Pharmaceutical combination comprising antibody-drug conjugate and immune checkpoint inhibitor, and application thereof

Abstract

Disclosed are a pharmaceutical combination comprising an antibody-drug conjugate and an immune checkpoint inhibitor, and an application thereof. The pharmaceutical combination can treat cancers, especially cancers expressed by HER2 (comprising cancers with high and low HER2 expression), cancers expressed by EGFR, and cancers expressed by B7-H3. Compared to monotherapy, the pharmaceutical combination, when used for treatment, may provide a better therapeutic effect and a longer survival time.

Description

Pharmaceutical combinations comprising antibody conjugate drugs and immune checkpoint inhibitors and uses thereof

[0001] This application claims priority to Chinese patent application 2024112429914 with a filing date of 2024 / 9 / 5. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application belongs to the field of biological medicine, and specifically relates to a pharmaceutical combination comprising an antibody conjugate drug and an immune checkpoint inhibitor and uses thereof, wherein the specific antibody conjugate drug and the immune checkpoint inhibitor are administered in combination for treating diseases that can be improved by anti-tumor immune activation. BACKGROUND

[0003] The antibody conjugate drug BB-1701 consists of an anti-HER2 antibody linked to a cytotoxic payload of eribulin, a synthetic analog of the marine-derived macrolide, halichondrin B. The anti-HER2 antibody sequence used in BB-1701 is identical to that of trastuzumab, which is produced in CHO cells by mammalian cell culture and purified by a process that includes three chromatography steps and a dedicated viral clearance step. The conjugation of the eribulin payload to the antibody is achieved through a maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl linker. The average drug antibody ratio (DAR) of each BB-1701 molecule is approximately 4, as determined by hydrophobic interaction chromatography (HIC).

[0004] BB-1701 has potent cytotoxic and tumor inhibitory activity against a variety of cancer types, including breast, lung, and gastric cancers, where HER2 expression levels vary widely. Bystander killing has been demonstrated to be one of the potential MOAs of BB-1701. ADCs containing eribulin exhibit higher in vitro cytotoxicity in HER2-low cancer cell lines compared to HER2-targeting ADCs with DM1 and Dxd payloads, as well as controllable safety. BB-1701 also effectively inhibited tumors in models that were resistant to ADCs containing DM1 or Dxd.

[0005] In a Phase la study (NCT 04257110) enrolling 29 patients, BB-1701 was generally well tolerated at dose levels up to 2.6 mg / kg and showed promising antitumor activity in patients with HER2 overexpressing solid tumors. In a cohort expansion Phase lb study, 40 patients with HER2 low breast cancer were enrolled at four dose levels (1.0-1.6 mg / kg Q3W), BB-1701 showed promising preliminary antitumor activity in HER2 low breast cancer, including patients who had received prior anti-HER2 ADCs, and manageable safety.

[0006] BB-1705 is a novel antibody conjugate drug (ADC) designed to target EGFR-expressing tumors while minimizing toxicity to normal tissues. The ADC combines an affinity-optimized anti-EGFR antibody with the cytotoxic payload eribulin. Conjugation of the eribulin payload to the EGFR-targeting antibody is achieved via a maleimide-PEG2-valine-citrulline-p-aminobenzyl carbamoyl linker. The DAR of each BB-1705 molecule is 2-4 according to HIC determination. In vitro studies have shown that BB-1705 has potent selective cytotoxicity against EGFR-expressing cancer cells with minimal impact on normal human keratinocytes. BB-1705 also exhibits a significant bystander effect, killing EGFR low / no cells that are co-cultured with EGFR high cells. In vivo, BB-1705 has shown robust antitumor activity in multiple xenograft models. Pharmacokinetic and safety profiles in cynomolgus monkeys show a safe dose up to 12 mg / kg. These preclinical data suggest that BB-1705 can provide a better EGFR-targeted therapy for cancers with medium to high EGFR expression levels. A clinical trial evaluating BB-1705 is currently ongoing (NCT05217693).

[0007] B7-H3 (also known as CD276) is low in most human normal tissues but is overexpressed in a variety of cancers, including bladder, breast, cervical, colorectal, esophageal, glioma, kidney, liver, lung, ovarian, pancreatic, prostate, intrahepatic bile duct, liver, oral squamous cell, endometrial, squamous cell, and gastric, glioma, and melanoma. Overexpression of B7-H3 in tumor cells and tumor ECs (TECs) makes it an attractive target for developing therapeutics that simultaneously destroy both cell types. To date, several CD276-targeting ADCs, such as DS-7300 (Phase III clinical trial), MGC-018 (Phase II / III clinical trial), have been developed and tested in clinical trials as immunotherapeutics. SUMMARY

[0008] The object of the present application is to provide a pharmaceutical combination and a treatment method that exerts an excellent anti-tumor effect and has good safety by administering an antibody conjugate drug and an immune checkpoint inhibitor in combination.

[0009] The present application solves the above technical problems by the following technical solutions.

[0010] The first aspect of the present application provides a pharmaceutical combination comprising an antibody conjugate drug and an immune checkpoint inhibitor; the antibody conjugate drug has the following structure:

[0011] Ab-Mal-PEG2-Val-Cit-PAB-D;

[0012] Wherein, the Ab is an antibody, the antibody targets HER2, EGFR or B7-H3; the D is eribulin (CAS: 253128-41-5).

[0013] In the present application, the structure of the antibody conjugate drug is as follows:

[0014] In the present application, the structure of Mal-PEG2-Val-Cit-PAB is as follows:

[0015] In some embodiments, the antibody conjugate drug satisfies one or more of the following conditions:

[0016] (1) the antibody is an IgG antibody, for example, IgG1;

[0017] (2) when the antibody targets HER2, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NO: 1, 2, 3, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NO: 4, 5, 6, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NO: 11, 12, 13, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NO: 14, 15, 16, respectively;

[0018] (3) when the antibody targets EGFR, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 21, 22, 23, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 24, 25, 26, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 31, 32, 33, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 34, 35, 36, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 41, 42, 43, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 44, 45, 46, respectively;

[0019] (4) when the antibody targets B7-H3, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 52, 53, 54, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 55, 56, 57, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 62, 63, 64, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 65, 66, 67, respectively;

[0020] (5) the antibody conjugate drug comprises, on average, 2-8 eribulin per molecule of the antibody; preferably 2-4.

[0021] In some embodiments, the antibody is an IgG antibody, e.g., an IgGl antibody.

[0022] In some embodiments, when the antibody targets HER2, the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 4, 5, 6, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 11, 12, 13, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 14, 15, 16, respectively.

[0023] In some embodiments, when the antibody targets EGFR, the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 21, 22, 23, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 24, 25, 26, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 31, 32, 33, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 34, 35, 36, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 41, 42, 43, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 44, 45, 46, respectively.

[0024] In some embodiments, when the antibody targets B7-H3, the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 52, 53, 54, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 55, 56, 57, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 62, 63, 64, respectively, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 65, 66, 67, respectively.

[0025] In some embodiments, the antibody conjugate drug comprises an average number of 2-8 eribulin per molecule of the antibody conjugate drug; preferably 2-4.

[0026] In some preferred embodiments, the antibody conjugate drug comprises an average number of 2-8, 3-8, 4-8, 5-8, 6-8, or 7-8 eribulin per molecule of the antibody conjugate drug.

[0027] In the present application, the average value of drug-antibody ratio (DAR) in the antibody conjugate drug is any value from 2-8, for example, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8.

[0028] In the present application, the CDR regions adopt Kabat numbering and definition.

[0029] In the present application, “comprising”, “including” or “having” includes “consisting of”.

[0030] In some embodiments, the antibody comprises a full-length antibody, Fab, Fab’, Fv, F(ab’)2, or scFv.

[0031] In some embodiments, the antibody comprises:

[0032] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 7 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 7, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 9 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 9; or,

[0033] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 17 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 17, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 19 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 19; or,

[0034] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 27 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 27, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 29 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 29; or,

[0035] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 37 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 37, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 39 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 39; or,

[0036] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 47 or that has at least 85% sequence identity to SEQ ID NO: 47, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 49 or that has at least 85% sequence identity to SEQ ID NO: 49; or,

[0037] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 58 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 58, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 60 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 60; or,

[0038] a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 68 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 70 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 70.

[0039] In some preferred embodiments, the antibody comprises:

[0040] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 8 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 8, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10 or that has at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 10; or,

[0041] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 18 or that has at least 85% sequence identity to SEQ ID NO: 18, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 20 or that has at least 85% sequence identity to SEQ ID NO: 20; or,

[0042] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 28 or that has at least 85% sequence identity to SEQ ID NO: 28, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 30 or that has at least 85% sequence identity to SEQ ID NO: 30; or,

[0043] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 38 or 51 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 51, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 40 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 40; or,

[0044] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 48 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 48, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 50 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 50; or,

[0045] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 59 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 59, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 61 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 61; or,

[0046] a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 69, 72, or 73 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 69, 72, or 73, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 71 or having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.9% sequence identity to SEQ ID NO: 71.

[0047] In some embodiments, the antibody targeting HER2 is Trastuzumab or Pertuzumab.

[0048] In some embodiments, the antibody targeting EGFR is Panitumumab, BB0500-2f, BB0500-2g, or BB0500-2n.

[0049] In some embodiments, the antibody targeting B7-H3 is Infinatamab, 27B4H4L3, BH73, or BH73-1.

[0050] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of monospecific antibodies, bispecific antibodies, and recombinant proteins thereof targeting immune checkpoints, multispecific antibodies, and recombinant proteins thereof, antigen-binding fragments of the aforementioned antibodies, and recombinant proteins thereof.

[0051] In some preferred embodiments, the immune checkpoint is PD-1 / PD-L1.

[0052] In some preferred embodiments, the immune checkpoint inhibitor is an immune checkpoint pathway antagonist, such as an antibody or an antigen-binding fragment thereof.

[0053] In some preferred embodiments, the recombinant protein comprises a second antigen or an antigen ligand specifically binding to a second antigen; the antigen ligand is preferably an antibody or an antigen-binding fragment thereof.

[0054] In some embodiments, the immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor.

[0055] In some embodiments, the immune checkpoint inhibitor comprises a PD-1 / PD-L1 inhibitor.

[0056] In the present application, when the immune checkpoint inhibitor is a PD-1 / PD-L1 inhibitor, the immunosuppressive signal is inactivated by inhibiting the PD-1 / PD-L1 axis, thereby improving the antitumor effect of the antibody-conjugated drug.

[0057] In some embodiments, the immune checkpoint inhibitor is an immune checkpoint pathway antagonist, such as an antibody.

[0058] In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0059] In the present application, the anti-PD-1 antibody or anti-PD-L1 antibody can be BioXCell J43 clone, Navulizumab, Sintilimab, Pembrolizumab, Atezolizuma, Durvalumab, Avelumab, Cemiplimab, Dostarlimab, Toripalimab, or Tislelizumab.

[0060] In some specific embodiments, the second antigen is IL-2 or a truncation thereof.

[0061] In some specific embodiments, the second antigen is VEGF, and the antigen ligand is an anti-VEGF antibody or an antigen-binding fragment thereof.

[0062] In some embodiments, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier and / or excipient.

[0063] In some embodiments, the antibody conjugate drug and the immune checkpoint inhibitor are in a single formulation, or are in separate formulations comprising the antibody conjugate drug and the immune checkpoint inhibitor, respectively.

[0064] In some embodiments, the pharmaceutical combination further comprises a therapeutic agent, which is preferably a chemotherapy agent or a radiotherapy agent.

[0065] A second aspect of the present application provides a kit comprising the pharmaceutical combination of the first aspect.

[0066] A third aspect of the present application provides a kit-of-parts comprising a kit A and a kit B;

[0067] wherein the kit A comprises an antibody conjugate drug, and the kit B comprises an immune checkpoint inhibitor;

[0068] The antibody conjugate drug and the immune checkpoint inhibitor are as described in the first aspect.

[0069] In some embodiments, the kit A and the kit B are administered simultaneously or separately.

[0070] In some embodiments, the kit-of-parts further comprises a kit C comprising a further therapeutic agent, such as a chemotherapy agent or a radiotherapy agent.

[0071] The fourth aspect of the present application provides use of the pharmaceutical combination according to the first aspect, the kit according to the second aspect, or the kit of parts according to the third aspect in the preparation of a medicament for treating a tumor.

[0072] In some embodiments, the tumor is a tumor with abnormal expression of HER2, EGFR, or B7-H3.

[0073] The fifth aspect of the present application provides a method of treating a subject with cancer, the method comprising administering to a subject in need thereof an effective amount of the pharmaceutical combination according to the first aspect, the kit according to the second aspect, or the kit of parts according to the third aspect.

[0074] In some embodiments, the subject has a tumor with high expression of HER2 or a tumor with low expression of HER2.

[0075] In some embodiments, the subject has a tumor with expression of EGFR.

[0076] In some embodiments, the subject has a tumor with expression of B7-H3.

[0077] The sixth aspect of the present application provides the pharmaceutical combination according to the first aspect, the kit according to the second aspect, or the kit of parts according to the third aspect for use in treating a tumor.

[0078] The seventh aspect of the present application provides an antibody conjugate drug for use in treating a tumor, wherein the antibody conjugate drug is administered in combination with an immune checkpoint inhibitor.

[0079] The antibody conjugate drug and the immune checkpoint inhibitor are as described above.

[0080] The eighth aspect of the present application provides an immune checkpoint inhibitor for use in treating a tumor, wherein the immune checkpoint inhibitor is administered in combination with an antibody conjugate drug.

[0081] The antibody conjugate drug and the immune checkpoint inhibitor are as described above.

[0082] The ninth aspect of the present application provides an antibody conjugate drug and an immune checkpoint inhibitor for use in treating a tumor; the antibody conjugate drug and the immune checkpoint inhibitor are as described above.

[0083] The tenth aspect of the present application provides a medicament comprising an antibody conjugate drug, wherein the medicament is administered in combination with an immune checkpoint inhibitor for treating a tumor.

[0084] The antibody conjugate drug and the immune checkpoint inhibitor are as described above.

[0085] The eleventh aspect of the present application provides a medicament comprising an immune checkpoint inhibitor, wherein the medicament is administered in combination with an antibody-drug conjugate for treating a tumor.

[0086] The antibody-drug conjugate and the immune checkpoint inhibitor are as described above.

[0087] The twelfth aspect of the present application provides a use of an antibody-drug conjugate in the preparation of a medicament for treating a tumor, wherein the medicament comprises instructions for administering the antibody-drug conjugate in combination with an immune checkpoint inhibitor.

[0088] The antibody-drug conjugate and the immune checkpoint inhibitor are as described above.

[0089] The thirteenth aspect of the present application provides a use of an immune checkpoint inhibitor in the preparation of a medicament for treating a tumor, wherein the medicament comprises instructions for administering the immune checkpoint inhibitor in combination with an antibody-drug conjugate.

[0090] The antibody-drug conjugate and the immune checkpoint inhibitor are as described above.

[0091] The fourteenth aspect of the present application provides a use of an antibody-drug conjugate and an immune checkpoint inhibitor in treating a tumor, wherein the treating a tumor comprises administering the antibody-drug conjugate and the immune checkpoint inhibitor simultaneously or separately.

[0092] The antibody-drug conjugate and the immune checkpoint inhibitor are as described above.

[0093] In the fourth to fourteenth aspects of the present application, the tumor is a tumor with abnormal expression of HER2, EGFR, or B7-H3.

[0094] In some embodiments, the tumor with abnormal expression of HER2 includes, but is not limited to, breast cancer, gastric cancer, gastroesophageal junction cancer, urothelial cancer, parotid cancer, non-small cell lung cancer, colorectal cancer, and ovarian cancer.

[0095] In some embodiments, the tumor with abnormal expression of EGFR includes, but is not limited to, non-small cell lung cancer, epidermoid carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, head and neck cancer, glioblastoma, and nasopharyngeal carcinoma.

[0096] In some embodiments, the tumor with abnormal expression of B7-H3 includes, but is not limited to, head and neck cancer, skin cancer, colon cancer, kidney cancer, glioblastoma, glioma, neuroblastoma, sarcoma, thyroid cancer, mesothelioma, melanoma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, and bladder cancer.

[0097] In the present application, "abnormal expression" of a protein refers to an increase or decrease in the expression of the protein in diseased cells relative to normal cells.

[0098] In the present application, "high expression" of a protein refers to an increase in the expression of the protein in diseased cells relative to normal cells.

[0099] In the present application, "low expression" of a protein refers to a decrease in the expression of the protein in diseased cells relative to normal cells.

[0100] On the basis of common sense in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e., to obtain each preferred example of the present application.

[0101] The positive progress effect of the present application is that:

[0102] The pharmaceutical combination of the present application can treat cancer, in particular HER2-expressing cancer (including HER2 high-expression and low-expression cancer), EGFR-expressing cancer, and B7-H3-expressing cancer. Compared with monotherapy, treatment with the pharmaceutical combination of the present application can provide better therapeutic effect and longer survival time. BRIEF DESCRIPTION OF DRAWINGS

[0103] FIGS. 1A-1D are characterizations of MC38-hHer2, MC38-hEGFR, and MC38-hB7-H3 cell lines. FIG. 1A: Flow cytometry analysis of HER2 expression. FIG. 1B: Cytotoxicity assay of BB-1701 on MC38-hHER2 cells (left panel) and cytotoxicity assay of eribulin on parental MC38 cells (right panel). FIG. 1C: Flow cytometry analysis of EGFR expression. FIG. 1D: Flow cytometry analysis of B7-H3 expression.

[0104] FIG. 2 shows that HER2-ADC treatment increases tumor cell surface PD-L1 expression. MC38-hHER2 cells were exposed to different doses of BB-1701 at different time points, and cell surface PD-L1 expression was measured as mean fluorescence intensity (MFI) by flow cytometry.

[0105] FIG. 3 is a tumor volume measurement in MC38-HER2 syngeneic model. Treatment with BB-1701 (20 mg / kg) and two doses (1 mg / kg and 3 mg / kg) of anti-mouse PD-1 and combination of BB-1701 and low dose anti-PD-1 at 1 mg / kg; each point represents the mean and standard error.

[0106] FIG. 4 is a survival curve of treated MC38-HER2 syngeneic model in the study, showing the effect of prolonged life of combined HER2-ADC and immune checkpoint inhibitors. *: P < 0.05; ns, not significant.

[0107] Figure 5 is a plot of tumor volume measurements in the MC38-EGFR syngeneic model. Treatment with 1 mg / kg of anti-mouse PD-1 antibody and BB-1705 in combination with anti-PD-1 antibody; each point represents the mean and standard error.

[0108] Figure 6 is a plot of tumor volume measurements in the MC38-hB7H3 syngeneic model. Treatment with 2 mg / kg of anti-mouse PD-1 antibody and BB-1712 in combination with anti-PD-1 antibody; each point represents the mean and standard error. DETAILED DESCRIPTION

[0109] The application is further illustrated by the following examples which in no way should be construed as limiting the parameters of the application. The experimental methods in the following examples, where no specific conditions are indicated, were carried out in accordance with standard procedures and conditions, or as selected by the manufacturer's instructions.

[0110] TERMINOLOGY

[0111] The practice of the present application will employ, unless otherwise indicated, conventional methods of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art.

[0112] The abbreviations for the amino acid residues are those used in the art to designate one of the 20 commonly occurring L-amino acids. As used herein, including the claims, the singular forms "a", "an" and "the" include the corresponding plural forms unless the context clearly dictates otherwise.

[0113] The term "antibody" refers to any form of antibody having the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to, monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies and camelized single domain antibodies.

[0114] The term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that can be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of antibodies directed against a variety of epitopes (or having specificity for different epitopes). The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0115] The term "CDR" refers to the complementarity determining region within the variable sequence of an antibody. There are three CDRs in each variable region of the heavy and light chains, which are designated HCDR1, HCDR2, and HCDR3 or LCDR1, LCDR2, and LCDR3 for each heavy and light chain variable region. The precise amino acid sequence boundaries of the variable region CDRs of the antibodies of the present application can be determined using any of a number of well-known schemes, including Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loops, Kabat based on the variability of antibody sequences, AbM (University of Bath), Contact (University College London), the international ImMunoGeneTics database (IMGT), and North CDR definition based on affinity propagation clustering with a large number of crystal structures. The CDRs of the antibodies of the present application can be determined by one of skill in the art to determine the boundaries according to any of the schemes in the art (e.g., different assignment systems or combinations).

[0116] In the present application, the term "antibody drug conjugate" generally refers to an antibody linked to a cytotoxic drug with biological activity through a stable linker. In the present application, "antibody drug conjugate" and "antibody conjugated drug" can be antibody-drug conjugate (ADC), which refers to a monoclonal antibody or antibody fragment linked to a cytotoxic drug with biological activity through a stable linker. In some embodiments, the linker is Mal-PEG2-Val-Cit-PAB. In some embodiments, the cytotoxic drug is eribulin.

[0117] In the present application, the terms "DAR", "drug-antibody ratio", "drug-antibody ratio" and "drug-antibody ratio" are used interchangeably. DAR can be used to characterize ADC, which refers to the amount of load (e.g., eribulin) coupled to each antibody in a molecule of ADC. The average DAR value of ADC is calculated as follows: the DAR of different components is qualitatively determined according to the mass number, the DAR value distribution information of ADC drug is obtained, and the average DAR value is calculated according to the mass spectrum intensity of different DAR value components.

[0118] In some embodiments of the present application, the antibody conjugated drug targeting HER2 is BB-1701, which is a conjugate of Trastuzumab protein sequence and eribulin.

[0119] In some embodiments of the present application, the antibody drug conjugate targeting EGFR is BB-1705, which is a conjugate of BB0500-2n and eribulin (its sequence and preparation are described in WO2022 / 105878A1).

[0120] In some embodiments of the present application, the antibody drug conjugate targeting B7-H3 is BB-1712, which is a conjugate of BH73-1 and eribulin (its preparation is described in WO2022 / 105879A1).

[0121] BB-1712 is a novel ADC designed to target tumors expressing B7-H3. BB-1712 conjugates the anti-B7-H3 antibody with the cytotoxic payload eribulin through a maleimide-PEG2-valine-citrulline-p-aminobenzyl carbamoyl linker. The inventors evaluated the anti-tumor potential of BB-1712, which showed superior anti-tumor efficacy in multiple xenograft tumor models, including human colon cancer HT-29 cells, glioma cancer U87MG cells, breast cancer BT-474 cells, and skin cancer A431 cells established in nude mice.

[0122] The term "pharmaceutically acceptable carrier" refers to a nontoxic component of a pharmaceutical formulation or composition other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. The pharmaceutically acceptable carrier includes, but is not limited to, physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, surfactants, thickening or emulsifying agents, solid binders, dispersion or suspension aids, solubilizers, colorants, flavoring agents, disintegrating agents, lubricants, sweeteners, preservatives, isotonic agents, and the like. The selection of a suitable carrier is within the knowledge of those skilled in the art.

[0123] The term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc.

[0124] "Therapeutically effective amount," "therapeutically effective dose," and "effective amount" refer to the amount of a pharmaceutical combination of the present application, alone or in combination with other therapeutic agents, which when administered to a cell, tissue, or subject, is effective to prevent or ameliorate the symptoms of, or the development of, one or more diseases or conditions. Therapeutically effective dose also refers to the amount of an ADC, or an antibody or antigen-binding fragment thereof, that is sufficient to result in amelioration of symptoms, e.g., an amount that treats, cures, prevents or ameliorates the relevant medical condition or increases the rate of treatment, cure, prevention or amelioration of such condition. When administered to an individual, a therapeutically effective dose refers only to the administered active ingredient. When administered in combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or concurrently. An effective amount of a therapeutic agent will result in an improvement of at least 10%, typically at least 20%, preferably at least about 30%, more preferably at least 40%, and most preferably at least 50% in a diagnostic standard or parameter.

[0125] The term "cancer" is used herein to refer to a group of cells that exhibit an abnormally high level of proliferation and growth. The cancer can be benign (also known as a benign tumor), premalignant, or malignant. The cancer cells can be solid cancer cells or leukemia cancer cells. The term "tumor" as used herein refers to one or more cells comprising a cancer. The term "tumor growth" is used herein to refer to the proliferation or growth of one or more cells comprising a cancer, which results in a corresponding increase in the size or extent of the cancer.

[0126] In administering a pharmaceutical combination, kit, or kit-of-parts to a subject, dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic response). A single bolus or in divided doses can be used depending on the subject, disease being treated, and the like. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated. Each unit contains a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Sustained-release formulations can be used where less frequent dosing is required, in which case less frequent dosing is required.

[0127] The pharmaceutical combination, kit or set can be suitable for intravenous, intramuscular, subcutaneous, parenteral, epicutaneous and other routes of administration, or prepared into a formulation form suitable for the above-mentioned routes of administration. Depending on the route of administration, the active ingredients can be coated with a material or loaded in a material or structure to protect them from the action of acids and other natural conditions that can inactivate them. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and sternal injection and infusion. Alternatively, the compositions of the present application can be administered by non-parenteral routes, such as topical, epicutaneous or mucosal routes of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.

[0128] Example 1: Anti-HER2 ADC Anti-tumor Experiments

[0129] MC38-hHER2 cells were prepared by transfecting human HER2 gene into mouse colon cancer cell line MC38 using lentiviral vector. These cells express human HER2 protein on their cell membrane (Fig. 1A and Fig. 1B), and the IC 50 was 178.8 nM. The conjugates of each antibody with eribulin were prepared according to the methods described in WO2022 / 105879A1 and WO2022 / 105878A1. BB-1701 treatment induced PD-L1 expression on the surface of MC38-hHER2 cells in vitro, which was measured using flow cytometry. PD-L1 induction was dose- and time-dependent (Fig. 2). Tumor volumes of mice subcutaneously transplanted with MC38-hHER2 cells were measured for groups using BB-1701 or anti-PD-1 antibody (clone J43, BioXCell) alone or in combination. MC38-hHER2 cells were suspended in normal saline and injected subcutaneously (6.0 x 10 5 C57BL / 6 mice (female, 7 weeks old) on the right side. The mice were randomly grouped (5 mice / group), and dosing was performed when the tumor volume reached 200 mm 3 BB-1701 was administered intravenously into the tail vein at a dose of 20 mg / kg once on day 0. Anti-PD-1 antibody (clone J43, BioXCell) was injected intravenously into the tail vein at a dose of 1.0 mg / kg or 3 mg / kg for a total of 6 times. The combination treatment group was administered BB-1701 at a dose of 20 mg / kg and anti-PD-1 antibody at a dose of 1 mg / kg.

[0130] As shown in Figure 3, at very high dose levels (20 mg / kg), BB-1701 alone resulted in a small reduction in tumor growth; anti-PD-1 antibody alone had a dose-dependent effect on reducing tumor growth. However, combination therapy of high dose BB-1701 and low dose PD-1 resulted in a reduction in tumor growth similar to that seen with anti-PD-1 antibody alone at high dose levels (3 mg / kg) (Figure 3). These results suggest that anti-PD-1 antibody can enhance the anti-tumor activity of BB-1701.

[0131] Example 2: Prolonged survival

[0132] Mice in Example 1 were sacrificed when they reached a tumor volume of about 2000 mm 3 or a 20% loss in body weight. These criteria were also used as endpoints for survival analysis. Notably, prolonged survival was observed in the group treated with BB-1701 (20 mg / kg) in combination with anti-PD-1 (1 mg / kg) and in the high dose anti-PD-1 group (3 mg / kg). However, neither BB-1701 monotherapy (20 mg / kg) nor low dose anti-PD-1 (1 mg / kg) monotherapy showed this survival benefit (Figure 4). BB-1701 and 1 mg / kg anti-PD-1 combination therapy was comparable to high dose anti-PD-1 (3 mg / kg) and superior to BB-1701 monotherapy. These results suggest that there is a synergistic survival benefit when BB-1701 is dosed concurrently with an immune checkpoint inhibitor.

[0133] Example 3: Anti-EGFR ADC anti-tumor experiment

[0134] MC38-hEGFR cells were prepared by transfecting human EGFR gene into mouse colon cancer cell line MC38 using lentiviral vector. These cells express human EGFR protein on their cell membrane (Figure 1C and Figure 1D). MC38-hEGFR cells were suspended in normal saline and injected subcutaneously (2.0 x 10 5 cells / mouse) into the right side of C57BL / 6 mice (female, 7 weeks old), and the tumor volume of the mice subcutaneously transplanted with MC38-hEGFR cells was measured. When the tumor volume reached about 200 mm3, the mice were randomly divided into groups (7 mice / group) for administration. BB-1705 was administered at a dose of 20 mg / kg by tail vein injection, and anti-PD-1 antibody (clone J43, BioXCell) was administered at a dose of 1.0 mg / kg by intraperitoneal injection, twice a week for a total of 5 times. In the combination therapy group, BB-1705 was administered at a dose of 20 mg / kg, and anti-PD-1 antibody was administered at a dose of 1 mg / kg, twice a week for a total of 5 times.

[0135] As shown in FIG. 5, at a very high dose level (20 mg / kg), both BB-1705 alone and anti-PD-1 antibody alone resulted in a small decrease in tumor growth; however, the combination treatment of high-dose BB-1712 and anti-PD-1 antibody resulted in a significant decrease in tumor growth, which indicates that anti-PD-1 antibody can enhance the anti-tumor activity of BB-1705.

[0136] Example 4: Anti-B7-H3 ADC Anti-tumor Experiment

[0137] MC38-hB7H3 cells were prepared by transfecting a human B7H3 gene into a mouse colon cancer cell line MC38 using a lentivirus vector. These cells express human B7H3 protein on their cell membranes. The MC38-hB7H3 cells were suspended in physiological saline and subcutaneously injected (2.0 x 105 cells / mouse) into the right side of C57BL / 6 mice (female, 7 weeks old), and the tumor volume of the mice subcutaneously transplanted with MC38-hB7H3 cells was measured. When the tumor volume reached about 200 mm3, the mice were randomly divided into groups (8 mice / group) for administration. In the single administration group, BB-1712 was administered at a dose of 20 mg / kg, and tail vein injection was performed once on Day 0 and Day 6. Anti-PD-1 antibody (clone J43, BioXCell) was administered at a dose of 2.0 mg / kg, and intraperitoneal injection was performed twice a week for a total of 6 times. In the combination treatment group, BB-1712 was administered at a dose of 20 mg / kg, and tail vein injection was performed once on Day 0 and Day 6. Anti-PD-1 antibody (clone J43, BioXCell) was administered at a dose of 2 mg / kg, and intraperitoneal injection was performed twice a week for a total of 6 times.

[0138] As shown in FIG. 6, at a very high dose level (20 mg / kg), both BB-1712 alone and PBS resulted in a similar trend in tumor growth, and anti-PD-1 antibody alone resulted in a small decrease in tumor growth; however, the combination treatment of high-dose BB-1712 and anti-PD-1 antibody resulted in a significant decrease in tumor growth, which indicates that anti-PD-1 antibody can enhance the anti-tumor activity of BB-1712.

[0139] From the above experimental results, the antibody-eribulin conjugate of the present application exhibits a very excellent anti-tumor effect by being administered in combination with an immune checkpoint inhibitor. In addition, the antibody conjugate drug of the present application was proven to have an anti-tumor immune activation effect. Therefore, the combination of the antibody drug conjugate and the immune checkpoint inhibitor can provide a pharmaceutical composition and a treatment method superior to monotherapy in terms of anti-tumor effect.

[0140] The sequences used in the present application are as follows:

Claims

1. A pharmaceutical combination, characterized in that, The pharmaceutical combination comprises an antibody conjugate drug and an immune checkpoint inhibitor; the antibody conjugate drug has the following structure: Ab-Mal-PEG2-Val-Cit-PAB-D; wherein the Ab is an antibody targeting HER2, EGFR or B7-H3; and the D is eribulin (CAS: 253128-41-5).

2. The pharmaceutical combination of claim 1, wherein, The antibody conjugate drug satisfies one or more of the following conditions: (1) the antibody is an IgG antibody, for example, IgG1; (2) when the antibody targets HER2, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 1, 2, 3, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 4, 5, 6, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 11, 12, 13, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 14, 15, 16, respectively; (3) when the antibody targets EGFR, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 21, 22, 23, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 24, 25, 26, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 31, 32, 33, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 34, 35, 36, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having the amino acid sequences shown in SEQ ID NOs: 41, 42, 43, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having the amino acid sequences shown in SEQ ID NOs: 44, 45, 46, respectively; (4) when the antibody targets B7-H3, the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 52, 53, 54, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 55, 56, 57, respectively; or the antibody has a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 of the amino acid sequences set forth in SEQ ID NOs: 62, 63, 64, respectively, and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 of the amino acid sequences set forth in SEQ ID NOs: 65, 66, 67, respectively; (5) the antibody conjugate drug comprises, per molecule of the antibody, an average number of eribulin of 2-8; preferably 2-4; (6) the antibody comprises a full-length antibody, a Fab, a Fab', a Fv, a F(ab')2, or a scFv.

3. The pharmaceutical combination of claim 1 or 2, wherein the antibody comprises: a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 7 or having at least 85% sequence identity to SEQ ID NO: 7, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 9 or having at least 85% sequence identity to SEQ ID NO: 9; or, a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 17 or having at least 85% sequence identity to SEQ ID NO: 17, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 19 or having at least 85% sequence identity to SEQ ID NO: 19; or, a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 27 or having at least 85% sequence identity to SEQ ID NO: 27, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 29 or having at least 85% sequence identity to SEQ ID NO: 29; or, a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 37 or having at least 85% sequence identity to SEQ ID NO: 37, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 39 or having at least 85% sequence identity to SEQ ID NO: 39; or, a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO: 47 or having at least 85% sequence identity to SEQ ID NO: 47, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO: 49 or having at least 85% sequence identity to SEQ ID NO: 49; or, a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 68, or that has at least 85% sequence identity to SEQ ID NO: 68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 70, or that has at least 85% sequence identity to SEQ ID NO: 70; or, a heavy chain variable region having an amino acid sequence as set forth in SEQ ID NO: 68, or that has at least 85% sequence identity to SEQ ID NO: 68, and a light chain variable region having an amino acid sequence as set forth in SEQ ID NO: 70, or that has at least 85% sequence identity to SEQ ID NO: 70; or, Preferably, the antibody comprises: a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 8, or that has at least 85% sequence identity to SEQ ID NO: 8, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 10, or that has at least 85% sequence identity to SEQ ID NO: 10; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 18, or that has at least 85% sequence identity to SEQ ID NO: 18, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 20, or that has at least 85% sequence identity to SEQ ID NO: 20; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 28, or that has at least 85% sequence identity to SEQ ID NO: 28, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 30, or that has at least 85% sequence identity to SEQ ID NO: 30; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 38 or 51, or that has at least 85% sequence identity to SEQ ID NO: 51, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 40, or that has at least 85% sequence identity to SEQ ID NO: 40; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 48, or that has at least 85% sequence identity to SEQ ID NO: 48, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 50, or that has at least 85% sequence identity to SEQ ID NO: 50; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 59, or that has at least 85% sequence identity to SEQ ID NO: 59, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 61, or that has at least 85% sequence identity to SEQ ID NO: 61; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 59, or that has at least 85% sequence identity to SEQ ID NO: 59, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 61, or that has at least 85% sequence identity to SEQ ID NO: 61; or, a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 69, 72, or 73, or having at least 85% sequence identity to SEQ ID NO: 69, 72, or 73, and a light chain having an amino acid sequence as set forth in SEQ ID NO: 71, or having at least 85% sequence identity to SEQ ID NO:

71.

4. The pharmaceutical combination according to any one of claims 1 to 3, wherein the immune checkpoint inhibitor is selected from the group consisting of a monospecific antibody, a bispecific antibody, and a recombinant protein thereof, targeting an immune checkpoint, a multispecific antibody, and a recombinant protein thereof, an antigen binding fragment of the aforementioned antibody and the recombinant protein thereof; preferably, the immune checkpoint is PD-1 / PD-L1; and / or, the immune checkpoint inhibitor inactivates the immunosuppressive signal by inhibiting the PD-1 / PD-L1 axis, thereby improving the antitumor effect of the antibody conjugate drug; and / or, the immune checkpoint inhibitor is an immune checkpoint pathway antagonist, such as an antibody or an antigen binding fragment thereof; and / or, the recombinant protein comprises a second antigen or an antigen ligand specifically binding to the second antigen; the antigen ligand is preferably an antibody or an antigen binding fragment thereof; more preferably, the immune checkpoint inhibitor comprises an anti-PD-1 antibody and / or an anti-PD-L1 antibody, such as BioXCell J43 clone, Navulizumab, Sintilimab, Pembrolizumab, Atezolizuma, Durvalumab, Avelumab, Cemiplimab, Dostarlimab, Toripalimab, or Tislelizumab; and / or, the second antigen is IL-2 or a truncation thereof; and / or, the second antigen is VEGF, and the antigen ligand is an anti-VEGF antibody or an antigen binding fragment thereof.

5. The pharmaceutical combination according to any one of claims 1 to 4, wherein the pharmaceutical combination further comprises a pharmaceutically acceptable carrier and / or excipient.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein the antibody conjugate drug and the immune checkpoint inhibitor are in a single preparation, or are in a preparation comprising the antibody conjugate drug and a preparation comprising the immune checkpoint inhibitor, respectively; and / or, the pharmaceutical combination further comprises a therapeutic agent, which is preferably a chemotherapy preparation or a radiotherapy preparation.

7. A pharmaceutical composition, characterized by, the pharmaceutical composition comprises an antibody conjugate drug and an immune checkpoint inhibitor, which are as described in any one of claims 1-6.

8. A kit characterized in that, the kit comprises a pharmaceutical combination as described in any one of claims 1-6, or a pharmaceutical composition as described in claim 7.

9. A kit, characterized in that the kit-of-parts comprises kit A and kit B; wherein, the kit A comprises an antibody conjugate drug, and the kit B comprises an immune checkpoint inhibitor; the antibody conjugate drug and the immune checkpoint inhibitor are as described in any one of claims 1-6; preferably, the kit A and the kit B are administered simultaneously or separately. and / or the kit further comprises a kit C comprising other therapeutic agents, such as a chemotherapeutic agent or a radiotherapeutic agent.

10. Use of the pharmaceutical combination of any one of claims 1-6, the pharmaceutical composition of claim 7, the kit of claim 8, or the kit of parts of claim 9 in the manufacture of a medicament for treating a tumor.

11. A method of treating a tumor, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-10. The method comprises administering to a subject in need thereof an effective amount of the pharmaceutical combination of any one of claims 1-6, the pharmaceutical composition of claim 7, the kit of claim 8, or the kit of parts of claim 9; Preferably, the subject has a tumor with high expression of HER2 or a tumor with low expression of HER2; and / or, the subject has a tumor with expression of EGFR; and / or, the subject has a tumor with expression of B7-H3; and / or, the subject has received a first therapy; the first therapy is preferably chemotherapy or radiotherapy.

12. The pharmaceutical combination of any one of claims 1-6, the pharmaceutical composition of claim 7, the kit of claim 8, or the kit of parts of claim 9 for use in treating a tumor.

13. The use according to claim 10, the pharmaceutical combination, kit or set according to claim 17, or the method according to claim 11, wherein The tumor is a tumor with abnormal expression of HER2, EGFR, or B7-H3; Preferably, The tumor with abnormal expression of HER2 comprises breast cancer, gastric cancer, gastroesophageal junction cancer, urothelial cancer, parotid cancer, non-small cell lung cancer, colorectal cancer, and ovarian cancer; The tumor with abnormal expression of EGFR comprises non-small cell lung cancer, epidermoid carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, bladder cancer, esophageal cancer, head and neck cancer, glioblastoma, and nasopharyngeal carcinoma; The tumor with abnormal expression of B7-H3 comprises head and neck cancer, skin cancer, colon cancer, kidney cancer, glioblastoma, neuroglioma, neuroblastoma, sarcoma, thyroid cancer, mesothelioma, melanoma, pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, and bladder cancer.

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