Anti-ILT4 antibody as well as preparation method and application thereof

Abstract

The invention discloses an anti-ILT4 antibody and a preparation method and application thereof, and the antibody comprises a heavy chain variable region and a light chain variable region, specifically as described in the text. The antibody has the capability of being combined with human ILT4, and part of the antibody has the activity of being combined with human ILT2 and ILT4 at the same time and can also be combined with cynomolgus monkey ILT4; the binding affinity of the antibody provided by the invention and human ILT4 is superior to that of MK-4830 (Merck); the antibody promotes differentiation of macrophages to M1 so as to secrete TNF-alpha, the differentiated M1 cells have a better antigen presentation function, and the killing effect of T cells on tumors is improved. The antibody provided by the invention acts on MDSC and TAM in a tumor microenvironment, and improves an immunosuppressive environment in the tumor microenvironment. The anti-tumor effect of the antibody disclosed by the invention is obviously superior to that of a control antibody MK-4830 (Merck) and NGM707 (NGM) in a mouse in-vivo pharmacological experiment.

Description

Anti-ILT4 antibody and its preparation method and application

[0001] This application claims priority to Chinese patent application No. 2022115841752, filed on December 9, 2022. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of biomedicine, and specifically relates to an anti-ILT4 antibody and a preparation method and application thereof. Background Art

[0003] Myeloid-derived suppressor cells (MDSCs) are a type of bone marrow-derived cell with potent immunosuppressive properties that reside in the tumor microenvironment. They can inhibit cell-mediated immune responses, including T cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages, while promoting the generation of regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Numerous studies have reported that both TAMs and MDSCs can, through their immunosuppressive functions, enable tumor cells to evade immune surveillance, playing a crucial role in tumor metastasis and reducing patients' responsiveness to tumor immunotherapy.

[0004] Immunoglobulin-like transcripts (ILTs), also known as the leukocyte immunoglobulin-like receptor family (LILR) and cluster of differentiation 85 (CD85), comprise inhibitory subtypes (LILRBs) and activating subtypes (LILRAs). Inhibitory receptors include LILRB1 / ILT2, LILRB2 / ILT4, LILRB3 / ILT5, LILRB4 / ILT3, and LILRB5 / LIR8. Activating receptors include LIRA1 / LIR6, LILRA2 / ILT1, LILRA3 / LIR4, LILRA4 / ILT7, LILRA5 / ILT11, and LILRA6 / ILT8. These receptors are primarily expressed on immune cells and can recognize different ligands, thereby exerting either immunosuppressive or activating effects.

[0005] Both ILT2 and ILT4 are inhibitory receptors. ILT2 is primarily expressed on monocytes, macrophages, dendritic cells, T cells, and NK cells, while ILT4 is primarily expressed on the surface of myeloid cells, such as monocytes, macrophages, and dendritic cells. Both ILT2 and ILT4 molecules are typical type I transmembrane proteins. Their extracellular domains consist of four tandem Ig-like domains, while their intracellular domains contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). ILT2 has four ITIMs, while ILT4 has three. The primary ligand for ILT2 is human leukocyte antigen class I G (HLA-G), while the primary ligands for ILT4 are HLA-G, angiopoietin-like protein 2 (ANGPTL2), and semaphorin 4A (SEMA4A). After binding to their ligands, ILT2 / ILT4 transduce inhibitory signals through ITIMs, inhibiting immune cell activation, antigen presentation, and immune responses. Recent studies have shown that ILT4 is also expressed in the tumor microenvironment, including tumor cells and tumor stromal cells such as hematopoietic stem cells (HSCs), MDSCs, and TAMs. It regulates the malignant biological behavior of tumor cells, HSC regeneration, and macrophage M2-like polarization, inhibiting DC cell maturation and reducing their antigen presentation ability, thereby inducing the dysfunction of effector T cells and the differentiation of suppressor T cells, thereby expanding the immunosuppressive microenvironment. ILT2 is expressed on the surface of T cells and can also inhibit T cell function. Therefore, ILT2 and ILT4 are both very promising targets in the field of tumor immunity.

[0006] Currently, there are several antibody drugs targeting ILT2 or ILT4 on the market, such as Biond Biologics' ILT2-blocking antibody BND-22, Merck's ILT4 antibody MK-4830, and Jounce's ILT4 antibody JTX-8064. Among them, Merck's ILT4 antibody is the most advanced and is in Phase II clinical trials. This antibody acts on ILT4 and exerts anti-tumor effects by inhibiting MDSCs and TAMs in the tumor microenvironment. In addition, studies have shown that MDSCs and TAMs in the tumor microenvironment can express both ILT2 and ILT4 molecules on their cell surfaces, and that T cells in the tumor microenvironment express ILT2 on their surfaces. Both ILT2 and ILT4 molecules on these cell surfaces can exert immunosuppressive functions. Antibodies that simultaneously target both ILT2 and ILT4 may have better anti-tumor effects, such as NGM's NGM707 antibody.

[0007] Therefore, the development of an antibody drug that targets ILT2 and ILT4 separately or simultaneously is of great significance in tumor immunotherapy.

[0008] Summary of the Invention

[0009] To address the above-mentioned technical problems, the present invention provides an anti-ILT4 antibody, its preparation method, and its use. The antibodies of the present invention possess the following properties: 1) They bind to human ILT4, with some antibodies showing binding activity to both human ILT2 and ILT4, and also to cynomolgus monkey ILT4. 2) The antibodies of the present invention have superior binding affinity to human ILT4 compared to MK-4830 (Merck). 3) The antibodies of the present invention enhance anti-tumor efficacy through multiple mechanisms of action. First, the antibodies of the present invention promote macrophage differentiation into M1 cells and secrete TNF-α, thereby enhancing anti-tumor efficacy. Second, the differentiated M1 cells possess enhanced antigen presentation, enhancing the anti-tumor efficacy of T cells. Third, the antibodies of the present invention act on MDSCs and TAMs in the tumor microenvironment, ameliorating the immunosuppressive environment and promoting enhanced tumor killing by T cells. 4) In in vivo efficacy experiments in mice, the antibodies of the present invention demonstrated significantly superior anti-tumor efficacy compared to control antibodies MK-4830 (Merck) and NGM707 (NGM).

[0010] In a first aspect, the present invention provides an anti-ILT4 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3, wherein the HCDR1 comprises an amino acid sequence as shown in SEQ ID NO: 1, SEQ ID NO: 12, SEQ ID NO: 18, SEQ ID NO: 23, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 44 or SEQ ID NO: 52, and the HCDR2 comprises an amino acid sequence as shown in SEQ ID NO: 8, SEQ ID NO: 13, SEQ ID NO: 2, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 27, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 50, SEQ ID NO: 53 or SEQ ID NO: 57, or the HCDR3 comprises an amino acid sequence as shown in SEQ ID NO: 1, SEQ ID NO: 12, SEQ ID NO: 18, SEQ ID NO: 23, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 44 or SEQ ID NO: 52. the amino acid sequence set forth in SEQ ID NO:3, SEQ ID NO:14, SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28, SEQ ID NO:34, SEQ ID NO:38, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:54, or SEQ ID NO:58;

[0011] The light chain variable region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid sequence as shown in SEQ ID NO:4, SEQ ID NO:15, SEQ ID NO:21, SEQ ID NO:29, SEQ ID NO:39 or SEQ ID NO:47, the LCDR2 comprises the amino acid sequence as shown in SEQ ID NO:5, SEQ ID NO:16, SEQ ID NO:30, SEQ ID NO:48 or SEQ ID NO:55, and the LCDR3 comprises the amino acid sequence as shown in SEQ ID NO:6, SEQ ID NO:17, SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:43, SEQ ID NO:49, SEQ ID NO:56 or SEQ ID NO:59.

[0012] In a preferred embodiment, the heavy chain variable region comprises:

[0013] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 8, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0014] HCDR1 with the sequence shown in SEQ ID NO: 12, HCDR2 with the sequence shown in SEQ ID NO: 13, and HCDR3 with the sequence shown in SEQ ID NO: 14;

[0015] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 2, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0016] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 7, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0017] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 9, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0018] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 10, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0019] HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 11, and HCDR3 with the sequence shown in SEQ ID NO: 3;

[0020] HCDR1 with the sequence shown in SEQ ID NO: 18, HCDR2 with the sequence shown in SEQ ID NO: 19, and HCDR3 with the sequence shown in SEQ ID NO: 20;

[0021] HCDR1 with the sequence shown in SEQ ID NO: 23, HCDR2 with the sequence shown in SEQ ID NO: 24, and HCDR3 with the sequence shown in SEQ ID NO: 25;

[0022] HCDR1 with the sequence shown in SEQ ID NO: 23, HCDR2 with the sequence shown in SEQ ID NO: 27, and HCDR3 with the sequence shown in SEQ ID NO: 28;

[0023] HCDR1 with the sequence shown in SEQ ID NO: 32, HCDR2 with the sequence shown in SEQ ID NO: 33, and HCDR3 with the sequence shown in SEQ ID NO: 34;

[0024] HCDR1 with the sequence shown in SEQ ID NO: 32, HCDR2 with the sequence shown in SEQ ID NO: 35, and HCDR3 with the sequence shown in SEQ ID NO: 34;

[0025] HCDR1 with the sequence shown in SEQ ID NO: 36, HCDR2 with the sequence shown in SEQ ID NO: 37, and HCDR3 with the sequence shown in SEQ ID NO: 38;

[0026] HCDR1 with the sequence shown in SEQ ID NO:23, HCDR2 with the sequence shown in SEQ ID NO:41, and HCDR3 with the sequence shown in SEQ ID NO:42;

[0027] HCDR1 with the sequence shown in SEQ ID NO:44, HCDR2 with the sequence shown in SEQ ID NO:45, and HCDR3 with the sequence shown in SEQ ID NO:46;

[0028] HCDR1 with the sequence shown in SEQ ID NO:23, HCDR2 with the sequence shown in SEQ ID NO:50, and HCDR3 with the sequence shown in SEQ ID NO:51;

[0029] HCDR1 with the sequence shown in SEQ ID NO:52, HCDR2 with the sequence shown in SEQ ID NO:53, and HCDR3 with the sequence shown in SEQ ID NO:54;

[0030] Or, the HCDR1 sequence shown in SEQ ID NO:32, the HCDR2 sequence shown in SEQ ID NO:57, and the HCDR3 sequence shown in SEQ ID NO:58.

[0031] In a preferred embodiment, the light chain variable region comprises:

[0032] LCDR1 having a sequence as shown in SEQ ID NO:4, LCDR2 having a sequence as shown in SEQ ID NO:5, and LCDR3 having a sequence as shown in SEQ ID NO:6;

[0033] LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 17;

[0034] LCDR1 having a sequence as shown in SEQ ID NO: 21, LCDR2 having a sequence as shown in SEQ ID NO: 5, and LCDR3 having a sequence as shown in SEQ ID NO: 22;

[0035] LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 26;

[0036] LCDR1 having a sequence as shown in SEQ ID NO: 29, LCDR2 having a sequence as shown in SEQ ID NO: 30, and LCDR3 having a sequence as shown in SEQ ID NO: 31;

[0037] LCDR1 having a sequence as shown in SEQ ID NO:39, LCDR2 having a sequence as shown in SEQ ID NO:30, and LCDR3 having a sequence as shown in SEQ ID NO:31;

[0038] LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 40;

[0039] LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 43;

[0040] LCDR1 having a sequence as shown in SEQ ID NO:47, LCDR2 having a sequence as shown in SEQ ID NO:48, and LCDR3 having a sequence as shown in SEQ ID NO:49;

[0041] LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 55, and LCDR3 having a sequence as shown in SEQ ID NO: 56;

[0042] Or, LCDR1 having a sequence as shown in SEQ ID NO:15, LCDR2 having a sequence as shown in SEQ ID NO:16, and LCDR3 having a sequence as shown in SEQ ID NO:59.

[0043] In a preferred embodiment, the light chain variable region and the heavy chain variable region are selected from any one of the following:

[0044] (1) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 8, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0045] (2) HCDR1 with a sequence as shown in SEQ ID NO: 12, HCDR2 with a sequence as shown in SEQ ID NO: 13, and HCDR3 with a sequence as shown in SEQ ID NO: 14; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17;

[0046] (3) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 2, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0047] (4) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 7, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0048] (5) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 9, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0049] (6) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 10, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0050] (7) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 11, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6;

[0051] (8) HCDR1 with a sequence as shown in SEQ ID NO: 18, HCDR2 with a sequence as shown in SEQ ID NO: 19, and HCDR3 with a sequence as shown in SEQ ID NO: 20; and LCDR1 with a sequence as shown in SEQ ID NO: 21, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 22;

[0052] (9) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 24, and HCDR3 with a sequence as shown in SEQ ID NO: 25; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 26;

[0053] (10) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 27, and HCDR3 with a sequence as shown in SEQ ID NO: 28; and LCDR1 with a sequence as shown in SEQ ID NO: 29, LCDR2 with a sequence as shown in SEQ ID NO: 30, and LCDR3 with a sequence as shown in SEQ ID NO: 31;

[0054] (11) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 27, and HCDR3 with a sequence as shown in SEQ ID NO: 28; and LCDR1 with a sequence as shown in SEQ ID NO: 39, LCDR2 with a sequence as shown in SEQ ID NO: 30, and LCDR3 with a sequence as shown in SEQ ID NO: 31;

[0055] (12) HCDR1 with a sequence as shown in SEQ ID NO: 32, HCDR2 with a sequence as shown in SEQ ID NO: 33, and HCDR3 with a sequence as shown in SEQ ID NO: 34; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17;

[0056] (13) HCDR1 with a sequence as shown in SEQ ID NO: 32, HCDR2 with a sequence as shown in SEQ ID NO: 35, and HCDR3 with a sequence as shown in SEQ ID NO: 34; and, LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17;

[0057] (14) HCDR1 with a sequence as shown in SEQ ID NO: 36, HCDR2 with a sequence as shown in SEQ ID NO: 37, and HCDR3 with a sequence as shown in SEQ ID NO: 38; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 40;

[0058] (15) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 41, and HCDR3 with a sequence as shown in SEQ ID NO: 42; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 43;

[0059] (16) HCDR1 with a sequence as shown in SEQ ID NO: 44, HCDR2 with a sequence as shown in SEQ ID NO: 45, and HCDR3 with a sequence as shown in SEQ ID NO: 46; and LCDR1 with a sequence as shown in SEQ ID NO: 47, LCDR2 with a sequence as shown in SEQ ID NO: 48, and LCDR3 with a sequence as shown in SEQ ID NO: 49;

[0060] (17) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 50, and HCDR3 with a sequence as shown in SEQ ID NO: 51; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17;

[0061] (18) HCDR1 with a sequence as shown in SEQ ID NO: 52, HCDR2 with a sequence as shown in SEQ ID NO: 53, and HCDR3 with a sequence as shown in SEQ ID NO: 54; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 55, and LCDR3 with a sequence as shown in SEQ ID NO: 56;

[0062] (19) HCDR1 with a sequence as shown in SEQ ID NO:32, HCDR2 with a sequence as shown in SEQ ID NO:57, and HCDR3 with a sequence as shown in SEQ ID NO:58; and LCDR1 with a sequence as shown in SEQ ID NO:15, LCDR2 with a sequence as shown in SEQ ID NO:16, and LCDR3 with a sequence as shown in SEQ ID NO:59.

[0063] In a preferred embodiment, the framework region of the light chain variable region is a human framework region, and / or the framework region of the heavy chain variable region is a human framework region.

[0064] Preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:64, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:62;

[0065] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:68, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:68, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:69, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:69;

[0066] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:61, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:61, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62;

[0067] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:63, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:63, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62;

[0068] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:65, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:65, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62;

[0069] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:66, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:66, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62;

[0070] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:67, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:67, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62;

[0071] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:68, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:68, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:69, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:69;

[0072] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:70, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:70, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:71, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:71;

[0073] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:72, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:72, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:73, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:73;

[0074] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:74, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:74, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:75, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:75;

[0075] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:74, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:74, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:76, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:76;

[0076] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:77, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:77, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:78;

[0077] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:79, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:79, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:78;

[0078] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:80, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:80, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:81, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:81;

[0079] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:82, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:82, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:83, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:83;

[0080] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:84, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:84, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:85, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:85;

[0081] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:86, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:86, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:78;

[0082] the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:87, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:87, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:88, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:88;

[0083] Alternatively, the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:60, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:60, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:89, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:89.

[0084] In a preferred embodiment, the antibody is a full-length antibody, Fab, Fab', F(ab')2, Fv, scFv, di-scFv, VHH or heavy chain antibody (HCAb);

[0085] In a preferred embodiment, the antibody is a monoclonal antibody or a polyclonal antibody prepared from the above-mentioned antibody.

[0086] In a preferred embodiment, the antibody comprises a heavy chain constant region and / or a light chain constant region, the heavy chain constant region of the antibody is derived from the heavy chain constant region of human antibody IgG1 or IgG4, and / or the light chain constant region of the antibody is derived from the κ chain of a human antibody.

[0087] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:93, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:93, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0088] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:99, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:99, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:98.

[0089] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:90, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:90, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0090] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:92, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:92, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0091] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:94, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:94, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0092] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:95, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:95, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0093] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:96, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:96, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:91.

[0094] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:97, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:97, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO:98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:98.

[0095] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 100, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 100, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 101, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 101.

[0096] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 102, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 102, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 101, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 101.

[0097] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 103, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 103, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 104, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 104.

[0098] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 105, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 104, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 104.

[0099] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 106, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 106, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 107, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 107.

[0100] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 108, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 108, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 109, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 109.

[0101] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 110, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 110, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 98.

[0102] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 111, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 111, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 98.

[0103] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 112, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 112, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 98.

[0104] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 113, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 113, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 114, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 114.

[0105] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 115, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 115, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 116, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 116.

[0106] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 117, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 117, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 118, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 118.

[0107] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 119, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 119, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 118, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 118.

[0108] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 120, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 120, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 98.

[0109] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 121, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 121, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 98.

[0110] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 122, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 123, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 123.

[0111] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 124, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 124, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 125, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 125.

[0112] In a preferred embodiment, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 126, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 126, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 125, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 125.

[0113] The second aspect of the present invention provides an isolated nucleic acid encoding the antibody according to the first aspect of the present invention.

[0114] The third aspect of the present invention provides a recombinant expression vector comprising the isolated nucleic acid according to the second aspect of the present invention.

[0115] Preferably, the backbone of the recombinant expression vector is a plasmid, a cosmid, a phage or a viral vector, and the viral vector is preferably a retroviral vector, a lentiviral vector, an adenoviral vector or an adeno-associated viral vector.

[0116] The fourth aspect of the present invention provides a transformant, which comprises the recombinant expression vector as described in the third aspect of the present invention.

[0117] Preferably, the host cell of the transformant is a prokaryotic cell or a eukaryotic cell.

[0118] More preferably, the eukaryotic cell is a yeast cell or a mammalian cell; for example, a HEK293 cell or a CHO cell.

[0119] The fifth aspect of the present invention provides a method for preparing an antibody, which comprises culturing the transformant according to the fourth aspect of the present invention, and obtaining the antibody from the culture.

[0120] The sixth aspect of the present invention provides an antigen-binding protein derivative, which comprises the antibody as described in the first aspect of the present invention and a detectable labeling molecule.

[0121] Preferably, the detectable labeling molecule is an enzyme, a radionuclide, a fluorescent dye, a luminescent substance or biotin.

[0122] The seventh aspect of the present invention provides an antibody-drug conjugate, which comprises a cytotoxic agent or a label, and the antibody according to the first aspect of the present invention.

[0123] The eighth aspect of the present invention provides a chimeric antigen receptor, which comprises the antibody according to the first aspect of the present invention.

[0124] The ninth aspect of the present invention provides a genetically modified cell, wherein the genetically modified cell comprises the chimeric antigen receptor as described in the eighth aspect of the present invention.

[0125] Preferably, the genetically modified cells are eukaryotic cells, such as isolated human cells.

[0126] In a preferred embodiment, the genetically modified cells are immune cells, such as T cells or NK cells.

[0127] The tenth aspect of the present invention provides a multispecific antibody comprising the antibody according to the first aspect of the present invention.

[0128] Preferably, the multispecific antibody is a bispecific antibody.

[0129] The eleventh aspect of the present invention provides a pharmaceutical composition, comprising the antibody according to the first aspect of the present invention, the nucleic acid according to the second aspect of the present invention, the recombinant vector according to the third aspect of the present invention, the antigen-binding protein derivative according to the sixth aspect of the present invention, the antibody-drug conjugate according to the seventh aspect of the present invention, the chimeric antigen receptor according to the eighth aspect of the present invention, the genetically modified cell according to the ninth aspect of the present invention, or the multispecific antibody according to the tenth aspect of the present invention, and a pharmaceutically acceptable carrier.

[0130] The twelfth aspect of the present invention provides a kit comprising the antibody described in the first aspect of the present invention, the nucleic acid described in the second aspect of the present invention, the recombinant vector described in the third aspect of the present invention, the antigen-binding protein derivative described in the sixth aspect of the present invention, the antibody-drug conjugate described in the seventh aspect of the present invention, the chimeric antigen receptor described in the eighth aspect of the present invention, the genetically modified cell described in the ninth aspect of the present invention, the multispecific antibody described in the tenth aspect of the present invention, or the pharmaceutical composition described in the eleventh aspect of the present invention.

[0131] Preferably, the kit further comprises (i) a device for administering the antibody, antigen binding protein derivative, antibody drug conjugate, chimeric antigen receptor, genetically modified cell or pharmaceutical composition; and / or (ii) instructions for use.

[0132] The thirteenth aspect of the present invention provides a set of medicine kits, comprising medicine kit A and medicine kit B:

[0133] The drug kit A contains the antibody according to the first aspect of the present invention, the nucleic acid according to the second aspect of the present invention, the recombinant vector according to the third aspect of the present invention, the antigen-binding protein derivative according to the sixth aspect of the present invention, the antibody-drug conjugate according to the seventh aspect of the present invention, the chimeric antigen receptor according to the eighth aspect of the present invention, the genetically modified cell according to the ninth aspect of the present invention, the multispecific antibody according to the tenth aspect of the present invention, or the pharmaceutical composition according to the eleventh aspect of the present invention;

[0134] The drug kit B contains other anti-tumor antibodies or pharmaceutical compositions comprising the other anti-tumor antibodies, and / or one or more of the group consisting of hormone preparations, targeted small molecule preparations, proteasome inhibitors, imaging agents, diagnostic agents, chemotherapeutic agents, oncolytic drugs, cytotoxic agents, cytokines, activators of co-stimulatory molecules, inhibitors of inhibitory molecules and vaccines.

[0135] In the fourteenth aspect, the present invention provides the use of the antibody as described in the first aspect of the present invention, the nucleic acid as described in the second aspect of the present invention, the recombinant vector as described in the third aspect of the present invention, the antigen-binding protein derivative as described in the sixth aspect of the present invention, the antibody-drug conjugate as described in the seventh aspect of the present invention, the chimeric antigen receptor as described in the eighth aspect of the present invention, the genetically modified cell as described in the ninth aspect of the present invention, or the multispecific antibody as described in the tenth aspect of the present invention, or the pharmaceutical composition as described in the eleventh aspect of the present invention, the kit as described in the twelfth aspect of the present invention, or the set of kits as described in the thirteenth aspect of the present invention in the preparation of products for diagnosing, treating and / or preventing cancer.

[0136] Preferably, the cancer is ILT4-positive, ILT2-positive, or ILT4-positive and ILT2-positive.

[0137] More preferably, the cancer is a solid cancer or a blood cancer.

[0138] The blood cancer is, for example, B-cell leukemia, lymphoma, acute myeloid leukemia, Burkitt's lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or marginal zone lymphoma.

[0139] The solid cancers include, for example, squamous cell carcinoma of the head and neck, renal cell carcinoma, ovarian cancer, urothelial carcinoma, diffuse large B-cell carcinoma, non-small cell lung cancer, melanoma, metastatic renal cell carcinoma, metastatic colorectal cancer, small cell lung cancer, metastatic non-small cell lung cancer, breast cancer, lung cancer, head and neck cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, intestinal cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, kidney cancer, testicular cancer, mesothelioma, glioblastoma, bile duct cancer, or pancreatic cancer.

[0140] In a preferred embodiment, the cancer is pancreatic cancer.

[0141] In a fifteenth aspect, the present invention provides a method for diagnosing, treating and / or preventing an ILT4-mediated disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of the antibody according to the first aspect of the present invention, the nucleic acid according to the second aspect of the present invention, the recombinant vector according to the third aspect of the present invention, the antigen-binding protein derivative according to the sixth aspect of the present invention, the antibody-drug conjugate according to the seventh aspect of the present invention, the chimeric antigen receptor according to the eighth aspect of the present invention, the genetically modified cell according to the ninth aspect of the present invention, or the multispecific antibody according to the tenth aspect of the present invention, or the pharmaceutical composition according to the eleventh aspect of the present invention, the kit according to the twelfth aspect of the present invention, or the set of medicine kits according to the thirteenth aspect of the present invention.

[0142] In a preferred embodiment, the disease or condition is cancer.

[0143] Preferably, the cancer is ILT4-positive and / or ILT2-positive cancer.

[0144] More preferably, the cancer is a solid cancer or a blood cancer.

[0145] The blood cancer is, for example, B-cell leukemia, lymphoma, acute myeloid leukemia, Burkitt's lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma or marginal zone lymphoma.

[0146] Such solid cancers are, for example, head and neck squamous cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial carcinoma, diffuse large B-cell carcinoma, non-small cell lung cancer, melanoma, metastatic renal cell carcinoma, metastatic colorectal cancer, small cell lung cancer, metastatic non-small cell lung cancer, breast cancer, lung cancer, head and neck cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, intestinal cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, kidney cancer, testicular cancer, mesothelioma, glioblastoma, bile duct cancer, or pancreatic cancer.

[0147] In a preferred embodiment, the cancer is pancreatic cancer.

[0148] The sixteenth aspect of the present invention provides a method for immunodetection or determination of ILT4, which comprises using the antibody as described in the first aspect of the present invention, the nucleic acid as described in the second aspect of the present invention, the recombinant vector as described in the third aspect of the present invention, the antigen-binding protein derivative as described in the sixth aspect of the present invention, the antibody-drug conjugate as described in the seventh aspect of the present invention, the chimeric antigen receptor as described in the eighth aspect of the present invention, the genetically modified cell as described in the ninth aspect of the present invention, or the multispecific antibody as described in the tenth aspect of the present invention, or the pharmaceutical composition as described in the eleventh aspect of the present invention, the kit as described in the twelfth aspect of the present invention, or the set of kits as described in the thirteenth aspect of the present invention.

[0149] Preferably, the detection is for non-diagnostic purposes, and the applicable scenarios of the non-diagnostic purposes may be laboratory research and development or immune detection or determination in the environment.

[0150] The seventeenth aspect of the present invention provides a combination therapy, comprising administering to a patient in need thereof the antibody according to the first aspect of the present invention, the nucleic acid according to the second aspect of the present invention, the recombinant vector according to the third aspect of the present invention, the antigen-binding protein derivative according to the sixth aspect of the present invention, the antibody-drug conjugate according to the seventh aspect of the present invention, the chimeric antigen receptor according to the eighth aspect of the present invention, the genetically modified cell according to the ninth aspect of the present invention, the multispecific antibody according to the tenth aspect of the present invention, the pharmaceutical composition according to the eleventh aspect of the present invention, the kit according to the twelfth aspect of the present invention, or the kit according to the thirteenth aspect of the present invention, respectively;

[0151] and a second therapeutic agent; the second therapeutic agent preferably comprises other anti-tumor antibodies or pharmaceutical compositions comprising the other anti-tumor antibodies, and / or one or more of the group consisting of hormone preparations, targeted small molecule preparations, proteasome inhibitors, imaging agents, diagnostic agents, chemotherapeutic agents, oncolytic drugs, cytotoxic agents, cytokines, activators of co-stimulatory molecules, inhibitors of inhibitory molecules and vaccines.

[0152] The eighteenth aspect of the present invention provides a drug delivery device, which comprises the antibody as described in the first aspect of the present invention, the nucleic acid as described in the second aspect of the present invention, the recombinant vector as described in the third aspect of the present invention, the antigen-binding protein derivative as described in the sixth aspect of the present invention, the antibody-drug conjugate as described in the seventh aspect of the present invention, the chimeric antigen receptor as described in the eighth aspect of the present invention, the genetically modified cell as described in the ninth aspect of the present invention, or the multispecific antibody as described in the tenth aspect of the present invention, or the pharmaceutical composition as described in the eleventh aspect of the present invention, the kit as described in the twelfth aspect of the present invention, or the set of medicines as described in the thirteenth aspect.

[0153] Preferably, the drug delivery device further comprises a component for containing or administering the antibody, the multispecific antibody, the antigen-binding protein derivative, the antibody-drug conjugate, the chimeric antigen receptor, the genetically modified cell, the pharmaceutical composition, the kit, or the set of kits to a subject, such as a syringe, an implantable drug delivery device, or an infusion device.

[0154] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0155] The present invention includes antibodies that specifically target ILT4, with higher affinity than Merck's control antibody, and antibodies that simultaneously target both ILT2 and ILT4 molecules.

[0156] Among them, PR302934, PR302264-2, and PR302264-3 can simultaneously target ILT4 and ILT2.

[0157] The reagents and raw materials used in the present invention are commercially available.

[0158] The positive progress effect of the present invention is:

[0159] The present invention provides a fully human antibody that can target ILT4. It has the following properties: 1) Some antibodies have the activity of binding to both human ILT2 and ILT4, and can also bind to cynomolgus monkey ILT4. 2) The antibody of the present invention has a better affinity for binding to human ILT4 than MK-4830 (Merck). 3) The antibody of the present invention improves its anti-tumor effect through multiple mechanisms of action. First, the antibody of the present invention can promote the differentiation of macrophages into M1 and secrete TNF-α, thereby improving the anti-tumor effect; second, the differentiated M1 cells have better antigen presentation function, which improves the anti-tumor effect of T cells; third, the antibody of the present invention acts on MDSCs and TAMs in the tumor microenvironment, improving the immunosuppressive environment in the tumor microenvironment and promoting better tumor killing by T cells. 4) In in vivo efficacy experiments in mice, the antibody of the present invention showed significantly better anti-tumor effects than the control antibodies MK-4830 (Merck) and NGM707 (NGM). BRIEF DESCRIPTION OF THE DRAWINGS

[0160] FIG1 is a graph showing the detection of the binding ability of ILT4 antibodies to human / monkey ILT4-ECD proteins.

[0161] FIG2 is a flow cytometry-based assay for the binding ability of ILT4 antibodies to CHO-huILT4 cells.

[0162] FIG3 shows the binding ability of ILT-4 antibody to ILT2-ECD protein detected by ELISA assay.

[0163] FIG4 is a flow cytometry assay showing the ability of ILT4 antibodies to block the binding of ILT4 to HLA-G.

[0164] FIG5 is an ELISA-based assay for the ability of ILT4 antibodies to block the binding of ILT4 to SEMA4A.

[0165] FIG6 shows the activation effect of ILT4 antibodies on macrophages detected by ELISA.

[0166] FIG7 shows the activation effect of ILT4 antibodies on peripheral blood mononuclear cells detected by ELISA.

[0167] FIG8 is an ELISA-based assay for detecting the activation effect of ILT4 antibodies in mixed lymphocyte reaction.

[0168] FIG9 is a pharmacodynamics experiment of ILT4 antibody in SU8686 mouse tumor model. DETAILED DESCRIPTION

[0169] Explanation of terms

[0170] In this application, the term "antibody" generally refers to a protein comprising a portion that binds to an antigen, and optionally a scaffold or backbone portion that allows the portion that binds to the antigen to adopt a conformation that promotes antibody binding to the antigen. It may typically comprise an antibody light chain variable region (VL), an antibody heavy chain variable region (VH), or both. For example, a "heavy chain antibody" in this application does not contain a VL region, but only a VH region. The VH or VL region can be further divided into hypervariable regions called complementary determining regions (CDRs), which are interspersed in more conserved regions called framework regions (FRs). Each VH or VL can be composed of three CDRs and four FR regions, which can be arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. Examples of antibodies include, but are not limited to, full-length antibodies, heavy-chain antibodies (HCAbs), antigen-binding fragments (Fab, Fab', F(ab)2, Fv fragments, F(ab')2, scFv, di-scFv and / or dAbs), immunoconjugates, multispecific antibodies (e.g., bispecific antibodies), antibody fragments, antibody derivatives, antibody analogs or fusion proteins, etc., as long as they exhibit the desired antigen-binding activity.

[0171] In this application, the term "variable" generally refers to the fact that some parts of the sequence of the variable domain of an antibody vary strongly, which forms the binding and specificity of various specific antibodies to their specific antigens. However, variability is not evenly distributed throughout the entire variable region of an antibody. It is concentrated in three segments in the light and heavy chain variable regions, called CDRs or hypervariable regions (HVRs), and FRs are more highly conserved parts of the variable domains. The variable domains of native heavy and light chains each comprise four FR regions, most of which adopt a β-sheet configuration, are connected by three CDRs, form loops connected, and in some cases form a part of a β-sheet structure. The CDRs in each chain are closely together through the FR region and form the antigen binding site of the antibody together with the CDRs from another chain. The constant regions do not directly participate in the binding of the antibody to the antigen, but they exhibit different effector functions, such as participating in the antibody's cytotoxicity that depends on the antibody.

[0172] In this application, the term "Fab" generally refers to the antigen-binding portion of a conventional antibody (e.g., IgG), comprising the antibody's heavy chain variable region VH, light chain variable region VL, heavy chain constant region domain CHI, and light chain constant region CL. In conventional antibodies, the C-terminus of VH is linked to the N-terminus of CHI to form the heavy chain Fd fragment, the C-terminus of VL is linked to the N-terminus of CL to form the light chain, and the C-terminus of CHI is further linked to the hinge region and other constant region domains of the heavy chain to form the heavy chain. In some embodiments, "Fab" also refers to variant structures of Fab. For example, in certain embodiments, the C-terminus of VH is linked to the N-terminus of CL to form one polypeptide chain, and the C-terminus of VL is linked to the N-terminus of CHI to form another polypeptide chain, forming a Fab (cross VH / VL) structure. In certain embodiments, the CHI of Fab is not linked to the hinge region, but the C-terminus of CL is linked to the hinge region of the heavy chain, forming a Fab (cross Fd / LC) structure.

[0173] In this application, the term "VH" generally refers to the heavy chain variable region VH domain of an antibody, that is, it can be the heavy chain variable region VH of a conventional antibody (H2L2 structure) of humans or other animals, or the heavy chain variable region VHH of a heavy chain antibody (HCAb structure) of animals such as camelids, or the heavy chain variable region VH of a fully human heavy chain antibody (HCAb structure) produced using Harbour HCAb transgenic mice.

[0174] The term "a" or "an" used in the present invention refers to one or more than one grammatical object. Unless the content clearly indicates otherwise, the term "or" is used in the present invention to mean the term "and / or" and is used interchangeably therewith.

[0175] The term "heavy chain antibody" of the present invention is also called HCAb antibody, which refers to an antibody that lacks the antibody light chain and only contains the heavy chain, specifically the heavy chain variable domain and the Fc constant domain, relative to the two-chain antibody (immunoglobulin).

[0176] A "human antibody" has an amino acid sequence that corresponds to the amino acid sequence of an antibody produced by a human or human cell, or derived from a non-human source utilizing human antibody libraries or other human antibody encoding sequences. This definition of a human antibody specifically excludes humanized antibodies comprising non-human antigen-binding residues.

[0177] The terms "polynucleotide" or "nucleic acid" or "nucleotide sequence" herein refer to isolated nucleic acid molecules, such as messenger RNA (mRNA), virally derived RNA, DNA, or plasmid DNA (pDNA). A polynucleotide may contain conventional phosphodiester bonds or unconventional bonds (e.g., amide bonds, such as those found in peptide nucleic acids (PNA)). The term "nucleic acid molecule" refers to any one or more nucleic acid segments, such as DNA or RNA fragments, present in a polynucleotide.

[0178] The term "isolated" nucleic acid molecule or polynucleotide of the present invention refers to a nucleic acid molecule, DNA or RNA, that has been separated from its natural environment. In the present invention, a recombinant polynucleotide encoding a polypeptide contained in a vector is also isolated. Other examples of isolated polynucleotides include recombinant polynucleotides in heterologous host cells or polynucleotides purified from solution. Isolated polynucleotides include polynucleotide molecules that are normally contained in cells, but the polynucleotide molecule is present extrachromosomally or at a chromosomal location that is different from its natural chromosomal location. Isolated RNA molecules include in vivo or in vitro RNA transcripts of the present invention, in plus or minus strand form, single-stranded or double-stranded form. Isolated polynucleotides or nucleic acids of the present invention further include such molecules that are synthetically produced. In addition, the polynucleotide or nucleic acid can be or can include regulatory elements, such as promoters, ribosome binding sites, or transcription terminators.

[0179] The terms "vector" or "expression vector" of the present invention are used interchangeably to refer to a DNA molecule that is operably linked to a specific gene and is introduced into a target cell and directed to expression. The vector includes a vector that is a self-replicating nucleic acid structure and a vector that is incorporated into the genome of the host cell into which it has been introduced. The expression vector of the present invention comprises an expression cassette. The expression vector can perform transcription of a large amount of stable mRNA. Once the expression vector is within the target cell, the ribonucleic acid molecule or protein encoded by the gene is generated by the cell's transcription and / or translation machinery. In one embodiment, the expression vector of the present invention comprises an expression cassette containing a polynucleotide sequence encoding a bispecific antigen binding molecule of the present invention or a fragment thereof.

[0180] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably to refer to cells into which exogenous nucleic acid has been introduced, and also include the progeny of such cells. Host cells include "transformants" and "transformed cells," including primary transformed cells and progeny derived therefrom. The nucleic acid of the progeny may not be completely identical to that of the parent cell and may contain mutations. Host cells are any type of cells that can be used to generate the bispecific antigen binding molecules of the present invention. Host cells include cultured cells, for example, cultured mammalian cells, such as CHO cells, HEK293 cells, BHK cells, NSO cells, SP2 / 0 cells, YO myeloma cells, P3X63 mouse myeloma cells, PER cells, PER.C6 cells, or hybridoma cells, for example, yeast cells, insect cells, or plant cells, and also include cells contained in transgenic animals, transgenic plants, or cultured plant or animal tissues.

[0181] "Affinity" or "binding affinity" refers to the strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its ligand (e.g., an antigen). Binding affinity can often be expressed in terms of the dissociation constant (Kd), which is the product of the dissociation rate constant and the association rate constant (kd, respectively). off and k on ). Thus, equivalent affinities can include different rate constants as long as the ratio of the rate constants remains the same. Affinity can be measured by conventional methods known in the art, such as surface plasmon resonance (SPR).

[0182] The term "Harbour HCAb transgenic mouse," as used herein, refers to a transgenic mouse carrying a human immunoglobulin repertoire, capable of producing novel heavy chain-only antibodies that are half the size of traditional IgG antibodies. These antibodies possess only the human heavy chain variable domain and the mouse Fc constant domain. By lacking light chains, these antibodies virtually eliminate the problems of light chain mispairing and heterodimerization, enabling the development of products that are difficult to achieve with traditional antibody platforms.

[0183] The term "chimeric antigen receptor" refers to a chimeric antigen receptor (CAR) T cell. The antigen-binding site of an antibody that recognizes a tumor antigen is coupled in vitro to the intracellular portion of the CD3-δ chain or FcεRIγ to form a chimeric protein. This protein is then transduced into the patient's T cells through gene transduction to express the CAR, effectively reprogramming the patient's T cells to produce large numbers of tumor-specific CAR-T cells. When these reprogrammed CAR T cells are introduced into the patient's body, they act like a GPS, specifically tracking, identifying, and guiding T cells to kill tumor cells. Most CARs consist of an extracellular antigen-binding domain (composed of light and heavy chains derived from monoclonal antibodies, connected by a flexible hinge region to form a single-chain antibody), a transmembrane region, and an intracellular signaling domain. The CAR structure is created by genetically recombining in vitro a scFv that recognizes a tumor-associated antigen with the intracellular signaling domain, the immunoreceptor tyrosine-based activation motif.

[0184] The term "immune cell" includes cells that have hematopoietic origin and play a role in the immune response, such as lymphocytes, such as B cells and T cells; natural killer cells; myeloid cells, such as monocytes, macrophages, eosinophils, mast cells, basophils or granulocytes.

[0185] The term "antibody drug conjugate" refers to both the antigen-binding protein portion and the coupling portion. The antigen-binding protein portion includes the "antigen-binding protein" described above, as well as antigen-binding fragments obtained based on the "antigen-binding protein." Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', Fv fragments, F(ab')2, scFv, di-scFv, and / or dAb. The coupling portion may contain at least one drug payload. The drug payload is a class of pharmaceutically active small molecule compounds or toxins or other drug molecules or the aforementioned labeled molecules, and may be, but is not limited to, small molecule compounds, toxin molecules, oligonucleotides, protein degradation targeting chimeras (PROTACs), affinity ligands, fluorescent groups, radionuclide groups, and the like. Various drug payloads are known in the art. For example, small molecule compounds generally refer to a class of substances with strong cytotoxicity. Exemplary small molecule compounds can exert such cytotoxic and cytostatic effects through mechanisms including, but not limited to, tubulin binding, DNA binding, inhibition of RNA polymerase, protein synthesis, or inhibition of topoisomerases. For example, the small molecule compound can be a tubulin inhibitor; exemplary tubulin inhibitors can be maytansine (e.g., DM1 or DM4) and auristatin (e.g., MMAE or MMAF), etc. For example, the small molecule compound can be a DNA damaging agent; exemplary DNA damaging agents can be calicheamicins, pyrrolobenzodiazepines (PBD, pyrrolobenzodiazepines), etc. For example, protein degradation targeting chimeras (PROTACs) are a class of compounds that can cause target protein degradation by inducing polyubiquitination of target proteins; exemplary PROTACs can be BET protein degraders. The drug conjugate can also include at least one linker. The linker is used to connect one or more payload drugs to the antigen binding protein. For example, the linker includes a cleavable linker or a non-cleavable linker. In the present application, the cleavable linker can be a "cleavable" linker that facilitates the release of the drug. Exemplary cleavable linkers can include but are not limited to acid-sensitive linkers, protease-sensitive linkers, light-sensitive linkers, or disulfide-containing linkers. The linker may comprise one or more linker components, and a variety of linker components are known in the art, for example, maleimidocaproyl (MC), maleimidopropionyl (MP), valine-citrulline (val-cit or vc), or paminobenzyloxycarbonyl (PAB).

[0186] The term "pharmaceutical composition" refers to a mixture containing one or more antibodies or antigen-binding fragments thereof disclosed herein and other chemical components, such as physiologically / pharmaceutically acceptable carriers or excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity. The "pharmaceutical composition" of the present invention may include a first active ingredient and a second active ingredient, the two active ingredients being present together in a unit dose or as a combination of a single entity, wherein the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, such as in a formulation.

[0187] The term "pharmaceutically acceptable carrier" refers to a component of a pharmaceutical composition other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable excipients include, but are not limited to, buffers, stabilizers, and / or preservatives.

[0188] The "kit of parts" of the present invention are used in a manner known to those skilled in the art and are defined as a combination in which the first active ingredient (kit A) and the second active ingredient (kit B) are present in more than one unit. An example of a kit of parts is a combination in which the first active ingredient and the second active ingredient are present separately. The components of the kit of parts can be administered separately, sequentially, simultaneously, concurrently, or in a chronologically staggered manner. The antibodies or antigen-binding proteins thereof of the present invention can be administered as a single agent or in combination with one or more other agents, wherein the combination does not cause unacceptable adverse reactions.

[0189] The term "cancer" is intended to describe a disorder in mammals characterized by unregulated cell growth. Cancer includes, but is not limited to, tumors such as lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of cancer include, but are not limited to, squamous cell carcinomas (e.g., epithelial squamous cell carcinomas), lung cancers (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma of the lung), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer and gastrointestinal stromal cancer), bone cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, breast cancer, colon cancer, rectal cancer, endometrial cancer or cervical cancer, salivary gland cancer, kidney cancer or ureteral cancer, prostate cancer, vaginal cancer, vulvar cancer, thyroid cancer, anal cancer, penile cancer, melanoma, bile duct cancer, central nervous system (CNS) tumors, spinal axis tumors, brain stem gliomas, glioblastomas such as glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinoma, pituitary adenoma and Ewing's sarcoma, superficial spreading melanoma, lentigo maligna melanoma, acral melanoma, nodular melanoma, multiple myeloma and B-cell lymphoma, chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), hairy cell leukemia, chronic myeloblastic leukemia and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal blood vessel proliferation associated with phakomatoses, edema (such as that associated with brain tumors) and Meigs syndrome, brain tumors and brain cancer, and head or neck cancer and related metastatic cancers.

[0190] "Treatment" refers to the administration of a therapeutic agent, whether internal or external, such as a composition comprising any of the antibodies or antigen-binding fragments thereof disclosed herein or a nucleic acid molecule encoding the same, to a patient suffering from one or more diseases or symptoms for which the therapeutic agent has a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate the one or more diseases or symptoms in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree.

[0191] The term "preventing cancer" refers to delaying, inhibiting, or preventing the onset of cancer in a mammal in which the initiation of carcinogenesis or tumorigenesis has not been demonstrated, but in which the mammal has been identified as having a predisposition to cancer, as determined, for example, by genetic screening or other methods. The term also includes treating a mammal with a precancerous condition to halt the progression of the precancerous condition to a malignant tumor or to cause its regression.

[0192] The term "drug delivery device" primarily refers to packaging materials and injection systems. Packaging materials include, but are not limited to, vials, syringes, or test tubes; injection systems include, but are not limited to, syringes, infusion pumps, injection pens, needle-free devices, or subcutaneous patch delivery devices. The components of the drug delivery device may be conventional in the art, including: a container, a sealant, and an injection needle. The container includes, but is not limited to, a vial, syringe, or test tube. The container may be made of conventional materials in the art, such as glass or plastic. The sealant includes, but is not limited to, a sealing plug or an O-ring. The sealant may be made of conventional materials in the art, such as rubber, plastic, or polymers. The injection needle includes, but is not limited to, a water-based injection, a single needle, or a microneedle assembly. The injection needle may be made of conventional materials in the art, such as metal, silicon, silicon dioxide, glass, nickel, titanium, or a biodegradable polymer. The water-based injection includes, but is not limited to, a vial-based injection, an ampoule-based injection, or a prefilled injection system. The ampoule-based injection may be a glass or plastic ampoule. The prefilled injection system can be conventional in the art, such as a prefilled syringe.

[0193] In the art, the CDRs of antibodies can be defined by a variety of methods, such as the Kabat definition rules based on sequence variability (see, Kabat et al., Protein Sequences in Immunology, 5th edition, National Institutes of Health, Bethesda, Maryland (1991)) and the Chothia definition rules based on structural loop region positions (see, Al-Lazikani et al., J Mol Biol 273:927-48, 1997). The application can also use the Combined definition rules comprising the Kabat definition and the Chothia definition to determine the amino acid residues in the variable domain sequence and the full-length antibody sequence. In the present invention, each sequence is determined as shown in the table below according to the combined definition rules.

[0194] The method for defining the antibody CDRs in this application is shown in Table 1 (see http: / / bioinf.org.uk / abs / )

[0195] Table 1 Antibody CDR definition method in this application

[0196] Among them, Laa-Lbb may refer to the amino acid sequence starting from the N-terminus of the antibody light chain, from position aa (Chothia numbering rules) to position bb (Chothia numbering rules); Haa-Hbb may refer to the amino acid sequence starting from the N-terminus of the antibody heavy chain, from position aa (Chothia numbering rules) to position bb (Chothia numbering rules). For example, L24-L34 may refer to the amino acid sequence starting from the N-terminus of the antibody light chain, from position 24 to position 34 according to the Chothia numbering rules; H26-H32 may refer to the amino acid sequence starting from the N-terminus of the antibody heavy chain, from position 26 to position 32 according to the Chothia numbering rules.

[0197] The CDR information of the antibodies of the present invention is shown in Table 2 below:

[0198] Table 2

[0199] The VH and VL information of the antibodies of the present invention are shown in Table 3 below:

[0200] Table 3

[0201] The light chain and heavy chain information of the antibodies of the present invention are shown in Table 4:

[0202] Table 4

[0203] The VH and VL information of the control antibodies of the present invention are shown in Table 5:

[0204] Table 5

[0205] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0206] Example 1 Immunization of Harbour transgenic mice

[0207] 1. Immunogen: Recombinant human ILT4 protein amino acid sequence (UniprotKB NO. Q8N423) extracellular domain positions 1-460 were cloned into the Fc-tagged pcDNA3.1 vector to generate a recombinant expression plasmid. HEK293 cells were transiently transfected and cultured. After 4 days, the cell culture fluid was harvested and the supernatant was purified to obtain highly pure huILT4-ECD-Fc protein (>90%) with biological activity. Aliquots were stored frozen at -80°C.

[0208] 2. Immunization of Harbour H2L2 Mice: huILT4-ECD-Fc protein was used to immunize 6-8 week-old Harbour H2L2 transgenic mice (Harbour Antibodies BV). These mice carry a human immunoglobulin repertoire, producing antibodies with intact human variable domains and rat constant domains. All transgenic mice were housed in a SPF-protected environment. For the primary immunization, 50 μg of huILT4-ECD-Fc protein was emulsified with complete Freund's adjuvant (Sigma, F5881) and injected intraperitoneally into the mice. For subsequent booster immunizations, 25 μg of huILT4-ECD-Fc protein was mixed with RIBI adjuvant (Sigma, S6322) and injected intraperitoneally into the mice. Immunizations were separated by 2 weeks. Serum antibody titers were measured by ELISA 7 days after immunization, and mice with high serum titers were selected for subsequent single B cell screening experiments.

[0209] Example 2 is based on Single B cell screening using the Optofluidic system

[0210] Optofluidic system uses optical-electric positioning (OEP TM ) technology to move individual cells. The Beacon optoelectronic system is an automated bioinstrumentation device that allows for simultaneous execution of multiple operations, including biological function testing, experimental analysis, and positive clone selection, under cell culture conditions. The Beacon platform can perform these tasks in a massively parallel, automated manner on thousands of cells.

[0211] This application uses a plasma cell discovery workflow, which can screen up to 14k single plasma cells in each experiment to select antigen-specific plasma cells that secrete antibodies. These plasma cells that secrete specific antibodies are then exported to 96-well plates containing cell lysate for subsequent single B cell sequencing to identify the heavy and light chain sequences of antibodies produced by single B cells (monoclonal).

[0212] Example 3 Single B cell sequencing

[0213] The present invention uses single B cell sequencing to recover antibody heavy and light chain sequences from a single plasma cell. Single B cell sequencing has become a powerful tool for obtaining antibody sequences. The general procedure includes RNA purification from single plasma cell lysate, reverse transcription synthesis of cDNA, amplification and purification of the cDNA, amplification of the heavy and light chains, cloning and transfection, and Sanger sequencing.

[0214] Among them, the heavy chain and light chain complementary region determining region (CDR) sequences, heavy chain and light chain variable region (V), and heavy chain and light chain sequences of the human ILT4 antibody obtained in the present invention are shown in Table 6 below.

[0215] Table 6 ILT4 antibody sequence

[0216] Example 4 Expression and purification of recombinant antibodies

[0217] The obtained sequences were analyzed for uniqueness and clustering, and then the paired heavy and light chain DNA sequences were synthesized into plasmids. CHO cells were used for antibody expression. The cell density was adjusted to 1×10e6 cells / mL. The heavy and light chain antibody plasmids were added to the tube at a ratio of 1:1.5, and then the transfection reagent PEI was added at a ratio of 4:1. After mixing, the mixture was incubated at room temperature for 15 minutes. The transfected cells were added to the cells and cultured in a 37°C, 5% CO2 incubator with shaking at 125 rpm. 24 hours after transfection, OPM-CHO PFF05 nutrients (OPM, catalog number FB1279-001) were supplemented to a final concentration of 3%. After 5 days of cell culture, when the cell viability dropped below 70%, the supernatant was collected. The transfection supernatant was purified using a protein G column.

[0218] Example 5 Mutation of Antibody Sequences

[0219] 5.1 IgG subtype transition

[0220] The Fc of the antibody was modified to convert the antibody type from IgG1 to IgG4. The antibody was expressed and purified as described in Example 4. The corresponding antibody sequence information is shown in Table 7.

[0221] Table 7 IgG4 ILT4 antibody sequences

[0222] 5.2 Antibody Sequence Analysis and Optimization

[0223] Amino acid mutations are introduced into potential post-translational modification (PTM) sites in the antibody sequence to obtain new antibody molecules (referred to as PTM variants). The amino acid sequences of the light and heavy chain variable domains, light chain, heavy chain (human IgG4), and CDRs defined according to the Combined of PTM variants in this example are listed in Table 8. All designed PTM variants were purified by the method described in Example 4 to obtain purified recombinant antibodies and further verified in subsequent functional experiments.

[0224] Table 8 PTM variant sequences

[0225] Example 6 Antibody affinity detection experiment

[0226] The binding kinetics of the multiple antibodies prepared according to the methods of Examples 1-5 of the present invention to human ILT4-ECD protein were detected by biolayer interferometry (BLI) method (Fortebio octet RED 96e).

[0227] The test antibody was diluted to a final concentration of 6 μg / mL and directly immobilized onto the AHC biosensor for kinetic measurements. The antigen protein (HuILT4, UniprotKB No. Q8N423) was diluted in 0.02% PBST20 to three concentrations: 100 nM, 50 nM, and 25 nM. The sample was injected for 70 s, with an association time of 300 s, a dissociation time of 300 s, and a regeneration time of 10 mM glycine-HCl (pH 1.5) for 15 s. The association rate (k₁) and dissociation rate (k₁₀) were calculated using a simple one-to-one Languir binding model (Octet Red 96 data analysis software). The equilibrium dissociation constant (k₁₀) was calculated as the ratio k₁₀ / k₁₀. The antibody affinity test results are shown in Table 9 below.

[0228] Table 9 Antibody affinity test results

[0229] As can be seen from the results in the above table, the affinities of PR302259, PR302934, PR302951, PR302261, PR302949, PR302927, PR302282, PR302264, PR302264-2 and PR302264-3 antibodies are all better than that of the control antibody PR001795 (Merck: US20180298096).

[0230] Example 7 Detection of the binding ability of antibodies to ILT4-ECD at the protein level

[0231] The binding ability of the multiple antibodies prepared by Examples 1-5 of the present invention to the ILT4-ECD protein was detected based on the ELISA assay. The binding ability of different antibodies to the ILT4-ECD protein was determined by comparing the binding curves of the different antibodies. The specific experimental process is as follows: first, human ILT4-ECD and cynomolgus monkey ILT4-ECD proteins were diluted to a concentration of 1 μg / mL, added to a 96-well plate, 100 μL per well, and placed at 4°C overnight. After washing the 96-well plate three times with PBST solution, a 2% BSA PBS solution was added and placed at 37°C for 1 hour. The antibody to be tested was diluted in a concentration gradient (100nM, 10-fold dilution), added to the 96-well plate, and incubated at 37°C for 1 hour. After washing three times with PBST solution, anti-human IgG Fc-HRP secondary antibody (5000× dilution) was added and incubated at 37°C for 30-60 minutes. After washing three times with PBST solution, TMB color development solution was added for 5-15 minutes, and then stop solution was added to stop color development.

[0232] Table 10 Results of antibody binding ability test with ILT4-ECD at the protein level

[0233] The test results are shown in Table 10 and Figure 1. PR302702, PR302927, PR302934, PR302949, PR302950, ​​PR302951, PR302264, PR302261, PR302282, PR302239-1, PR302259-1, and PR303413 antibodies all have the ability to bind to human ILT4-ECD protein, and are comparable to the control antibody PR301366 (Five Prime: WO2020014132). Among them, PR302934, PR302261, and PR302264 antibodies also have the ability to bind to monkey ILT4-ECD protein.

[0234] Example 8 Detection of Antibody Binding Ability to ILT4 at the Cellular Level

[0235] The binding ability of the multiple antibodies prepared by Examples 1-5 of the present invention to the human ILT4 molecule expressed on the surface of 293T cells was detected based on flow cytometry. The binding ability of different antibodies to the human ILT4 molecule expressed on the surface of CHO cells was determined by comparing the binding curves of different antibodies. The specific experimental process is as follows: (1) CHO cells were infected with lenti-huILT4 lentivirus, and the infected cells were screened with puromycin to obtain a stable cell pool: CHO-huILT4; (2) The stable cell pool was subcloned to obtain a monoclonal cell line that highly expressed the target gene; (3) The monoclonal cell line was incubated with different concentrations of the test antibody at 4°C for 30 minutes, washed three times with PBS, and then incubated with FITC-labeled goat anti-human secondary antibody at 4°C for 30 minutes. After washing again three times with PBS, the cells were resuspended in 100 μL FACS buffer; (4) The median fluorescence value of one channel was measured using a flow cytometer. The EC50 values ​​were compared using the logarithm of the antibody concentration to the base 10 as the abscissa and the median fluorescence value of a channel as the ordinate.

[0236] Table 11 Results of antibody binding ability to ILT4 at the cellular level

[0237] The test results are shown in Table 11 and Figure 2. PR302702, PR302927, PR302934, PR302949, PR302951, PR302950, ​​PR302239-1, PR302282, PR303413 and PR302259-1 antibodies all have strong binding abilities to CHO-huILT4 cells.

[0238] Example 9 Detection of Antibody Binding Ability to ILT2-ECD at the Protein Level

[0239] The binding ability of the various antibodies prepared in Examples 1-5 of the present invention to the ILT2-ECD (UniprotKB NO. Q8NHL6) protein was tested using an ELISA assay. Binding abilities were determined by comparing the binding curves of the different antibodies to the ILT2-ECD protein. The specific experimental procedure was as follows: Human ILT2-ECD protein (UniprotKB NO. Q8NHL6) was diluted sequentially to a concentration of 1 μg / mL and added to a 96-well plate, 100 μL per well, and incubated at 4°C overnight. The 96-well plate was washed three times with PBST solution, followed by addition of 2% BSA in PBS and incubation at 37°C for 1 hour. The test antibody was serially diluted (100 nM, 10-fold dilution) and added to the 96-well plate, incubated at 37°C for 1 hour. After washing three times with PBST solution, an anti-human IgG Fc-HRP secondary antibody (5000x dilution) was added and incubated at 37°C for 30-60 minutes. After washing three times with PBST solution, TMB colorimetric solution was added for 5-15 minutes, and then the color development was terminated by adding stop solution. The test results are shown in Figure 3. PR302264-2, PR302264-3, and PR302934 antibodies have strong binding ability to human ILT2.

[0240] Example 10 Detection of the ability of antibodies to block the binding of ILT4 to HLA-G

[0241] The ability of the multiple antibodies prepared in Examples 1-5 of the present invention to block the binding of huILT4 protein to human HLA-G-β2M (HLA-G: UniprotKB NO.P17693; β2M: UniprotKB NO.P61769) expressed on the surface of CHO cells was detected based on flow cytometry. The blocking ability of different antibodies was determined by comparing the curves of blocking the binding of huILT4 protein to CHO-HLA-G-β2M cells. The specific experimental process was as follows: (1) HLA-G-β2M was first constructed into the PEE6.4 plasmid and transfected into CHO cells. The infected cells were screened with puromycin to obtain a stable cell pool: CHO-HLA-G-β2M; (2) The stable cell pool was subcloned to obtain a monoclonal cell line that highly expressed the target gene. (3) The selected CHO-HLA-G-β2M cell line was transfected with the PEE6.4 plasmid containing OS8 and selected with hygromycin B to obtain a CHO-HLA-G-β2M-OS8 cell pool. (4) The cell pool was subcloned to obtain a monoclonal cell line that highly expressed the target gene. (5) The EC80 concentration of huILT4 protein binding to CHO-HLA-G-β2M cells was determined. The huILT4 protein was biotin labeled to obtain huILT4-biotin protein; (6) CHO-HLA-G-β2M cells were incubated with different concentrations of the test antibody and huILT4 protein (final concentration was the EC80 value) at 4°C for 1 hour. After washing three times with PBS, the cells were incubated with APC-labeled Strepavidin secondary antibody at 4°C for 30 minutes. After washing three times with PBS, the cells were resuspended in 100 μL FACS buffer; (7) The median fluorescence value of the four channels was measured using a flow cytometer. The logarithm of the antibody concentration to the base 10 was used as the horizontal axis and the median fluorescence value of the four channels was used as the vertical axis to compare the IC50 values.

[0242] Table 12 Results of the ability test of antibodies to block the binding of ILT4 to HLA-G

[0243] The test results are shown in Table 12 and Figure 4. Compared with the negative control Isotype control, PR302927, PR302949, PR302950, ​​PR302951, PR302239, PR302259 and PR303413 antibodies all significantly blocked the binding function of huILT4 to CHO-HLA-G-β2M.

[0244] Example 11 Detection of the ability of antibodies to block the binding of ILT4 to SEMA4A

[0245] The ability of the multiple antibodies prepared by Examples 1-5 of the present invention to block the binding of huILT4 protein to human SEMA4A (UniprotKB NO.Q9H3S1) protein was detected based on ELISA. The blocking ability of different antibodies was determined by comparing the curves of blocking the binding of huILT4 to human SEMA4A protein. The specific experimental process is as follows: (1) First, the EC80 concentration of huILT4 protein binding to human SEMA4A protein was determined. (2) Human SEMA4A protein was diluted to a concentration of 10 μg / mL and added to a 96-well plate, 100 μL per well, and placed at 4°C overnight. After washing the 96-well plate three times with PBST solution, a 2% BSA PBS solution was added and placed at 37°C for 1 hour. The antibody to be tested was diluted in a concentration gradient (2000nM, 3-fold-dilution) and huILT4-biotin protein at a concentration of 2×EC80, 50 μL each was taken, added to the 96-well plate, mixed, and incubated at 37°C for 1 hour. After washing three times with PBST solution, add Strepavidin-HRP secondary antibody (5000× dilution) and incubate at 37°C for 30-60 minutes. After washing three times with PBST solution, add TMB color development solution for 5-15 minutes, and then add stop solution to stop color development.

[0246] Table 13 Results of the ability test of antibodies to block the binding of ILT4 to SEMA4A

[0247] The test results are shown in Table 13 and Figure 5. Compared with the negative control Isotype control, PR302259, PR303413, PR302949, PR302951, PR302282, PR302950 and PR302927 antibodies all significantly blocked the binding function of huILT4 to SEMA4A.

[0248] Example 12 Cross-reaction of antibodies with other ILT4 family proteins

[0249] Take 100 μL of human LILRA1 (R&D System, Cat: 9226-T4-050), LILRA2 (R&D System, Cat: 9040-T4-050), LILRA3 (R&D System, Cat: 9517-T4-100), LILRA4 (R&D System, Cat: 9517-T4-100) with a concentration of 1 μg / ml. System, Cat: 8914-T4-050), LILRA5 (R&D System, Cat: 8956-T4-100), LILRA6 (R&D System, Cat: 9088-T4-050), LILRB3 (R&D System, Cat: 9159-T5-050), LILRB4 (R&D System, Cat: 8488-T4-025), LILRB5 (R&D ELISA coating was performed using the protein from the ELISA system (Cat. No. 8478-T4-025) at 4°C overnight. The cells were washed four times with PBST, and 200 μl of the solution was dissolved in PBST (PBS + 0.05% Tween 20) + 2% BSA for blocking at 37°C for 1 hour. The cells were then washed four times with PBST. 100 μl of 100 nM ILT4 antibody and positive control antibodies of each protein (LILRA1 Antibody: R&D System, Cat: MAB30851; LILRA2 Antibody: R&D System, Cat: MAB6364; LILRA3 Antibody: R&D System, Cat: MAB2574; LILRA4 Antibody: R&D System, Cat: MAB6287; LILRA5 Antibody: R&D System, Cat: MAB6754; LILRA6 Antibody: R&D System, Cat: MAB8656; LILRA3 Antibody: R&D System, Cat: MAB1806-100; LILRA4 Antibody: R&D System, Cat: MAB24251 ... System, Cat: MAB3065). Incubate at 37°C for 1 hour. Wash four times with PBST. Add 100 μl of Goat Anti-Human IgG, (Fab)-HRP (1:5000, Jackson, Cat: 109-035-098) and incubate at 37°C for 1 hour. Wash four times with PBST.Add 100 μl of TMB substrate (Biopanda, Cat: TMB-S-003) and incubate at room temperature for 5 minutes. Terminate the reaction by adding 50 μl of stop buffer (Solarbio, Cat# C1058). OD 450 nm readings were recorded using a microplate reader (Molecular Devices, Spectramax 384plus). A control antibody, PR304683 (NGM: WO2021127200), was used.

[0250] Table 14 Cross-reaction results of antibodies with other ILT4 family proteins

[0251] The results are shown in Table 14. In addition to binding to ILT4, the PR302934 antibody cross-binds with other LILR family members such as LIR6, ILT7, ILT8, ILT2, and ILT5; PR302264-2 cross-binds with LIR6 and ILT2. The PR302259, PR302951, PR302282, PR302927, PR302949, and PR302939 antibodies specifically bind to ILT4 only.

[0252] Example 13 Detection of Antibody Activation Effect on Macrophages - Cytokine TNF-α Secretion

[0253] CD14 positive cells were isolated from human PBMC (Shanghai Saili Biotechnology Co., Ltd., XFB-HP050A) using a human CD14 cell isolation kit (Miltenyi, 130-050-021). The isolated CD14 positive cells were resuspended and diluted to 8 × 10 5 / ml, add 100 μl of cell suspension to each well of a 96-well cell culture plate; dispense 50 μl of serially diluted (5-fold dilutions, starting and ending at 50 nM) antibody into the 96-well plate; dilute MCSF (R&D System, 216-MC-025 / CF) to 400 ng / ml and add 50 μl to each well. Incubate at 37°C in a CO2 incubator. Change the medium on the third day, maintaining the same antibody and MCSF concentrations. Change the medium again on the sixth day, maintaining the same antibody and MCSF concentrations, and add LPS to a final concentration of 50 ng / ml. After 24 hours, collect the cell supernatant and measure TNF-α levels using an ELISA kit (Ebioscience, 88-7346-88). The results are shown in Figure 6 . PR302261, PR302264, PR302934, PR302949, PR302702, PR302950, ​​PR302282, PR302239, and PR302927 antibodies all had a strong activation effect on macrophages.

[0254] Example 14 Detection of the Effect of Antibodies on Peripheral Blood Mononuclear Cells - Cytokine TNF-α Secretion

[0255] Use healthy human PBMC and resuspend the cells in 1640 complete medium to dilute them to 2*10 6 / ml, 100μl of cell suspension was added to each well of a 96-well cell culture plate. 50μl of serially diluted antibodies (maximum final concentration: 30nM, diluted to 1nM, and then diluted 5-fold) were added to the 96-well plate. LPS was diluted to 400ng / ml and 50μl was added to each well. After three days of incubation at 37°C in a CO2 incubator, the cell supernatant was collected and assayed for TNF-α levels using an ELISA kit. As shown in Figure 7, antibodies PR302259, PR302951, PR302934, PR302264-2, PR302264-3, PR302282-1, PR302282-2, PR304341, and PR302951-1 all had a strong activating effect on PBMCs.

[0256] Example 15: Detection of the Effect of Antibodies in Mixed Lymphocyte Reaction - Cytokine IFN-γ Secretion

[0257] CD14 positive cells were isolated from human PBMC using a human CD14 cell isolation kit (Miltenyi, 130-050-021). The isolated CD14 positive cells were resuspended and diluted to 1.5*10 5 / ml, take a 96-well cell culture plate and add 100μl of cell suspension to each well; take 50μl of serial dilution (5-fold dilution, starting and ending at 50nM) of antibody to the 96-well cell plate; dilute MSCF (R&D System, 216-MC-025 / CF) to 400ng / ml and add 50μl to each well. Incubate at 37℃ in a CO2 incubator. Change the medium on the third day, keeping the concentration of antibody and MCSF unchanged. Change the medium again on the sixth day, keeping the concentration of antibody and MCSF unchanged, and add LPS to a final concentration of 50ng / ml. On the seventh day, take another human PBMC and use the human CD3 sorting kit (Miltenyi, 130-045-501) to sort out CD3-positive cells. Use 1640 complete medium to resuspend the isolated CD3-positive cells and dilute them to 1.5*10 6 / ml. The supernatant from the 96-well cell culture plate was removed, and 100 μl of CD3-positive cell suspension and 50 μl of diluted antibody were added, and the volume was finally refilled to 200 μl. After 72 hours of co-incubation, the cell supernatant was collected and the IFN-γ content was measured using an ELISA kit. The results, as shown in Figure 8, showed that antibodies PR302239, PR302259, PR302927, PR302951, PR302951-1, and PR302264-2 had a good activation effect in the mixed lymphocyte reaction assay.

[0258] Example 16 Pharmacodynamics of Antibodies in Vivo

[0259] This study investigated the antitumor activity of anti-human ILT4 antibodies using the SU8686 mouse tumor model. The pharmacodynamics of PR302951-1 and PR302264-2 antibodies administered alone (20 mg / kg) in the SU8686 mouse model were investigated. Human pancreatic cancer SU8686 cells (ATCC) were subcutaneously inoculated into female hHSC-NOG-EXL humanized mice (Vitamin B). Antibody treatment was as follows: After tumor cell inoculation, the tumors were allowed to grow to 100 mm in size. 3 The first administration was started at 3:10 p.m. on the 3rd, 7th, 10th, 14th, and 17th days, and the corresponding antibodies were intraperitoneally injected into each group of mice. The tumor volume was measured at the same time, and the mice were euthanized. As shown in Figure 9, the anti-human ILT4 antibodies PR302951-1 and PR302264-2 of the present application had a significant inhibitory effect on tumor growth compared with the negative control, among which the PR302264-2 antibody had a better inhibitory effect on tumors than the control antibodies PR001795 (Merck: US20180298096) and PR304683 (NGM: WO2021127200).

[0260] Other sequences involved in the embodiment are shown in Table 15 below:

[0261] Table 15

Claims

1. An anti-ILT4 antibody comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 1, SEQ ID NO: 12, SEQ ID NO: 18, SEQ ID NO: 23, SEQ ID NO: 32, SEQ ID NO: 36, SEQ ID NO: 44, or SEQ ID NO: 52, and the HCDR2 comprises the amino acid sequence of SEQ ID NO: 8, SEQ ID NO: 13, SEQ ID NO: 2, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 19, SEQ ID NO: 24, SEQ ID NO: 27, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 41, SEQ ID NO: 45, SEQ ID NO: 50, SEQ ID NO: 53, or SEQ ID NO:

57. the amino acid sequence set forth in SEQ ID NO:3, SEQ ID NO:14, SEQ ID NO:20, SEQ ID NO:25, SEQ ID NO:28, SEQ ID NO:34, SEQ ID NO:38, SEQ ID NO:42, SEQ ID NO:46, SEQ ID NO:51, SEQ ID NO:54 or SEQ ID NO:58; The light chain variable region comprises LCDR1, LCDR2 and LCDR3, wherein the LCDR1 comprises the amino acid sequence as shown in SEQ ID NO:4, SEQ ID NO:15, SEQ ID NO:21, SEQ ID NO:29, SEQ ID NO:39 or SEQ ID NO:47, the LCDR2 comprises the amino acid sequence as shown in SEQ ID NO:5, SEQ ID NO:16, SEQ ID NO:30, SEQ ID NO:48 or SEQ ID NO:55, and the LCDR3 comprises the amino acid sequence as shown in SEQ ID NO:6, SEQ ID NO:17, SEQ ID NO:22, SEQ ID NO:26, SEQ ID NO:31, SEQ ID NO:40, SEQ ID NO:43, SEQ ID NO:49, SEQ ID NO:56 or SEQ ID NO:

59.

2. The antibody according to claim 1, wherein The heavy chain variable region comprises: HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 8, and HCDR3 with the sequence shown in SEQ ID NO: 3; HCDR1 with the sequence shown in SEQ ID NO: 12, HCDR2 with the sequence shown in SEQ ID NO: 13, and HCDR3 with the sequence shown in SEQ ID NO: 14; HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 2, and HCDR3 with the sequence shown in SEQ ID NO: 3; HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 7, and HCDR3 with the sequence shown in SEQ ID NO: 3; HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 9, and HCDR3 with the sequence shown in SEQ ID NO: 3; HCDR1 with the sequence shown in SEQ ID NO: 1, HCDR2 with the sequence shown in SEQ ID NO: 10, and HCDR3 with the sequence shown in SEQ ID NO: 3; The HCDR1 sequence is shown in SEQ ID NO: 1, the HCDR2 sequence is shown in SEQ ID NO: 11, and the HCDR3 as shown in SEQ ID NO: 3; HCDR1 with the sequence shown in SEQ ID NO: 18, HCDR2 with the sequence shown in SEQ ID NO: 19, and HCDR3 with the sequence shown in SEQ ID NO: 20; HCDR1 with the sequence shown in SEQ ID NO: 23, HCDR2 with the sequence shown in SEQ ID NO: 24, and HCDR3 with the sequence shown in SEQ ID NO: 25; HCDR1 with the sequence shown in SEQ ID NO: 23, HCDR2 with the sequence shown in SEQ ID NO: 27, and HCDR3 with the sequence shown in SEQ ID NO: 28; HCDR1 with the sequence shown in SEQ ID NO: 32, HCDR2 with the sequence shown in SEQ ID NO: 33, and HCDR3 with the sequence shown in SEQ ID NO: 34; HCDR1 with the sequence shown in SEQ ID NO: 32, HCDR2 with the sequence shown in SEQ ID NO: 35, and HCDR3 with the sequence shown in SEQ ID NO: 34; HCDR1 with the sequence shown in SEQ ID NO: 36, HCDR2 with the sequence shown in SEQ ID NO: 37, and HCDR3 with the sequence shown in SEQ ID NO: 38; HCDR1 with the sequence shown in SEQ ID NO:23, HCDR2 with the sequence shown in SEQ ID NO:41, and HCDR3 with the sequence shown in SEQ ID NO:42; HCDR1 with the sequence shown in SEQ ID NO:44, HCDR2 with the sequence shown in SEQ ID NO:45, and HCDR3 with the sequence shown in SEQ ID NO:46; HCDR1 with the sequence shown in SEQ ID NO:23, HCDR2 with the sequence shown in SEQ ID NO:50, and HCDR3 with the sequence shown in SEQ ID NO:51; HCDR1 with the sequence shown in SEQ ID NO:52, HCDR2 with the sequence shown in SEQ ID NO:53, and HCDR3 with the sequence shown in SEQ ID NO:54; Or, the HCDR1 sequence shown in SEQ ID NO: 32, the HCDR2 sequence shown in SEQ ID NO: 57, and the HCDR3 sequence shown in SEQ ID NO: 58; and / or, The light chain variable region comprises: LCDR1 as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO: 5, and LCDR3 as shown in SEQ ID NO: 6; LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 17; LCDR1 having a sequence as shown in SEQ ID NO: 21, LCDR2 having a sequence as shown in SEQ ID NO: 5, and LCDR3 having a sequence as shown in SEQ ID NO: 22; LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 26; LCDR1 having a sequence as shown in SEQ ID NO: 29, LCDR2 having a sequence as shown in SEQ ID NO: 30, and LCDR3 having a sequence as shown in SEQ ID NO: 31; LCDR1 having a sequence as shown in SEQ ID NO:39, LCDR2 having a sequence as shown in SEQ ID NO:30, and LCDR3 having a sequence as shown in SEQ ID NO:31; LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 40; LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 43; LCDR1 having a sequence as shown in SEQ ID NO:47, LCDR2 having a sequence as shown in SEQ ID NO:48, and LCDR3 having a sequence as shown in SEQ ID NO:49; LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 55, and LCDR3 having a sequence as shown in SEQ ID NO: 56; or, LCDR1 having a sequence as shown in SEQ ID NO: 15, LCDR2 having a sequence as shown in SEQ ID NO: 16, and LCDR3 having a sequence as shown in SEQ ID NO: 59; Preferably, the light chain variable region and the heavy chain variable region are selected from any one of the following: (1) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 8, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6; (2) HCDR1 with a sequence as shown in SEQ ID NO: 12, HCDR2 with a sequence as shown in SEQ ID NO: 13, and HCDR3 with a sequence as shown in SEQ ID NO: 14; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17; (3) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 2, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6; (4) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 7, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6; (5) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 9, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6; (6) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 10, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 as shown in SEQ ID NO:5 and LCDR3 as shown in SEQ ID NO:6; (7) HCDR1 with a sequence as shown in SEQ ID NO: 1, HCDR2 with a sequence as shown in SEQ ID NO: 11, and HCDR3 with a sequence as shown in SEQ ID NO: 3; and LCDR1 with a sequence as shown in SEQ ID NO: 4, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 6; (8) HCDR1 with a sequence as shown in SEQ ID NO: 18, HCDR2 with a sequence as shown in SEQ ID NO: 19, and HCDR3 with a sequence as shown in SEQ ID NO: 20; and LCDR1 with a sequence as shown in SEQ ID NO: 21, LCDR2 with a sequence as shown in SEQ ID NO: 5, and LCDR3 with a sequence as shown in SEQ ID NO: 22; (9) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 24, and HCDR3 with a sequence as shown in SEQ ID NO: 25; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 26; (10) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 27, and HCDR3 with a sequence as shown in SEQ ID NO: 28; and LCDR1 with a sequence as shown in SEQ ID NO: 29, LCDR2 with a sequence as shown in SEQ ID NO: 30, and LCDR3 with a sequence as shown in SEQ ID NO: 31; (11) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 27, and HCDR3 with a sequence as shown in SEQ ID NO: 28; and LCDR1 with a sequence as shown in SEQ ID NO: 39, LCDR2 with a sequence as shown in SEQ ID NO: 30, and LCDR3 with a sequence as shown in SEQ ID NO: 31; (12) HCDR1 with a sequence as shown in SEQ ID NO: 32, HCDR2 with a sequence as shown in SEQ ID NO: 33, and HCDR3 with a sequence as shown in SEQ ID NO: 34; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17; (13) HCDR1 with a sequence as shown in SEQ ID NO: 32, HCDR2 with a sequence as shown in SEQ ID NO: 35, and HCDR3 with a sequence as shown in SEQ ID NO: 34; and, LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 17; (14) HCDR1 with a sequence as shown in SEQ ID NO: 36, HCDR2 with a sequence as shown in SEQ ID NO: 37, and HCDR3 with a sequence as shown in SEQ ID NO: 38; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 40; (15) HCDR1 with a sequence as shown in SEQ ID NO: 23, HCDR2 with a sequence as shown in SEQ ID NO: 41, and HCDR3 with a sequence as shown in SEQ ID NO: 42; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 16, and LCDR3 with a sequence as shown in SEQ ID NO: 43; (16) HCDR1 with a sequence as shown in SEQ ID NO: 44, HCDR2 with a sequence as shown in SEQ ID NO: 45, and HCDR3 with a sequence as shown in SEQ ID NO: 46; and LCDR1 with a sequence as shown in SEQ ID NO: 47, LCDR2 with a sequence as shown in SEQ ID NO: 48, and LCDR3 with a sequence as shown in SEQ ID NO: 49; (17) HCDR1 with the sequence shown in SEQ ID NO: 23, and HCDR2 with the sequence shown in SEQ ID NO: 50 and a HCDR3 having a sequence as shown in SEQ ID NO:51; and a LCDR1 having a sequence as shown in SEQ ID NO:15, a LCDR2 having a sequence as shown in SEQ ID NO:16, and a LCDR3 having a sequence as shown in SEQ ID NO:17; (18) HCDR1 with a sequence as shown in SEQ ID NO: 52, HCDR2 with a sequence as shown in SEQ ID NO: 53, and HCDR3 with a sequence as shown in SEQ ID NO: 54; and LCDR1 with a sequence as shown in SEQ ID NO: 15, LCDR2 with a sequence as shown in SEQ ID NO: 55, and LCDR3 with a sequence as shown in SEQ ID NO: 56; (19) HCDR1 with a sequence as shown in SEQ ID NO:32, HCDR2 with a sequence as shown in SEQ ID NO:57, and HCDR3 with a sequence as shown in SEQ ID NO:58; and LCDR1 with a sequence as shown in SEQ ID NO:15, LCDR2 with a sequence as shown in SEQ ID NO:16, and LCDR3 with a sequence as shown in SEQ ID NO:

59.

3. The antibody according to claim 1 or 2, wherein The framework region of the light chain variable region is a human framework region, and / or the framework region of the heavy chain variable region is a human framework region; Preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:64, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:64, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:62; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:68, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:68, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:69, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:69; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:61, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:61, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:63, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:63, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:65, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:65, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62; The heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 66 or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 66, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 66 or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: the chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:62; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:67, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:67, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:62, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:62; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:68, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:68, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:69, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:69; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:70, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:70, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:71, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:71; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:72, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:72, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:73, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:73; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:74, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:74, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:75, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:75; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:74, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:74, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:76, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:76; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:77, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:77, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:78; The heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 79 or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 79, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO: 79 or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: the chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:78; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:80, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:80, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:81, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:81; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:82, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:82, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:83, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:83; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:84, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:84, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:85, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:85; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:86, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:86, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:78, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:78; the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:87, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:87, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:88, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:88; Alternatively, the heavy chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:60, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:60, and the light chain variable region comprises an amino acid sequence as set forth in SEQ ID NO:89, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

89.

4. The antibody according to any one of claims 1 to 3, wherein The antibody satisfies one or both of the following: (1) The antibody is a full-length antibody, Fab, Fab', F(ab')2, Fv, scFv, di-scFv, VHH or heavy chain antibody (HCAb); (2) The antibody is a monoclonal antibody or a polyclonal antibody prepared from the above-mentioned antibody.

5. The antibody according to claim 4, wherein The antibody comprises a heavy chain constant region and / or a light chain constant region; The heavy chain constant region of the antibody is derived from the heavy chain constant region of human antibody IgG1 or IgG4, and / or the light chain constant region of the antibody is derived from the κ chain of a human antibody; More preferably, the heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 93, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 93, and the light chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 91; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:99, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:99, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:98; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:90, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:90, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:91; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:92, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:92, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:91; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:94, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:94, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:91; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:95, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:95, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:91; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:96, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:96, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO:91, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:91; The heavy chain of the antibody comprises an amino acid sequence as shown in SEQ ID NO: 97 or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 97, and the antibody the light chain of the antibody comprising an amino acid sequence as set forth in SEQ ID NO:98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:98; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 100, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 100, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 101, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 102, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 102, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 101, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 101; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 103, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 103, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 104, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 104; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 105, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 105, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 104, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 104; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 106, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 106, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 107, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 107; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 108, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 108, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 109, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 109; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 110, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 110, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 111, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 111, and the light chain of the antibody comprising an amino acid sequence as set forth in SEQ ID NO:98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:98; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 112, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 112, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 113, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 113, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 114, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 114; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 115, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 115, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 116, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 116; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 117, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 117, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 118, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 118; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 119, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 119, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 118, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 118; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 120, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 120, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 121, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 121, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 98, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 98; The heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 122, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 122, and the light chain of the antibody comprising an amino acid sequence as set forth in SEQ ID NO: 123, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 123; the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 124, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 124, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 125, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 125; Alternatively, the heavy chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 126, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 126, and the light chain of the antibody comprises an amino acid sequence as set forth in SEQ ID NO: 125, or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:

125.

6. An isolated nucleic acid encoding the antibody according to any one of claims 1 to 5.

7. A recombinant expression vector, characterized in that: The recombinant expression vector comprises the isolated nucleic acid according to claim 6; preferably, the backbone of the recombinant expression vector is a plasmid, a cosmid, a phage or a viral vector, and the viral vector is preferably a retroviral vector, a lentiviral vector, an adenoviral vector or an adeno-associated viral vector.

8. A transformant, characterized in that The transformant comprises the recombinant expression vector according to claim 7; preferably, the host cell of the transformant is a prokaryotic cell or a eukaryotic cell, more preferably, the eukaryotic cell is a yeast cell or a mammalian cell; wherein the mammalian cell is, for example, a HEK293 cell or a CHO cell.

9. A method for producing an antibody, comprising culturing the transformant according to claim 8, and obtaining the antibody from the culture.

10. An antigen-binding protein derivative, characterized in that: The antigen-binding protein derivative comprises the antibody according to any one of claims 1 to 5, and a detectable labeling molecule; preferably, the detectable labeling molecule is an enzyme, a radionuclide, a fluorescent dye, a luminescent substance or biotin.

11. An antibody-drug conjugate, characterized in that: The antibody-drug conjugate comprises a cytotoxic agent or a label, and the antibody according to any one of claims 1 to 5.

12. A chimeric antigen receptor, characterized in that The chimeric antigen receptor comprises the antibody according to any one of claims 1 to 5.

13. A genetically modified cell, characterized in that The genetically modified cells comprise the chimeric antigen receptor as described in claim 12; the genetically modified cells are preferably eukaryotic cells, more preferably isolated human cells; further preferably immune cells such as T cells or NK cells.

14. A multispecific antibody comprising the antibody according to any one of claims 1 to 5; preferably, the multispecific antibody is a bispecific antibody.

15. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13 or the multispecific antibody according to claim 14, and a pharmaceutically acceptable carrier.

16. A kit comprising the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13, the multispecific antibody according to claim 14, or the pharmaceutical composition according to claim 15; Preferably, the kit further comprises (i) a device for administering the antibody, antigen binding protein derivative, antibody drug conjugate, chimeric antigen receptor, genetically modified cell or pharmaceutical composition; and / or (ii) instructions for use.

17. A medicine kit, characterized in that: The kit includes kit A and kit B: The drug kit A contains the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13, the multispecific antibody according to claim 14, or the pharmaceutical composition according to claim 15; The drug kit B contains other anti-tumor antibodies or pharmaceutical compositions comprising the other anti-tumor antibodies, and / or one or more of the group consisting of hormone preparations, targeted small molecule preparations, proteasome inhibitors, imaging agents, diagnostic agents, chemotherapeutic agents, oncolytic drugs, cytotoxic agents, cytokines, activators of co-stimulatory molecules, inhibitors of inhibitory molecules and vaccines.

18. Use of the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13, the multispecific antibody according to claim 14, the pharmaceutical composition according to claim 15, the kit according to claim 16, or the kit according to claim 17 in the preparation of a product for diagnosing, treating, and / or preventing cancer; preferably, the cancer is ILT4-positive and / or ILT2-positive cancer; more preferably, a solid cancer or a hematological cancer; The blood cancer is, for example, B-cell leukemia, lymphoma, acute myeloid leukemia, Burkitt's lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or marginal zone lymphoma; The solid cancer is, for example, head and neck squamous cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial carcinoma, diffuse large B-cell carcinoma, non-small cell lung cancer, melanoma, metastatic renal cell carcinoma, metastatic colorectal cancer, small cell lung cancer, metastatic Metastatic non-small cell lung cancer, breast cancer, lung cancer, head and neck cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, bowel cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, kidney cancer, testicular cancer, mesothelioma, glioblastoma, bile duct cancer, or pancreatic cancer.

19. A method for diagnosing, treating and / or preventing an ILT4-mediated disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of the antibody of any one of claims 1 to 5, the nucleic acid of claim 6, the recombinant vector of claim 7, the antigen-binding protein derivative of claim 10, the antibody-drug conjugate of claim 11, the chimeric antigen receptor of claim 12, the genetically modified cell of claim 13, the multispecific antibody of claim 14, the pharmaceutical composition of claim 15, the kit of claim 16, or the kit of claim 17.

20. The method according to claim 19, wherein The disease or disorder is cancer, preferably, the cancer is ILT4-positive and / or ILT2-positive cancer; more preferably, it is solid cancer or blood cancer; The blood cancer is, for example, B-cell leukemia, lymphoma, acute myeloid leukemia, Burkitt's lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, or marginal zone lymphoma; The solid cancer is, for example, head and neck squamous cell carcinoma, renal cell carcinoma, ovarian cancer, urothelial carcinoma, diffuse large B-cell carcinoma, non-small cell lung cancer, melanoma, metastatic renal cell carcinoma, metastatic colorectal cancer, small cell lung cancer, metastatic non-small cell lung cancer, breast cancer, lung cancer, head and neck cancer, colorectal cancer, prostate cancer, skin cancer, stomach cancer, intestinal cancer, cervical cancer, uterine cancer, endometrial cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, kidney cancer, testicular cancer, mesothelioma, glioblastoma, bile duct cancer, or pancreatic cancer.

21. A method for immunodetection or determination of ILT4, characterized in that: The method comprises using the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13, the multispecific antibody according to claim 14, the pharmaceutical composition according to claim 15, the kit according to claim 16 or the kit according to claim 17; preferably, the detection is for non-diagnostic purposes.

22. A combination therapy comprising administering to a patient in need thereof the antibody of any one of claims 1 to 5, the nucleic acid of claim 6, the recombinant vector of claim 7, the antigen-binding protein derivative of claim 10, the antibody-drug conjugate of claim 11, the chimeric antigen receptor of claim 12, the genetically modified cell of claim 13, the multispecific antibody of claim 14, the pharmaceutical composition of claim 15, the kit of claim 16, or the kit of claim 17, respectively. and a second therapeutic agent; the second therapeutic agent preferably comprises other anti-tumor antibodies or comprises the other anti-tumor The invention also relates to a pharmaceutical composition comprising a hormonal agent, a targeted small molecule agent, a proteasome inhibitor, an imaging agent, a diagnostic agent, a chemotherapeutic agent, an oncolytic drug, a cytotoxic agent, a cytokine, an activator of a co-stimulatory molecule, an inhibitor of an inhibitory molecule, and a vaccine.

23. A drug delivery device, characterized in that: The drug delivery device comprises the antibody according to any one of claims 1 to 5, the nucleic acid according to claim 6, the recombinant vector according to claim 7, the antigen-binding protein derivative according to claim 10, the antibody-drug conjugate according to claim 11, the chimeric antigen receptor according to claim 12, the genetically modified cell according to claim 13, the multispecific antibody according to claim 14, the pharmaceutical composition according to claim 15, the kit according to claim 16, or the kit according to claim 17; Preferably, the drug delivery device further comprises a component for containing or administering the antibody, the multispecific antibody, the antigen-binding protein derivative, the antibody-drug conjugate, the chimeric antigen receptor, the genetically modified cell, the pharmaceutical composition, the kit, or the set of kits to a subject, such as a syringe, an implantable drug delivery device, or an infusion device.

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