No. PCT / CN2023 / 074276, filed on February 2, 2023, the disclosure of which is incorporated herein by reference in its entirety.

[0003] sequence list This application includes a computer-readable sequence list submitted together with this application in XML file format, the entire contents of which are incorporated herein by reference. The sequence list XML file submitted together with this application is named "2600074-FI-IP-JONESD.xml", created on January 30, 2026, and has a size of 1,480,704 bytes. Technical Field

[0004] This disclosure relates in its entirety to binding agents, such as antibodies (including fragments thereof) that bind to LILRB1 and / or LILRB2, including anti-LILRB1 antibodies (including humanized anti-LILRB1 antibodies), anti-LILRB2 antibodies (including humanized anti-LILRB2 antibodies), and multispecific antibodies (including humanized multispecific antibodies) that bind to both LILRB1 and LILRB2, and methods of using thereof. Background Technology

[0005] Leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), also known as Ig-like transcript 2 (ILT2), is a receptor for class I major histocompatibility complex (MHC) antigens containing an immunoreceptor tyrosine-based inhibitory motif and recognizes a broad spectrum of human leukocyte antigen (HLA)-A, HLA-B, HLA-C, and HLA-G alleles. LILRB1 uses its two distal membrane domains (D1 and D2) to recognize the a3 domain and b2m subunit of MHC molecules. LILRB1 is also the receptor for H301 / UL18 (a class I MHC homolog of human cytomegalovirus) (Yu et al. (2018) J Clin Invest 1523-1537). LILRB1 is expressed on all B cells, monocytes, macrophages, dendritic cells, myeloid-derived suppressor cells (MDSCs), as well as NK cells and T cell subsets, and transduces negative signals that downregulate the immune response (Chen et al. (2020) J Immunother Cancere000515).

[0006] Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), also known as Ig-like transcript 4 (ILT4), is a receptor for class I MHC antigens containing an immunoreceptor tyrosine-based inhibitory motif and recognizes a broad spectrum of HLA-A, HLA-B, HLA-C, and HLA-G alleles. LILRB2 uses its two distal membrane domains (D1 and D2) to recognize the α3 domain of MHC molecules. Angiopoietin-like protein (ANGPTL), CD1d, Ab oligomers, and myelin inhibitors are also ligands of LILRB2 (Zhang et al. (2017) J Leukoc Biol 351-360). Ligand binding leads to inhibitory signaling and downregulation of the immune response. LILRB2 is expressed on monocytes, macrophages, dendritic cells, granulocytes, and myeloid-derived suppressor cells (MDSCs) (Siu et al. (2021) Clin Cancer Res 57-60).

[0007] LILRB1 and LILRB2 inhibit immune activation by binding to MHC-I via cis and trans. They recruit SHP-1 and SHP-2 phosphatases that mediate inhibition of various intracellular signaling pathways (Chen et al. (2018) J Clin Invest 5647-5662). Both LILRB1 and LILRB2 are associated with advanced disease stages and poor prognosis in multiple tumor types (Chen et al. (2022) Int Immunopharmacol 108798 and Zhang et al. (2021) Front Oncol 668707). HLA plays a crucial role in cancer immunology. Strategies used by tumor cells to evade innate and adaptive immune responses are associated with aberrant expression of human leukocyte antigen (HLA)-G (Carosella et al. (2015) Adv Immunol 33-144). HLA-A, HLA-B, HLA-C, and HLA-G bound to LILRB1 and LILRB2 can directly suppress immune cell function through receptor binding and / or through chemotactic impairment and phagocytosis (Morandi et al. (2014) Cytokine Growth Factor Rev 327-335). HLA-G is highly expressed in multiple tumor types and is associated with poor prognosis (Carosella et al. (2015) Adv Immunol 33-144). HLA-macrophage interaction induced by LILRB1 inhibits phagocytic function (Barkal et al. (2018) Nat Immunol 76-84). HLA bound to LILRB1 can suppress the cytotoxic activity of NK and T cells (Dumont et al. (2019) Cancer Immunol Res 1619-1632 and Chen et al. (2020) JImmunother Cancer e000515). The interaction between HLA and monocytes induced by LILRB2 inhibits the maturation of human monocyte-derived antigen-presenting cells (APCs) (Liang et al. (2008) Proc Natl Acad Sci U SA 8357-8362). HLA binding to LILRB1 and LILRB2 can suppress the immune system by inducing dendritic cells and MDSCs (Zhang et al. (2017) J Leukoc Biol 351-360).

[0008] Many patients do not respond to T-cell therapy due to tumor immune escape or the tumor microenvironment. Some of these patients may experience remission with NK and myeloid cell therapy. Antibody-mediated blockade of LILRB1 and LILRB2 function will fill this unmet medical need by reversing the immunosuppressive tumor microenvironment. Summary of the Invention

[0009] This disclosure provides an antibody or antigen-binding fragment thereof that binds to LILRB1, such as the antibodies or antigen-binding fragments provided in Tables 4 to 6 and Tables 13 to 15.

[0010] This disclosure provides an antibody or antigen-binding fragment thereof that binds to LILRB2, such as the antibodies or antigen-binding fragments provided in Tables 4 to 6 and Tables 13 to 15.

[0011] This disclosure also provides a multispecific antibody or antigen-binding fragment thereof comprising a first binding arm to LILRB1 and a second binding arm to LILRB2. The first binding domain contains VH and VL and contains the same CDR as any antibody or fragment thereof provided herein (e.g., in Tables 5-6 and 14-15). The second binding domain contains VH and VL and contains the same CDR as any antibody or fragment thereof provided herein (e.g., in Tables 5-6 and 14-15).

[0012] In some embodiments, the multispecific antibodies or fragments thereof provided herein are in the form of immunoglobulin-single-chain antibody fragments (IgG-ScFv). In some embodiments, the multispecific antibodies or fragments thereof provided herein are in the form of dual variable domain-immunoglobulin (DVD-Ig) antibodies.

[0013] In some embodiments, the antibody provided herein is IgG. In some embodiments, the antibody is a humanized antibody.

[0014] In another respect, this article provides a nucleic acid molecule that encodes an antibody or antigen-binding fragment provided herein.

[0015] In another respect, this article provides a vector comprising a nucleic acid molecule encoding an antibody or antigen-binding fragment provided herein.

[0016] In another aspect, this article provides a host cell transformed with a vector encoding an antibody or antigen-binding fragment provided herein.

[0017] In another aspect, this document provides a composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment, a nucleic acid molecule or carrier encoding the antibody or antigen-binding fragment provided herein, and a pharmaceutically acceptable excipient.

[0018] In another aspect, this document provides a method for preventing the suppression or activation of immune cell-mediated responses, the method comprising contacting immune cells with an antibody or fragment thereof provided herein or a pharmaceutical composition provided herein. In some embodiments, the immune cells are NK cells, monocytes, macrophages, T cells, or dendritic cells. In some embodiments, the T cells are CD8 cells. + T cells. In some embodiments, the immune cells express LILRB1 and / or LILRB2. In some embodiments, the immune cell-mediated response is an anti-tumor response. In some embodiments, the tumor cells express HLA-A2, ANGPTL, and / or HLA-G.

[0019] In another aspect, this document provides a method for treating a subject with a disease or disorder, the method comprising administering to the subject an antibody or antigen-binding fragment provided herein or a pharmaceutical composition provided herein. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer expresses HLA-A2, ANGPTL, and / or HLA-G. In some embodiments, the disease or disorder is a solid tumor or a hematologic malignancy. In some embodiments, the subject is a human subject.

[0020] In some embodiments, the antibody or antigen-binding fragment is used as part of a combination therapy. In some embodiments, the antibody or antigen-binding fragment is used in combination with a PD-1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the antibody or antigen-binding fragment is used in combination with a PD-L1 inhibitor. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is LAE005. In some embodiments, the antibody or antigen-binding fragment is used in combination with an anti-CD47 antibody. In some embodiments, the anti-CD47 antibody is Hu5F9-G4. In some embodiments, the antibody or antigen-binding fragment is used in combination with an anti-CD3 antibody. In some embodiments, the anti-CD3 antibody is OKT3. Attached Figure Description

[0021] Figure 1A and Figure 1BThe ability of exemplary anti-LILRB1 and anti-LILRB2 antibodies, as assessed by flow cytometry, to block the interaction between LILRB1 or LILRB2 expressed at the cell line surface and the APC-HLA-A2 / human MLANA (AAGIGILTV (SEQ ID NO: 1285)) MHC tetramer is demonstrated. Anti-LILRB1 antibodies LK-RB1-3, LK-RB1-9, LK-RB1-12, LK-RB1-16, and LK-RB1-39 all block the interaction between LILRB1 and HLA-A2. Figure 1A Anti-LILRB2 antibodies LK-RB2-24, LK-RB2-1, LK-RB2-2, LK-RB2-3, LK-RB2-14, and LK-RB2-15 all block the interaction between LILRB2 and HLA-A2. Figure 1B ).

[0022] Figure 2A and Figure 2B This demonstrates that LK-RB1-9 binds to human LILRA1 with low affinity. Figure 2A The ability of hz73D1.v1, LK-RB1-9 and 15G8 to bind to the CHOK1-human LILRA2 cell line was demonstrated by flow cytometry analysis. Figure 2B The ability of hz73D1.v1, LK-RB1-9, and 15G8 to bind to human LILRA1 protein was demonstrated by ELISA analysis.

[0023] Figures 3A to 3E Exemplary anti-LILRB1 and anti-LILRB2 antibodies are shown to bind in a dose-dependent manner to LILRB1 and LILRB2 in cynomolgus monkeys. Figure 3A The dose-dependent binding of anti-LILRB1 antibodies LK-RB1-43, LK-RB1-11, LK-RB1-50, LK-RB1-58 and hz73D1.v1 to cynomolgus monkey LILRB1 protein, as analyzed by ELISA, is shown. Figure 3B The dose-dependent binding of anti-LILRB2 antibodies LK-RB2-30, LK-RB2-31, and hz73D1.v1 to LLRB1 protein in cynomolgus monkeys, as analyzed by ELISA, is shown. Figures 3C to 3E The exemplary anti-LILRB2 antibody, analyzed by flow cytometry, shows the dose-dependent binding of the antibody to the CHOK1 cell line overexpressing cynomolgus monkey LILRB2 / cynomolgus monkey LILRB2-Flag.

[0024] Figures 4A to 4KHumanized anti-LILRB1 and anti-LILRB2 antibodies were demonstrated to bind to human LILRB1 and / or LILRB2 with high affinity and to block the interaction between human LILRB1 / 2 and HLA-G. Figure 4A and Figure 4B The ability of LK-RB1-9, LK-RB1-9.h1, LK-RB1-9.h2, LK-RB1-9.h3, LK-RB1-16, LK-RB1-16.h1, LK-RB1-16.h2, and LK-RB1-16.h3 to bind to the CHOK1-human LILRB1 cell line was demonstrated by flow cytometry analysis. Figure 4C and Figure 4D The ability of LK-RB1-9, LK-RB1-9.h1, LK-RB1-9.112, LK-RB1-9.h3, LK-RB1-16, LK-RB1-16.h1, LK-RB1-16.h2 and LK-RB1-16.h3 to block the interaction between human LILRB1 and the PE-HLA-G / human H2AFX (RIIPRHLQL (SEQ ID NO:1284)) MHC tetramer, as assessed by flow cytometry, was demonstrated. Figure 4E The dose-dependent binding of LK-RB1-9, LK-RB1-9.h1, LK-RB1-9.h2, and LK-RB1-9.h3 to the CHOK1-human LILRA2 cell line, as analyzed by flow cytometry, is shown. Figure 4F and Figure 4G The ability of LK-RB2-2, LK-RB2-2.h1, LK-RB2-2.h2, LK-RB2-2.h3, LK-RB2-24, LK-RB2-24.h1, LK-RB2-24.h2, and LK-RB2-24.h3 to bind to the CHOK1-human LILRB2 cell line was demonstrated by flow cytometry analysis. Figures 4H to 4I The ability of LK-RB2-2, LK-RB2-2.h1, LK-RB2-2.h2, LK-RB2-2.h3, LK-RB2-24, LK-RB2-24.h1, LK-RB2-24.h2 and LK-RB2-24.h3 to block the interaction between human LILRB2 and PE-HLA-G / human H2AFX (RIIPRHLQL (SEQ ID NO:1284)) MHC tetramer was demonstrated, as assessed by flow cytometry. Figure 4J The dose-dependent binding of LK-RB2-24, LK-RB2-24.h1, LK-RB2-24.h2, and LK-RB2-24.h3 to the CHOK1-human LILRB1 cell line, as analyzed by flow cytometry, is shown. Figure 4KThe dose-dependent ability of LK-RB2-24, LK-RB2-24.h1, LK-RB2-24.h2 and LK-RB2-24.h3 to block the interaction between human LILRB1 and PE-HLA-G / human H2AFX (RIIPRHLQL (SEQ ID NO:1284)) MHC tetramer, as assessed by flow cytometry, was demonstrated.

[0025] Figures 5A to 5D The bispecific antibodies LK-RBi-05 and LK-RBi-08 were shown to bind to human LILRB1 / 2 with high affinity and block the interaction between human LILRB1 / 2 and HLA-G. Figure 5A The dose-dependent binding of LK-RBi-05, LK-RBi-08, LK-RB1-9.h1, LK-RB1-16.h3, 15G8 and hz73D1.v1 to human LILRB1 was shown by flow cytometry analysis. Figure 5B The ability of LK-RBi-05, LK-RBi-08, LK-RB1-9.h1, LK-RB1-16.h3, 15G8 and hz73D1.v1 to block the interaction between human LILRB1 and the PE-HLA-G / human H2AFX (RIIPRHLQL (SEQ ID NO:1284)) MHC tetramer, as assessed by flow cytometry, was demonstrated. Figure 5C The dose-dependent binding of LK-RBi-05, LK-RBi-08, LK-RB2-2.h1, J19.h1 and hz73D1.v1 to human LILRB2 was shown by flow cytometry analysis. Figure 5D The ability of LK-RBi-05, LK-RBi-08, LK-RB2-2.h1, J19.h1 and hz73D1.v1 to block the interaction between human LILRB2 and PE-HLA-G / human H2AFX (RIIPRHLQL (SEQ ID NO:1284)) MHC tetramer, as assessed by flow cytometry, was demonstrated.

[0026] Figures 6A to 6R An exemplary anti-LILRB1 antibody was shown to potently activate LILRB1-positive NK cells in a co-culture of primary human NK cells and HLA-G-expressing K562 tumor cells. Figures 6A to 6D The results showed that the percentage of CD107a-positive cells in LILRB1-negative NK cells did not increase after treatment with 0.5 ug / ml and 0.05 ug / ml anti-LILRB1 antibody. Figures 6E to 6H The results showed a significant increase in the percentage of CD107a-positive cells in LILRB1-positive NK cells after treatment with 0.5 ug / ml and 0.05 ug / ml anti-LILRB1 antibody. Figures 6I to 6K This study showed a lack of dose-dependent increase in the percentage of CD107a-positive cells in LILRB1-negative NK cells after treatment with anti-LILRB1 antibody. Figures 6L to 6N This study showed a dose-dependent increase in the percentage of CD107a-positive cells in LILRB1-positive NK cells after treatment with anti-LILRB1 antibody. Figure 6O and Figure 6P The dose-dependent effect of treatment with LK-RB1-9, LK-RB1-9.h1, LK-RB1-9.h2, LK-RB1-9.h3, LK-RB1-16, LK-RB1-16.h1, LK-RB1-16.h2, and LK-RB1-16.h3 on the percentage of CD107a-positive cells in LILRB1-negative NK cells is shown. Figure 6Q and Figure 6R The study showed a dose-dependent increase in the percentage of CD107a-positive cells in LILRB1-positive NK cells after treatment with LK-RB1-9, LK-RB1-9.h1, LK-RB1-9.h2, LK-RB1-9.h3, LK-RB1-16, LK-RB1-16.h1, LK-RB1-16.h2, and LK-RB1-16.h3.

[0027] Figures 7A to 7I This demonstrates that the exemplary anti-LILRB1 antibody dose-dependently increases Hu5F9-G4 (anti-CD47)-induced macrophage phagocytosis in a co-culture of human monocyte-derived macrophages and Raji (HLA-A2-positive) tumor cells. Figures 7A to 7C The macrophage phagocytosis of Raji cells by Hu5F9-G4 was further increased by treatment with 2.5 μg / ml anti-LILRB1 antibody. Figures 7D to 7G This study demonstrated a dose-dependent increase in macrophage phagocytosis induced by Hu5F9-G4 in Raji cells treated with anti-LILRB1 antibody. Figure 7H and Figure 7I A dose-dependent increase in macrophage phagocytosis induced by Hu5F9-G4 treatment with LK-RB1-9, LK-RB1-9.h1, LK-RB1-16, LK-RB1-16.h3 and LK-RB1-55 was shown.

[0028] Figure 8A and Figure 8B The results showed that LK-RB1-9 and LK-RB1-9.h1 further increased nivolumab-induced IFNγ release from primary human CD8+ T cells in co-cultures of primary CD8+ T cells and CHOK1-HLA-G, PDL-1, and OKT3 cells.

[0029] Figures 9A to 9H The exemplary antibody enhances LPS-induced TNFα release in macrophages differentiated from human primary monocytes. Figure 9A The study showed that LK-RB1-9 increased LPS-induced TNFα release in human primary macrophages. Figure 9B The results showed that LK-RB1-9 did not alter IL-10 release in LPS-stimulated human primary macrophages. Figure 9C The results showed that LK-RB1-9.h1 and LK-RB1-16.h3 increased LPS-induced TNFα release in human primary macrophages. Figures 9D to 9F The results showed that LPS-induced TNFα release was significantly increased after treatment with 6 μg / ml anti-LILRB2 antibody. Figure 9G The study showed that LK-RB2-2.h1 increases LPS-induced TNFα release in human primary macrophages. Figure 9H The study showed that LK-RB2-2.h1 reduced LPS-induced IL-10 release in human primary macrophages.

[0030] Figures 10A to 10I This demonstrates how an exemplary anti-LILRB2 antibody enhances LPS-induced TNFα release in human PBMCs. Figure 10A and Figure 10B The study showed that LPS-induced TNFα release was significantly increased after treatment with 60 μg / ml anti-LILRB2 antibody. Figures 10C to 10H This study demonstrated a dose-dependent increase in LPS-induced TNFα release in human PBMCs following treatment with anti-LILRB2 antibody. Figure 10I A dose-dependent increase in LPS-induced TNFα release in human PBMCs was shown after treatment with LK-RB2-2.h1 and LK-RB2-24.h3.

[0031] Figures 11A to 11F This demonstrates that an exemplary anti-LILRB2 antibody enhances the release of TNFα and IFN-γ induced by an anti-CD3 antibody in human primary PBMCs. Figure 11A and Figure 11B A dose-dependent increase in anti-CD3 antibody-induced TNFα release in human PBMCs was shown after treatment with LK-RB2-2, LK-RB2-24, and LK-RB2-15. Figure 11C and Figure 11D A dose-dependent increase in anti-CD3 antibody-induced IFN-γ release in human PBMCs was demonstrated after treatment with LK-RB2-2, LK-RB2-24, and LK-RB2-15. Figure 11E A dose-dependent increase in anti-CD3 antibody-induced TNFα release in human PBMCs was shown after treatment with LK-RB2-2.h1 and LK-RB2-24.h3. Figure 11FA dose-dependent increase in anti-CD3 antibody-induced IFN-γ release in human PBMCs was demonstrated after treatment with LK-RB2-2.h1 and LK-RB2-24.h3.

[0032] Figures 12A to 12C The results show that LK-RB1-9.h1 and LK-RB1-16.h3 bind to human LILRB1 wild-type, variant 2 and variant 3 with similar affinity. Figure 12A The ability of LK-RB1-9.h1 and LK-RB1-16.h3 to bind to human LILRB1 wild-type was demonstrated by ELISA analysis. Figure 12B The ability of LK-RB1-9.h1 and LK-RB1-16.h3 to bind to human LILRB1 variant 2 was demonstrated by ELISA analysis. Figure 12C The ability of LK-RB1-9.h1 and LK-RB1-16.h3 to bind to human LILRB1 variant 3 was demonstrated by ELISA analysis.

[0033] Figures 13A to 13H This study showed a dose-dependent increase in the percentage of CD107a-positive cells in NK cells after treatment with anti-LILRB1 antibody and anti-LILRB1 / LILRB2 bispecific antibody. Figures 13A to 13D The effects of LK-RBi-01, LK-RBi-02, LK-RBi-05, LK-RBi-06, LK-RBi-07, LK-RBi-08, LK-RBi-09, LK-RBi-10, LK-RBi-11, LK-RB1-9.h1, LK-RB1-16.h3, 15G8, and hz73D1.v1 on the percentage of CD107a-positive cells in LILRB1-negative NK cells were demonstrated. Figures 13E to 13H The effects of LK-RBi-01, LK-RBi-02, LK-RBi-05, LK-RBi-06, LK-RBi-07, LK-RBi-08, LK-RBi-09, LK-RBi-10, LK-RBi-11, LK-RB1-9.h1, LK-RB1-16.h3, 15G8, and hz73D1.v1 on the percentage of CD107a-positive cells in LILRB1-positive NK cells were demonstrated.

[0034] Figures 14A to 14FA dose-dependent increase in phagocytosis was observed in the presence of Hu5F9-G4 after treatment with the bispecific antibodies LK-RBi-01, LK-RBi-02, LK-RBi-05, LK-RBi-06, LK-RBi-07, LK-RBi-08, LK-RBi-09, LK-RBi-10, LK-RBi-11, LK-RB1-9.h1, LK-RB1-16.h3, 15G8, and hz73D1.v1.

[0035] Figure 15 The results showed that LK-RBi-05, LK-RBi-08, LK-RB1-9.h1, and LK-RB1-16.h3 increased LAE005-induced IFNγ release from primary human CD8+ T cells in primary CD8+ T cells and in co-cultures of CHOK1-HLA-G, PDL-1, and OKT3 cells.

[0036] Figure 16A and Figure 16B The study showed that anti-LILRB1 antibody, anti-LILRB2 antibody, and bispecific anti-LILRB1 / LILRB2 antibody activated LPS-induced human primary monocyte differentiation macrophages. Figure 16A The results showed that LK-RB1-9.h1, LK-RB1-16.h3, LK-RB2-2.h1, LK-RBi-05, LK-RBi-08, the combination of LK-RB1-9.h1 / LK-RB2-2.h1 and the combination of LK-RB1-16.h3 / LK-RB2-2.h1 increased LPS-induced TNFα release in human primary macrophages. Figure 16B The combination of LK-RB2-2.h1, LK-RBi-05, LK-RBi-08, LK-RB1-9.h1 / LK-RB2-2.h1 and LK-RB1-16.h3 / LK-RB2-2.h1 showed that LK-RB2-2.h1 reduced the release of IL-10 in LPS-stimulated human primary macrophages.

[0037] Figures 17A to 17C A dose-dependent increase in LPS-induced TNFα release in human PBMCs was demonstrated after treatment with bispecific anti-LILRB1 / LILRB2 antibodies LK-RBi-01, LK-RBi-02, LK-RBi-05, LK-RBi-06, LK-RBi-07, LK-RBi-08 and LK-RBi-10.

[0038] Figure 18A and Figure 18BThis study demonstrated a dose-dependent increase in anti-CD3 antibody-induced TNFα and IFN-γ release in human PBMCs after treatment with bispecific anti-LILRB1 / LILRB2 antibodies LK-RBi-05 and LK-RBi-08. Figure 18A LK-RBi-05, LK-RBi-08, and hz73D1.v1 showed that they increased OKT3-induced TNFα release in human PBMCs in a dose-dependent manner. Figure 18B LK-RBi-05, LK-RBi-08, and hz73D1.v1 showed that they increased OKT3-induced IFN-γ release in human PBMCs in a dose-dependent manner.

[0039] Figure 19 Exemplary anti-LILRB1 antibodies, anti-LILRB2 antibodies, anti-LILRB1 / LILRB2 bispecific antibodies, and antibody combinations demonstrate increased TNFα release induced by Fc receptor crosslinking in human primary dendritic cells. Compared to anti-LILRB1 antibodies LK-RB1-9.h1, LK-RB1-16.h3, and anti-LILRB2 antibody LK-RB2-2.h1, the bispecific anti-LILRB1 / LILRB2 antibodies LK-RBi-05 and LK-RBi-08 showed a stronger effect in increasing cytokine production. Detailed Implementation

[0040] This disclosure is based in part on novel antibodies that bind to LILRB1 and / or LILRB2 and their superior properties.

[0041] 5.1. definition The techniques and procedures described or cited herein include those that are generally well understood by those skilled in the art and / or commonly employed using conventional methodologies, such as those widely used methods described, for example, in the following literature: Sambrook et al., Molecular Cloning: A Laboratory Manual (3rd edition, 2001); Current Protocols in Molecular Biology (edited by Ausubel et al., 2003); Therapeutic Monoclonal Antibodies: From Bench to Clinic (edited by An, 2009); Monoclonal Antibodies Methods and Protocols (Edited by Albitar, 2010); and Antibody EngineeringVolumes 1 and 2 (edited by Kontermann and Dubel, 2nd edition, 2010). Unless otherwise defined herein, the technical and scientific terms used in this specification have the meanings commonly understood by one of ordinary skill in the art. For the purposes of interpreting this specification, the following descriptions of terms will apply, and whenever appropriate, terms used in the singular will also include the plural form, and vice versa. In the event of any conflict between any description of the terms set forth and any reference incorporated herein by reference, the description of the terms set forth below shall prevail.

[0042] The term "LILRB1," also known as CD85J, LIR1, or ILT2, is a single-pass type I transmembrane protein with a predicted molecular weight of approximately 71 kDa. LILRB1 (human, rhesus macaque, and cynomolgus monkey) is characterized by an extracellular domain containing four Ig-like C2-type domains, a transmembrane domain, and a long cytoplasmic domain containing four ITIM domains (see, for example, Borges et al., 1997, J. Immunol., 159:5192-5196). These four Ig-like C2-type domains are referred to herein as domain 1 (D1), domain 2 (D2), domain 3 (D3), and domain 4 (D4). D1 is located at the N-terminal portion of the protein, followed by D2, D3, and D4 located closest to the transmembrane region. As characterized in UniProtKB, human LILRB1 is a 650-amino acid (aa) protein—the signal sequence is aa 1-23, the extracellular domain is aa 24-461, the transmembrane domain is aa 462-482, and the cytoplasmic domain is aa 483-650. Within the extracellular domain, D1 is aa 27-115, D2 is aa 116-221, D3 is aa 222-312, D4 is aa 313-409, and the "stem region" is aa 410-461. Within the cytoplasmic domain, ITIM is aa 531-536, 560-565, 612-617, and 642-647. LILRB1 is expressed (to varying degrees) on natural killer (NK) cells, monocytes, macrophages, eosinophils, basophils, dendritic cells (DCs), T cell subsets, and B cells. Various ligands are known to interact with LILRB1, including HLA class I molecules (e.g., HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, and HLA-G).

[0043] The term "LILRB2," also known as CD85D, LIR2, or ILT4, is a single-pass type I transmembrane protein with a predicted molecular weight of approximately 65 kDa. ILT4 is characterized by an extracellular domain containing four Ig-like C2-type domains, a transmembrane domain, and a long cytoplasmic domain containing three ITIM domains (see, for example, Borges et al., 1997, J. Immunol., 159:5192-5196). As described for ILT2, these four Ig-like C2-type domains are referred to herein as D1, D2, D3, and D4. D1 is located at the N-terminal portion of the protein, and then D2, D3, and D4 are located closest to the transmembrane region. As characterized in UniProtKB, human ILT4 is a 598-amino acid (aa) protein—the signaling sequence is aa 1-21, the extracellular domain is aa 22-461, the transmembrane domain is aa 462-482, and the cytoplasmic domain is aa 483-598. Within the extracellular domain, D1 is aa 27-110, D2 is aa 111-229, D3 is aa 230-318, D4 is aa 330-419, and the "stem region" is aa 420-461. Within the cytoplasmic domain, ILT4 is aa 531-536, 560-565, and 590-595. ILT4 is expressed in myeloid cells such as monocytes, macrophages, and dendritic cells, but not in lymphocytes. ILT4 has been observed to bind to a variety of ligands, particularly HLA class I molecules, ANGPTL protein, myelin inhibitors, and β-amyloid protein.

[0044] As used herein, the term "conjugate" or its grammatical equivalent refers to a molecule (e.g., an antibody) having one or more antigen-binding sites that bind to an antigen. In some embodiments, the conjugate as described herein is an antibody (including multispecific antibodies and antibody fragments, such as antigen-binding fragments or epitope-binding fragments) or other peptide-based molecules that bind to LILRB1 (such as human LILRB1) and / or LILRB2 (such as human LILRB2), as well as conjugates of antibodies, antibody fragments, or peptide-based molecules (e.g., antibody-drug conjugates).

[0045] The terms “antibody,” “immunoglobulin,” and “Ig” are used interchangeably herein and in the broadest sense, and specifically encompass, for example, polyclonal antibodies, monoclonal antibodies (including agonists, antagonists, neutralizing antibodies, and full-length monoclonal antibodies), antibody compositions having multiple or single epitope specificity, recombinant antibodies, single-domain (e.g., VHH) antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), synthetic antibodies, chimeric antibodies, humanized antibodies, or human antibody forms having full-length heavy chains and / or light chains. As used herein, VHH refers to a domain antibody derived from the variable region of a heavy-chain-only antibody. Exemplary single-domain antibodies include, but are not limited to, antibodies naturally lacking the light chain, such as those from camel species (e.g., llamas), single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. Single-domain antibodies can be derived from any species, including but not limited to mice, humans, camels, llamas, goats, rabbits, and cattle. VHHs can also be derived from species other than camels, which can produce heavy-chain antibodies naturally lacking the light chain. Antibodies also include antibody fragments (and / or peptides containing antibody fragments) that retain the binding characteristics of LILRB1 and / or LILRB2. Non-limiting examples of antibody fragments include antigen-binding and / or effector regions of antibodies, such as Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, single-chain antibody molecules, bivariate domain IgG (DVD-Ig), single variable domain, linear antibodies, V regions, multispecific antibodies formed from antibody fragments, F(ab)2, Fd, Fc, biantibodies, dibispyridoxines, disulfide-linked Fv (dsFv), single-domain antibodies (e.g., nanobodies), or other fragments (e.g., fragments consisting of variable regions of non-covalently coupled heavy and light chains). Generally, the variable (V) region domain can be any suitable arrangement of immunoglobulin heavy (VH) and / or light (VL) variable domains. For example, antibodies also include tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, and antibody heavy chain monomers. Therefore, for example, the V region domain can be a dimer and contain VHH-VHH, VH-VH, VH-VL, or VL-VL dimers that bind LILRB1 and / or LILRB2. If desired, VH and VL can be covalently coupled directly or via a linker to form a single-chain Fv (scFv). For ease of reference, scFv proteins are referred to herein as included in the category “antibody fragments.” Another form of antibody fragment is a peptide containing one or more complementarity-determining regions (CDRs) of an antibody. CDRs (also known as “minimum recognition units” or “hypervariates”) can be obtained by constructing polynucleotides encoding one or more CDRs of interest.Such polynucleotides are prepared, for example, by using polymerase chain reaction to synthesize variable regions using mRNA from antibody-producing cells as templates (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology, 2:106 (1991); Courtenay-Luck, “Genetic Manipulation of Monoclonal Antibodies,” Monoclonal Antibodies Production, Engineering and Clinical Application, Ritter et al. (eds.), p. 166, Cambridge University Press (1995); and Ward et al., “Genetic Manipulation and Expression of Antibodies,” in Monoclonal Antibodies: Principles and Applications, Birch et al. (eds.), p. 137, Wiley-Liss, Inc. (1995)). Antibody fragments may be incorporated into, for example, single-domain antibodies, large antibodies, micro antibodies, intracellular antibodies, biantibodies, triantibodies, tetraantibodies, variable domains (v-NARs) of neoantigen receptors, and double single-chain Fv regions (see, for example, Hollinger and Hudson, Nature Biotechnology, 23(9): 1126-1136, 2005). In some embodiments, antibodies containing VH and / or VL contain light chain and / or heavy chain constant regions, such as one or more constant regions, including one or more IgG1, IgG2, IgG3, and / or IgG4 constant regions. In some embodiments, antibodies may include epitope-binding fragments of any of the above. The antibodies described herein may be any class of immunoglobulin molecules (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2).

[0046] When used to refer to a binder (e.g., an antibody) as used herein, the term “single-specific” means a binder having one or more binding sites, each binding to the same epitope of the same antigen.

[0047] When used to refer to conjugates (e.g., antibodies), the term "multispecific" means that the conjugate can specifically bind to at least two different epitopes, such as two binding sites, each formed by a pair of antibody heavy chain variable domains (VH) and antibody light chain variable domains (VL), or a pair of VHH domains that bind to different antigens or different epitopes on the same antigen. Such bispecific conjugates (e.g., antibodies) may have a 1+1 form (containing one binding site for a first antigen or epitope and one binding site for a second antigen or epitope). Other bispecific conjugates (e.g., antibodies) may be in 2+1 or 1+2 forms (containing two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 forms (containing two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). When a bispecific conjugate (e.g., antibody) contains two antigen-binding sites, each antigen-binding site may bind to a different epitope. Such bispecific binders (e.g., antibodies) can bind to two different epitopes on the same antigen (e.g., epitopes on LILRB1 or LILRB2).

[0048] In the context of two or more nucleic acids or peptides, the term "identical" or "percentage of identity" refers to two or more sequences or subsequences being identical or having a specified percentage of identical nucleotide or amino acid residues when compared and aligned (with gaps introduced if necessary) to achieve maximum correspondence, without considering any conserved amino acid substitutions as part of sequence identity. The percentage of identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software available for obtaining amino acid or nucleotide sequence alignments are well known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, the GCG Wisconsin package, and variants thereof. In some embodiments, the two nucleic acids or peptides are substantially identical, meaning that when compared and aligned to achieve maximum correspondence, they have at least 70%, at least 75%, at least 80%, at least 85%, or at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, or 99%, of nucleotide or amino acid residue identity, as measured using sequence comparison algorithms or by visual inspection. In some embodiments, identity exists in regions of amino acid sequences of at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues, or any integer value therebetween. In some embodiments, identity exists in regions longer than 60-80 residues (e.g., at least about 80-100 residues), and in some embodiments, the sequences are substantially identical across the full length of the compared sequences (e.g., the coding region of a target protein or antibody). In some embodiments, identity exists in regions of nucleotide sequences of at least about 10 bases, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases, or any integer value therebetween. In some embodiments, identity exists in regions longer than 60-80 bases (e.g., at least about 80-1000 bases or more), and in some embodiments, the sequences are substantially identical across the full length of the compared sequences (e.g., the nucleotide sequence encoding a protein of interest).

[0049] "Conservative amino acid substitution" refers to the substitution in which one amino acid residue is replaced by another amino acid residue with a similar chemical side chain. Families of amino acid residues with similar side chains are generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). For example, phenylalanine replacing tyrosine is a conservative substitution. Generally, conservative substitutions in the sequences of peptides, soluble proteins, and / or antibodies disclosed herein do not eliminate the binding of the peptide, soluble protein, or antibody containing the amino acid sequence to the target binding site. Methods for identifying conserved substitutions of amino acids that do not eliminate the binding are well known in the art.

[0050] As used herein, an "antigen" is a portion or molecule containing an epitope that a binding agent (e.g., an antibody) can bind. Therefore, an antigen can be bound by an antibody. In some embodiments, the antigen bound by the binding agent (e.g., an antibody) described herein is LILRB1 (e.g., human LILRB1) or a fragment thereof, including fragments containing one or more domains of LILRB1. In some embodiments, the antigen bound by the binding agent (e.g., an antibody) described herein is LILRB2 (e.g., human LILRB2) or a fragment thereof, including fragments containing one or more domains of LILRB2. The target antigen can be a polypeptide, carbohydrate, nucleic acid, lipid, hapten, or other naturally occurring or synthetic compound. In some embodiments, the target antigen is a polypeptide. In some embodiments, the antigen is cell-related, e.g., present on or within cells.

[0051] As used herein, "epitope" is a term in the art and refers to a localized region of an antigen that a binding molecule (e.g., an antibody) can specifically bind to. An epitope can be a linear epitope or a conformational, non-linear, or discontinuous epitope. In the case of a polypeptide antigen, for example, the epitope can be a continuous amino acid of the polypeptide ("linear" epitope), or the epitope can comprise amino acids from two or more discontinuous regions of the polypeptide ("conformational," "non-linear," or "discontinuous" epitope). Those skilled in the art will understand that, in general, a linear epitope may or may not depend on secondary, tertiary, or quaternary structures. For example, in some embodiments, the binding molecule binds a set of amino acids regardless of whether they are folded in the native three-dimensional protein structure. In other embodiments, the binding molecule requires the amino acid residues constituting the epitope to exhibit a specific conformation (e.g., bending, twisting, flipping, or folding) in order to recognize and bind to the epitope.

[0052] When two antibodies recognize the same, overlapping, or adjacent epitopes in three-dimensional space, the antibody binds to a reference antibody at the “epitope”, “substantially identical epitope”, or “identical epitope.” The most widely used and rapid method for determining whether two antibodies bind to the same, overlapping, or adjacent epitopes in three-dimensional space is a competition assay, which can be configured in many different ways, for example, using labeled antigens or labeled antibodies. In some assays, the antigen is immobilized on a 96-well plate or expressed on a cell surface, and radioactive, fluorescent, or enzyme labeling is used to measure the ability of the unlabeled antibody to block the binding of the labeled antibody.

[0053] Epitope binning is the process of grouping antibodies based on the epitopes they recognize. More specifically, epitope binning includes methods and systems for distinguishing the epitope recognition characteristics of different antibodies. It uses competitive assays combined with computational processes to cluster antibodies based on their epitope recognition characteristics and identify antibodies with different binding specificities.

[0054] A "complete" antibody is an antibody that contains an antigen-binding site, as well as a CL and at least heavy chain constant regions CH1, CH2, and CH3. The constant regions may include human constant regions or amino acid sequence variants thereof. In some embodiments, a complete antibody has one or more effector functions.

[0055] The terms "binds" or "binding" refer to interactions between molecules, including, for example, the formation of complexes. Interactions can be, for example, non-covalent interactions, including hydrogen bonds, ionic bonds, hydrophobic interactions, and / or van der Waals interactions. Complexes can also comprise the binding of two or more molecules held together by covalent or non-covalent bonds, interactions, or forces. The strength of the total non-covalent interaction between a single antigen-binding site on an antibody and a single epitope of a target molecule (such as an antigen) is the affinity of the antibody or functional fragment for that epitope. The dissociation rate (k0) of a binding molecule (e.g., an antibody) to a monovalent antigen is also known as the rate of dissociation (k0) of the binding molecule. off ) and association rate (k on The ratio (k) off / k on ) is the dissociation constant K D It is negatively correlated with affinity. K D The lower the value, the higher the antibody affinity. K D The value varies for different antibody and antigen complexes and depends on k. on and k off Both. The dissociation constant K of the antibody presented in this article. DThis can be determined using any of the methods provided herein or any other methods well known to those skilled in the art. Affinity at a single binding site does not always reflect the true strength of the interaction between the antibody and the antigen. When a complex antigen containing multiple repeating antigenic determinants (such as a multivalent antigen) comes into contact with an antibody containing multiple binding sites, the interaction between the antibody and the antigen at one site increases the likelihood of a reaction at a second site. The strength of such multiple interactions between a multivalent antibody and an antigen is called affinity.

[0056] Regarding the binding molecules described herein, terms such as "binds to," "specifically binds to," and similar terms are used interchangeably herein and refer to binding molecules or antigen-binding domains that specifically bind to antigens (such as peptides). Binding molecules or antigen-binding domains that bind to or specifically bind to antigens can be identified, for example, by immunoassay, Octet... ® Biacore ® Or other techniques known to those skilled in the art for identification. In some embodiments, when a binding molecule or antigen-binding domain binds an antigen with a higher affinity than binding any cross-reactive antigen, the binding molecule or antigen-binding domain binds or specifically binds the antigen, as determined using experimental techniques such as enzyme-linked immunosorbent assay (ELISA). Typically, the specific or selective reaction will be at least twice the background signal or noise, and can be more than 10 times the background. For a discussion of binding specificity, see, for example... Fundamental Immunology 332-36 (Paul, ed., 2nd edition, 1989). In some embodiments, the degree to which the binding molecule or antigen-binding domain binds to the "non-target" protein is less than about 10% of the binding of the binding molecule or antigen-binding domain to its specific target antigen, for example, as determined by fluorescence activated cell sorting (FACS) analysis. Binding molecules or antigen-binding domains that bind to antigens include those capable of binding antigens with sufficient affinity such that the binding molecule can be used as, for example, a therapeutic agent and / or diagnostic agent targeting the antigen. In some embodiments, the binding molecule or antigen-binding domain that binds to the antigen has a dissociation constant (KB) less than or equal to 1 µM, 800 nM, 600 nM, 550 nM, 500 nM, 300 nM, 250 nM, 100 nM, 50 nM, 10 nM, 5 nM, 4 nM, 3 nM, 2 nM, 1 nM, 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. d In some implementations, the binding molecule or antigen-binding domain binds to a conserved antigenic epitope in antigens from different species.

[0057] "Binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., a binder, such as an antibody) and its binding partner (e.g., an antigen, such as LILRB1 and / or LILRB2). Unless otherwise specified, as used herein, "binding affinity" refers to the intrinsic binding affinity that reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a binding molecule X for its binding partner Y can generally be determined by the dissociation constant (K). D The affinity is expressed as (K). Affinity can be measured by conventional methods known in the art, including those described herein. Low-affinity antibodies typically bind to antigens slowly and tend to dissociate easily, while high-affinity antibodies typically bind to antigens more quickly and tend to remain bound for longer periods. A variety of methods for measuring binding affinity are known in the art, any of which can be used for the purposes of this disclosure. In one embodiment, “K D "or "K D The "value" can be measured using biological layer interferometry (BLI) with a system such as the Octet QK384 (ForteBio, Menlo Park, CA). Alternatively, K... D It can also be measured in radiolabeled antigen binding assays (RIA), for example, using the Fab form of the antibody of interest and its antigen (Chen et al., (1999) J. Mol Biol 293:865-881) or by measuring via BIACORE using surface plasmon resonance (SPR). ™ Use, for example, BIACORE ™ -2000 or BIACORE ™ -3000 (BIACORE) ™ (Indone by Piscataway, NJ). "On-rate" or "rate of association" or "association rate" or "k on "and "off-rate" or "rate of dissociation" or "dissociation rate" or "k off "The same SPR or BLI technologies described above can also be used with systems such as Octet QK384 (ForteBio, Menlo Park, CA) or BIACORE." ™ -2000 or BIACORE ™ -3000 (BIACORE) ™ (Indonesia, Inc., Piscataway, NJ) to determine.

[0058] When used in the context of binders (e.g., antibodies), the term "competitive" refers to binders that compete for the same epitope or binding site on a target. This includes competition between such binders, as determined by assays, where the binder under study prevents or inhibits the specific binding of a reference molecule (e.g., a reference ligand or reference antigen-binding protein, such as a reference antibody) to a common antigen (e.g., LILRB1 and / or LILRB2). Numerous types of competitive binding assays can be used to determine whether a test binder competes with a reference molecule for binding to LILRB1 (e.g., human LILRB1) or LILRB2 (e.g., human LILRB2). Examples of assays that may be used include solid-phase direct or indirect radioimmunoassays (RIA); solid-phase direct or indirect enzyme immunoassays (EIA), sandwich competitive assays (see, for example, Stahli et al., (1983) Methods in Enzymology 9:242-253); solid-phase direct biotin-avidin EIA (see, for example, Kirkland et al., (1986) J. Immunol. 137:3614-3619 or Cheung et al., (1990) Virology 176:546-552); solid-phase direct labeling assays; solid-phase direct labeling sandwich assays (see, for example, Harlow and Lane, (1988) Antibodies, A Laboratory Manual, Cold Spring Harbor Pres); solid-phase direct labeling RIAs using 1-125 labels (see, for example, Morel et al., (1988)). Molec. Immunol. 25:7-15); and directly labeled RIAs (Moldenhauer et al., (1990) Scand. J. Immunol. 32:77-82). Typically, such assays involve using a purified antigen (e.g., LILRB1, such as human LILRB1, or LILRB2, such as human LILRB2) bound to a solid surface or cell carrying an unlabeled test antigen-binding protein (e.g., a test LILRB1 antibody or a test LILRB2 antibody) or a labeled reference antigen-binding protein (e.g., a reference LILRB1 antibody or a reference LILRB2 antibody). Competitive inhibition can be measured by determining the amount of label bound to the solid surface or cell in the presence of the test antigen-binding protein. Typically, an excess of the test antigen-binding protein is present. Antibodies identified by competitive assays (competitive antibodies) include antibodies that bind to the same epitope as the reference antibody and / or antibodies that bind to an adjacent epitope sufficiently close to the epitope bound by the reference antibody to cause antibody steric hindrance (e.g., similar epitopes or overlapping epitopes).Typically, when an excess of competing antibody is present, it will inhibit the specific binding of the reference antibody to the common antigen by at least 20%, such as at least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%. In some cases, binding is inhibited by at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more.

[0059] Antibody "effector functions" refer to those biological activities attributable to the Fc region of the antibody (such as the native Fc region or the Fc region of an amino acid sequence variant), and these vary with antibody isotypes. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity; Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (such as B cell receptors); and B cell activation.

[0060] The term "Fc region" is used herein to define the C-terminal region of the immunoglobulin heavy chain, including, for example, the native sequence Fc region, the recombinant Fc region, and the variant Fc region. Although the boundaries of the Fc region of the immunoglobulin heavy chain may vary, the human IgG heavy chain Fc region is generally defined as extending from an amino acid residue at position Cys226 or from Pro230 to its carboxyl terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, a composition of a complete antibody may comprise a population of antibodies with all K447 residues removed, a population of antibodies without K447 residues removed, and a population of antibodies containing and without K447 residues. A "functional Fc region" possesses the "effective function" of the native sequence Fc region. Exemplary "effective functions" include C1q binding; CDC; Fc receptor binding; ADCC; phagocytosis; downregulation of cell surface receptors (e.g., B cell receptors), etc. Such effector functions typically require the combination of an Fc region with a binding region or binding domain (e.g., an antibody variable region or domain) and can be evaluated using various assays known to those skilled in the art. A “native sequence Fc region” contains the same amino acid sequence as a naturally occurring Fc region and is not manipulated, modified, and / or altered (e.g., isolated, purified, selected, including or combined with other sequences such as variable region sequences). Natural sequence human Fc regions include the natural sequence human IgG1 Fc region (non-A and A allotypes); the natural sequence human IgG2 Fc region; the natural sequence human IgG3 Fc region; and the natural sequence human IgG4 Fc region and their naturally occurring variants. A “variant Fc region” contains an amino acid sequence that differs from the amino acid sequence of the natural sequence Fc region due to at least one amino acid modification (e.g., substitution, addition, or deletion). In some embodiments, the variant Fc region has at least one amino acid substitution compared to the natural sequence Fc region or the Fc region of the parent peptide, for example, about one to about ten amino acid substitutions, or about one to about five amino acid substitutions, in the natural sequence Fc region or the Fc region of the parent peptide. The variant Fc region described herein may have at least about 80% homology with the natural sequence Fc region and / or with the Fc region of the parent polypeptide, or at least about 90% homology with it, for example, at least about 95% homology with it.

[0061] In some embodiments, the binding molecule or antigen-binding domain may include a “chimeric” sequence in which a portion of the heavy and / or light chain is identical or homologous to a corresponding sequence in an antibody derived from a specific species or belonging to a specific antibody class or subclass, while the remainder of the chain is identical or homologous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, provided they exhibit the desired biological activity (see U.S. Patent No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81:6851-55). The chimeric sequence may include a humanized sequence.

[0062] In some embodiments, the binding molecule or antigen-binding domain may comprise a portion of a “humanized” form of a non-human (e.g., camel, murine, or non-human primate) antibody, which comprises a sequence derived from a human immunoglobulin (e.g., a recipient antibody), wherein native CDR residues are replaced by residues of the corresponding CDR from a non-human species (e.g., a donor antibody) having the desired specificity, affinity, and capability. In some cases, one or more FR region residues of the human immunoglobulin sequence are replaced by corresponding non-human residues. Furthermore, the humanized antibody may contain residues not found in the recipient antibody or in the donor antibody. These modifications are made to further optimize antibody performance. The heavy or light chain of the humanized antibody may comprise substantially all of at least one or more variable regions, wherein all or substantially all CDRs correspond to those CDRs of the non-human immunoglobulin, and all or substantially all FRs are those FRs of the human immunoglobulin sequence. In some implementations, the humanized antibody will contain at least a portion of the immunoglobulin constant region (Fc), typically the constant region of human immunoglobulins. For further details, see Jones et al., Nature 321:522-25 (1986); Riechmann et al., Nature 332:323-29 (1988); Presta, Curr. Op. Struct. Biol. 2:593-96 (1992); Carter et al., Proc. Natl. Acad. Sci. USA 89:4285-89 (1992); U.S. Patents: No. 6,800,738; No. 6,719,971; No. 6,639,055; No. 6,407,213; and No. 6,054,297.

[0063] In some embodiments, the binding molecule or antigen-binding domain may comprise a portion of a “fully human antibody” or “human antibody,” wherein the terms are used interchangeably herein and refer to an antibody comprising a human variable region and, for example, a human constant region. The binding molecule may comprise an antibody sequence. In a particular embodiment, the term refers to an antibody comprising a human-derived variable region and a constant region. In some embodiments, a “fully human” antibody may also encompass an antibody that binds a polypeptide and is encoded by a nucleic acid sequence that is a naturally occurring somatic variant of a human germline immunoglobulin nucleic acid sequence. The term “fully human antibody” includes antibodies having variable and constant regions corresponding to human germline immunoglobulin sequences as described by Kabat et al. (see Kabat et al. (1991)). Sequences of Proteins of Immunological Interest , 5th Edition, US Department of Health and Human Services, NIH Publication No. 91-3242. A “human antibody” is an antibody having an amino acid sequence corresponding to that of an antibody produced by humans and / or having an amino acid sequence produced using any technology for producing human antibodies. This definition of a human antibody specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries (Hoogenboom and Winter, J. Mol. Biol. 227:381 (1991); Marks et al., J. Mol. Biol. 222:581 (1991)) and yeast display libraries (Chao et al., Nature Protocols 1:755-68 (2006)). Methods also available for preparing human monoclonal antibodies are described in Cole et al. Monoclonal Antibodies and Cancer Therapy 77 (1985); Boerner et al., J. Immunol. 147(1):86-95 (1991); and van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5: 368-74 (2001). Human antibodies can be prepared by administering antigens to transgenic animals that have been modified to produce such antibodies in response to antigen stimulation but whose endogenous loci have been disabled, such as mice (regarding XENOMOUSE). ™For techniques, see, for example, Jakobovits, Curr. Opin. Biotechnol. 6(5):561-66 (1995); Brüggemann and Taussing, Curr. Opin. Biotechnol. 8(4):455-58 (1997); and U.S. Patent Nos. 6,075,181 and 6,150,584. Regarding human antibodies produced via human B-cell hybridoma technology, also see, for example, Li et al., Proc. Natl. Acad. Sci. USA 103:3557-62 (2006).

[0064] In some embodiments, the binding molecule or antigen-binding domain may include the term "recombinant human antibody," wherein this phrase includes human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells, antibodies isolated from a recombinant combined human antibody library, antibodies isolated from transgenic and / or transchromosomally transgenic animals (e.g., mice or cattle) for which the human immunoglobulin gene is transgenic (see, for example, Taylor, LD et al., Nucl. Acids Res. 20:6287-6295 (1992)), or antibodies prepared, expressed, generated, or isolated by any other means involving splicing a human immunoglobulin gene sequence into another DNA sequence. Such recombinant human antibodies may have variable and constant regions derived from human germline immunoglobulin sequences (see Kabat, EA et al. (1991)). Sequences of Proteins of Immunological Interest (5th edition, US Department of Health and Human Services, NIH Publication No. 91-3242). However, in some embodiments, such recombinant human antibodies are mutagenized in vitro (or, when using animals that are transgenic for the human Ig sequence, in vivo somatic cell mutagenesis), so that the amino acid sequences of the VH and VL regions of the recombinant antibody are sequences that, although derived from and associated with human germline VH and VL sequences, may not be naturally present in the human antibody germline library in vivo.

[0065] In some embodiments, the binding molecule or antigen-binding domain may comprise a portion of a “monoclonal antibody,” wherein the term as used herein refers to an antibody obtained from a substantially homogeneous group of antibodies, for example, the individual antibodies constituting that group are identical except for possibly present naturally occurring mutations or well-known post-translational modifications, such as amino acid isomerization or deamidation, methionine oxidation, or asparagine or glutamine deamidation, each monoclonal antibody typically recognizing a single epitope on the antigen. In specific embodiments, a “monoclonal antibody” as used herein is an antibody produced from a single hybridoma or other cell. The term “monoclonal” is not limited to any particular method used to prepare the antibody. For example, monoclonal antibodies that can be used in this disclosure can be prepared by the hybridoma methodology first described by Kohler et al., Nature 256:495 (1975), or can be prepared using recombinant DNA methods in bacterial cells or eukaryotic animal cells or eukaryotic plant cells (see, for example, U.S. Patent No. 4,816,567). For example, "monoclonal antibodies" can also be isolated from phage antibody libraries using techniques described in Clackson et al., Nature 352:624-28 (1991) and Marks et al., J. Mol. Biol. 222:581-97 (1991). Other methods for preparing clonal cell lines and the monoclonal antibodies expressed therefrom are well known in the art. See, for example, Short Protocols in Molecular Biology (Edited by Ausubel et al., 5th edition, 2002).

[0066] The terms “antigen-binding fragment,” “antigen-binding domain,” “antigen-binding region,” and similar terms refer to a portion of an antibody that contains amino acid residues (e.g., CDRs) that interact with an antigen and confer specificity and affinity to the antigen on the binding fragment, domain, or region. As used herein, “antigen-binding fragment” includes “antibody fragment,” which contains a portion of an antibody, including one or more CDRs, such as antigen-binding regions or variable regions of an antibody.

[0067] The antibodies described herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, recombinant antibodies, multispecific antibodies (e.g., bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intracellular antibodies, single-chain Fv (scFv) (e.g., including monospecific, bispecific, etc.), camelified antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fv (sdFv), anti-idiotype (anti-Id) antibodies, and epitope-binding fragments of any of the above.

[0068] In some embodiments, the antibodies described herein include immunoglobulin molecules and immunoactive portions of immunoglobulin molecules, including molecules containing one or more antigen-binding sites that bind to LILRB1 antigen and / or LILRB2 antigen.

[0069] Antibodies can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b). In some embodiments, the antibodies described herein are IgG antibodies (e.g., human IgG) or their classes (e.g., human IgG1, IgG2, IgG3, or IgG4) or subclasses.

[0070] A typical 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. In the case of IgG, this 4-chain unit is typically about 150,000 Daltons. Each L chain is linked to the H chain by a covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isoform. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (VH) at its N-terminus, followed by three constant domains (CH) for each α and γ chain, and four CH domains for the p and e isoforms. Each L chain has a variable domain (VL) at its N-terminus, followed by a constant domain (CL) at its other end. The VL is aligned with the VH, and the CL is aligned with the first constant domain (CH1) of the heavy chain. Specific amino acid residues are believed to form an interface between the light chain variable domain and the heavy chain variable domain. The pairing of VH and VL together forms a single antigen-binding site. For the structure and properties of different classes of antibodies, see, for example... Basic and Clinical Immunology 71 (edited by Stites et al., 8th edition, 1994); and Immunobiology (Janeway et al., 5th edition, 2001).

[0071] In some embodiments, the antibody is a 4-chain antibody unit comprising two heavy (H) chain / light (L) chain pairs. In another embodiment, the amino acid sequences of the H chains are identical, and the amino acid sequences of the L chains are identical. In other embodiments, the amino acid sequences of the H chains are different from each other. Additionally or alternatively, the amino acid sequences of the L chains are different from each other. In some embodiments, the antibody comprises a first H / L chain pair and a second H / L chain pair, wherein the first H / L chain pair binds to the LILRB1 antigen, and the second H / L chain pair binds to a non-LILRB1 antigen (such as LILRB2). In some embodiments, the antibody is a 2-chain antibody unit comprising a VHH-VHH pair. In another embodiment, the amino acid sequences of the VHHs are identical. In other embodiments, the amino acid sequences of the VHHs are different from each other. For example, the antibody comprises a first VHH and a second VHH, wherein the first VHH binds to the LILRB1 antigen, and the second VHH binds to a non-LILRB1 antigen (such as LILRB2). In some embodiments, the H and / or L chains contain constant regions, such as human constant regions. In some embodiments, the L chain constant region of such antibodies is a κ or λ light chain constant region, such as human κ or λ light chain constant regions. In some embodiments, the H chain constant region of such antibodies contains a γ heavy chain constant region, such as human γ heavy chain constant regions. In some embodiments, such antibodies contain IgG constant regions, such as human IgG constant regions (e.g., IgG1, IgG2, IgG3, and / or IgG4 constant regions).

[0072] Antibodies or fragments thereof may preferentially bind to LILRB1 (such as human LILRB1) and / or LILRB2 (such as human LILRB2), meaning that antibodies or fragments thereof bind to LILRB1 and / or LILRB2 with a greater affinity than they bind to control proteins (e.g., unrelated control proteins, such as egg white lysozyme), and / or bind to human LILRB1 and / or LILRB2 with a greater affinity than they bind to unrelated control proteins. For example, antibodies or fragments thereof may specifically recognize and bind to LILRB1 and / or LILRB2 or portions thereof. “Specific binding” means that antibodies or fragments thereof bind to LILRB1 and / or LILRB2 with an affinity of at least 5, 10, 15, 20, 25, 50, 100, 250, 500, 1000, or 10,000 times that of unrelated control proteins (e.g., egg white lysozyme). In some embodiments, the antibody or a fragment thereof may bind substantially exclusively to LILRB1 and / or LILRB2 (e.g., capable of distinguishing LILRB1 and / or LILRB2 from other known peptides, for example, by measurable differences in binding affinity). In some embodiments, the LILRB1 binder (e.g., an antibody) may react with LILRB1 sequences other than the human LILRB1 sequence (e.g., the cynomolgus monkey LILRB1 sequence). In other embodiments, the LILRB1 binder (e.g., an antibody) does not react with non-human sequences (such as the cynomolgus monkey LILRB1 sequence). In some embodiments, the LILRB2 binder (e.g., an antibody) may react with LILRB2 sequences other than the human LILRB2 sequence (e.g., the cynomolgus monkey LILRB2 sequence). In other embodiments, the LILRB2 binder (e.g., an antibody) does not react with non-human sequences (such as the cynomolgus monkey LILRB2 sequence).

[0073] The term "Fab" or "Fab region" refers to an antibody region that binds to an antigen. Conventional IgG typically contains two Fab regions, each located on one of the two arms of a Y-shaped IgG structure. Each Fab region typically consists of a variable region and a constant region for each heavy and light chain. More specifically, the variable and constant regions of the heavy chain in the Fab region are the VH and CH1 regions, and the variable and constant regions of the light chain in the Fab region are the VL and CL regions. The VH, CH1, VL, and CL regions in the Fab region can be arranged in various ways to confer antigen-binding capability according to this disclosure. For example, the VH and CH1 regions can be on a single polypeptide, and the VL and CL regions can be on separate polypeptides, similar to the Fab regions of conventional IgG. Alternatively, the VH, CH1, VL, and CL regions can all be on the same polypeptide and oriented in different orders, as described in more detail below.

[0074] The terms "variable region," "variable domain," "V region," or "V domain" refer to a portion of the light or heavy chain of an antibody, typically located at the amino terminus of the light or heavy chain and having a length of approximately 120 to 130 amino acids in the heavy chain and approximately 100 to 110 amino acids in the light chain, and are used for the binding and specificity of each specific antibody to its specific antigen. The variable region of the heavy chain may be referred to as "VH." The variable region of the light chain may be referred to as "VL." The term "variable" refers to the fact that certain segments of the variable region differ widely in sequence between antibodies. The V region mediates antigen binding and defines the specificity of a particular antibody to its specific antigen. However, variability is not uniformly distributed across the 110-amino acid span of the variable region. Instead, the V region consists of less variable (e.g., relatively constant) extensions of approximately 15 to 30 amino acids called frame regions (FRs), which are separated by shorter regions of approximately 9 to 12 amino acids each called "hypervariates," which have greater variability (e.g., extreme variability). The variable regions of both the heavy and light chains each contain four free-floating regions (FRs), predominantly employing a β-sheet configuration, connected by three hypervariable regions that form loops connecting the β-sheet structure and, in some cases, form part of the β-sheet structure. The hypervariable regions in each chain are held together closely by the FRs and, together with hypervariable regions from the other chain, contribute to the formation of the antibody's antigen-binding site (see, for example, Rabat et al.). Sequences of Proteins of Immunological Interest (5th edition, 1991). Constant regions do not directly participate in antibody-antigen binding but exhibit various effector functions, such as antibody involvement in antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Variable regions vary widely in sequence among different antibodies. In a specific implementation, the variable region is the human variable region.

[0075] The terms “residue numbering according to Kabat” or “amino acid position numbering as in Rabat” and their variations refer to the numbering system used for heavy chain or light chain variable regions in antibody compilations, as described by Rabat et al., see above. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortened or inserted FRs or CDRs of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 (residue 52a according to Kabat) and three inserted residues after residue 82 (e.g., residues 82a, 82b, and 82c according to Kabat). For a given antibody, the Kabat number of the residues can be determined by aligning the sequence of homologous regions in the antibody sequence with the “standard” Kabat number. The Kabat numbering system (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain) is commonly used when referring to residues in the variable domain (e.g., Kabat et al., see above). When referring to residues in the constant region of the immunoglobulin heavy chain, the “EU numbering system” or “EU index” is commonly used (e.g., the EU index reported above in Kabat et al.). The “EU index as in Kabat” refers to the residue number of the human IgG1 EU antibody. Other numbering systems have been described, such as AbM, Chothia, Contact, IMGT, and AHon.

[0076] As used herein, when referring to antibodies, the term "heavy chain" refers to a polypeptide chain of approximately 50 kDa–70 kDa, wherein the N-terminal portion comprises a variable region of approximately 120 to 130 or more amino acids, and the C-terminal portion comprises a constant region. Based on the amino acid sequence of the heavy chain's constant region, the constant region can be one of five different types (e.g., isotypes) known as alpha (α), delta (δ), epsilon (ε), gamma (γ), and muon (μ). The different heavy chains vary in size: α, δ, and γ contain approximately 450 amino acids, while μ and ε contain approximately 550 amino acids. When combined with light chains, these different types of heavy chains respectively produce five well-known classes (e.g., isotypes) of antibodies: IgA, IgD, IgE, IgG, and IgM, including four IgG subclasses: IgG1, IgG2, IgG3, and IgG4.

[0077] As used herein, when referring to antibodies, the term "light chain" refers to a polypeptide chain of approximately 25 kDa, wherein the N-terminal portion includes a variable region of approximately 100 to approximately 110 or more amino acids, and the C-terminal portion includes a constant region. Light chains are approximately 211 to 217 amino acids in length. Two distinct types exist, based on amino acid sequences with constant domains, termed Kappa (κ) or Lambda (λ).

[0078] As used herein, the terms “hypervariant region,” “HVR,” “complementarity-determining region,” and “CDR” are used interchangeably. “CDR” refers to one of the three hypervariable regions (H1, H2, or H3) within the non-framework region of the VH β-sheet frame of an immunoglobulin (Ig or antibody), or one of the three hypervariable regions (L1, L2, or L3) within the non-framework region of the VLP sheet frame of an antibody. CDR1, CDR2, and CDR3 in the VH domain are also referred to as HCDR1, HCDR2, and HCDR3, respectively. Similarly, CDR1, CDR2, and CDR3 in the VL domain are also referred to as LCDR1, LCDR2, and LCDR3, respectively. Therefore, CDRs are variable region sequences scattered within the frame region sequence.

[0079] The CDR region is well known to those skilled in the art and has been defined by well-known numbering systems. For example, the Rabat Complementarity Determination Region (CDR) is based on sequence variability and is the most commonly used (see, for example, Kabat et al., above; Nick Deschacht et al., J Immunol 2010; 184:5696-5704). Chothia, on the other hand, refers to the position of the structural loop (see, for example, Chothia and Lesk, J. Mol. Biol. 196:901-17 (1987)). When numbered using the Kabat numbering rules, the end of the Chothia CDR-H1 loop varies between H32 and H34, depending on the length of the loop (this is because the Kabat numbering scheme places the insertion at H35A and H35B; if neither 35A nor 35B exists, the loop ends at 32; if only 35A exists, the loop ends at 33; if both 35A and 35B exist, the loop ends at 34). The AbM hypervariable region represents a compromise between the Kabat CDR and the Chothia structural loop, and is used by Oxford Molecular's AbM antibody modeling software (see, for example, Antibody Engineering Volume 2 (edited by Kontermann and Dübel, 2nd edition, 2010). The "contact" high-variance region is based on the analysis of available complex crystal structures. Another universal numbering system that has been developed and widely adopted is the ImMunoGeneTics (IMGT) information system. ®(Lafranc et al., Dev. Comp. Immunol. 27(1):55-77(2003)). IMGT is an integrated information system dedicated to immunoglobulins (IG), T-cell receptors (TCR), and major histocompatibility complex (MHC) in humans and other vertebrates. In this paper, CDR refers to both the amino acid sequence and its position within the light or heavy chain. Since the “position” of CDR within the structure of the variable domain of an immunoglobulin is conserved across species and exists in structures called loops, CDRs and frame residues can be readily identified by using a numbering system that aligns the variable domain sequence according to structural features. This information can be used to transplant and substitute CDR residues from immunoglobulins of one species into the recipient frame, typically derived from human antibodies. An additional numbering system (AHon) has been developed by Honegger and Pluckthun, J. Mol. Biol. 309: 657-70 (2001). The correspondences between numbering systems (including, for example, the Kabat numbering and the IMGT unique numbering system) are well known to those skilled in the art (see, for example, Kabat, above; Chothia and Lesk, above; Martin, above; Lefranc et al., above). Residues from each of these hypervariable regions or CDRs are illustrated in the table below.

[0080] Exemplary CDRs based on various numbering systems

[0081] Depending on the protocol used for identification, the boundaries of a given CDR can vary. Therefore, unless otherwise stated, the terms “CDR” and “complementarity-determining region” for a given antibody or its region (such as a variable region), and individual CDRs of an antibody or its region (e.g., CDR-H1, CDR-H2), should be understood to encompass complementarity-determining regions as defined above by any known protocol described herein. In some cases, protocols for identifying a particular CDR or multiple CDRs (such as CDRs defined by the IMGT, Kabat, Chothia, or Contact methods) are described. In other cases, a specific amino acid sequence of the CDR is given. It should be noted that CDR regions can also be defined by combinations of various numbering systems (e.g., a combination of the Kabat and Chothia numbering systems or a combination of the Kabat and IMGT numbering systems). Therefore, terms such as “CDR1 as shown in a particular VH” include, but are not limited to, any CDR1 as defined by the exemplary CDR numbering systems described above. Once a variable region (e.g., VH or VL) is given, those skilled in the art will understand that CDRs within that region can be defined by different numbering systems or combinations thereof.

[0082] The high-variable region may include the following "extended high-variable regions": 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in VL, and 26-35 or 26-35A (H1), 50-65 or 49-65 (H2) and 93-102, 94-102 or 95-102 (H3) in VH.

[0083] The term "constant region" or "constant domain" refers to the carboxyl-terminal portion of the light and heavy chains that does not directly participate in antibody-antigen binding but exhibits various effector functions, such as interaction with Fc receptors. The term also refers to a portion of an immunoglobulin molecule with a more conserved amino acid sequence compared to other parts of the immunoglobulin containing antigen-binding sites (i.e., variable regions). Constant regions can contain the CH1, CH2, and CH3 regions of the heavy chain and the CL region of the light chain.

[0084] The term "frame" or "FR" refers to the variable domain residues flanking the CDR. FR residues are found in, for example, chimeric antibodies, humanized antibodies, human antibodies, domain antibodies, biantibodies, linear antibodies, and bispecific antibodies. FR residues are variable domain residues other than hypervariable region residues or CDR residues.

[0085] The "percentage of amino acid sequence identity (%)" and "homology" for peptide, polypeptide, or antibody sequences are defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in a specific peptide or polypeptide sequence after sequence alignment, introducing gaps where necessary to achieve the maximum percentage of sequence identity, and without considering any conserved substitutions as part of sequence identity. Alignment for the purpose of determining the percentage of amino acid sequence identity can be performed in various ways within the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, or MEGALIGN. ™ This can be achieved using the DNASTAR software. Those skilled in the art can determine the appropriate parameters for measuring alignment, including any algorithms required to achieve maximum alignment across the full length of the sequences being compared.

[0086] The term "specificity" refers to the selective recognition of a specific epitope of an antigen by an antigen-binding protein. For example, natural antibodies are monospecific. The term "multispecific," as used herein, indicates that an antigen-binding protein has two or more antigen-binding sites, at least two of which bind to different antigens. The term "bispecific," as used herein, indicates that an antigen-binding protein has two different antigen-binding specificities. The term "monospecific" antibody, as used herein, refers to an antigen-binding protein having one or more binding sites, each binding to the same antigen.

[0087] As used herein, the term "valence" indicates the presence of a specific number of binding sites in an antigen-binding protein. For example, a natural antibody or a full-length antibody has two binding sites and is divalent. Therefore, the terms "trivalent," "tetravalent," "pentavalent," and "hexavalent" indicate the presence of two, three, four, five, and six binding sites in an antigen-binding protein, respectively.

[0088] The terms “polypeptide” and “protein” are used interchangeably herein and refer to a polymer of amino acids of any length. This polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid groups. The term also covers amino acid polymers that have been naturally modified or modified by intervention. Examples include disulfide bond formation, glycosylation, esterification, acetylation, phosphorylation, or any other manipulation or modification. This definition also includes polypeptides containing, for example, one or more amino acid analogs (including, but not limited to, non-natural amino acids) and other modifications known in the art. It should be understood that because the polypeptides of this disclosure may be based on antibodies or other members of the immunoglobulin superfamily, in some embodiments, a “polypeptide” may exist as a single chain or as two or more associated chains.

[0089] The terms “polynucleotide” and “nucleic acid” are used interchangeably herein and refer to nucleotide polymers of any length, including DNA and RNA. Nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases and / or their analogues, or any substrate that can be incorporated into the polymer by DNA or RNA polymerase or by a synthetic reaction. Polynucleotides can contain modified nucleotides, such as methylated nucleotides and their analogues. As used herein, “oligonucleotide” refers to a short, usually single-stranded, synthetic polynucleotide whose length is usually, but not necessarily, less than about 200 nucleotides. The terms “oligonucleotide” and “polynucleotide” are mutually exclusive. The above description of polynucleotides applies equally and entirely to oligonucleotides. Cells that produce the binding molecules of this disclosure can include parental hybridoma cells, as well as bacterial and eukaryotic host cells in which nucleic acids encoding antibodies have been introduced. Unless otherwise stated, the left-hand end of any single-stranded polynucleotide sequence disclosed herein is the 5' end; the left-hand direction of a double-stranded polynucleotide sequence is referred to as the 5' direction. The direction of addition from 5' to 3' to the nascent RNA transcript is called the transcription direction; the sequence region on the DNA strand that has the same sequence as the RNA transcript and is located at 5' for the 5' end of the RNA transcript is called the "upstream sequence"; the sequence region on the DNA strand that has the same sequence as the RNA transcript and is located at 3' for the 3' end of the RNA transcript is called the "downstream sequence".

[0090] "Isolated nucleic acid" is a nucleic acid (e.g., RNA, DNA, or a mixture of nucleic acids) that is substantially isolated from other genomic DNA sequences and proteins or complexes (such as ribosomes and polymerases) that naturally accompany the natural sequences. An "isolated" nucleic acid molecule is a nucleic acid molecule isolated from other nucleic acid molecules present in the natural source of that nucleic acid molecule. Furthermore, "isolated" nucleic acid molecules (such as cDNA molecules) may be substantially free of other cellular material or culture medium when produced by recombinant technology, or substantially free of chemical precursors or other chemicals when chemically synthesized. In a specific embodiment, one or more nucleic acid molecules encoding antibodies as described herein are isolated or purified. This term includes nucleic acid sequences that have been removed from their natural environment and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analogs biosynthesized via heterologous systems. A substantially pure molecule may include the isolated form of that molecule. Specifically, an "isolated" nucleic acid molecule encoding an antibody as described herein is a nucleic acid molecule identified and isolated from at least one contaminating nucleic acid molecule that is normally associated with it in the environment in which it is produced.

[0091] Unless otherwise stated, "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate forms of each other and encode the same amino acid sequence. A nucleotide sequence encoding a protein or RNA phrase may also include introns to such an extent that a nucleotide sequence encoding a protein may contain introns in certain forms.

[0092] The term "control sequence" refers to the DNA sequence necessary for the expression of an operable coding sequence in a particular host organism. For example, control sequences suitable for prokaryotes include promoters, optionally operon sequences, and ribosome binding sites. Eukaryotic cells are known to utilize promoters, polyadenylation signals, and enhancers.

[0093] As used herein, the term "operably linked" and similar phrases (e.g., gene fusion), when used to refer to nucleic acids or amino acids, refer to the operable linking of nucleic acid sequences or amino acid sequences that are in a functional relationship with each other. For example, operably linked promoter, enhancer elements, open reading frames, 5' and 3' UTRs, and terminator sequences result in the accurate production of a nucleic acid molecule (e.g., RNA). In some embodiments, operably linked nucleic acid elements result in transcription of open reading frames and ultimately the production of peptides (i.e., expression of open reading frames). As another example, an operably linked peptide is a peptide in which functional domains are positioned at appropriate distances from each other to confer the intended function of each domain.

[0094] The term "vector" refers to a substance used to carry or include a nucleic acid sequence (including, for example, a nucleic acid sequence encoding a binding molecule (e.g., an antibody) as described herein) for the introduction of the nucleic acid sequence into a host cell. Suitable vectors for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes, and artificial chromosomes, which may include selectable sequences or markers operable for stable integration into the host cell chromosome. Additionally, a vector may include one or more selectable marker genes and appropriate expression control sequences. Selectable marker genes may include, for example, providing resistance to antibiotics or toxins, supplementing auxotrophic deficiencies, or supplying critical nutrients not present in the culture medium. Expression control sequences may include constitutive and inducible promoters, transcription enhancers, transcription terminators, etc., which are well known in the art. When two or more nucleic acid molecules are to be co-expressed (e.g., both the heavy and light chains of an antibody or both VH and VL antibodies), the two nucleic acid molecules may be inserted, for example, into a single expression vector or separate expression vectors. For single-vector expression, the encoding nucleic acid may be operably ligated to a common expression control sequence or to different expression control sequences, such as an inducible promoter and a constitutive promoter. The introduction of nucleic acid molecules into host cells can be confirmed using methods well known in the art. Such methods include, for example, nucleic acid analysis (such as Northern blotting or polymerase chain reaction (PCR) amplification of mRNA), immunoblotting of gene product expression, or other suitable analytical methods for testing the expression of the introduced nucleic acid sequence or its corresponding gene product. Those skilled in the art will understand that nucleic acid molecules are expressed in an amount sufficient to produce the desired product, and will also understand that expression levels can be optimized using methods well known in the art to obtain adequate expression.

[0095] As used in this article, the term “host” refers to an animal, such as a mammal (e.g., a human).

[0096] As used herein, the term "host cell" refers to a specific test cell that can be transfected with nucleic acid molecules, as well as the offspring or potential offspring of such cells. Due to mutations or environmental influences that may occur in subsequent generations or during the integration of nucleic acid molecules into the host cell genome, the offspring of such cells may differ from the parent cells transfected with nucleic acid molecules.

[0097] As used herein, the terms “transfected,” “transformed,” or “transduced” refer to the process of transferring or introducing exogenous nucleic acids into host cells. “Transfected,” “transformed,” or “transduced” cells are cells that have been transfected, transformed, or transduced with exogenous nucleic acids. These cells include primary test cells and their progeny.

[0098] As used in this article, "pharmaceutically acceptable" means approved by federal or state regulatory agencies, or... United States Pharmacopeia , European PharmacopeiaIt is listed in other generally accepted pharmacopoeias for use in animals and more specifically in humans.

[0099] "Excipient" means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients include, for example, encapsulating materials or additives such as absorption enhancers, antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, swelling agents, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, release agents, bactericides, sweeteners, solubilizers, wetting agents, and mixtures thereof. The term "excipient" can also refer to a diluent, adjuvant (e.g., Freund's adjuvant (complete or incomplete)), or medium.

[0100] In some embodiments, the excipient is a pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid; low molecular weight (e.g., fewer than about 10 amino acid residues) peptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN. ™ Polyethylene glycol (PEG) and PLURONICS ™ Other examples of pharmaceutically acceptable excipients are described in Remington and Gennaro. Remington's Pharmaceutical Sciences (18th edition, 1990).

[0101] In one embodiment, each component is "pharmaceutically acceptable" in the sense of compatibility with other components of the pharmaceutical preparation and is suitable for contact with human or animal tissues or organs without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, in proportion to a reasonable benefit / risk ratio. See, for example, Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash, eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson, ed.; CRC Publishing Ltd: Boca Raton, FL, 2009. In some embodiments, the pharmaceutically acceptable excipients are non-toxic to the cells or mammals exposed to them at the doses and concentrations used. In some implementations, the pharmaceutically acceptable excipient is a pH-buffered aqueous solution.

[0102] In some embodiments, the excipients are sterile liquids, such as water and oils, including oils of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Water is an exemplary excipient when the composition (e.g., a pharmaceutical composition) is administered intravenously. Saline solutions and aqueous solutions of glucose and glycerol can also be used as liquid excipients, particularly for injectable solutions. Excipients may also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene, ethylene glycol, water, ethanol, etc. If desired, the composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers. The composition may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations, etc. Oral compositions (including formulations) may include standard excipients such as pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, etc.

[0103] Compositions (including pharmaceutical compounds) may contain preventatively or therapeutically effective amounts, such as isolated or purified forms of LILRB1 and / or LILRB2 conjugates (e.g., antibodies), and appropriate amounts of excipients to provide a form suitable for appropriate administration to a subject (e.g., a patient). The formulation should be suitable for the mode of administration.

[0104] An "effective amount" is generally an amount sufficient to reduce the severity and / or frequency of symptoms, eliminate symptoms and / or underlying causes, prevent or delay the occurrence of symptoms and / or underlying causes, and / or improve or remedy damage caused by or associated with a disease, disorder, or condition. In some implementations, the effective amount is a therapeutic effective amount or a preventive effective amount.

[0105] As used herein, the term "therapeuticly effective amount" refers to an amount of a pharmaceutical agent (e.g., the antibody described herein or any other pharmaceutical agent described herein) sufficient to reduce and / or improve the severity and / or duration of a given disease, disorder, or condition and / or associated symptoms. A therapeutically effective amount of a pharmaceutical agent (including therapeutic agents) may be an amount desired to: (i) reduce, delay, or improve the progression or course of a given disease, disorder, or condition; (ii) reduce, delay, or improve the recurrence, development, or onset of a given disease, disorder, or condition; and / or (iii) improve or enhance the preventive or therapeutic effect of another therapy (e.g., a therapy other than the administration of the antibody described herein). The "therapeuticly effective amount" of the substances / molecules / pharmaceutical agents disclosed herein (e.g., anti-LILRB1 antibody, anti-LILRB2 antibody, or multispecific antibodies binding to both LILRB1 and LILRB2) may vary depending on factors such as an individual's disease state, age, sex, and weight, and the ability of the substance / molecule / pharmaceutical agent to elicit a desired response in the individual. A therapeutically effective amount encompasses an amount in which the beneficial therapeutic effect exceeds any toxic or harmful effects of the substance / molecule / pharmaceutical agent. In some implementations, the term "therapeutic effective amount" refers to the amount of binder that effectively "treats" a disease, disorder, or ailment of a subject or mammal.

[0106] The terms "subject" and "patient" are used interchangeably. As used herein, in some embodiments, the subject is a mammal, such as a non-primate or primate (e.g., a human). In a particular embodiment, the subject is a human. In one embodiment, the subject is a mammal diagnosed with a disease or disorder (e.g., a human). In another embodiment, the subject is a mammal at risk of developing a disease or disorder (e.g., a human).

[0107] "Administer" or "administration" means the act of injecting or otherwise physically delivering a substance that is present outside the body into a patient, such as by means of mucosal, intradermal, intravenous, intramuscular delivery and / or any other physical delivery method described herein or known in the art.

[0108] As used herein, the term “treatment” means reducing or improving the progression, severity, and / or duration of a given disease, disorder, or condition and / or associated symptoms, such as (i) reducing, delaying, or improving the progression or course of a given disease, disorder, or condition; (ii) reducing, delaying, or improving the recurrence, development, or onset of a given disease, disorder, or condition; and / or (iii) improving or enhancing the preventive or therapeutic effect of another therapy (e.g., a therapy other than the application of the combination described herein). The term “treatment” includes managing and improving a disease. The terms “manage,” “managing,” and “management” refer to a beneficial effect obtained by a subject from a therapy that does not necessarily lead to a cure for the disease.

[0109] "Prophylactic effective amount" is the amount of a pharmaceutical composition that, when administered to a subject, will have the expected preventive effect (e.g., prevent or delay the onset (or recurrence) of a disease, disorder, or condition, or reduce the likelihood of the onset (or recurrence) of a disease, disorder, or condition or related symptoms).

[0110] A complete therapeutic or preventative effect does not necessarily occur with the administration of a single dose, but may occur only after a series of doses have been administered. Therefore, an effective dose for treatment or prevention can be administered in one or more doses.

[0111] The terms “prevent,” “preventing,” and “prevention” refer to reducing the likelihood of the onset (or recurrence) of a disease, disorder, condition, or associated symptoms (such as diabetes or cancer).

[0112] As used herein, the term "immune response" includes responses from both the innate and adaptive immune systems. It includes cell-mediated and / or humoral immune responses. It includes both T-cell and B-cell responses, as well as responses from other cells of the immune system, such as natural killer (NK) cells, monocytes, macrophages, dendritic cells, etc.

[0113] As used herein, “delaying” cancer development means postponing, hindering, slowing, delaying, stabilizing, and / or postponing the progression of the disease. This delay can be of varying lengths, depending on the patient’s medical history and / or the individual being treated. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively cover prevention, as the individual does not develop the disease. Methods of “delaying” cancer development reduce the likelihood of disease development and / or the severity of the disease within a given timeframe compared to not using such methods. Such comparisons are typically based on clinical studies using a statistically significant number of individuals. Cancer development can be detected using standard methods, including but not limited to computed axial computed tomography (CAT scan), magnetic resonance imaging (MRI), abdominal ultrasound, coagulation tests, arteriography, or biopsy. Development can also refer to cancer progression that may initially be undetectable and includes occurrence, recurrence, and onset.

[0114] The terms “about” and “approximately” mean within 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less of a given value or range.

[0115] As used herein, comparative terms such as reduction, decrease, increase, or any grammatical variation thereof may refer to certain changes in reference. In some embodiments, such a change may refer to a change that is about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 1, or about 2, or about 3, or about 4, or about 5, or about 10, or about 20, or about 30, or about 40, or about 100 times or more than the reference. In some implementations, such variation may refer to approximately 1%, or approximately 2%, or approximately 3%, or approximately 4%, or approximately 5%, or approximately 6%, or approximately 7%, or approximately 8%, or approximately 9%, or approximately 10%, or approximately 20%, or approximately 30%, or approximately 40%, or approximately 50%, or approximately 60%, or approximately 70%, or approximately 80%, or approximately 90%, or approximately 95%, or approximately 96%, or approximately 97%, or approximately 98%, or approximately 99%.

[0116] As used in this disclosure and claims, the singular forms “a,” “an,” and “the” include the plural forms unless the context clearly indicates otherwise.

[0117] In some implementations, the terms "first," "second," "third," "fourth," and similar terms in component names are used to distinguish and identify more than one component that shares a specific identity in its name. For example, "first antibody" and "second antibody" are used to distinguish two antibodies.

[0118] It should be understood that wherever the term "comprising" is used to describe an implementation scheme throughout this document, other similar implementation schemes described as "consisting of" and / or "substantially consisting of" are also provided. It should also be understood that wherever the phrase "substantially consisting of" is used to describe an implementation scheme throughout this document, other similar implementation schemes described as "consisting of" are also provided.

[0119] The term "between" as used in phrases such as "between A and B" or "between A and B" refers to a range that includes both A and B.

[0120] The term "and / or" as used herein in phrases such as "A and / or B" is intended to include both A and B. A or B; A (alone); and B (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0121] The terms “optional” or “optionally” mean that the situation described below may or may not occur, and therefore the description includes both the situation in which the situation occurs and the situation in which the situation does not occur.

[0122] 5.2. Combined molecules 5.2.1. Antibodies binding to LILRB1 In one aspect, this document provides binding agents (e.g., antibodies, including fragments thereof) capable of binding to LILRB1. In some embodiments, the antibodies provided herein bind to human LILRB1. In some embodiments, the antibodies provided herein bind to rhesus monkey LILRB1. In some embodiments, the antibodies provided herein bind to cynomolgus monkey LILRB1.

[0123] As used herein, LILRB1 refers to the LILRB1 polypeptide, LILRB1 polypeptide fragment, LILRB1 peptide, or LILRB1 epitope. In some embodiments, the LILRB1 binder is derived from a human or humanized antibody (e.g., containing a human framework region) that binds to LILRB1 (including the LILRB1 polypeptide, LILRB1 polypeptide fragment, LILRB1 peptide, or LILRB1 epitope). In some embodiments, the binder (e.g., an antibody, including fragments thereof) may bind to LILRB1 expressed on the surface of mammalian (e.g., human) cells (including immune cells expressing LILRB1, such as NK cells or T cells)). In some embodiments, the binders provided herein (e.g., antibodies, including fragments thereof) bind to LILRB1 extracellular epitopes exposed on cells (such as immune cells). In some embodiments, a binder (e.g., an antibody, including fragments thereof) that binds to LILRB1 (such as human LILRB1 or a portion thereof) is described herein. In some embodiments, LILRB1 is human LILRB1. In some embodiments, the binding agent provided herein is a human LILRB1 binding agent (e.g., an antibody that binds to human LILRB1).

[0124] In some embodiments, the anti-LILRB1 antibody provided herein is an antagonist antibody. In one embodiment, the antibody according to this disclosure is a LILRB1 antagonist that has no agonistic activity or low agonistic activity. In another embodiment, an antibody or functional fragment comprising an antigen-binding moiety binds to the target protein LILRB1 and reduces the binding of a LILRB1 ligand to LILRB1 to a basal level. In one aspect of this embodiment, the antibody or functional fragment reduces the amount of ligand bound to LILRB1. In another aspect of this embodiment, the antibody or functional fragment completely prevents the binding of a LILRB1 ligand to LILRB1. In some embodiments, the ligand is an MHC I molecule. In some embodiments, the ligand is HLA-A2. In some embodiments, the ligand is HLA-G. In some embodiments, the anti-LILRB1 antibody or functional fragment provided herein inhibits one or more of these LILRB1 functional properties. As determined according to the methods known in the art and described herein, antibodies that inhibit one or more of these LILRB1 functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biological activities) will be understood to be associated with a statistically significant reduction in a specific activity observed in the absence of an antibody (e.g., or when a control antibody of unrelated specificity is present). In some embodiments, antibodies inhibiting LILRB1 activity achieve such a statistically significant reduction of at least 10%, at least 50%, 80%, or 90% of the measured parameter, and in some embodiments, the antibodies of this disclosure inhibit greater than 95%, 98%, or 99% of LILRB1 functional activity.

[0125] In some embodiments, the anti-LILRB1 antibody provided herein is available in quantities of ≤1µM, ≤100nM, ≤10nM, ≤1nM, ≤0.1nM, ≤0.01nM, or ≤0.001nM (e.g., 10µM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The dissociation constant (K) of M) D The antibody binds to LILRB1 (e.g., human LILRB1). Various methods for measuring binding affinity are known in the art, any of which can be used for the purposes of this disclosure, including by RIA, e.g., with the Fab form of the antibody of interest and its antigen (Chen et al., 1999, J. Mol Biol 293:865-81); by biolayer interferometry (BLI) or surface plasmon resonance (SPR), via Octet... ® (Using, for example, Octet) ®Red96 system) or via Biacore ® (Using, for example, Biacore) ® TM-2000 or Biacore ® TM-3000). "Association rate (on-rate or rate of association)" or "kon" can also be used with the same biolayer interferometry (BLI) or surface plasmon resonance (SPR) techniques described above, such as OCTET. ® Red96, BIACORE ® TM-2000, BIACORE ® TM-3000 system, BIACORE ® TM-8K or BIACORE ® The TM-8K+ system is used to determine this.

[0126] In one embodiment, the anti-LILRB1 antibody of this disclosure does not cross-react with one or more LILRB or LILRA family members (e.g., LILRB2, LILRA1, LILRA2, etc.). In one embodiment, the anti-LILRB1 antibody of this disclosure cross-reacts with one or more LILRB and LILRA family members (e.g., LILRB2, LILRA1, LILRA2, etc.).

[0127] In some embodiments, the anti-LILRB1 antibodies provided herein are those described in Section 7 below. Therefore, in some embodiments, the antibodies provided herein comprise one or more CDR sequences of any of SEQ ID NO: 283-400 and 1155-1166. The CDR sequence can be determined according to well-known numbering systems. In some embodiments, the CDR is numbered according to IMGT. In some embodiments, the CDR is numbered according to Kabat. In some embodiments, the CDR is numbered according to AbM. In other embodiments, the CDR is numbered according to Chothia. In other embodiments, the CDR is numbered according to Contact. In some embodiments, the anti-LILRB1 antibody is humanized. In some embodiments, the anti-LILRB1 antibody comprises a recipient human frame, such as a human immunoglobulin frame or a human common frame.

[0128] In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:283. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:285. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:287. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:289. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:291. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:293. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:295. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:297. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:299. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:301. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:303. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:305. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:307.In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:309. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:311. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:313. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:315. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:317. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:319. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:321. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:323. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:325. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:327. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:329. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:331. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:333.In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:335. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:337. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:339. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:341. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:343. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:345. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:347. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:349. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:351. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:353. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:355. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:357. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:359.In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:361. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:363. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:365. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:367. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:369. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:371. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:373. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:375. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:377. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:379. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:381. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:383. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:385.In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:387. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:389. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:391. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:393. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:395. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:397. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:399. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1155. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1157. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1159. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1161. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1163. In some embodiments, the anti-LILRB1 antibody provided herein comprises HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1165. The CDR sequence can be determined according to a well-known numbering system or a combination thereof. In some embodiments, the CDR is based on IMGT numbering.In some implementations, the CDR is numbered according to Kabat. In some implementations, the CDR is numbered according to AbM. In other implementations, the CDR is numbered according to Chothia. In still other implementations, the CDR is numbered according to Contact.

[0129] In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:284. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:286. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:288. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:290. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:292. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:294. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:296. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:298. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:300. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:302. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:304. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:306. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:308.In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:310. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:312. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:314. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:316. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:318. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:320. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:322. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:324. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:326. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:328. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:330. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:332. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:334.In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:336. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:338. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:340. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:342. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:344. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:346. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:348. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:350. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:352. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:354. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:356. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:358. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:360.In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:362. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:364. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:366. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:368. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:370. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:372. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:374. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:376. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:378. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:380. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:382. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:384. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:386.In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:388. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:390. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:392. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:394. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:396. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:398. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:400. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1156. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1158. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1160. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1162. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1164. In some embodiments, the anti-LILRB1 antibody provided herein comprises LCDR1, LCDR2, and LCDR3 as shown in the VL containing the amino acid sequence of SEQ ID NO:1166. The CDR sequence can be determined according to a well-known numbering system or a combination thereof. In some embodiments, the CDR is numbered according to IMGT.In some implementations, the CDR is numbered according to Kabat. In some implementations, the CDR is numbered according to AbM. In other implementations, the CDR is numbered according to Chothia. In still other implementations, the CDR is numbered according to Contact.

[0130] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:283, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:284. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:283, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:284.

[0131] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:285, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:286. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:285, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:286.

[0132] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:287, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:288. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:287, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:288.

[0133] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:289, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:290. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:289, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:290.

[0134] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:291, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:292. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:291, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:292.

[0135] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:293, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:294. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:293, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:294.

[0136] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:295, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:296. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:295, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:296.

[0137] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:297, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:298. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:297, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:298.

[0138] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:299, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:300. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:299, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:300.

[0139] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:301, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:302. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:301, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:302.

[0140] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:303, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:304. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:303, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:304.

[0141] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:305, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:306. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:305, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:306.

[0142] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:307, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:308. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:307, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:308.

[0143] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:309, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:310. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:309, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:310.

[0144] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:311, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:312. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:311, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:312.

[0145] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:313, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:314. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:313, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:314.

[0146] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:315, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:316. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:315, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:316.

[0147] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:317, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:318. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:317, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:318.

[0148] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:319, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:320. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:319, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:320.

[0149] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:321, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:322. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:321, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:322.

[0150] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:323, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:324. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:323, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:324.

[0151] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:325, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:326. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:325, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:326.

[0152] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:327, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:328. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:327, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:328.

[0153] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:329, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:330. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:329, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:330.

[0154] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:331, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:332. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:331, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:332.

[0155] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:333, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:334. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:333, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:334.

[0156] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:335, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:336. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:335, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:336.

[0157] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:337, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:338. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:337, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:338.

[0158] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:339, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:340. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:339, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:340.

[0159] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:341, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:342. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:341, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:342.

[0160] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:343, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:344. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:343, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:344.

[0161] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:345, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:346. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:345, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:346.

[0162] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:347, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:348. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:347, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:348.

[0163] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:349, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:350. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:349, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:350.

[0164] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:351, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:352. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:351, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:352.

[0165] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:353, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:354. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:353, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:354.

[0166] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:355, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:356. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:355, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:356.

[0167] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:357, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:358. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:357, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:358.

[0168] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:359, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:360. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:359, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:360.

[0169] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:361, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:362. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:361, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:362.

[0170] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:363, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:364. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:363, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:364.

[0171] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:365, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:366. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:365, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:366.

[0172] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:367, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:368. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:367, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:368.

[0173] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:369, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:370. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:369, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:370.

[0174] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:371, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:372. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:371, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:372.

[0175] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:373, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:374. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:373, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:374.

[0176] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:375, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:376. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:375, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:376.

[0177] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:377, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:378. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:377, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:378.

[0178] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:379, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:380. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:379, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:380.

[0179] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:381, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:382. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:381, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:382.

[0180] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:383, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:384. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:383, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:384.

[0181] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:385, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:386. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:385, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:386.

[0182] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:387, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:388. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:387, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:388.

[0183] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:389, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:390. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:389, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:390.

[0184] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:391, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:392. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:391, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:392.

[0185] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:393, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:394. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:393, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:394.

[0186] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:395, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:396. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:395, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:396.

[0187] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:397, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:398. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:397, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:398.

[0188] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:399, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:400. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:399, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:400.

[0189] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1155, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1156. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1155, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1156.

[0190] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1157, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1158. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1157, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1158.

[0191] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1159, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1160. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1159, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1160.

[0192] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1161, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1162. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1161, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1162.

[0193] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1163, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1164. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1163, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1164.

[0194] In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and / or HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1165, and / or LCDR1, LCDR2, and / or LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1166. In some embodiments, the antibody or antigen-binding fragments provided herein comprise HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1165, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1166.

[0195] CDR sequences can be determined based on well-known numbering systems or combinations thereof. In some embodiments, CDRs are numbered according to IMGT. In some embodiments, CDRs are numbered according to Rabat. In some embodiments, CDRs are numbered according to AbM. In other embodiments, CDRs are numbered according to Chothia. In other embodiments, CDRs are numbered according to Contact.

[0196] In other embodiments, this document provides an antibody that binds to LILRB1, the antibody comprising (a) a VH region, the VH region comprising (i) a region containing the same as SEQ ID NO: 495, 501, 507, 513, 519, 525, 531, 537, 543, 549, 555, 561, 567, 573, 579, 585, 591, 597, 603, 609, 615, 621, 627, 633, 639, 645, 651, 657, 663, 669, 675, 681, 687, 693, 699, 705, 711, 717, 723, 729, 735, 741, 74 7, 753, 759, 765, 771, 777, 783, 789, 795, 801, 807, 813, 819, 825, 831, 837, and 843, having an amino acid sequence with at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity; (ii) containing an amino acid sequence identical to SEQ ID. NO:496, 502, 508, 514, 520, 526, 532, 538, 544, 550, 556, 562, 568, 574, 580, 586, 592, 598, 604, 610, 6 16, 622, 628, 634, 640, 646, 652, 658, 664, 670, 676, 682, 688, 694, 700, 706, 712, 718, 724, 730, 736, 7 HCDR2 having an amino acid sequence of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 796, 802, 808, 814, 820, 826, 832, 838, and 844 with sequence identity of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity.(iii) Contains the following sequences: SEQ ID NO: 497, 503, 509, 515, 521, 527, 533, 539, 545, 551, 557, 563, 569, 575, 581, 587, 593, 599, 605, 611, 617, 623, 629, 635, 641, 647, 653, 659, 665, 671, 677, 683, 689, 695, 701, 707, 713, 719, 725, 731, 737, 743, 749 HCDR3 having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with any one of SEQ ID NO; and / or (b) a VL region comprising (i) an amino acid sequence containing SEQ ID NO. NO:498, 504, 510, 516, 522, 528, 534, 540, 546, 552, 558, 564, 570, 576, 582, 588, 594, 600, 606, 612, 6 18, 624, 630, 636, 642, 648, 654, 660, 666, 672, 678, 684, 690, 696, 702, 708, 714, 720, 726, 732, 738, 7 LCDR1 having an amino acid sequence of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity among any one of 44, 750, 756, 762, 768, 774, 780, 846;(ii) Contains the following sequences: SEQ ID NO: 499, 505, 511, 517, 523, 529, 535, 541, 547, 553, 559, 565, 571, 577, 583, 589, 595, 601, 607, 613, 619, 625, 631, 637, 643, 649, 655, 661, 667, 673, 679, 685, 691, 697, 703, 709, 715, 721, 727, 733, 739, 745, 751, 75 LCDR2 having at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity of any one of 7, 763, 769, 775, 781, 787, 793, 799, 805, 811, 817, 823, 829, 835, 841, 847, and 1281 amino acid sequences; and (iii) containing an amino acid sequence identical to SEQ ID NO. NO:500, 506, 512, 518, 524, 530, 536, 542, 548, 554, 560, 566, 572, 578, 584, 590, 596, 602, 608, 614, 6 20, 626, 632, 638, 644, 650, 656, 662, 668, 674, 680, 686, 692, 698, 704, 710, 716, 722, 728, 734, 740, 7 LCDR3 having an amino acid sequence of at least 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity, among any one of 46, 752, 758, 764, 770, 776, 78%, 842, and 848. In some embodiments, the anti-LILRB1 antibody is humanized. In some embodiments, the anti-LILRB1 antibody comprises a recipient human framework, such as a human immunoglobulin framework or a human common framework.

[0197] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:495, HCDR2 contains the amino acid sequence of SEQ ID NO:496, HCDR3 contains the amino acid sequence of SEQ ID NO:497, LCDR1 contains the amino acid sequence of SEQ ID NO:498, LCDR2 contains the amino acid sequence of SEQ ID NO:499, and LCDR3 contains the amino acid sequence of SEQ ID NO:500.

[0198] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:501, HCDR2 contains the amino acid sequence of SEQ ID NO:502, HCDR3 contains the amino acid sequence of SEQ ID NO:503, LCDR1 contains the amino acid sequence of SEQ ID NO:504, LCDR2 contains the amino acid sequence of SEQ ID NO:505, and LCDR3 contains the amino acid sequence of SEQ ID NO:506.

[0199] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:507, HCDR2 contains the amino acid sequence of SEQ ID NO:508, HCDR3 contains the amino acid sequence of SEQ ID NO:509, LCDR1 contains the amino acid sequence of SEQ ID NO:510, LCDR2 contains the amino acid sequence of SEQ ID NO:511, and LCDR3 contains the amino acid sequence of SEQ ID NO:512.

[0200] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:513, HCDR2 contains the amino acid sequence of SEQ ID NO:514, HCDR3 contains the amino acid sequence of SEQ ID NO:515, LCDR1 contains the amino acid sequence of SEQ ID NO:516, LCDR2 contains the amino acid sequence of SEQ ID NO:517, and LCDR3 contains the amino acid sequence of SEQ ID NO:518.

[0201] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:519, HCDR2 contains the amino acid sequence of SEQ ID NO:520, HCDR3 contains the amino acid sequence of SEQ ID NO:521, LCDR1 contains the amino acid sequence of SEQ ID NO:522, LCDR2 contains the amino acid sequence of SEQ ID NO:523, and LCDR3 contains the amino acid sequence of SEQ ID NO:524.

[0202] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:525, HCDR2 contains the amino acid sequence of SEQ ID NO:526, HCDR3 contains the amino acid sequence of SEQ ID NO:527, LCDR1 contains the amino acid sequence of SEQ ID NO:528, LCDR2 contains the amino acid sequence of SEQ ID NO:529, and LCDR3 contains the amino acid sequence of SEQ ID NO:530.

[0203] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:531, HCDR2 contains the amino acid sequence of SEQ ID NO:532, HCDR3 contains the amino acid sequence of SEQ ID NO:533, LCDR1 contains the amino acid sequence of SEQ ID NO:534, LCDR2 contains the amino acid sequence of SEQ ID NO:535, and LCDR3 contains the amino acid sequence of SEQ ID NO:536.

[0204] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:537, HCDR2 contains the amino acid sequence of SEQ ID NO:538, HCDR3 contains the amino acid sequence of SEQ ID NO:539, LCDR1 contains the amino acid sequence of SEQ ID NO:540, LCDR2 contains the amino acid sequence of SEQ ID NO:541, and LCDR3 contains the amino acid sequence of SEQ ID NO:542.

[0205] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:543, HCDR2 contains the amino acid sequence of SEQ ID NO:544, HCDR3 contains the amino acid sequence of SEQ ID NO:545, LCDR1 contains the amino acid sequence of SEQ ID NO:546, LCDR2 contains the amino acid sequence of SEQ ID NO:547, and LCDR3 contains the amino acid sequence of SEQ ID NO:548.

[0206] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:549, HCDR2 contains the amino acid sequence of SEQ ID NO:550, HCDR3 contains the amino acid sequence of SEQ ID NO:551, LCDR1 contains the amino acid sequence of SEQ ID NO:552, LCDR2 contains the amino acid sequence of SEQ ID NO:553, and LCDR3 contains the amino acid sequence of SEQ ID NO:554.

[0207] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:555, HCDR2 contains the amino acid sequence of SEQ ID NO:556, HCDR3 contains the amino acid sequence of SEQ ID NO:557, LCDR1 contains the amino acid sequence of SEQ ID NO:558, LCDR2 contains the amino acid sequence of SEQ ID NO:559, and LCDR3 contains the amino acid sequence of SEQ ID NO:560.

[0208] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:561, HCDR2 contains the amino acid sequence of SEQ ID NO:562, HCDR3 contains the amino acid sequence of SEQ ID NO:563, LCDR1 contains the amino acid sequence of SEQ ID NO:564, LCDR2 contains the amino acid sequence of SEQ ID NO:565, and LCDR3 contains the amino acid sequence of SEQ ID NO:566.

[0209] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:567, HCDR2 contains the amino acid sequence of SEQ ID NO:568, HCDR3 contains the amino acid sequence of SEQ ID NO:569, LCDR1 contains the amino acid sequence of SEQ ID NO:570, LCDR2 contains the amino acid sequence of SEQ ID NO:571, and LCDR3 contains the amino acid sequence of SEQ ID NO:572.

[0210] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:573, HCDR2 contains the amino acid sequence of SEQ ID NO:574, HCDR3 contains the amino acid sequence of SEQ ID NO:575, LCDR1 contains the amino acid sequence of SEQ ID NO:576, LCDR2 contains the amino acid sequence of SEQ ID NO:577, and LCDR3 contains the amino acid sequence of SEQ ID NO:578.

[0211] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:579, HCDR2 contains the amino acid sequence of SEQ ID NO:580, HCDR3 contains the amino acid sequence of SEQ ID NO:581, LCDR1 contains the amino acid sequence of SEQ ID NO:582, LCDR2 contains the amino acid sequence of SEQ ID NO:583, and LCDR3 contains the amino acid sequence of SEQ ID NO:584.

[0212] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:585, HCDR2 contains the amino acid sequence of SEQ ID NO:586, HCDR3 contains the amino acid sequence of SEQ ID NO:587, LCDR1 contains the amino acid sequence of SEQ ID NO:588, LCDR2 contains the amino acid sequence of SEQ ID NO:589, and LCDR3 contains the amino acid sequence of SEQ ID NO:590.

[0213] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:591, HCDR2 contains the amino acid sequence of SEQ ID NO:592, HCDR3 contains the amino acid sequence of SEQ ID NO:593, LCDR1 contains the amino acid sequence of SEQ ID NO:594, LCDR2 contains the amino acid sequence of SEQ ID NO:595, and LCDR3 contains the amino acid sequence of SEQ ID NO:596.

[0214] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:597, HCDR2 contains the amino acid sequence of SEQ ID NO:598, HCDR3 contains the amino acid sequence of SEQ ID NO:599, LCDR1 contains the amino acid sequence of SEQ ID NO:600, LCDR2 contains the amino acid sequence of SEQ ID NO:601, and LCDR3 contains the amino acid sequence of SEQ ID NO:602.

[0215] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:603, HCDR2 contains the amino acid sequence of SEQ ID NO:604, HCDR3 contains the amino acid sequence of SEQ ID NO:605, LCDR1 contains the amino acid sequence of SEQ ID NO:606, LCDR2 contains the amino acid sequence of SEQ ID NO:607, and LCDR3 contains the amino acid sequence of SEQ ID NO:608.

[0216] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:609, HCDR2 contains the amino acid sequence of SEQ ID NO:610, HCDR3 contains the amino acid sequence of SEQ ID NO:611, LCDR1 contains the amino acid sequence of SEQ ID NO:612, LCDR2 contains the amino acid sequence of SEQ ID NO:613, and LCDR3 contains the amino acid sequence of SEQ ID NO:614.

[0217] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:615, HCDR2 contains the amino acid sequence of SEQ ID NO:616, HCDR3 contains the amino acid sequence of SEQ ID NO:617, LCDR1 contains the amino acid sequence of SEQ ID NO:618, LCDR2 contains the amino acid sequence of SEQ ID NO:619, and LCDR3 contains the amino acid sequence of SEQ ID NO:620.

[0218] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:621, HCDR2 contains the amino acid sequence of SEQ ID NO:622, HCDR3 contains the amino acid sequence of SEQ ID NO:623, LCDR1 contains the amino acid sequence of SEQ ID NO:624, LCDR2 contains the amino acid sequence of SEQ ID NO:625, and LCDR3 contains the amino acid sequence of SEQ ID NO:626.

[0219] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:627, HCDR2 contains the amino acid sequence of SEQ ID NO:628, HCDR3 contains the amino acid sequence of SEQ ID NO:629, LCDR1 contains the amino acid sequence of SEQ ID NO:630, LCDR2 contains the amino acid sequence of SEQ ID NO:631, and LCDR3 contains the amino acid sequence of SEQ ID NO:632.

[0220] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:633, HCDR2 contains the amino acid sequence of SEQ ID NO:634, HCDR3 contains the amino acid sequence of SEQ ID NO:635, LCDR1 contains the amino acid sequence of SEQ ID NO:636, LCDR2 contains the amino acid sequence of SEQ ID NO:637, and LCDR3 contains the amino acid sequence of SEQ ID NO:638.

[0221] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:639, HCDR2 contains the amino acid sequence of SEQ ID NO:640, HCDR3 contains the amino acid sequence of SEQ ID NO:641, LCDR1 contains the amino acid sequence of SEQ ID NO:642, LCDR2 contains the amino acid sequence of SEQ ID NO:643, and LCDR3 contains the amino acid sequence of SEQ ID NO:644.

[0222] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:645, HCDR2 contains the amino acid sequence of SEQ ID NO:646, HCDR3 contains the amino acid sequence of SEQ ID NO:647, LCDR1 contains the amino acid sequence of SEQ ID NO:648, LCDR2 contains the amino acid sequence of SEQ ID NO:649, and LCDR3 contains the amino acid sequence of SEQ ID NO:650.

[0223] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:651, HCDR2 contains the amino acid sequence of SEQ ID NO:652, HCDR3 contains the amino acid sequence of SEQ ID NO:653, LCDR1 contains the amino acid sequence of SEQ ID NO:654, LCDR2 contains the amino acid sequence of SEQ ID NO:655, and LCDR3 contains the amino acid sequence of SEQ ID NO:656.

[0224] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:657, HCDR2 contains the amino acid sequence of SEQ ID NO:658, HCDR3 contains the amino acid sequence of SEQ ID NO:659, LCDR1 contains the amino acid sequence of SEQ ID NO:660, LCDR2 contains the amino acid sequence of SEQ ID NO:661, and LCDR3 contains the amino acid sequence of SEQ ID NO:662.

[0225] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:663, HCDR2 contains the amino acid sequence of SEQ ID NO:664, HCDR3 contains the amino acid sequence of SEQ ID NO:665, LCDR1 contains the amino acid sequence of SEQ ID NO:666, LCDR2 contains the amino acid sequence of SEQ ID NO:667, and LCDR3 contains the amino acid sequence of SEQ ID NO:668.

[0226] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:669, HCDR2 contains the amino acid sequence of SEQ ID NO:670, HCDR3 contains the amino acid sequence of SEQ ID NO:671, LCDR1 contains the amino acid sequence of SEQ ID NO:672, LCDR2 contains the amino acid sequence of SEQ ID NO:673, and LCDR3 contains the amino acid sequence of SEQ ID NO:674.

[0227] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:675, HCDR2 contains the amino acid sequence of SEQ ID NO:676, HCDR3 contains the amino acid sequence of SEQ ID NO:677, LCDR1 contains the amino acid sequence of SEQ ID NO:678, LCDR2 contains the amino acid sequence of SEQ ID NO:679, and LCDR3 contains the amino acid sequence of SEQ ID NO:680.

[0228] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:681, HCDR2 contains the amino acid sequence of SEQ ID NO:682, HCDR3 contains the amino acid sequence of SEQ ID NO:683, LCDR1 contains the amino acid sequence of SEQ ID NO:684, LCDR2 contains the amino acid sequence of SEQ ID NO:685, and LCDR3 contains the amino acid sequence of SEQ ID NO:686.

[0229] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:687, HCDR2 contains the amino acid sequence of SEQ ID NO:688, HCDR3 contains the amino acid sequence of SEQ ID NO:689, LCDR1 contains the amino acid sequence of SEQ ID NO:690, LCDR2 contains the amino acid sequence of SEQ ID NO:691, and LCDR3 contains the amino acid sequence of SEQ ID NO:692.

[0230] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:693, HCDR2 contains the amino acid sequence of SEQ ID NO:694, HCDR3 contains the amino acid sequence of SEQ ID NO:695, LCDR1 contains the amino acid sequence of SEQ ID NO:696, LCDR2 contains the amino acid sequence of SEQ ID NO:697, and LCDR3 contains the amino acid sequence of SEQ ID NO:698.

[0231] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:699, HCDR2 contains the amino acid sequence of SEQ ID NO:700, HCDR3 contains the amino acid sequence of SEQ ID NO:701, LCDR1 contains the amino acid sequence of SEQ ID NO:702, LCDR2 contains the amino acid sequence of SEQ ID NO:703, and LCDR3 contains the amino acid sequence of SEQ ID NO:704.

[0232] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:705, HCDR2 contains the amino acid sequence of SEQ ID NO:706, HCDR3 contains the amino acid sequence of SEQ ID NO:707, LCDR1 contains the amino acid sequence of SEQ ID NO:708, LCDR2 contains the amino acid sequence of SEQ ID NO:709, and LCDR3 contains the amino acid sequence of SEQ ID NO:710.

[0233] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:711, HCDR2 contains the amino acid sequence of SEQ ID NO:712, HCDR3 contains the amino acid sequence of SEQ ID NO:713, LCDR1 contains the amino acid sequence of SEQ ID NO:714, LCDR2 contains the amino acid sequence of SEQ ID NO:715, and LCDR3 contains the amino acid sequence of SEQ ID NO:716.

[0234] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:717, HCDR2 contains the amino acid sequence of SEQ ID NO:718, HCDR3 contains the amino acid sequence of SEQ ID NO:719, LCDR1 contains the amino acid sequence of SEQ ID NO:720, LCDR2 contains the amino acid sequence of SEQ ID NO:721, and LCDR3 contains the amino acid sequence of SEQ ID NO:722.

[0235] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:723, HCDR2 contains the amino acid sequence of SEQ ID NO:724, HCDR3 contains the amino acid sequence of SEQ ID NO:725, LCDR1 contains the amino acid sequence of SEQ ID NO:726, LCDR2 contains the amino acid sequence of SEQ ID NO:727, and LCDR3 contains the amino acid sequence of SEQ ID NO:728.

[0236] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:729, HCDR2 contains the amino acid sequence of SEQ ID NO:730, HCDR3 contains the amino acid sequence of SEQ ID NO:731, LCDR1 contains the amino acid sequence of SEQ ID NO:732, LCDR2 contains the amino acid sequence of SEQ ID NO:733, and LCDR3 contains the amino acid sequence of SEQ ID NO:734.

[0237] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:735, HCDR2 contains the amino acid sequence of SEQ ID NO:736, HCDR3 contains the amino acid sequence of SEQ ID NO:737, LCDR1 contains the amino acid sequence of SEQ ID NO:738, LCDR2 contains the amino acid sequence of SEQ ID NO:739, and LCDR3 contains the amino acid sequence of SEQ ID NO:740.

[0238] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:741, HCDR2 contains the amino acid sequence of SEQ ID NO:742, HCDR3 contains the amino acid sequence of SEQ ID NO:743, LCDR1 contains the amino acid sequence of SEQ ID NO:744, LCDR2 contains the amino acid sequence of SEQ ID NO:745, and LCDR3 contains the amino acid sequence of SEQ ID NO:746.

[0239] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:747, HCDR2 contains the amino acid sequence of SEQ ID NO:748, HCDR3 contains the amino acid sequence of SEQ ID NO:749, LCDR1 contains the amino acid sequence of SEQ ID NO:750, LCDR2 contains the amino acid sequence of SEQ ID NO:751, and LCDR3 contains the amino acid sequence of SEQ ID NO:752.

[0240] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:753, HCDR2 contains the amino acid sequence of SEQ ID NO:754, HCDR3 contains the amino acid sequence of SEQ ID NO:755, LCDR1 contains the amino acid sequence of SEQ ID NO:756, LCDR2 contains the amino acid sequence of SEQ ID NO:757, and LCDR3 contains the amino acid sequence of SEQ ID NO:758.

[0241] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:759, HCDR2 contains the amino acid sequence of SEQ ID NO:760, HCDR3 contains the amino acid sequence of SEQ ID NO:761, LCDR1 contains the amino acid sequence of SEQ ID NO:762, LCDR2 contains the amino acid sequence of SEQ ID NO:763, and LCDR3 contains the amino acid sequence of SEQ ID NO:764.

[0242] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:765, HCDR2 contains the amino acid sequence of SEQ ID NO:766, HCDR3 contains the amino acid sequence of SEQ ID NO:767, LCDR1 contains the amino acid sequence of SEQ ID NO:768, LCDR2 contains the amino acid sequence of SEQ ID NO:769, and LCDR3 contains the amino acid sequence of SEQ ID NO:770.

[0243] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:771, HCDR2 contains the amino acid sequence of SEQ ID NO:772, HCDR3 contains the amino acid sequence of SEQ ID NO:773, LCDR1 contains the amino acid sequence of SEQ ID NO:774, LCDR2 contains the amino acid sequence of SEQ ID NO:775, and LCDR3 contains the amino acid sequence of SEQ ID NO:776.

[0244] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:777, HCDR2 contains the amino acid sequence of SEQ ID NO:778, HCDR3 contains the amino acid sequence of SEQ ID NO:779, LCDR1 contains the amino acid sequence of SEQ ID NO:780, LCDR2 contains the amino acid sequence of SEQ ID NO:781, and LCDR3 contains the amino acid sequence of SEQ ID NO:782.

[0245] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:783, HCDR2 contains the amino acid sequence of SEQ ID NO:784, HCDR3 contains the amino acid sequence of SEQ ID NO:785, LCDR1 contains the amino acid sequence of SEQ ID NO:786, LCDR2 contains the amino acid sequence of SEQ ID NO:787, and LCDR3 contains the amino acid sequence of SEQ ID NO:788.

[0246] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:789, HCDR2 contains the amino acid sequence of SEQ ID NO:790, HCDR3 contains the amino acid sequence of SEQ ID NO:791, LCDR1 contains the amino acid sequence of SEQ ID NO:792, LCDR2 contains the amino acid sequence of SEQ ID NO:793, and LCDR3 contains the amino acid sequence of SEQ ID NO:794.

[0247] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:795, HCDR2 contains the amino acid sequence of SEQ ID NO:796, HCDR3 contains the amino acid sequence of SEQ ID NO:797, LCDR1 contains the amino acid sequence of SEQ ID NO:798, LCDR2 contains the amino acid sequence of SEQ ID NO:799, and LCDR3 contains the amino acid sequence of SEQ ID NO:800.

[0248] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:801, HCDR2 contains the amino acid sequence of SEQ ID NO:802, HCDR3 contains the amino acid sequence of SEQ ID NO:803, LCDR1 contains the amino acid sequence of SEQ ID NO:804, LCDR2 contains the amino acid sequence of SEQ ID NO:805, and LCDR3 contains the amino acid sequence of SEQ ID NO:806.

[0249] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:807, HCDR2 contains the amino acid sequence of SEQ ID NO:808, HCDR3 contains the amino acid sequence of SEQ ID NO:809, LCDR1 contains the amino acid sequence of SEQ ID NO:810, LCDR2 contains the amino acid sequence of SEQ ID NO:811, and LCDR3 contains the amino acid sequence of SEQ ID NO:812.

[0250] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:813, HCDR2 contains the amino acid sequence of SEQ ID NO:814, HCDR3 contains the amino acid sequence of SEQ ID NO:815, LCDR1 contains the amino acid sequence of SEQ ID NO:816, LCDR2 contains the amino acid sequence of SEQ ID NO:817, and LCDR3 contains the amino acid sequence of SEQ ID NO:818.

[0251] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:819, HCDR2 contains the amino acid sequence of SEQ ID NO:820, HCDR3 contains the amino acid sequence of SEQ ID NO:821, LCDR1 contains the amino acid sequence of SEQ ID NO:822, LCDR2 contains the amino acid sequence of SEQ ID NO:823, and LCDR3 contains the amino acid sequence of SEQ ID NO:824.

[0252] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:825, HCDR2 contains the amino acid sequence of SEQ ID NO:826, HCDR3 contains the amino acid sequence of SEQ ID NO:827, LCDR1 contains the amino acid sequence of SEQ ID NO:828, LCDR2 contains the amino acid sequence of SEQ ID NO:829, and LCDR3 contains the amino acid sequence of SEQ ID NO:830.

[0253] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:831, HCDR2 contains the amino acid sequence of SEQ ID NO:832, HCDR3 contains the amino acid sequence of SEQ ID NO:833, LCDR1 contains the amino acid sequence of SEQ ID NO:834, LCDR2 contains the amino acid sequence of SEQ ID NO:835, and LCDR3 contains the amino acid sequence of SEQ ID NO:836.

[0254] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:837, HCDR2 contains the amino acid sequence of SEQ ID NO:838, HCDR3 contains the amino acid sequence of SEQ ID NO:839, LCDR1 contains the amino acid sequence of SEQ ID NO:840, LCDR2 contains the amino acid sequence of SEQ ID NO:841, and LCDR3 contains the amino acid sequence of SEQ ID NO:842.

[0255] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:843, HCDR2 contains the amino acid sequence of SEQ ID NO:844, HCDR3 contains the amino acid sequence of SEQ ID NO:845, LCDR1 contains the amino acid sequence of SEQ ID NO:846, LCDR2 contains the amino acid sequence of SEQ ID NO:847, and LCDR3 contains the amino acid sequence of SEQ ID NO:848.

[0256] In some specific embodiments, in the antibody or antigen-binding fragments provided herein, HCDR1 contains the amino acid sequence of SEQ ID NO:543, HCDR2 contains the amino acid sequence of SEQ ID NO:544, HCDR3 contains the amino acid sequence of SEQ ID NO:1179, LCDR1 contains the amino acid sequence of SEQ ID NO:546, LCDR2 contains the amino acid sequence of SEQ ID NO:1281, and LCDR3 contains the amino acid sequence of SEQ ID NO:548.

[0257] In some implementations, the antibody also includes one or more frame regions of SEQ ID NO:283-400 and 1155-1166.

[0258] In some implementations, the antibodies provided herein are humanized antibodies. The frame region described herein is defined based on the boundaries of the CDR numbering system. In other words, if the CDR is determined by, for example, Kabat, IMGT, or Chothia, the frame region is an amino acid residue surrounding the CDR in a variable region of the format FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 from the N-terminus to the C-terminus. For example, FR1 is defined as the amino acid residue located at the N-terminus of the CDR1 amino acid residue as defined by, for example, the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; FR2 is defined as the amino acid residue between the CDR1 amino acid residue and the CDR2 amino acid residue as defined by, for example, the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; FR3 is defined as the amino acid residue between the CDR2 amino acid residue and the CDR3 amino acid residue as defined by, for example, the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system; and FR4 is defined as the amino acid residue located at the C-terminus of the CDR3 amino acid residue as defined by, for example, the Kabat numbering system, the IMGT numbering system, or the Chothia numbering system.

[0259] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:283. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:284. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:283 and a VL containing the amino acid sequence of SEQ ID NO:284.

[0260] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:285. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:286. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:285 and a VL containing the amino acid sequence of SEQ ID NO:286.

[0261] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:287. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:288. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:287 and a VL containing the amino acid sequence of SEQ ID NO:288.

[0262] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:289. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:290. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:289 and a VL containing the amino acid sequence of SEQ ID NO:290.

[0263] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:291. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:292. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:291 and a VL containing the amino acid sequence of SEQ ID NO:292.

[0264] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:293. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:294. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:293 and a VL containing the amino acid sequence of SEQ ID NO:294.

[0265] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:295. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:296. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:295 and a VL containing the amino acid sequence of SEQ ID NO:296.

[0266] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:297. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:298. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:297 and a VL containing the amino acid sequence of SEQ ID NO:298.

[0267] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:299. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:300. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:299 and a VL containing the amino acid sequence of SEQ ID NO:300.

[0268] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:301. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:302. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:301 and a VL containing the amino acid sequence of SEQ ID NO:302.

[0269] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:303. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:304. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:303 and a VL containing the amino acid sequence of SEQ ID NO:304.

[0270] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:305. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:306. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:305 and a VL containing the amino acid sequence of SEQ ID NO:306.

[0271] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:307. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:308. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:307 and a VL containing the amino acid sequence of SEQ ID NO:308.

[0272] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:309. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:310. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:309 and a VL containing the amino acid sequence of SEQ ID NO:310.

[0273] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:311. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:312. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:311 and a VL containing the amino acid sequence of SEQ ID NO:312.

[0274] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:313. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:314. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:313 and a VL containing the amino acid sequence of SEQ ID NO:314.

[0275] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:315. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:316. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:315 and a VL containing the amino acid sequence of SEQ ID NO:316.

[0276] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:317. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:318. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:317 and a VL containing the amino acid sequence of SEQ ID NO:318.

[0277] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:319. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:320. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:319 and a VL containing the amino acid sequence of SEQ ID NO:320.

[0278] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:321. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:322. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:321 and a VL containing the amino acid sequence of SEQ ID NO:322.

[0279] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:323. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:324. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:323 and a VL containing the amino acid sequence of SEQ ID NO:324.

[0280] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:325. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:326. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:325 and a VL containing the amino acid sequence of SEQ ID NO:326.

[0281] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:327. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:328. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:327 and a VL containing the amino acid sequence of SEQ ID NO:328.

[0282] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:329. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:330. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:329 and a VL containing the amino acid sequence of SEQ ID NO:330.

[0283] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:331. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:332. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:331 and a VL containing the amino acid sequence of SEQ ID NO:332.

[0284] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:333. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:334. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:333 and a VL containing the amino acid sequence of SEQ ID NO:334.

[0285] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:335. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:336. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:335 and a VL containing the amino acid sequence of SEQ ID NO:336.

[0286] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:337. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:338. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:337 and a VL containing the amino acid sequence of SEQ ID NO:338.

[0287] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:339. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:340. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:339 and a VL containing the amino acid sequence of SEQ ID NO:340.

[0288] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:341. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:342. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:341 and a VL containing the amino acid sequence of SEQ ID NO:342.

[0289] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:343. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:344. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:343 and a VL containing the amino acid sequence of SEQ ID NO:344.

[0290] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:345. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:346. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:345 and a VL containing the amino acid sequence of SEQ ID NO:346.

[0291] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:347. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:348. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:347 and a VL containing the amino acid sequence of SEQ ID NO:348.

[0292] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:349. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:350. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:349 and a VL containing the amino acid sequence of SEQ ID NO:350.

[0293] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:351. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:352. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:351 and a VL containing the amino acid sequence of SEQ ID NO:352.

[0294] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:353. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:354. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:353 and a VL containing the amino acid sequence of SEQ ID NO:354.

[0295] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:355. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:356. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:355 and a VL containing the amino acid sequence of SEQ ID NO:356.

[0296] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:357. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:358. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:357 and a VL containing the amino acid sequence of SEQ ID NO:358.

[0297] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:359. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:360. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:359 and a VL containing the amino acid sequence of SEQ ID NO:360.

[0298] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:361. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:362. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:361 and a VL containing the amino acid sequence of SEQ ID NO:362.

[0299] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:363. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:364. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:363 and a VL containing the amino acid sequence of SEQ ID NO:364.

[0300] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:365. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:366. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:365 and a VL containing the amino acid sequence of SEQ ID NO:366.

[0301] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:367. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:368. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:367 and a VL containing the amino acid sequence of SEQ ID NO:368.

[0302] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:369. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:370. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:369 and a VL containing the amino acid sequence of SEQ ID NO:370.

[0303] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:371. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:372. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:371 and a VL containing the amino acid sequence of SEQ ID NO:372.

[0304] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:373. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:374. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:373 and a VL containing the amino acid sequence of SEQ ID NO:374.

[0305] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:375. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:376. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:375 and a VL containing the amino acid sequence of SEQ ID NO:376.

[0306] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:377. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:378. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:377 and a VL containing the amino acid sequence of SEQ ID NO:378.

[0307] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:379. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:380. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:379 and a VL containing the amino acid sequence of SEQ ID NO:380.

[0308] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:381. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:382. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:381 and a VL containing the amino acid sequence of SEQ ID NO:382.

[0309] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:383. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:384. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:383 and a VL containing the amino acid sequence of SEQ ID NO:384.

[0310] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:385. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:386. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:385 and a VL containing the amino acid sequence of SEQ ID NO:386.

[0311] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:387. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:388. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:387 and a VL containing the amino acid sequence of SEQ ID NO:388.

[0312] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:389. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:390. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:389 and a VL containing the amino acid sequence of SEQ ID NO:390.

[0313] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:391. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:392. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:391 and a VL containing the amino acid sequence of SEQ ID NO:392.

[0314] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:393. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:394. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:393 and a VL containing the amino acid sequence of SEQ ID NO:394.

[0315] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:395. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:396. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:395 and a VL containing the amino acid sequence of SEQ ID NO:396.

[0316] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:397. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:398. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:397 and a VL containing the amino acid sequence of SEQ ID NO:398.

[0317] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:399. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:400. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:399 and a VL containing the amino acid sequence of SEQ ID NO:400.

[0318] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1155. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1156. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1155 and a VL containing the amino acid sequence of SEQ ID NO:1156.

[0319] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1157. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1158. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1157 and a VL containing the amino acid sequence of SEQ ID NO:1158.

[0320] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1159. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1160. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1159 and a VL containing the amino acid sequence of SEQ ID NO:1160.

[0321] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1161. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1162. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1161 and a VL containing the amino acid sequence of SEQ ID NO:1162.

[0322] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1163. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1164. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1163 and a VL containing the amino acid sequence of SEQ ID NO:1164.

[0323] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1165. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VL containing the amino acid sequence of SEQ ID NO:1166. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH containing the amino acid sequence of SEQ ID NO:1165 and a VL containing the amino acid sequence of SEQ ID NO:1166.

[0324] In some embodiments, the antibody or its antigen-binding fragment described herein comprises an amino acid sequence having a certain percentage of identity with any antibody provided herein (e.g., those described in Section 7 below).

[0325] In some embodiments, the antibodies or antigen-binding fragments described herein comprise an amino acid sequence having a certain percentage of identity (such as at least about 80%, or at least about 81%, or at least about 82%, or at least about 83%, or at least about 84%, or at least about 85%, or at least about 86%, or at least about 87%, or at least about 88%, or at least about 89%, or at least about 90%, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99% or higher) with respect to any antibody or fragment provided herein (e.g., as described in Tables 5-6 and 14-15). In some embodiments, the antibodies or antigen-binding fragments described herein comprise a CDR of any antibody or fragment provided herein (e.g., as described in Tables 5-6 and 14-15).

[0326] The determination of the percentage of identity between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be accomplished using mathematical algorithms. A non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm in Karlin and Altschul, Proc. Natl. Acad. Sci. USA 87:2264 2268 (1990), modified as in Karlin and Altschul, Proc. Natl. Acad. Sci. USA 90:5873 5877 (1993). This algorithm is incorporated into the NBLAST and XBLAST procedures of Altschul et al., J. Mol. Biol. 215:403 (1990). BLAST nucleotide searches can be performed using NBLAST nucleotide procedure parameters set, for example, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed using XBLAST program parameters set, for example, score=50, word length=3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gap alignments for comparative purposes, gap BLAST can be used as described in Altschul et al., Nucleic Acids Res. 25:3389 3402 (1997). In some embodiments, the percentage of identity between two sequences is calculated by dividing the number of varied residues (excluding or including conserved amino acid substitutions or degenerate nucleotide substitutions) between the two sequences in the alignment by the number of residues of either: (i) the full length of the shorter sequence, (ii) the full length of the longer sequence, (iii) the average length of the two sequences, (iv) the total length of the non-gap portion of the alignment, (v) the length of the alignment excluding protrusions, or (vi) the length of the alignment including protrusions. As used herein, a protrusion in sequence alignment refers to either end or both ends of the alignment, where residues in one sequence are considered to be aligned with residues-free (i.e., gaps) in the other sequence. Alternatively, PSI BLAST can be used for iterative searches to detect long-distance relationships (Id.) between molecules. When using the BLAST, nick BLAST, and PSI BLAST procedures, the default parameters of the respective procedures can be used (e.g., the default parameters for XBLAST and NBLAST) (see, for example, the National Center for Biotechnology Information (NCBI), World Wide Web: ncbi.nlm.nih.gov). Another non-limiting example of a mathematical algorithm for sequence alignment is the algorithm of Myers and Miller, CABIOS 4:11-17 (1998). This algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package.When comparing amino acid sequences using the ALIGN program, the PAM120 weighted residue table, gap length penalty 12, and gap penalty 4 can be used. Techniques similar to those described above can be used to determine the percentage of identity between two sequences, with or without gaps. Typically, only exact matches are counted when calculating the percentage of identity.

[0327] In some embodiments, the antibodies described herein or the antigen-binding fragments thereof provided herein contain substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, but the antibodies containing this sequence retain their ability to bind to LILRB1. In some embodiments, a total of 1 to 10 amino acids in the reference amino acid sequence have been substituted, inserted, and / or deleted. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDR (i.e., in the FR and / or constant regions).

[0328] In some embodiments, the position of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) regions of the LILRB1 binding domain described herein may vary by one, two, three, four, five, or six amino acid positions, provided that binding to LILRB1 (e.g., human LILRB1) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). For example, in some embodiments, the position of a CDR defined in any of Tables 5-6 and 14-15 may be varied by shifting the N-terminal and / or C-terminal boundary of the CDR relative to the current CDR position by one, two, three, four, five, or six amino acids, provided that binding to LILRB1 (e.g., human LILRB1) is maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%). Additionally or alternatively, in some embodiments, the length of one or more CDRs along the VH (e.g., CDR1, CDR2, or CDR3) and / or VL (e.g., CDR1, CDR2, or CDR3) regions of the LILRB1 binding domain described herein may vary (e.g., shorter or longer) by one, two, three, four, five, or more amino acids, as long as they remain (e.g., substantially remain, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%) bound to LILRB1 (e.g., human LILRB1). For example, in some embodiments, the VH and / or VL CDR1, CDR2 and / or CDR3 described herein may be one, two, three, four, five or more amino acids shorter than one or more of the CDRs described by SEQ ID NO:495-848, 1179 and 1281, provided that they are retained (e.g., substantially retained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%) bound to LILRB1 (e.g., human LILRB1). In other embodiments, the VH and / or VL CDR1, CDR2 and / or CDR3 described herein may be longer than one, two, three, four, five or more amino acids of one or more of the CDRs described by SEQ ID NO:495-848, 1179 and 1281, provided that they are maintained (e.g., substantially maintained, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%) bound to LILRB1 (e.g., human LILRB1).In some embodiments, the amino termini of VH and / or VL CDR1, CDR2 and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NO:495-848, 1179 and 1281, provided that they remain (e.g., substantially remain, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%) bound to LILRB1 (e.g., human LILRB1). Additionally or alternatively, in some embodiments, the carboxyl termini of the VH and / or VL CDR1, CDR2 and / or CDR3 described herein may be extended or shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described by SEQ ID NO:495-848, 1179 and 1281, provided that they remain (e.g., substantially remain, e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95%) bound to LILRB1 (e.g., human LILRB1). Any method known in the art may be used to determine whether binding to LILRB1 (e.g., human LILRB1) is maintained, such as the binding assays and conditions described in the "Examples" section herein.

[0329] In other embodiments, the antibody or its antigen-binding fragment described herein further comprises conserved sequence modifications (e.g., in the LILRB1 binding domain). Conserved sequence modifications include conserved amino acid substitutions, wherein the amino acid residue is replaced by a conserved amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. Thus, in some embodiments, a predicted non-essential amino acid residue in LILRB1 is replaced by another amino acid residue from the same side chain family. Methods for identifying conserved amino acid substitutions that do not eliminate antigen binding and their encoding nucleotides are well known in the art (see, for example, Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al., Protein Eng. 12(10):879-884 (1999); and Burks et al., Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). In some embodiments, the conserved sequence modifications described herein modify the amino acid sequence of a binding agent (e.g., an antibody) by 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 98%, or 99%, including human LILRB1 binding agents. In some embodiments, the amino acid sequence modification refers to the substitution of up to 1, 2, 3, 4, 5, or 6 amino acids in the CDR, such as those described in any of Tables 5-6 and 14-15. Thus, for example, each such CDR may contain up to 5 conserved amino acid substitutions, for example, up to (no more than) 4 conserved amino acid substitutions, for example, up to (no more than) 3 conserved amino acid substitutions, for example, up to (no more than) 2 conserved amino acid substitutions, or no more than 1 conserved amino acid substitution. In some implementations, the LILRB1 binding domain contains one or more (including six) CDRs that have at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% identity with any antibody or fragment thereof provided herein (e.g., in Tables 5 to 6 and Tables 14 to 15).

[0330] In some embodiments, the LILRB1 binding domain contains VH and VL containing the same CDR as any antibody or fragment thereof provided herein (e.g., in Tables 5-6 and 14-15). In some embodiments, the amino acid sequence modification does not include any modification within the SDR. In some embodiments, the amino acid sequence modification does not include any modification within the CDR (such as CDR1, CDR2, CDR3, or any combination thereof). In another embodiment, the amino acid sequence modification is in the frame or constant region.

[0331] In some embodiments, the antibodies provided herein contain substitutions (e.g., conserved substitutions), insertions, or deletions relative to the reference sequence, but the anti-LILRB1 antibody containing this sequence retains its ability to bind to LILRB1. In some embodiments, a total of 1 to 10 amino acids in the reference amino acid sequence have been substituted, inserted, and / or deleted. In some embodiments, the substitutions, insertions, or deletions occur in regions outside the CDR (i.e., in the FR). Optionally, the anti-LILRB1 antibodies provided herein include post-translational modifications of the reference sequence.

[0332] In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:283, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:284. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:285, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:286. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:287, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:288. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:289, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:290.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:291, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:292. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:293, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:294. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:295, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:296. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:297, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:298.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:299, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:300. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:301, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:302. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:303, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:304. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:305, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:306.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:307, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:308. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:309, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:310. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:311, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:312. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:313, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:314.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:315, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:316. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:317, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:318. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:319, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:320. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:321, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:322.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:323, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:324. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:325, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:326. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:327, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:328. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:329, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:330.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:331, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:332. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:333, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:334. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:335, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:336. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:337, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:338.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:339, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:340. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:341, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:342. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:343, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:344. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:345, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:346.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:347, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:348. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:349, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:350. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:351, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:352. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:353, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:354.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:355, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:356. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:357, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:358. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:359, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:360. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:361, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:362.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:363, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:364. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:365, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:366. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:367, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:368. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:369, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:370.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:371, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:372. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:373, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:374. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:375, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:376. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:377, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:378.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:379, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:380. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:381, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:382. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:383, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:384. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:385, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:386.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:387, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:388. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:389, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:390. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:391, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:392. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:393, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:394.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:395, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:396. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:397, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:398. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:399, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:400.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1155, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1156. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1157, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1158. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1159, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1160.In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1161, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1162. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1163, and a VL domain having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:1164. In some embodiments, the antibody or antigen-binding fragment provided herein comprises a VH domain having at least 75%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 1165, and a VL domain having at least 75%, 80%, 95%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 1166. In all the above embodiments, the antibody binds to LILRB1.

[0333] In some embodiments, functional epitopes can be mapped, for example, by combining alanine scans, to identify the amino acids in the LILRB1 protein essential for interaction with the anti-LILRB1 antibodies provided herein. In some embodiments, the conformation and crystal structure of the anti-LILRB1 antibody bound to LILRB1 can be used to identify the epitope. In some embodiments, this disclosure provides antibodies that specifically bind to the same epitope as any of the anti-LILRB1 antibodies provided herein. For example, in some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody comprising a VH containing the amino acid sequence of SEQ ID NO:283 and a VL containing the amino acid sequence of SEQ ID NO:284. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody comprising a VH containing the amino acid sequence of SEQ ID NO:285 and a VL containing the amino acid sequence of SEQ ID NO:286. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:287 and a VL containing the amino acid sequence of SEQ ID NO:288. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:289 and a VL containing the amino acid sequence of SEQ ID NO:290. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:291 and a VL containing the amino acid sequence of SEQ ID NO:292. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:293 and a VL containing the amino acid sequence of SEQ ID NO:294. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:295 and a VL containing the amino acid sequence of SEQ ID NO:296. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:297 and a VL containing the amino acid sequence of SEQ ID NO:298.In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:299 and a VL containing the amino acid sequence of SEQ ID NO:300. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:301 and a VL containing the amino acid sequence of SEQ ID NO:302. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:303 and a VL containing the amino acid sequence of SEQ ID NO:304. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:305 and a VL containing the amino acid sequence of SEQ ID NO:306. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:307 and a VL containing the amino acid sequence of SEQ ID NO:308. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:309 and a VL containing the amino acid sequence of SEQ ID NO:310. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:311 and a VL containing the amino acid sequence of SEQ ID NO:312. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:313 and a VL containing the amino acid sequence of SEQ ID NO:314. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as the anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:315 and a VL containing the amino acid sequence of SEQ ID NO:316.In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:317 and a VL containing the amino acid sequence of SEQ ID NO:318. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:319 and a VL containing the amino acid sequence of SEQ ID NO:320. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:321 and a VL containing the amino acid sequence of SEQ ID NO:322. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:323 and a VL containing the amino acid sequence of SEQ ID NO:324. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:325 and a VL containing the amino acid sequence of SEQ ID NO:326. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:327 and a VL containing the amino acid sequence of SEQ ID NO:328. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:329 and a VL containing the amino acid sequence of SEQ ID NO:330. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:331 and a VL containing the amino acid sequence of SEQ ID NO:332. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as the anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:333 and a VL containing the amino acid sequence of SEQ ID NO:334.In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:335 and a VL containing the amino acid sequence of SEQ ID NO:336. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:337 and a VL containing the amino acid sequence of SEQ ID NO:338. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:339 and a VL containing the amino acid sequence of SEQ ID NO:340. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:341 and a VL containing the amino acid sequence of SEQ ID NO:342. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:343 and a VL containing the amino acid sequence of SEQ ID NO:344. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:345 and a VL containing the amino acid sequence of SEQ ID NO:346. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:347 and a VL containing the amino acid sequence of SEQ ID NO:348. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:349 and a VL containing the amino acid sequence of SEQ ID NO:350. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as the anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:351 and a VL containing the amino acid sequence of SEQ ID NO:352.In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:353 and a VL containing the amino acid sequence of SEQ ID NO:354. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:355 and a VL containing the amino acid sequence of SEQ ID NO:356. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:357 and a VL containing the amino acid sequence of SEQ ID NO:358. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:359 and a VL containing the amino acid sequence of SEQ ID NO:360. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:361 and a VL containing the amino acid sequence of SEQ ID NO:362. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:363 and a VL containing the amino acid sequence of SEQ ID NO:364. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:365 and a VL containing the amino acid sequence of SEQ ID NO:366. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:367 and a VL containing the amino acid sequence of SEQ ID NO:368. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as the anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:369 and a VL containing the amino acid sequence of SEQ ID NO:370.In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:371 and a VL containing the amino acid sequence of SEQ ID NO:372. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:373 and a VL containing the amino acid sequence of SEQ ID NO:374. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:375 and a VL containing the amino acid sequence of SEQ ID NO:376. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1 antibody, which comprises a VH containing the amino acid sequence of SEQ ID NO:377 and a VL containing the amino acid sequence of SEQ ID NO:378. In some embodiments, the antibody or antigen-binding fragment provided herein binds to the same epitope as an anti-LILRB1...

Claims

1. An antibody or antigen-binding fragment thereof that binds to LILRB1, wherein the antibody or antigen-binding fragment comprises: (1). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1155 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1156. (2). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1157 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1158. (3). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1159 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1160. (4). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1161 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1162. (5). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1163 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1164. (6). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1165 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1166. (7). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:283 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:284; (8). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:285 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:286; (9). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:287 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

288. (10). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:289 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:290; (11). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:291 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:292; (12). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:293 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:294; (13). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:295 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:296; (14). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:297 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:298; (15). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:299 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

300. (16). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:301 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

302. (17). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:303 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

304. (18). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:305 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

306. (19). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:307 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

308. (20). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:309 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

310. (21). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:311 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

312. (22). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:313 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

314. (23). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:315 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

316. (24). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:317 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

318. (25). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:319 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

320. (26). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:321 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:322; (27). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:323 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:324; (28). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:325 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:326; (29). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:327 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

328. (30). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:329 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:330; (31). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:331 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

332. (32). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:333 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:334; (33). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:335 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

336. (34). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:337 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

338. (35). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:339 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

340. (36). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:341 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

342. (37). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:343 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

344. (38). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:345 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

346. (39). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:347 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

348. (40). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:349 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

350. (41). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:351 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

352. (42). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:353 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:354; (43). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:355 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

356. (44). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:357 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

358. (45). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:359 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

360. (46). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:361 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

362. (47). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:363 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

364. (48). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:365 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

366. (49). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:367 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

368. (50). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:369 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

370. (51). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:371 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

372. (52). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:373 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

374. (53). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:375 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

376. (54). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:377 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

378. (55). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:379 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

380. (56). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:381 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

382. (57). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:383 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

384. (58). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:385 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

386. (59). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:387 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

388. (60). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:389 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

390. (61). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:391 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

392. (62). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:393 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:394; (63). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:395 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

396. (64). HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:397, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:398; or (65). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:399 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

400.

2. The antibody or antigen-binding fragment according to claim 1, wherein: (1). The HCDR1 contains the amino acid sequence of SEQ ID NO:543, the HCDR2 contains the amino acid sequence of SEQ ID NO:544, the HCDR3 contains the amino acid sequence of SEQ ID NO:1179, the LCDR1 contains the amino acid sequence of SEQ ID NO:546, the LCDR2 contains the amino acid sequence of SEQ ID NO:1281, and the LCDR3 contains the amino acid sequence of SEQ ID NO:548; (2). The HCDR1 contains the amino acid sequence of SEQ ID NO:585, the HCDR2 contains the amino acid sequence of SEQ ID NO:586, the HCDR3 contains the amino acid sequence of SEQ ID NO:587, the LCDR1 contains the amino acid sequence of SEQ ID NO:588, the LCDR2 contains the amino acid sequence of SEQ ID NO:589, and the LCDR3 contains the amino acid sequence of SEQ ID NO:590; (3). The HCDR1 contains the amino acid sequence of SEQ ID NO:495, the HCDR2 contains the amino acid sequence of SEQ ID NO:496, the HCDR3 contains the amino acid sequence of SEQ ID NO:497, the LCDR1 contains the amino acid sequence of SEQ ID NO:498, the LCDR2 contains the amino acid sequence of SEQ ID NO:499, and the LCDR3 contains the amino acid sequence of SEQ ID NO:500; (4). The HCDR1 contains the amino acid sequence of SEQ ID NO:501, the HCDR2 contains the amino acid sequence of SEQ ID NO:502, the HCDR3 contains the amino acid sequence of SEQ ID NO:503, the LCDR1 contains the amino acid sequence of SEQ ID NO:504, the LCDR2 contains the amino acid sequence of SEQ ID NO:505, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

506. (5). The HCDR1 contains the amino acid sequence of SEQ ID NO:507, the HCDR2 contains the amino acid sequence of SEQ ID NO:508, the HCDR3 contains the amino acid sequence of SEQ ID NO:509, the LCDR1 contains the amino acid sequence of SEQ ID NO:510, the LCDR2 contains the amino acid sequence of SEQ ID NO:511, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

512. (6). The HCDR1 contains the amino acid sequence of SEQ ID NO:513, the HCDR2 contains the amino acid sequence of SEQ ID NO:514, the HCDR3 contains the amino acid sequence of SEQ ID NO:515, the LCDR1 contains the amino acid sequence of SEQ ID NO:516, the LCDR2 contains the amino acid sequence of SEQ ID NO:517, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

518. (7). The HCDR1 contains the amino acid sequence of SEQ ID NO:519, the HCDR2 contains the amino acid sequence of SEQ ID NO:520, the HCDR3 contains the amino acid sequence of SEQ ID NO:521, the LCDR1 contains the amino acid sequence of SEQ ID NO:522, the LCDR2 contains the amino acid sequence of SEQ ID NO:523, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

524. (8). The HCDR1 contains the amino acid sequence of SEQ ID NO:525, the HCDR2 contains the amino acid sequence of SEQ ID NO:526, the HCDR3 contains the amino acid sequence of SEQ ID NO:527, the LCDR1 contains the amino acid sequence of SEQ ID NO:528, the LCDR2 contains the amino acid sequence of SEQ ID NO:529, and the LCDR3 contains the amino acid sequence of SEQ ID NO:530; (9). The HCDR1 contains the amino acid sequence of SEQ ID NO:531, the HCDR2 contains the amino acid sequence of SEQ ID NO:532, the HCDR3 contains the amino acid sequence of SEQ ID NO:533, the LCDR1 contains the amino acid sequence of SEQ ID NO:534, the LCDR2 contains the amino acid sequence of SEQ ID NO:535, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

536. (10). The HCDR1 contains the amino acid sequence of SEQ ID NO:537, the HCDR2 contains the amino acid sequence of SEQ ID NO:538, the HCDR3 contains the amino acid sequence of SEQ ID NO:539, the LCDR1 contains the amino acid sequence of SEQ ID NO:540, the LCDR2 contains the amino acid sequence of SEQ ID NO:541, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

542. (11). The HCDR1 contains the amino acid sequence of SEQ ID NO:543, the HCDR2 contains the amino acid sequence of SEQ ID NO:544, the HCDR3 contains the amino acid sequence of SEQ ID NO:545, the LCDR1 contains the amino acid sequence of SEQ ID NO:546, the LCDR2 contains the amino acid sequence of SEQ ID NO:547, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

548. (12). The HCDR1 contains the amino acid sequence of SEQ ID NO:549, the HCDR2 contains the amino acid sequence of SEQ ID NO:550, the HCDR3 contains the amino acid sequence of SEQ ID NO:551, the LCDR1 contains the amino acid sequence of SEQ ID NO:552, the LCDR2 contains the amino acid sequence of SEQ ID NO:553, and the LCDR3 contains the amino acid sequence of SEQ ID NO:554; (13). The HCDR1 contains the amino acid sequence of SEQ ID NO:555, the HCDR2 contains the amino acid sequence of SEQ ID NO:556, the HCDR3 contains the amino acid sequence of SEQ ID NO:557, the LCDR1 contains the amino acid sequence of SEQ ID NO:558, the LCDR2 contains the amino acid sequence of SEQ ID NO:559, and the LCDR3 contains the amino acid sequence of SEQ ID NO:560; (14). The HCDR1 contains the amino acid sequence of SEQ ID NO:561, the HCDR2 contains the amino acid sequence of SEQ ID NO:562, the HCDR3 contains the amino acid sequence of SEQ ID NO:563, the LCDR1 contains the amino acid sequence of SEQ ID NO:564, the LCDR2 contains the amino acid sequence of SEQ ID NO:565, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

566. (15). The HCDR1 contains the amino acid sequence of SEQ ID NO:567, the HCDR2 contains the amino acid sequence of SEQ ID NO:568, the HCDR3 contains the amino acid sequence of SEQ ID NO:569, the LCDR1 contains the amino acid sequence of SEQ ID NO:570, the LCDR2 contains the amino acid sequence of SEQ ID NO:571, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

572. (16). The HCDR1 contains the amino acid sequence of SEQ ID NO:573, the HCDR2 contains the amino acid sequence of SEQ ID NO:574, the HCDR3 contains the amino acid sequence of SEQ ID NO:575, the LCDR1 contains the amino acid sequence of SEQ ID NO:576, the LCDR2 contains the amino acid sequence of SEQ ID NO:577, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

578. (17). The HCDR1 contains the amino acid sequence of SEQ ID NO:579, the HCDR2 contains the amino acid sequence of SEQ ID NO:580, the HCDR3 contains the amino acid sequence of SEQ ID NO:581, the LCDR1 contains the amino acid sequence of SEQ ID NO:582, the LCDR2 contains the amino acid sequence of SEQ ID NO:583, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

584. (18). The HCDR1 contains the amino acid sequence of SEQ ID NO:591, the HCDR2 contains the amino acid sequence of SEQ ID NO:592, the HCDR3 contains the amino acid sequence of SEQ ID NO:593, the LCDR1 contains the amino acid sequence of SEQ ID NO:594, the LCDR2 contains the amino acid sequence of SEQ ID NO:595, and the LCDR3 contains the amino acid sequence of SEQ ID NO:596; (19). The HCDR1 contains the amino acid sequence of SEQ ID NO:597, the HCDR2 contains the amino acid sequence of SEQ ID NO:598, the HCDR3 contains the amino acid sequence of SEQ ID NO:599, the LCDR1 contains the amino acid sequence of SEQ ID NO:600, the LCDR2 contains the amino acid sequence of SEQ ID NO:601, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

602. (20). The HCDR1 contains the amino acid sequence of SEQ ID NO:603, the HCDR2 contains the amino acid sequence of SEQ ID NO:604, the HCDR3 contains the amino acid sequence of SEQ ID NO:605, the LCDR1 contains the amino acid sequence of SEQ ID NO:606, the LCDR2 contains the amino acid sequence of SEQ ID NO:607, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

608. (21). The HCDR1 contains the amino acid sequence of SEQ ID NO:609, the HCDR2 contains the amino acid sequence of SEQ ID NO:610, the HCDR3 contains the amino acid sequence of SEQ ID NO:611, the LCDR1 contains the amino acid sequence of SEQ ID NO:612, the LCDR2 contains the amino acid sequence of SEQ ID NO:613, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

614. (22). The HCDR1 contains the amino acid sequence of SEQ ID NO:615, the HCDR2 contains the amino acid sequence of SEQ ID NO:616, the HCDR3 contains the amino acid sequence of SEQ ID NO:617, the LCDR1 contains the amino acid sequence of SEQ ID NO:618, the LCDR2 contains the amino acid sequence of SEQ ID NO:619, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

620. (23). The HCDR1 contains the amino acid sequence of SEQ ID NO:621, the HCDR2 contains the amino acid sequence of SEQ ID NO:622, the HCDR3 contains the amino acid sequence of SEQ ID NO:623, the LCDR1 contains the amino acid sequence of SEQ ID NO:624, the LCDR2 contains the amino acid sequence of SEQ ID NO:625, and the LCDR3 contains the amino acid sequence of SEQ ID NO:626; (24). The HCDR1 contains the amino acid sequence of SEQ ID NO:627, the HCDR2 contains the amino acid sequence of SEQ ID NO:628, the HCDR3 contains the amino acid sequence of SEQ ID NO:629, the LCDR1 contains the amino acid sequence of SEQ ID NO:630, the LCDR2 contains the amino acid sequence of SEQ ID NO:631, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

632. (25). The HCDR1 contains the amino acid sequence of SEQ ID NO:633, the HCDR2 contains the amino acid sequence of SEQ ID NO:634, the HCDR3 contains the amino acid sequence of SEQ ID NO:635, the LCDR1 contains the amino acid sequence of SEQ ID NO:636, the LCDR2 contains the amino acid sequence of SEQ ID NO:637, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

638. (26). The HCDR1 contains the amino acid sequence of SEQ ID NO:639, the HCDR2 contains the amino acid sequence of SEQ ID NO:640, the HCDR3 contains the amino acid sequence of SEQ ID NO:641, the LCDR1 contains the amino acid sequence of SEQ ID NO:642, the LCDR2 contains the amino acid sequence of SEQ ID NO:643, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

644. (27). The HCDR1 contains the amino acid sequence of SEQ ID NO:645, the HCDR2 contains the amino acid sequence of SEQ ID NO:646, the HCDR3 contains the amino acid sequence of SEQ ID NO:647, the LCDR1 contains the amino acid sequence of SEQ ID NO:648, the LCDR2 contains the amino acid sequence of SEQ ID NO:649, and the LCDR3 contains the amino acid sequence of SEQ ID NO:650; (28). The HCDR1 contains the amino acid sequence of SEQ ID NO:651, the HCDR2 contains the amino acid sequence of SEQ ID NO:652, the HCDR3 contains the amino acid sequence of SEQ ID NO:653, the LCDR1 contains the amino acid sequence of SEQ ID NO:654, the LCDR2 contains the amino acid sequence of SEQ ID NO:655, and the LCDR3 contains the amino acid sequence of SEQ ID NO:656; (29). The HCDR1 contains the amino acid sequence of SEQ ID NO:657, the HCDR2 contains the amino acid sequence of SEQ ID NO:658, the HCDR3 contains the amino acid sequence of SEQ ID NO:659, the LCDR1 contains the amino acid sequence of SEQ ID NO:660, the LCDR2 contains the amino acid sequence of SEQ ID NO:661, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

662. (30). The HCDR1 contains the amino acid sequence of SEQ ID NO:663, the HCDR2 contains the amino acid sequence of SEQ ID NO:664, the HCDR3 contains the amino acid sequence of SEQ ID NO:665, the LCDR1 contains the amino acid sequence of SEQ ID NO:666, the LCDR2 contains the amino acid sequence of SEQ ID NO:667, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

668. (31). The HCDR1 contains the amino acid sequence of SEQ ID NO:669, the HCDR2 contains the amino acid sequence of SEQ ID NO:670, the HCDR3 contains the amino acid sequence of SEQ ID NO:671, the LCDR1 contains the amino acid sequence of SEQ ID NO:672, the LCDR2 contains the amino acid sequence of SEQ ID NO:673, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

674. (32). The HCDR1 contains the amino acid sequence of SEQ ID NO:675, the HCDR2 contains the amino acid sequence of SEQ ID NO:676, the HCDR3 contains the amino acid sequence of SEQ ID NO:677, the LCDR1 contains the amino acid sequence of SEQ ID NO:678, the LCDR2 contains the amino acid sequence of SEQ ID NO:679, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

680. (33). The HCDR1 contains the amino acid sequence of SEQ ID NO:681, the HCDR2 contains the amino acid sequence of SEQ ID NO:682, the HCDR3 contains the amino acid sequence of SEQ ID NO:683, the LCDR1 contains the amino acid sequence of SEQ ID NO:684, the LCDR2 contains the amino acid sequence of SEQ ID NO:685, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

686. (34). The HCDR1 contains the amino acid sequence of SEQ ID NO:687, the HCDR2 contains the amino acid sequence of SEQ ID NO:688, the HCDR3 contains the amino acid sequence of SEQ ID NO:689, the LCDR1 contains the amino acid sequence of SEQ ID NO:690, the LCDR2 contains the amino acid sequence of SEQ ID NO:691, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

692. (35). The HCDR1 contains the amino acid sequence of SEQ ID NO:693, the HCDR2 contains the amino acid sequence of SEQ ID NO:694, the HCDR3 contains the amino acid sequence of SEQ ID NO:695, the LCDR1 contains the amino acid sequence of SEQ ID NO:696, the LCDR2 contains the amino acid sequence of SEQ ID NO:697, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

698. (36). The HCDR1 contains the amino acid sequence of SEQ ID NO:699, the HCDR2 contains the amino acid sequence of SEQ ID NO:700, the HCDR3 contains the amino acid sequence of SEQ ID NO:701, the LCDR1 contains the amino acid sequence of SEQ ID NO:702, the LCDR2 contains the amino acid sequence of SEQ ID NO:703, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

704. (37). The HCDR1 contains the amino acid sequence of SEQ ID NO:705, the HCDR2 contains the amino acid sequence of SEQ ID NO:706, the HCDR3 contains the amino acid sequence of SEQ ID NO:707, the LCDR1 contains the amino acid sequence of SEQ ID NO:708, the LCDR2 contains the amino acid sequence of SEQ ID NO:709, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

710. (38). The HCDR1 contains the amino acid sequence of SEQ ID NO:711, the HCDR2 contains the amino acid sequence of SEQ ID NO:712, the HCDR3 contains the amino acid sequence of SEQ ID NO:713, the LCDR1 contains the amino acid sequence of SEQ ID NO:714, the LCDR2 contains the amino acid sequence of SEQ ID NO:715, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

716. (39). The HCDR1 contains the amino acid sequence of SEQ ID NO:717, the HCDR2 contains the amino acid sequence of SEQ ID NO:718, the HCDR3 contains the amino acid sequence of SEQ ID NO:719, the LCDR1 contains the amino acid sequence of SEQ ID NO:720, the LCDR2 contains the amino acid sequence of SEQ ID NO:721, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

722. (40). The HCDR1 contains the amino acid sequence of SEQ ID NO:723, the HCDR2 contains the amino acid sequence of SEQ ID NO:724, the HCDR3 contains the amino acid sequence of SEQ ID NO:725, the LCDR1 contains the amino acid sequence of SEQ ID NO:726, the LCDR2 contains the amino acid sequence of SEQ ID NO:727, and the LCDR3 contains the amino acid sequence of SEQ ID NO:728; (41). The HCDR1 contains the amino acid sequence of SEQ ID NO:729, the HCDR2 contains the amino acid sequence of SEQ ID NO:730, the HCDR3 contains the amino acid sequence of SEQ ID NO:731, the LCDR1 contains the amino acid sequence of SEQ ID NO:732, the LCDR2 contains the amino acid sequence of SEQ ID NO:733, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

734. (42). The HCDR1 contains the amino acid sequence of SEQ ID NO:735, the HCDR2 contains the amino acid sequence of SEQ ID NO:736, the HCDR3 contains the amino acid sequence of SEQ ID NO:737, the LCDR1 contains the amino acid sequence of SEQ ID NO:738, the LCDR2 contains the amino acid sequence of SEQ ID NO:739, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

740. (43). The HCDR1 contains the amino acid sequence of SEQ ID NO:741, the HCDR2 contains the amino acid sequence of SEQ ID NO:742, the HCDR3 contains the amino acid sequence of SEQ ID NO:743, the LCDR1 contains the amino acid sequence of SEQ ID NO:744, the LCDR2 contains the amino acid sequence of SEQ ID NO:745, and the LCDR3 contains the amino acid sequence of SEQ ID NO:746; (44). The HCDR1 contains the amino acid sequence of SEQ ID NO:747, the HCDR2 contains the amino acid sequence of SEQ ID NO:748, the HCDR3 contains the amino acid sequence of SEQ ID NO:749, the LCDR1 contains the amino acid sequence of SEQ ID NO:750, the LCDR2 contains the amino acid sequence of SEQ ID NO:751, and the LCDR3 contains the amino acid sequence of SEQ ID NO:752; (45). The HCDR1 contains the amino acid sequence of SEQ ID NO:753, the HCDR2 contains the amino acid sequence of SEQ ID NO:754, the HCDR3 contains the amino acid sequence of SEQ ID NO:755, the LCDR1 contains the amino acid sequence of SEQ ID NO:756, the LCDR2 contains the amino acid sequence of SEQ ID NO:757, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

758. (46). The HCDR1 contains the amino acid sequence of SEQ ID NO:759, the HCDR2 contains the amino acid sequence of SEQ ID NO:760, the HCDR3 contains the amino acid sequence of SEQ ID NO:761, the LCDR1 contains the amino acid sequence of SEQ ID NO:762, the LCDR2 contains the amino acid sequence of SEQ ID NO:763, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

764. (47). The HCDR1 contains the amino acid sequence of SEQ ID NO:765, the HCDR2 contains the amino acid sequence of SEQ ID NO:766, the HCDR3 contains the amino acid sequence of SEQ ID NO:767, the LCDR1 contains the amino acid sequence of SEQ ID NO:768, the LCDR2 contains the amino acid sequence of SEQ ID NO:769, and the LCDR3 contains the amino acid sequence of SEQ ID NO:770; (48). The HCDR1 contains the amino acid sequence of SEQ ID NO:771, the HCDR2 contains the amino acid sequence of SEQ ID NO:772, the HCDR3 contains the amino acid sequence of SEQ ID NO:773, the LCDR1 contains the amino acid sequence of SEQ ID NO:774, the LCDR2 contains the amino acid sequence of SEQ ID NO:775, and the LCDR3 contains the amino acid sequence of SEQ ID NO:776; (49). The HCDR1 contains the amino acid sequence of SEQ ID NO:777, the HCDR2 contains the amino acid sequence of SEQ ID NO:778, the HCDR3 contains the amino acid sequence of SEQ ID NO:779, the LCDR1 contains the amino acid sequence of SEQ ID NO:780, the LCDR2 contains the amino acid sequence of SEQ ID NO:781, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

782. (50). The HCDR1 contains the amino acid sequence of SEQ ID NO:783, the HCDR2 contains the amino acid sequence of SEQ ID NO:784, the HCDR3 contains the amino acid sequence of SEQ ID NO:785, the LCDR1 contains the amino acid sequence of SEQ ID NO:786, the LCDR2 contains the amino acid sequence of SEQ ID NO:787, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

788. (51). The HCDR1 contains the amino acid sequence of SEQ ID NO:789, the HCDR2 contains the amino acid sequence of SEQ ID NO:790, the HCDR3 contains the amino acid sequence of SEQ ID NO:791, the LCDR1 contains the amino acid sequence of SEQ ID NO:792, the LCDR2 contains the amino acid sequence of SEQ ID NO:793, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

794. (52). The HCDR1 contains the amino acid sequence of SEQ ID NO:795, the HCDR2 contains the amino acid sequence of SEQ ID NO:796, the HCDR3 contains the amino acid sequence of SEQ ID NO:797, the LCDR1 contains the amino acid sequence of SEQ ID NO:798, the LCDR2 contains the amino acid sequence of SEQ ID NO:799, and the LCDR3 contains the amino acid sequence of SEQ ID NO:800; (53). The HCDR1 contains the amino acid sequence of SEQ ID NO:801, the HCDR2 contains the amino acid sequence of SEQ ID NO:802, the HCDR3 contains the amino acid sequence of SEQ ID NO:803, the LCDR1 contains the amino acid sequence of SEQ ID NO:804, the LCDR2 contains the amino acid sequence of SEQ ID NO:805, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

806. (54). The HCDR1 contains the amino acid sequence of SEQ ID NO:807, the HCDR2 contains the amino acid sequence of SEQ ID NO:808, the HCDR3 contains the amino acid sequence of SEQ ID NO:809, the LCDR1 contains the amino acid sequence of SEQ ID NO:810, the LCDR2 contains the amino acid sequence of SEQ ID NO:811, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

812. (55). The HCDR1 contains the amino acid sequence of SEQ ID NO:813, the HCDR2 contains the amino acid sequence of SEQ ID NO:814, the HCDR3 contains the amino acid sequence of SEQ ID NO:815, the LCDR1 contains the amino acid sequence of SEQ ID NO:816, the LCDR2 contains the amino acid sequence of SEQ ID NO:817, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

818. (56). The HCDR1 contains the amino acid sequence of SEQ ID NO:819, the HCDR2 contains the amino acid sequence of SEQ ID NO:820, the HCDR3 contains the amino acid sequence of SEQ ID NO:821, the LCDR1 contains the amino acid sequence of SEQ ID NO:822, the LCDR2 contains the amino acid sequence of SEQ ID NO:823, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

824. (57). The HCDR1 contains the amino acid sequence of SEQ ID NO:825, the HCDR2 contains the amino acid sequence of SEQ ID NO:826, the HCDR3 contains the amino acid sequence of SEQ ID NO:827, the LCDR1 contains the amino acid sequence of SEQ ID NO:828, the LCDR2 contains the amino acid sequence of SEQ ID NO:829, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

830. (58). The HCDR1 contains the amino acid sequence of SEQ ID NO:831, the HCDR2 contains the amino acid sequence of SEQ ID NO:832, the HCDR3 contains the amino acid sequence of SEQ ID NO:833, the LCDR1 contains the amino acid sequence of SEQ ID NO:834, the LCDR2 contains the amino acid sequence of SEQ ID NO:835, and the LCDR3 contains the amino acid sequence of SEQ ID NO:836; (59). HCDR1 contains the amino acid sequence of SEQ ID NO:837, HCDR2 contains the amino acid sequence of SEQ ID NO:838, HCDR3 contains the amino acid sequence of SEQ ID NO:839, LCDR1 contains the amino acid sequence of SEQ ID NO:840, LCDR2 contains the amino acid sequence of SEQ ID NO:841, and LCDR3 contains the amino acid sequence of SEQ ID NO:842; or (60). The HCDR1 contains the amino acid sequence of SEQ ID NO:843, the HCDR2 contains the amino acid sequence of SEQ ID NO:844, the HCDR3 contains the amino acid sequence of SEQ ID NO:845, the LCDR1 contains the amino acid sequence of SEQ ID NO:846, the LCDR2 contains the amino acid sequence of SEQ ID NO:847, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

848.

3. The antibody or antigen-binding fragment according to claim 1 or 2, comprising: (1). VH containing the amino acid sequence of SEQ ID NO:1155 and VL containing the amino acid sequence of SEQ ID NO:1156; (2). VH containing the amino acid sequence of SEQ ID NO:1157 and VL containing the amino acid sequence of SEQ ID NO:1158; (3). VH containing the amino acid sequence of SEQ ID NO:1159 and VL containing the amino acid sequence of SEQ ID NO:1160; (4). VH containing the amino acid sequence of SEQ ID NO:1161 and VL containing the amino acid sequence of SEQ ID NO:1162; (5). VH containing the amino acid sequence of SEQ ID NO:1163 and VL containing the amino acid sequence of SEQ ID NO:1164; (6). VH containing the amino acid sequence of SEQ ID NO:1165 and VL containing the amino acid sequence of SEQ ID NO:1166; (7). VH containing the amino acid sequence of SEQ ID NO:283 and VL containing the amino acid sequence of SEQ ID NO:284; (8). VH containing the amino acid sequence of SEQ ID NO:285 and VL containing the amino acid sequence of SEQ ID NO:286; (9). VH containing the amino acid sequence of SEQ ID NO:287 and VL containing the amino acid sequence of SEQ ID NO:288; (10). VH containing the amino acid sequence of SEQ ID NO:289 and VL containing the amino acid sequence of SEQ ID NO:290; (11). VH containing the amino acid sequence of SEQ ID NO:291 and VL containing the amino acid sequence of SEQ ID NO:292; (12). VH containing the amino acid sequence of SEQ ID NO:293 and VL containing the amino acid sequence of SEQ ID NO:294; (13). VH containing the amino acid sequence of SEQ ID NO:295 and VL containing the amino acid sequence of SEQ ID NO:296; (14). VH containing the amino acid sequence of SEQ ID NO:297 and VL containing the amino acid sequence of SEQ ID NO:298; (15). VH containing the amino acid sequence of SEQ ID NO:299 and VL containing the amino acid sequence of SEQ ID NO:300; (16). VH containing the amino acid sequence of SEQ ID NO:301 and VL containing the amino acid sequence of SEQ ID NO:302; (17). VH containing the amino acid sequence of SEQ ID NO:303 and VL containing the amino acid sequence of SEQ ID NO:304; (18). VH containing the amino acid sequence of SEQ ID NO:305 and VL containing the amino acid sequence of SEQ ID NO:306; (19). VH containing the amino acid sequence of SEQ ID NO:307 and VL containing the amino acid sequence of SEQ ID NO:308; (20). VH containing the amino acid sequence of SEQ ID NO:309 and VL containing the amino acid sequence of SEQ ID NO:310; (21). VH containing the amino acid sequence of SEQ ID NO:311 and VL containing the amino acid sequence of SEQ ID NO:312; (22). VH containing the amino acid sequence of SEQ ID NO:313 and VL containing the amino acid sequence of SEQ ID NO:314; (23). VH containing the amino acid sequence of SEQ ID NO:315 and VL containing the amino acid sequence of SEQ ID NO:316; (24). VH containing the amino acid sequence of SEQ ID NO:317 and VL containing the amino acid sequence of SEQ ID NO:318; (25). VH containing the amino acid sequence of SEQ ID NO:319 and VL containing the amino acid sequence of SEQ ID NO:320; (26). VH containing the amino acid sequence of SEQ ID NO:321 and VL containing the amino acid sequence of SEQ ID NO:322; (27). VH containing the amino acid sequence of SEQ ID NO:323 and VL containing the amino acid sequence of SEQ ID NO:324; (28). VH containing the amino acid sequence of SEQ ID NO:325 and VL containing the amino acid sequence of SEQ ID NO:326; (29). VH containing the amino acid sequence of SEQ ID NO:327 and VL containing the amino acid sequence of SEQ ID NO:328; (30). VH containing the amino acid sequence of SEQ ID NO:329 and VL containing the amino acid sequence of SEQ ID NO:330; (31). VH containing the amino acid sequence of SEQ ID NO:331 and VL containing the amino acid sequence of SEQ ID NO:332; (32). VH containing the amino acid sequence of SEQ ID NO:333 and VL containing the amino acid sequence of SEQ ID NO:334; (33). VH containing the amino acid sequence of SEQ ID NO:335 and VL containing the amino acid sequence of SEQ ID NO:336; (34). VH containing the amino acid sequence of SEQ ID NO:337 and VL containing the amino acid sequence of SEQ ID NO:338; (35). VH containing the amino acid sequence of SEQ ID NO:339 and VL containing the amino acid sequence of SEQ ID NO:340; (36). VH containing the amino acid sequence of SEQ ID NO:341 and VL containing the amino acid sequence of SEQ ID NO:342; (37). VH containing the amino acid sequence of SEQ ID NO:343 and VL containing the amino acid sequence of SEQ ID NO:344; (38). VH containing the amino acid sequence of SEQ ID NO:345 and VL containing the amino acid sequence of SEQ ID NO:346; (39). VH containing the amino acid sequence of SEQ ID NO:347 and VL containing the amino acid sequence of SEQ ID NO:348; (40). VH containing the amino acid sequence of SEQ ID NO:349 and VL containing the amino acid sequence of SEQ ID NO:350; (41). VH containing the amino acid sequence of SEQ ID NO:351 and VL containing the amino acid sequence of SEQ ID NO:352; (42). VH containing the amino acid sequence of SEQ ID NO:353 and VL containing the amino acid sequence of SEQ ID NO:354; (43). VH containing the amino acid sequence of SEQ ID NO:355 and VL containing the amino acid sequence of SEQ ID NO:356; (44). VH containing the amino acid sequence of SEQ ID NO:357 and VL containing the amino acid sequence of SEQ ID NO:358; (45). VH containing the amino acid sequence of SEQ ID NO:359 and VL containing the amino acid sequence of SEQ ID NO:360; (46). VH containing the amino acid sequence of SEQ ID NO:361 and VL containing the amino acid sequence of SEQ ID NO:362; (47). VH containing the amino acid sequence of SEQ ID NO:363 and VL containing the amino acid sequence of SEQ ID NO:364; (48). VH containing the amino acid sequence of SEQ ID NO:365 and VL containing the amino acid sequence of SEQ ID NO:366; (49). VH containing the amino acid sequence of SEQ ID NO:367 and VL containing the amino acid sequence of SEQ ID NO:368; (50). VH containing the amino acid sequence of SEQ ID NO:369 and VL containing the amino acid sequence of SEQ ID NO:370; (51). VH containing the amino acid sequence of SEQ ID NO:371 and VL containing the amino acid sequence of SEQ ID NO:372; (52). VH containing the amino acid sequence of SEQ ID NO:373 and VL containing the amino acid sequence of SEQ ID NO:374; (53). VH containing the amino acid sequence of SEQ ID NO:375 and VL containing the amino acid sequence of SEQ ID NO:376; (54). VH containing the amino acid sequence of SEQ ID NO:377 and VL containing the amino acid sequence of SEQ ID NO:378; (55). VH containing the amino acid sequence of SEQ ID NO:379 and VL containing the amino acid sequence of SEQ ID NO:380; (56). VH containing the amino acid sequence of SEQ ID NO:381 and VL containing the amino acid sequence of SEQ ID NO:382; (57). VH containing the amino acid sequence of SEQ ID NO:383 and VL containing the amino acid sequence of SEQ ID NO:384; (58). VH containing the amino acid sequence of SEQ ID NO:385 and VL containing the amino acid sequence of SEQ ID NO:386; (59). VH containing the amino acid sequence of SEQ ID NO:387 and VL containing the amino acid sequence of SEQ ID NO:388; (60). VH containing the amino acid sequence of SEQ ID NO:389 and VL containing the amino acid sequence of SEQ ID NO:390; (61). VH containing the amino acid sequence of SEQ ID NO:391 and VL containing the amino acid sequence of SEQ ID NO:392; (62). VH containing the amino acid sequence of SEQ ID NO:393 and VL containing the amino acid sequence of SEQ ID NO:394; (63). VH containing the amino acid sequence of SEQ ID NO:395 and VL containing the amino acid sequence of SEQ ID NO:396; (64). VH containing the amino acid sequence of SEQ ID NO:397 and VL containing the amino acid sequence of SEQ ID NO:398; or (65). VH containing the amino acid sequence of SEQ ID NO:399 and VL containing the amino acid sequence of SEQ ID NO:

400.

4. An antibody or antigen-binding fragment thereof that binds to LILRB2, wherein the antibody or antigen-binding fragment comprises: (1). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1167 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1168. (2). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1169 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1170. (3). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1171 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1172. (4). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1173 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1174. (5). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1175 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1176. (6). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1177 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1178. (7). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:401 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:402; (8). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:403 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:404; (9). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:405 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

406. (10). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:407 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

408. (11). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:409 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

410. (12). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:411 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

412. (13). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:413 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

414. (14). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:415 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

416. (15). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:417 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

418. (16). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:419 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

420. (17). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:421 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

422. (18). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:423 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:424; (19). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:425 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

426. (20). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:427 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:428; (21). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:429 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:430; (22). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:431 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:432; (23). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:433 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:434; (24). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:435 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

436. (25). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:437 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

438. (26). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:439 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:440; (27). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:441 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

442. (28). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:443 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:444; (29). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:445 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

446. (30). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:447 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

448. (31). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:449 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

450. (32). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:451 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

452. (33). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:453 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

454. (34). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:455 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

456. (35). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:457 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

458. (36). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:459 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

460. (37). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:461 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

462. (38). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:463 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:464; (39). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:465 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

466. (40). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:467 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

468. (41). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:469 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

470. (42). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:471 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:472; (43). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:473 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:474; (44). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:475 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

476. (45). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:477 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

478. (46). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:479 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

480. (47). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:481 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

482. (48). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:483 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

484. (49). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:485 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

486. (50). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:487 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

488. (51). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:489 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

490. (52). HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:491, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:492; or (53). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:493 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:

494.

5. The antibody or antigen-binding fragment according to claim 4, wherein: (1). The HCDR1 contains the amino acid sequence of SEQ ID NO:855, the HCDR2 contains the amino acid sequence of SEQ ID NO:856, the HCDR3 contains the amino acid sequence of SEQ ID NO:857, the LCDR1 contains the amino acid sequence of SEQ ID NO:858, the LCDR2 contains the amino acid sequence of SEQ ID NO:1282, and the LCDR3 contains the amino acid sequence of SEQ ID NO:860; (2). The HCDR1 contains the amino acid sequence of SEQ ID NO:987, the HCDR2 contains the amino acid sequence of SEQ ID NO:988, the HCDR3 contains the amino acid sequence of SEQ ID NO:989, the LCDR1 contains the amino acid sequence of SEQ ID NO:990, the LCDR2 contains the amino acid sequence of SEQ ID NO:991, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

992. (3). The HCDR1 contains the amino acid sequence of SEQ ID NO:849, the HCDR2 contains the amino acid sequence of SEQ ID NO:850, the HCDR3 contains the amino acid sequence of SEQ ID NO:851, the LCDR1 contains the amino acid sequence of SEQ ID NO:852, the LCDR2 contains the amino acid sequence of SEQ ID NO:853, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

854. (4). The HCDR1 contains the amino acid sequence of SEQ ID NO:855, the HCDR2 contains the amino acid sequence of SEQ ID NO:856, the HCDR3 contains the amino acid sequence of SEQ ID NO:857, the LCDR1 contains the amino acid sequence of SEQ ID NO:858, the LCDR2 contains the amino acid sequence of SEQ ID NO:859, and the LCDR3 contains the amino acid sequence of SEQ ID NO:860; (5). The HCDR1 contains the amino acid sequence of SEQ ID NO:861, the HCDR2 contains the amino acid sequence of SEQ ID NO:862, the HCDR3 contains the amino acid sequence of SEQ ID NO:863, the LCDR1 contains the amino acid sequence of SEQ ID NO:864, the LCDR2 contains the amino acid sequence of SEQ ID NO:865, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

866. (6). The HCDR1 contains the amino acid sequence of SEQ ID NO:867, the HCDR2 contains the amino acid sequence of SEQ ID NO:868, the HCDR3 contains the amino acid sequence of SEQ ID NO:869, the LCDR1 contains the amino acid sequence of SEQ ID NO:870, the LCDR2 contains the amino acid sequence of SEQ ID NO:871, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

872. (7). The HCDR1 contains the amino acid sequence of SEQ ID NO:873, the HCDR2 contains the amino acid sequence of SEQ ID NO:874, the HCDR3 contains the amino acid sequence of SEQ ID NO:875, the LCDR1 contains the amino acid sequence of SEQ ID NO:876, the LCDR2 contains the amino acid sequence of SEQ ID NO:877, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

878. (8). The HCDR1 contains the amino acid sequence of SEQ ID NO:879, the HCDR2 contains the amino acid sequence of SEQ ID NO:880, the HCDR3 contains the amino acid sequence of SEQ ID NO:881, the LCDR1 contains the amino acid sequence of SEQ ID NO:882, the LCDR2 contains the amino acid sequence of SEQ ID NO:883, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

884. (9). The HCDR1 contains the amino acid sequence of SEQ ID NO:885, the HCDR2 contains the amino acid sequence of SEQ ID NO:886, the HCDR3 contains the amino acid sequence of SEQ ID NO:887, the LCDR1 contains the amino acid sequence of SEQ ID NO:888, the LCDR2 contains the amino acid sequence of SEQ ID NO:889, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

890. (10). The HCDR1 contains the amino acid sequence of SEQ ID NO:891, the HCDR2 contains the amino acid sequence of SEQ ID NO:892, the HCDR3 contains the amino acid sequence of SEQ ID NO:893, the LCDR1 contains the amino acid sequence of SEQ ID NO:894, the LCDR2 contains the amino acid sequence of SEQ ID NO:895, and the LCDR3 contains the amino acid sequence of SEQ ID NO:896; (11). The HCDR1 contains the amino acid sequence of SEQ ID NO:897, the HCDR2 contains the amino acid sequence of SEQ ID NO:898, the HCDR3 contains the amino acid sequence of SEQ ID NO:899, the LCDR1 contains the amino acid sequence of SEQ ID NO:900, the LCDR2 contains the amino acid sequence of SEQ ID NO:901, and the LCDR3 contains the amino acid sequence of SEQ ID NO:902; (12). The HCDR1 contains the amino acid sequence of SEQ ID NO:903, the HCDR2 contains the amino acid sequence of SEQ ID NO:904, the HCDR3 contains the amino acid sequence of SEQ ID NO:905, the LCDR1 contains the amino acid sequence of SEQ ID NO:906, the LCDR2 contains the amino acid sequence of SEQ ID NO:907, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

908. (13). The HCDR1 contains the amino acid sequence of SEQ ID NO:909, the HCDR2 contains the amino acid sequence of SEQ ID NO:910, the HCDR3 contains the amino acid sequence of SEQ ID NO:911, the LCDR1 contains the amino acid sequence of SEQ ID NO:912, the LCDR2 contains the amino acid sequence of SEQ ID NO:913, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

914. (14). The HCDR1 contains the amino acid sequence of SEQ ID NO:915, the HCDR2 contains the amino acid sequence of SEQ ID NO:916, the HCDR3 contains the amino acid sequence of SEQ ID NO:917, the LCDR1 contains the amino acid sequence of SEQ ID NO:918, the LCDR2 contains the amino acid sequence of SEQ ID NO:919, and the LCDR3 contains the amino acid sequence of SEQ ID NO:920; (15). The HCDR1 contains the amino acid sequence of SEQ ID NO:921, the HCDR2 contains the amino acid sequence of SEQ ID NO:922, the HCDR3 contains the amino acid sequence of SEQ ID NO:923, the LCDR1 contains the amino acid sequence of SEQ ID NO:924, the LCDR2 contains the amino acid sequence of SEQ ID NO:925, and the LCDR3 contains the amino acid sequence of SEQ ID NO:926; (16). The HCDR1 contains the amino acid sequence of SEQ ID NO:927, the HCDR2 contains the amino acid sequence of SEQ ID NO:928, the HCDR3 contains the amino acid sequence of SEQ ID NO:929, the LCDR1 contains the amino acid sequence of SEQ ID NO:930, the LCDR2 contains the amino acid sequence of SEQ ID NO:931, and the LCDR3 contains the amino acid sequence of SEQ ID NO:932; (17). The HCDR1 contains the amino acid sequence of SEQ ID NO:933, the HCDR2 contains the amino acid sequence of SEQ ID NO:934, the HCDR3 contains the amino acid sequence of SEQ ID NO:935, the LCDR1 contains the amino acid sequence of SEQ ID NO:936, the LCDR2 contains the amino acid sequence of SEQ ID NO:937, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

938. (18). The HCDR1 contains the amino acid sequence of SEQ ID NO:939, the HCDR2 contains the amino acid sequence of SEQ ID NO:940, the HCDR3 contains the amino acid sequence of SEQ ID NO:941, the LCDR1 contains the amino acid sequence of SEQ ID NO:942, the LCDR2 contains the amino acid sequence of SEQ ID NO:943, and the LCDR3 contains the amino acid sequence of SEQ ID NO:944; (19). The HCDR1 contains the amino acid sequence of SEQ ID NO:945, the HCDR2 contains the amino acid sequence of SEQ ID NO:946, the HCDR3 contains the amino acid sequence of SEQ ID NO:947, the LCDR1 contains the amino acid sequence of SEQ ID NO:948, the LCDR2 contains the amino acid sequence of SEQ ID NO:949, and the LCDR3 contains the amino acid sequence of SEQ ID NO:950; (20). The HCDR1 contains the amino acid sequence of SEQ ID NO:951, the HCDR2 contains the amino acid sequence of SEQ ID NO:952, the HCDR3 contains the amino acid sequence of SEQ ID NO:953, the LCDR1 contains the amino acid sequence of SEQ ID NO:954, the LCDR2 contains the amino acid sequence of SEQ ID NO:955, and the LCDR3 contains the amino acid sequence of SEQ ID NO:956; (21). The HCDR1 contains the amino acid sequence of SEQ ID NO:957, the HCDR2 contains the amino acid sequence of SEQ ID NO:958, the HCDR3 contains the amino acid sequence of SEQ ID NO:959, the LCDR1 contains the amino acid sequence of SEQ ID NO:960, the LCDR2 contains the amino acid sequence of SEQ ID NO:961, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

962. (22). The HCDR1 contains the amino acid sequence of SEQ ID NO:963, the HCDR2 contains the amino acid sequence of SEQ ID NO:964, the HCDR3 contains the amino acid sequence of SEQ ID NO:965, the LCDR1 contains the amino acid sequence of SEQ ID NO:966, the LCDR2 contains the amino acid sequence of SEQ ID NO:967, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

968. (23). The HCDR1 contains the amino acid sequence of SEQ ID NO:969, the HCDR2 contains the amino acid sequence of SEQ ID NO:970, the HCDR3 contains the amino acid sequence of SEQ ID NO:971, the LCDR1 contains the amino acid sequence of SEQ ID NO:972, the LCDR2 contains the amino acid sequence of SEQ ID NO:973, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

974. (24). The HCDR1 contains the amino acid sequence of SEQ ID NO:975, the HCDR2 contains the amino acid sequence of SEQ ID NO:976, the HCDR3 contains the amino acid sequence of SEQ ID NO:977, the LCDR1 contains the amino acid sequence of SEQ ID NO:978, the LCDR2 contains the amino acid sequence of SEQ ID NO:979, and the LCDR3 contains the amino acid sequence of SEQ ID NO:980; (25). The HCDR1 contains the amino acid sequence of SEQ ID NO:981, the HCDR2 contains the amino acid sequence of SEQ ID NO:982, the HCDR3 contains the amino acid sequence of SEQ ID NO:983, the LCDR1 contains the amino acid sequence of SEQ ID NO:984, the LCDR2 contains the amino acid sequence of SEQ ID NO:985, and the LCDR3 contains the amino acid sequence of SEQ ID NO:986; (26). The HCDR1 contains the amino acid sequence of SEQ ID NO:993, the HCDR2 contains the amino acid sequence of SEQ ID NO:994, the HCDR3 contains the amino acid sequence of SEQ ID NO:995, the LCDR1 contains the amino acid sequence of SEQ ID NO:996, the LCDR2 contains the amino acid sequence of SEQ ID NO:997, and the LCDR3 contains the amino acid sequence of SEQ ID NO:

998. (27). The HCDR1 contains the amino acid sequence of SEQ ID NO:999, the HCDR2 contains the amino acid sequence of SEQ ID NO:1000, the HCDR3 contains the amino acid sequence of SEQ ID NO:1001, the LCDR1 contains the amino acid sequence of SEQ ID NO:1002, the LCDR2 contains the amino acid sequence of SEQ ID NO:1003, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1004. (28). The HCDR1 contains the amino acid sequence of SEQ ID NO:1005, the HCDR2 contains the amino acid sequence of SEQ ID NO:1006, the HCDR3 contains the amino acid sequence of SEQ ID NO:1007, the LCDR1 contains the amino acid sequence of SEQ ID NO:1008, the LCDR2 contains the amino acid sequence of SEQ ID NO:1009, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1010. (29). The HCDR1 contains the amino acid sequence of SEQ ID NO:1011, the HCDR2 contains the amino acid sequence of SEQ ID NO:1012, the HCDR3 contains the amino acid sequence of SEQ ID NO:1013, the LCDR1 contains the amino acid sequence of SEQ ID NO:1014, the LCDR2 contains the amino acid sequence of SEQ ID NO:1015, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1016. (30). The HCDR1 contains the amino acid sequence of SEQ ID NO:1017, the HCDR2 contains the amino acid sequence of SEQ ID NO:1018, the HCDR3 contains the amino acid sequence of SEQ ID NO:1019, the LCDR1 contains the amino acid sequence of SEQ ID NO:1020, the LCDR2 contains the amino acid sequence of SEQ ID NO:1021, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1022; (31). The HCDR1 contains the amino acid sequence of SEQ ID NO:1023, the HCDR2 contains the amino acid sequence of SEQ ID NO:1024, the HCDR3 contains the amino acid sequence of SEQ ID NO:1025, the LCDR1 contains the amino acid sequence of SEQ ID NO:1026, the LCDR2 contains the amino acid sequence of SEQ ID NO:1027, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1028. (32). The HCDR1 contains the amino acid sequence of SEQ ID NO:1029, the HCDR2 contains the amino acid sequence of SEQ ID NO:1030, the HCDR3 contains the amino acid sequence of SEQ ID NO:1031, the LCDR1 contains the amino acid sequence of SEQ ID NO:1032, the LCDR2 contains the amino acid sequence of SEQ ID NO:1033, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1034. (33). The HCDR1 contains the amino acid sequence of SEQ ID NO:1035, the HCDR2 contains the amino acid sequence of SEQ ID NO:1036, the HCDR3 contains the amino acid sequence of SEQ ID NO:1037, the LCDR1 contains the amino acid sequence of SEQ ID NO:1038, the LCDR2 contains the amino acid sequence of SEQ ID NO:1039, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1040. (34). The HCDR1 contains the amino acid sequence of SEQ ID NO:1041, the HCDR2 contains the amino acid sequence of SEQ ID NO:1042, the HCDR3 contains the amino acid sequence of SEQ ID NO:1043, the LCDR1 contains the amino acid sequence of SEQ ID NO:1044, the LCDR2 contains the amino acid sequence of SEQ ID NO:1045, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1046. (35). The HCDR1 contains the amino acid sequence of SEQ ID NO:1047, the HCDR2 contains the amino acid sequence of SEQ ID NO:1048, the HCDR3 contains the amino acid sequence of SEQ ID NO:1049, the LCDR1 contains the amino acid sequence of SEQ ID NO:1050, the LCDR2 contains the amino acid sequence of SEQ ID NO:1051, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1052; (36). The HCDR1 contains the amino acid sequence of SEQ ID NO:1053, the HCDR2 contains the amino acid sequence of SEQ ID NO:1054, the HCDR3 contains the amino acid sequence of SEQ ID NO:1055, the LCDR1 contains the amino acid sequence of SEQ ID NO:1056, the LCDR2 contains the amino acid sequence of SEQ ID NO:1057, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1058. (37). The HCDR1 contains the amino acid sequence of SEQ ID NO:1059, the HCDR2 contains the amino acid sequence of SEQ ID NO:1060, the HCDR3 contains the amino acid sequence of SEQ ID NO:1061, the LCDR1 contains the amino acid sequence of SEQ ID NO:1062, the LCDR2 contains the amino acid sequence of SEQ ID NO:1063, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1064. (38). The HCDR1 contains the amino acid sequence of SEQ ID NO:1065, the HCDR2 contains the amino acid sequence of SEQ ID NO:1066, the HCDR3 contains the amino acid sequence of SEQ ID NO:1067, the LCDR1 contains the amino acid sequence of SEQ ID NO:1068, the LCDR2 contains the amino acid sequence of SEQ ID NO:1069, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1070. (39). The HCDR1 contains the amino acid sequence of SEQ ID NO:1071, the HCDR2 contains the amino acid sequence of SEQ ID NO:1072, the HCDR3 contains the amino acid sequence of SEQ ID NO:1073, the LCDR1 contains the amino acid sequence of SEQ ID NO:1074, the LCDR2 contains the amino acid sequence of SEQ ID NO:1075, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1076. (40). The HCDR1 contains the amino acid sequence of SEQ ID NO:1077, the HCDR2 contains the amino acid sequence of SEQ ID NO:1078, the HCDR3 contains the amino acid sequence of SEQ ID NO:1079, the LCDR1 contains the amino acid sequence of SEQ ID NO:1080, the LCDR2 contains the amino acid sequence of SEQ ID NO:1081, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1082. (41). The HCDR1 contains the amino acid sequence of SEQ ID NO:1083, the HCDR2 contains the amino acid sequence of SEQ ID NO:1084, the HCDR3 contains the amino acid sequence of SEQ ID NO:1085, the LCDR1 contains the amino acid sequence of SEQ ID NO:1086, the LCDR2 contains the amino acid sequence of SEQ ID NO:1087, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1088. (42). The HCDR1 contains the amino acid sequence of SEQ ID NO:1089, the HCDR2 contains the amino acid sequence of SEQ ID NO:1090, the HCDR3 contains the amino acid sequence of SEQ ID NO:1091, the LCDR1 contains the amino acid sequence of SEQ ID NO:1092, the LCDR2 contains the amino acid sequence of SEQ ID NO:1093, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1094. (43). The HCDR1 contains the amino acid sequence of SEQ ID NO:1095, the HCDR2 contains the amino acid sequence of SEQ ID NO:1096, the HCDR3 contains the amino acid sequence of SEQ ID NO:1097, the LCDR1 contains the amino acid sequence of SEQ ID NO:1098, the LCDR2 contains the amino acid sequence of SEQ ID NO:1099, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1100. (44). The HCDR1 contains the amino acid sequence of SEQ ID NO:1101, the HCDR2 contains the amino acid sequence of SEQ ID NO:1102, the HCDR3 contains the amino acid sequence of SEQ ID NO:1103, the LCDR1 contains the amino acid sequence of SEQ ID NO:1104, the LCDR2 contains the amino acid sequence of SEQ ID NO:1105, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1106. (45). The HCDR1 contains the amino acid sequence of SEQ ID NO:1107, the HCDR2 contains the amino acid sequence of SEQ ID NO:1108, the HCDR3 contains the amino acid sequence of SEQ ID NO:1109, the LCDR1 contains the amino acid sequence of SEQ ID NO:1110, the LCDR2 contains the amino acid sequence of SEQ ID NO:1111, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1112. (46). The HCDR1 contains the amino acid sequence of SEQ ID NO:1113, the HCDR2 contains the amino acid sequence of SEQ ID NO:1114, the HCDR3 contains the amino acid sequence of SEQ ID NO:1115, the LCDR1 contains the amino acid sequence of SEQ ID NO:1116, the LCDR2 contains the amino acid sequence of SEQ ID NO:1117, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1118. (47). HCDR1 contains the amino acid sequence of SEQ ID NO:1119, HCDR2 contains the amino acid sequence of SEQ ID NO:1120, HCDR3 contains the amino acid sequence of SEQ ID NO:1121, LCDR1 contains the amino acid sequence of SEQ ID NO:1122, LCDR2 contains the amino acid sequence of SEQ ID NO:1123, and LCDR3 contains the amino acid sequence of SEQ ID NO:1124; or (48). The HCDR1 contains the amino acid sequence of SEQ ID NO:1125, the HCDR2 contains the amino acid sequence of SEQ ID NO:1126, the HCDR3 contains the amino acid sequence of SEQ ID NO:1127, the LCDR1 contains the amino acid sequence of SEQ ID NO:1128, the LCDR2 contains the amino acid sequence of SEQ ID NO:1129, and the LCDR3 contains the amino acid sequence of SEQ ID NO:1130.

6. The antibody or antigen-binding fragment according to claim 4 or 5, comprising: (1). VH containing the amino acid sequence of SEQ ID NO:1167 and VL containing the amino acid sequence of SEQ ID NO:1168; (2). VH containing the amino acid sequence of SEQ ID NO:1169 and VL containing the amino acid sequence of SEQ ID NO:1170; (3). VH containing the amino acid sequence of SEQ ID NO:1171 and VL containing the amino acid sequence of SEQ ID NO:1172; (4). VH containing the amino acid sequence of SEQ ID NO:1173 and VL containing the amino acid sequence of SEQ ID NO:1174; (5). VH containing the amino acid sequence of SEQ ID NO:1175 and VL containing the amino acid sequence of SEQ ID NO:1176; (6). VH containing the amino acid sequence of SEQ ID NO:1177 and VL containing the amino acid sequence of SEQ ID NO:1178; (7). VH containing the amino acid sequence of SEQ ID NO:401 and VL containing the amino acid sequence of SEQ ID NO:402; (8). VH containing the amino acid sequence of SEQ ID NO:403 and VL containing the amino acid sequence of SEQ ID NO:404; (9). VH containing the amino acid sequence of SEQ ID NO:405 and VL containing the amino acid sequence of SEQ ID NO:406; (10). VH containing the amino acid sequence of SEQ ID NO:407 and VL containing the amino acid sequence of SEQ ID NO:408; (11). VH containing the amino acid sequence of SEQ ID NO:409 and VL containing the amino acid sequence of SEQ ID NO:410; (12). VH containing the amino acid sequence of SEQ ID NO:411 and VL containing the amino acid sequence of SEQ ID NO:412; (13). VH containing the amino acid sequence of SEQ ID NO:413 and VL containing the amino acid sequence of SEQ ID NO:414; (14). VH containing the amino acid sequence of SEQ ID NO:415 and VL containing the amino acid sequence of SEQ ID NO:416; (15). VH containing the amino acid sequence of SEQ ID NO:417 and VL containing the amino acid sequence of SEQ ID NO:418; (16). VH containing the amino acid sequence of SEQ ID NO:419 and VL containing the amino acid sequence of SEQ ID NO:420; (17). VH containing the amino acid sequence of SEQ ID NO:421 and VL containing the amino acid sequence of SEQ ID NO:422; (18). VH containing the amino acid sequence of SEQ ID NO:423 and VL containing the amino acid sequence of SEQ ID NO:424; (19). VH containing the amino acid sequence of SEQ ID NO:425 and VL containing the amino acid sequence of SEQ ID NO:426; (20). VH containing the amino acid sequence of SEQ ID NO:427 and VL containing the amino acid sequence of SEQ ID NO:428; (21). VH containing the amino acid sequence of SEQ ID NO:429 and VL containing the amino acid sequence of SEQ ID NO:430; (22). VH containing the amino acid sequence of SEQ ID NO:431 and VL containing the amino acid sequence of SEQ ID NO:432; (23). VH containing the amino acid sequence of SEQ ID NO:433 and VL containing the amino acid sequence of SEQ ID NO:434; (24). VH containing the amino acid sequence of SEQ ID NO:435 and VL containing the amino acid sequence of SEQ ID NO:436; (25). VH containing the amino acid sequence of SEQ ID NO:437 and VL containing the amino acid sequence of SEQ ID NO:438; (26). VH containing the amino acid sequence of SEQ ID NO:439 and VL containing the amino acid sequence of SEQ ID NO:440; (27). VH containing the amino acid sequence of SEQ ID NO:441 and VL containing the amino acid sequence of SEQ ID NO:442; (28). VH containing the amino acid sequence of SEQ ID NO:443 and VL containing the amino acid sequence of SEQ ID NO:444; (29). VH containing the amino acid sequence of SEQ ID NO:445 and VL containing the amino acid sequence of SEQ ID NO:446; (30). VH containing the amino acid sequence of SEQ ID NO:447 and VL containing the amino acid sequence of SEQ ID NO:448; (31). VH containing the amino acid sequence of SEQ ID NO:449 and VL containing the amino acid sequence of SEQ ID NO:450; (32). VH containing the amino acid sequence of SEQ ID NO:451 and VL containing the amino acid sequence of SEQ ID NO:452; (33). VH containing the amino acid sequence of SEQ ID NO:453 and VL containing the amino acid sequence of SEQ ID NO:454; (34). VH containing the amino acid sequence of SEQ ID NO:455 and VL containing the amino acid sequence of SEQ ID NO:456; (35). VH containing the amino acid sequence of SEQ ID NO:457 and VL containing the amino acid sequence of SEQ ID NO:458; (36). VH containing the amino acid sequence of SEQ ID NO:459 and VL containing the amino acid sequence of SEQ ID NO:460; (37). VH containing the amino acid sequence of SEQ ID NO:461 and VL containing the amino acid sequence of SEQ ID NO:462; (38). VH containing the amino acid sequence of SEQ ID NO:463 and VL containing the amino acid sequence of SEQ ID NO:464; (39). VH containing the amino acid sequence of SEQ ID NO:465 and VL containing the amino acid sequence of SEQ ID NO:466; (40). VH containing the amino acid sequence of SEQ ID NO:467 and VL containing the amino acid sequence of SEQ ID NO:468; (41). VH containing the amino acid sequence of SEQ ID NO:469 and VL containing the amino acid sequence of SEQ ID NO:470; (42). VH containing the amino acid sequence of SEQ ID NO:471 and VL containing the amino acid sequence of SEQ ID NO:472; (43). VH containing the amino acid sequence of SEQ ID NO:473 and VL containing the amino acid sequence of SEQ ID NO:474; (44). VH containing the amino acid sequence of SEQ ID NO:475 and VL containing the amino acid sequence of SEQ ID NO:476; (45). VH containing the amino acid sequence of SEQ ID NO:477 and VL containing the amino acid sequence of SEQ ID NO:478; (46). VH containing the amino acid sequence of SEQ ID NO:479 and VL containing the amino acid sequence of SEQ ID NO:480; (47). VH containing the amino acid sequence of SEQ ID NO:481 and VL containing the amino acid sequence of SEQ ID NO:482; (48). VH containing the amino acid sequence of SEQ ID NO:483 and VL containing the amino acid sequence of SEQ ID NO:484; (49). VH containing the amino acid sequence of SEQ ID NO:485 and VL containing the amino acid sequence of SEQ ID NO:486; (50). VH containing the amino acid sequence of SEQ ID NO:487 and VL containing the amino acid sequence of SEQ ID NO:488; (51). VH containing the amino acid sequence of SEQ ID NO:489 and VL containing the amino acid sequence of SEQ ID NO:490; (52). VH containing the amino acid sequence of SEQ ID NO:491 and VL containing the amino acid sequence of SEQ ID NO:492; or (53). VH containing the amino acid sequence of SEQ ID NO:493 and VL containing the amino acid sequence of SEQ ID NO:

494.

7. A multispecific antibody or a fragment thereof, the multispecific antibody or fragment thereof comprising a first binding domain to LILRB1 and a second binding domain to LILRB2, wherein the first binding domain comprises the antibody or antigen-binding fragment thereof according to claims 1 to 3, and wherein optionally the second binding domain comprises the antibody or antigen-binding fragment thereof according to claims 4 to 6.

8. A multispecific antibody or a fragment thereof, the multispecific antibody or fragment thereof comprising a first binding domain to LILRB1 and a second binding domain to LILRB2, wherein the second binding domain comprises the antibody or antigen-binding fragment thereof according to claims 4 to 6, and wherein optionally the first binding domain comprises the antibody or antigen-binding fragment thereof according to claims 1 to 3.

9. The multispecific antibody or fragment thereof according to claim 7 or 8, wherein the multispecific antibody or fragment thereof is in the antibody form of an immunoglobulin-single-chain antibody fragment (IgG-ScFv).

10. The multispecific antibody or fragment thereof according to claim 7 or 8, wherein the multispecific antibody or fragment thereof has an antibody form with a dual variable domain-immunoglobulin (DVD-Ig).

11. The multispecific antibody or a fragment thereof according to claim 7 or 8, The first binding domain includes any one or more of (1) to (6): (1). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1155 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1156. (2). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1157 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1158. (3). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1159 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1160. (4). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1161 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1162. (5). HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO: 1163, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO: 1164; or (6). HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO: 1165, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO: 1166; and The second binding domain comprises one or more of (1) to (6): (1). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1167 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1168. (2). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1169 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1170. (3). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1171 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1172. (4). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1173 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1174. (5). HCDR1, HCDR2, and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO: 1175, and LCDR1, LCDR2, and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO: 1176; or (6). HCDR1, HCDR2 and HCDR3 as shown in VH containing the amino acid sequence of SEQ ID NO:1177 and LCDR1, LCDR2 and LCDR3 as shown in VL containing the amino acid sequence of SEQ ID NO:1178.

12. The multispecific antibody or fragment thereof according to claim 11, The first binding domain includes any one or more of (1) to (6): (1). VH containing the amino acid sequence of SEQ ID NO:1155 and VL containing the amino acid sequence of SEQ ID NO:1156; (2). VH containing the amino acid sequence of SEQ ID NO:1157 and VL containing the amino acid sequence of SEQ ID NO:1158; (3). VH containing the amino acid sequence of SEQ ID NO:1159 and VL containing the amino acid sequence of SEQ ID NO:1160; (4). VH containing the amino acid sequence of SEQ ID NO:1161 and VL containing the amino acid sequence of SEQ ID NO:1162; (5). VH containing the amino acid sequence of SEQ ID NO:1163 and VL containing the amino acid sequence of SEQ ID NO:1164; or (6). VH containing the amino acid sequence of SEQ ID NO:1165 and VL containing the amino acid sequence of SEQ ID NO:1166; and The second binding domain comprises one or more of (1) to (6): (1). VH containing the amino acid sequence of SEQ ID NO:1167 and VL containing the amino acid sequence of SEQ ID NO:1168; (2). VH containing the amino acid sequence of SEQ ID NO:1169 and VL containing the amino acid sequence of SEQ ID NO:1170; (3). VH containing the amino acid sequence of SEQ ID NO:1171 and VL containing the amino acid sequence of SEQ ID NO:1172; (4). VH containing the amino acid sequence of SEQ ID NO:1173 and VL containing the amino acid sequence of SEQ ID NO:1174; (5). VH containing the amino acid sequence of SEQ ID NO:1175 and VL containing the amino acid sequence of SEQ ID NO:1176; or (6). VH containing the amino acid sequence of SEQ ID NO:1177 and VL containing the amino acid sequence of SEQ ID NO:1178.

13. The multispecific antibody or fragment thereof according to claim 11 or 12, wherein the multispecific antibody or fragment thereof comprises: (1). A first polypeptide containing the amino acid sequence of SEQ ID NO:1180 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1181; (2). A first polypeptide containing the amino acid sequence of SEQ ID NO:1182 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1183; (3). A first polypeptide containing the amino acid sequence of SEQ ID NO:1184 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1185; (4). A first polypeptide containing the amino acid sequence of SEQ ID NO:1186 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1187; (5). A first polypeptide containing the amino acid sequence of SEQ ID NO:1188 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1189; (6). A first polypeptide containing the amino acid sequence of SEQ ID NO:1190 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1191; (7). A first polypeptide containing the amino acid sequence of SEQ ID NO:1192 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1193; (8). A first polypeptide containing the amino acid sequence of SEQ ID NO:1194 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1195; (9). A first polypeptide containing the amino acid sequence of SEQ ID NO:1196 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1197; (10). A first polypeptide containing the amino acid sequence of SEQ ID NO:1198 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1199; (11). A first polypeptide containing the amino acid sequence of SEQ ID NO:1200 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1201; or (12). A first polypeptide containing the amino acid sequence of SEQ ID NO:1202 and a second polypeptide containing the amino acid sequence of SEQ ID NO:1203.

14. The antibody or antigen-binding fragment according to any one of claims 1 to 13, wherein the antibody is IgG.

15. A nucleic acid molecule encoding an antibody or antigen-binding fragment according to any one of claims 1 to 14.

16. A vector comprising the nucleic acid molecule according to claim 15.

17. A host cell, said host cell being transformed with the vector according to claim 16.

18. A composition comprising a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of claims 1 to 14, a nucleic acid molecule according to claim 15, or a carrier according to claim 16, and a pharmaceutically acceptable excipient.

19. A method for preventing the inhibition or activation of immune cell-mediated responses by immune cells, the method comprising contacting the immune cells with an antibody or fragment thereof according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 18.

20. The method of claim 19, wherein the immune cell is an NK cell, macrophage, T cell, or dendritic cell.

21. The method of claim 20, wherein the T cell is CD8. + T cells.

22. The method according to any one of claims 19 to 21, wherein the immune cells express LILRB1 and / or LILRB2.

23. The method according to any one of claims 19 to 22, wherein the response mediated by the immune cells is an antitumor response, optionally wherein the tumor cells express HLA-A2, HLA-G and / or ANGPTL.

24. A method for treating a disease or disorder in a subject, the method comprising administering to the subject an antibody or antigen-binding fragment according to any one of claims 1 to 14 or a pharmaceutical composition according to claim 18.

25. The method of claim 24, wherein the disease or disorder is cancer, optionally the cancer expressing HLA-A2, HLA-G and / or ANGPTL.

26. The method of claim 24, wherein the disease or disorder is a solid tumor or a hematologic malignancy.

27. The method according to any one of claims 24 to 26, wherein the subject is a human subject.

28. The method of claim 24, wherein the antibody or antigen-binding fragment is used as part of a combination therapy.

29. The method of claim 28, wherein the antibody or antigen-binding fragment is used in combination with a PD-1 inhibitor, wherein optionally, the PD-1 inhibitor is an anti-PD-1 antibody, wherein optionally, the anti-PD-1 antibody is nivolumab.

30. The method of claim 28, wherein the antibody or antigen-binding fragment is used in combination with a PD-L1 inhibitor, wherein optionally, the PD-L1 inhibitor is an anti-PD-L1 antibody, wherein optionally, the anti-PD-L1 antibody is LAE005.

31. The method of claim 28, wherein the antibody or antigen-binding fragment is used in combination with an anti-CD47 antibody, wherein optionally the anti-CD47 antibody is Hu5F9-G4.

32. The method of claim 28, wherein the antibody or antigen-binding fragment is used in combination with an anti-CD3 antibody, wherein optionally the anti-CD3 antibody is OKT3.

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