Combination of antibody drug conjugates and anti-vegf antibodies

Abstract

The present application relates to the use of an antibody drug conjugate as a monotherapy or in combination for the preparation of a medicament for the prevention and / or treatment of cancer. In particular, the present application provides the use of an antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof as a monotherapy or in combination with an anti-VEGF antibody for the preparation of a medicament for the prevention and / or treatment of cancer.

Description

Combination application of antibody-drug conjugates and anti-VEGF antibodies Technical Field

[0001] This application relates to the field of medicine and relates to the use of an antibody-drug conjugate, alone or in combination, in the preparation of a drug for the prevention and / or treatment of cancer. Specifically, the present invention provides the use of an antibody-drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, alone or in combination with an anti-VEGF antibody, in the preparation of a drug for the prevention and / or treatment of cancer. Background Art

[0002] Antibody-drug conjugates (ADCs) are a class of targeted biologics that link cytotoxic drugs to monoclonal antibodies via a linker. Using the monoclonal antibody as a carrier, small-molecule cytotoxic drugs are efficiently and effectively delivered to target tumor cells in a targeted manner. Tumor-specific antibodies enable ADCs to selectively deliver small-molecule cytotoxic drugs, minimizing off-target effects while preserving their anti-tumor properties, effectively improving the benefit-risk ratio of anti-tumor therapy. B7 homolog 4 is a newly discovered member of the B7 family. It plays a crucial role in multiple cellular biological processes, such as cell differentiation, proliferation, and apoptosis, and may influence tumor cell invasion and metastasis. Furthermore, the B7 family is an important costimulatory molecule that influences processes such as T cell proliferation and B cell activation. Studies have shown that B7 homolog 4 is highly expressed in various tumors, including cholangiocarcinoma, breast cancer, endometrial cancer, non-small cell lung cancer, ovarian cancer, gastric cancer, and pancreatic cancer, while its expression is limited in normal tissues. Therefore, B7 homolog 4 has great potential as a target for ADCs.

[0003] VEGF is a major growth factor that promotes angiogenesis, acting through three tyrosine kinase receptors. The primary VEGF signaling pathway is VEGF receptor 2 (VEGFR2), along with VEGFR1 and VEGFR3. Drugs targeting VEGF, VEGFR, and other related molecules, developed to block the mechanisms of tumor angiogenesis, are collectively referred to as anti-angiogenic drugs. Bevacizumab, the first approved anti-angiogenic targeted drug, has been approved for multiple indications, including metastatic colorectal cancer, advanced / metastatic or recurrent non-squamous non-small cell lung cancer, recurrent glioblastoma, hepatocellular carcinoma, renal cell carcinoma, cervical cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, and breast cancer.

[0004] Currently, anti-angiogenic drugs combined with multiple basic chemotherapy drugs are widely used as first-line treatment for various cancer diseases. This is due to the common side effects of basic chemotherapy drugs, such as bone marrow suppression, peripheral neurotoxicity, leukopenia, anemia, and especially the common side effect of anti-angiogenic drugs, cardiovascular toxicity.

[0005] Therefore, there is an urgent need to develop new combination therapies that can improve efficacy while having lower side effects of combined medication, so as to maximize the survival benefits of patients receiving anti-angiogenic drugs. Summary of the Invention

[0006] The present disclosure provides a use of an antibody-drug conjugate and an anti-VEGF antibody in combination for preparing a drug for treating cancer. The structure of the antibody-drug conjugate is shown in formula (I):

[0007] wherein n is a non-zero integer or decimal from 1 to 10, preferably a decimal or integer from 1 to 8, preferably a decimal or integer from 2 to 8, more preferably from 3 to 8, and can be an integer or a decimal, more preferably 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, or 6.5.

[0008] Wherein Pc is an anti-B7H4 antibody or an antigen-binding fragment thereof.

[0009] In some embodiments, the anti-B7H4 antibody or antigen-binding fragment thereof comprises: heavy chain HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NOs: 01, 02 and 03, respectively, and light chain LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NOs: 04, 05 and 06, respectively.

[0010] In the present invention, the amino acid sequences of the CDRs listed above are all shown according to the Kabat definition rules. However, it is well known in the art that antibody CDRs can be defined by various methods in the art. Although the scope of protection claimed in the present invention is based on the sequences shown in the Kabat definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of the present invention.

[0011] Among them, the CDR sequences mentioned above are shown in Table a below:

[0012] Table a Heavy chain and light chain CDR sequences

[0013] Note: CDR sequences are derived from those shown in the Kabat definition.

[0014] Preferably, the anti-B7H4 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.

[0015] In some alternative embodiments, the anti-B7H4 antibody or antigen-binding fragment thereof described herein is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0016] In some optional embodiments, the anti-B7H4 antibody or antigen-binding fragment thereof described herein comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, preferably a heavy chain constant region of IgG1 or IgG4 isotype.

[0017] In other alternative embodiments, the anti-B7H4 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.

[0018] Furthermore, it is preferred that the heavy chain variable region sequence of the anti-B7H4 antibody or antigen-binding fragment thereof is the sequence shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence is the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0019] The sequences of the heavy and light chain variable regions of the aforementioned anti-B7H4 antibodies or antigen-binding fragments thereof are as follows: Heavy chain variable region sequence

[0020] Light chain variable region sequence

[0021] Note: The order is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The italics in the sequence are FR sequences, and the underlines are CDR sequences. The CDR sequences are derived from the Kabat definition rules.

[0022] Furthermore, it is preferred that the heavy chain sequence of the anti-B7H4 antibody or antigen-binding fragment thereof is the sequence shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is the sequence shown in SEQ ID NO: 10 or a variant thereof.

[0023] The sequences of the heavy and light chains of the aforementioned anti-B7H4 antibodies or antigen-binding fragments thereof are shown below:

[0024] Heavy chain (IgG1) amino acid sequence: (SEQ ID NO: 09)

[0025] Light chain (λ) amino acid sequence: (SEQ ID NO: 10)

[0026] In some embodiments, the anti-VEGF antibody is selected from Bevacizumab, Ranibizumab, Sevacizumab, Suvemcitug, Varisacumab, CMAB-801, LYN-00101, preferably Bevacizumab.

[0027] The sequences of the heavy and light chains of the aforementioned bevacizumab are shown below:

[0028] Heavy chain amino acid sequence: (SEQ ID NO: 11)

[0029] Light chain amino acid sequence: (SEQ ID NO: 12)

[0030] On the other hand, the present application discloses the use of the antibody-drug conjugate and the anti-VEGF antibody in combination with a platinum drug in the preparation of a drug for treating cancer.

[0031] In an optional embodiment, the above-mentioned platinum drug is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, and dicycloplatin; preferably carboplatin and / or cisplatin.

[0032] In an alternative embodiment, the antibody drug conjugate and the anti-VEGF antibody are contained in different preparations as active ingredients, and are administered simultaneously, concurrently, sequentially, continuously, alternately or separately.

[0033] In an optional embodiment, the antibody drug conjugate, the anti-VEGF antibody, and the platinum drug are contained in different preparations as active ingredients, and are administered simultaneously, concurrently, sequentially, continuously, alternately, or separately.

[0034] On the other hand, the present application discloses the use of the antibody-drug conjugate and the anti-VEGF antibody in combination with a poly(ADP-ribose) polymerase inhibitor in the preparation of a drug for treating cancer.

[0035] In an optional embodiment, the poly(ADP-ribose) polymerase inhibitor is selected from one or more of Olaparib, Fluzoparib, Niraparib, Pamiparib, Rucaparib, Talazoparib, Veliparib, Senaparib, CEP-8983, BGB-290 or 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.

[0036] In an alternative embodiment, the antibody drug conjugate, anti-VEGF antibody and poly(ADP-ribose) polymerase inhibitor are contained in different preparations as active ingredients and are administered simultaneously, concurrently, sequentially, continuously, alternately or separately.

[0037] On the other hand, the above-mentioned antibody drug conjugate and anti-VEGF antibody are contained in a single preparation as active ingredients and administered.

[0038] On the other hand, the above-mentioned antibody drug conjugate, anti-VEGF antibody, and platinum drug are contained in a single preparation as active ingredients and administered.

[0039] On the other hand, the above-mentioned antibody drug conjugate, anti-VEGF antibody, and poly(ADP-ribose) polymerase inhibitor are contained in a single preparation as active ingredients and administered.

[0040] In an optional embodiment, the dose of the antibody drug conjugate is 0.1 mg / kg to 12.0 mg / kg, preferably 1.0 mg / kg to 12.0 mg / kg, more preferably 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, 4.8 mg / kg, 5.0 mg / kg, 5.2 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 5.8 mg / kg, 6.0mg / kg, 6.2mg / kg, 6.4mg / kg, 6.6mg / kg, 6.8mg / kg, 7.0mg / kg, 7.2mg / kg, 7.4mg / kg, 7.6mg / kg, 7.8mg / kg, 8.0mg / kg, 8.2mg / kg, 8.4mg / kg, 8.6mg / kg, 8.8mg / kg, 9.0mg / kg, 9 .2mg / kg, 9.4mg / kg, 9.6mg / kg, 9.8mg / kg, 10.0mg / kg, 10.2mg / kg, 10.4mg / kg, 10.6mg / kg, 10.8mg / kg, 11.0mg / kg, 11.2mg / kg, 11.4mg / kg, 11.6mg / kg, 11.8mg / kg or 12.0mg / kg.

[0041] In alternative embodiments, the antibody drug conjugate is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0042] In a preferred embodiment, the antibody drug conjugate is administered at a starting dose of 2.8 mg / kg, 3.8 mg / kg, or 4.8 mg / kg, and the dosing frequency is once every three weeks.

[0043] In an alternative embodiment, the dose of the anti-VEGF antibody is from 1.0 mg / kg to 100 mg / kg, preferably from 1.0 mg / kg to 40 mg / kg, more preferably from 1.0 mg / kg to 30 mg / kg, and further preferably 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.2 mg / kg, 3.4 mg / kg, 3.6 mg / kg, 3.8 mg / kg, 4.0 mg / kg, 4.2 mg / kg, 4.4 mg / kg, 4.6 mg / kg, 4.8 mg / kg, 5.0 mg / kg, 5.2 mg / kg, 5.4 mg / kg, 5.6 mg / kg, 5.8 mg / kg, 6.0 mg / kg, 6.2 mg / kg, 6.4 mg / kg, 6.6 mg / kg, 6.8 mg / kg, 7.0 mg / kg, 7.2 mg / kg, 7.4 mg / kg, 7.6 mg / kg, 7.8 mg / kg, 8.0 mg / kg, 8.2 mg / kg, 8.4 mg / kg, 8.6 mg / kg, 8.8 mg / kg, 9.0 mg / kg, 9.2 mg / kg, 9.4 mg / kg, 9.6 mg / kg, 9.8 mg / kg, 10.0 mg / kg, 10.2 mg / kg, 10.4 mg / kg, 10.6 mg / kg, 10.8 mg / kg, 11.0 mg / kg, 11.2 mg / kg, 11.4 mg / kg, 11.6 mg / kg, 11.8 mg / kg, 12.0 mg / kg, 12.2 mg / kg, 12.4 mg / kg, 12.6 mg / kg, 12.8 mg / kg, 13.0 mg / kg, 13.2 mg / kg, 13.4 mg / kg, 13.6 mg / kg, 13.8 mg / kg, 14.0 mg / kg, 14.2 mg / kg, 14.4 mg / kg, 14.6 mg / kg, 14.8 mg / kg, 15.0 mg / kg, 15.2 mg / kg, 15.4 mg / kg, 15.6 mg / kg, 15.8 mg / kg, 16.0 mg / kg, 16.2 mg / kg, 16.4 mg / kg, 16.6 mg / kg, 16.8 mg / kg, 17.0 mg / kg, 17.2 mg / kg, 17.4 mg / kg, 17.6 mg / kg, 17.8 mg / kg, 18.0 mg / kg, 18.2 mg / kg, 18.4 mg / kg, 18.6 mg / kg, 18.8 mg / kg, 19.0 mg / kg, 19.2 mg / kg, 19.4 mg / kg, 19.6 mg / kg, 19.8 mg / kg, 20.0mg / kg, 20.2mg / kg, 20.4mg / kg, 20.6mg / kg, 20.8mg / kg, 30.0mg / kg. .

[0044] In alternative embodiments, the anti-VEGF antibody is administered once a week, once every two weeks, or once every three weeks.

[0045] In a preferred embodiment, the dose of the anti-VEGF antibody is 15 mg / kg and the administration frequency is once every three weeks.

[0046] In an optional embodiment, the platinum drug is administered at a dose of 10 mg / m 2 Up to 500 mg / m 2 , preferably 10 mg / m 2 Up to 200 mg / m 2 , more preferably 25 mg / m 2 , 50mg / m 2 , 75mg / m 2 , 100mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 or 200 mg / m 2 The dosing frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

[0047] In an optional embodiment, the dosage of the platinum drug is calculated as the area under the curve (AUC) and is 1 to 20 mg / ml / min, preferably 1 to 10 mg / ml / min, more preferably 2 mg / ml / min, 3 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, 8 mg / ml / min, 9 mg / ml / min, and the frequency of administration is once a week, once every two weeks, once every three weeks or once every four weeks.

[0048] In an alternative embodiment, the platinum drug is administered for up to 6 cycles.

[0049] In a preferred embodiment, the dosage of the platinum drug is: cisplatin 75 mg / m2 or carboplatin AUC 5 mg / ml / min intravenous drip, and the administration frequency is once every three weeks.

[0050] In an alternative embodiment, the dose of the poly(ADP-ribose) polymerase inhibitor is 1 mg / kg to 500 mg / m 2, preferably 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80 mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, 110mg / kg, 120mg / kg, 130mg / kg, 140mg / kg, 150mg / kg, 160mg / kg, 170mg / kg, 180mg / kg, 190mg / k The dosage of the drug may be 200 mg / kg, 210 mg / kg, 220 mg / kg, 230 mg / kg, 240 mg / kg, 250 mg / kg, 260 mg / kg, 270 mg / kg, 280 mg / kg, 290 mg / kg, 300 mg / kg, 320 mg / kg, 340 mg / kg, 350 mg / kg, 360 mg / kg, 380 mg / kg, 400 mg / kg, 420 mg / kg, 440 mg / kg, 450 mg / kg, 460 mg / kg, 480 mg / kg or 500 mg / kg, more preferably 20 mg / kg, 40 mg / kg or 80 mg / kg.

[0051] In an optional embodiment, the frequency of administration of the poly(ADP-ribose) polymerase inhibitor is once a day, twice a day, three times a day, once every two days, or once every three days, preferably once a day.

[0052] In a preferred embodiment, the dosage of the poly(ADP-ribose) polymerase inhibitor is 40 mg / kg, and the administration frequency is once a day.

[0053] In alternative embodiments, the cancer is an advanced solid tumor for which adequate standard treatment has failed or is intolerant, or for which there is no effective standard treatment.

[0054] In alternative embodiments, the cancer is a recurrent, metastatic and / or drug-resistant cancer.

[0055] In an optional embodiment, the cancer is selected from at least one of the following: ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma. Further, ovarian cancer is selected from epithelial ovarian cancer, uterine cancer is selected from endometrial cancer, and peritoneal cancer is selected from primary peritoneal cancer.

[0056] In preferred embodiments, the cancer is platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, or advanced endometrial cancer for which adequate standard therapy has failed or for which no standard therapy is effective.

[0057] In preferred embodiments, the cancer is platinum-sensitive recurrent, epithelial ovarian, fallopian tube or primary peritoneal cancer, or recurrent / metastatic endometrial cancer.

[0058] In a preferred embodiment, the cancer is platinum-sensitive recurrent ovarian cancer, or newly diagnosed advanced ovarian cancer that has not received systemic anti-tumor treatment.

[0059] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate, an anti-VEGF antibody, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0060] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate, an anti-VEGF antibody and a platinum drug, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0061] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate, an anti-VEGF antibody and a poly(ADP-ribose) polymerase inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0062] The present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate, an anti-VEGF antibody, and optionally a platinum drug in combination to a subject in need thereof, wherein the combined administration can be simultaneous, concurrent, sequential, continuous, alternating, or separate administration.

[0063] The present disclosure also provides a method for treating or preventing cancer, which comprises administering the above-mentioned antibody-drug conjugate, an anti-VEGF antibody, and a platinum drug in combination to a subject in need thereof during an induction therapy phase, wherein the combined administration may be simultaneous, concurrent, sequential, continuous, alternating, or separate administration; and the method further comprises administering the above-mentioned antibody-drug conjugate, an anti-VEGF antibody, and a poly(ADP-ribose) polymerase inhibitor in combination to a subject in need thereof during a maintenance therapy phase after the induction therapy, wherein the combined administration may be simultaneous, concurrent, sequential, continuous, alternating, or separate administration.

[0064] In alternative embodiments, the cancer is an advanced solid tumor for which adequate standard treatment has failed or is intolerant, or for which there is no effective standard treatment.

[0065] In alternative embodiments, the cancer is a recurrent, metastatic and / or drug-resistant cancer.

[0066] In an optional embodiment, the cancer is selected from at least one of the following: ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.

[0067] Furthermore, the ovarian cancer is selected from epithelial ovarian cancer, the uterine cancer is selected from endometrial cancer, and the peritoneal cancer is selected from primary peritoneal cancer.

[0068] In preferred embodiments, the cancer is platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, or advanced endometrial cancer for which adequate standard therapy has failed or for which no standard therapy is effective.

[0069] In preferred embodiments, the cancer is platinum-sensitive recurrent, epithelial ovarian, fallopian tube or primary peritoneal cancer, or recurrent / metastatic endometrial cancer.

[0070] In preferred embodiments, the cancer is platinum-sensitive recurrent ovarian cancer, high-grade serous ovarian cancer, high-grade endometrioid epithelial ovarian cancer, or newly diagnosed advanced ovarian cancer that has not received systemic anti-tumor therapy.

[0071] In this disclosure, "including" and "comprising" are used herein in an open and non-limiting sense unless otherwise indicated.

[0072] In the present disclosure, the so-called "combination" is a mode of administration, which includes various situations in which two or more drugs are administered sequentially or simultaneously.

[0073] Administration by simultaneous administration, independently formulated and co-administered, or independently formulated and sequentially administered all fall within the scope of combined administration described herein. "Simultaneously" herein refers to administration of at least one dose of an anti-VEGF antibody, an anti-B7H4 antibody-drug conjugate, and an optional platinum drug within a certain timeframe, optionally within 3 days, 2 days, or 1 day, wherein both or more agents exhibit pharmacological effects. "Sequential" administration includes administration of the anti-VEGF antibody, the anti-B7H4 antibody-drug conjugate, and an optional platinum drug within different dosing cycles. The timeframe can be within a single dosing cycle, optionally within 4 weeks, 3 weeks, 2 weeks, or 1 week. This timeframe includes treatments in which the anti-VEGF antibody, the anti-B7H4 antibody-drug conjugate, and an optional platinum drug are administered via the same or different routes of administration.

[0074] the term

[0075] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0076] The present disclosure incorporates the entire contents of application WO into this application.

[0077] The term "antibody drug conjugate" refers to an antibody linked to a biologically active drug via a stable linker. In the present disclosure, "antibody drug conjugate" refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a stable linker.

[0078] The term "antibody" refers to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and order of the constant region of immunoglobulins' heavy chains vary, resulting in different antigenicity. Consequently, immunoglobulins can be divided into five classes, or isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Within the same class, Igs are further divided into subclasses based on the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five Ig classes can have either kappa or lambda chains.

[0079] The approximately 110 amino acids near the N-terminus of an antibody's heavy and light chains vary greatly in sequence, forming the variable region (Fv region); the remaining amino acid sequences near the C-terminus are relatively stable, forming the constant region. The variable region comprises three hypervariable regions (HVRs) and four framework regions (FRs), whose sequences are relatively conserved. These three hypervariable regions determine the antibody's specificity and are also known as complementarity-determining regions (CDRs). Each light chain variable region (LCVR) and heavy chain variable region (HCVR) consists of three CDR regions and four FR regions, arranged in the following order from amino to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain are LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3.

[0080] In the present disclosure, the amino acid sequences of the above CDRs are shown according to the Kabat definition rules. However, it is well known to those skilled in the art that antibody CDRs can be defined in the art by a variety of methods, such as Chothia based on the three-dimensional structure of the antibody and the topology of the CDR loop (Chothia et al. (1989) Nature 342: 877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the international ImMunoGeneTics database (IMGT) (world wide web imgt.cines.fr / ), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures. It will be understood by those skilled in the art that, unless otherwise specified, the terms "CDR" and "complementarity determining region" of a given antibody or region thereof (e.g., variable region) should be understood to encompass complementarity determining regions defined by any of the above-mentioned known schemes described herein. Although the scope of protection claimed in the present invention is based on the sequences shown in the Kabat definition rules, amino acid sequences corresponding to other CDR definition rules should also fall within the scope of protection of the present invention.

[0081] The term "antigen-binding fragment" refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Examples of binding fragments included in "antigen-binding fragments" include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge on the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a single domain or dAb fragment (Ward et al., (1989) Nature 341: 544-546), which consists of a VH domain; and (vi) isolated complementarity determining regions (CDRs) or (vii) a combination of two or more isolated CDRs, optionally connected by a synthetic linker.

[0082] The term "drug loading" refers to the average number of cytotoxic drugs loaded per ligand in a molecule of Formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody. The drug loading can range from 0 to 12, preferably 1 to 10, cytotoxic drugs (D) attached per antibody (Pc). In the embodiments of the present disclosure, the drug loading is expressed as n, also known as the DAR value, and exemplary values ​​are 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The average number of drug products per ADC molecule after the conjugation reaction can be determined by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays, and HPLC characterization.

[0083] The term "combination" or "pharmaceutical combination" defines a fixed combination in dosage unit form or a kit for combined administration, wherein the therapeutic agents can be administered simultaneously or separately at intervals such that the therapeutic agents exhibit a synergistic effect, such as a synergistic effect.

[0084] The term "pharmaceutically acceptable" is defined herein to refer to those compounds, materials, biological agents, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject (e.g., a mammal or a human) without excessive toxicity, irritation, allergic response and other problematic complications, and commensurate with a reasonable benefit / risk ratio.

[0085] The term "pharmaceutical composition" is a product comprising one or more active ingredients (e.g., antibodies, ADCs) in optionally specified amounts, as well as any product produced directly or indirectly by combining one or more active ingredients in optionally specified amounts. The different active ingredients in the pharmaceutical composition can be administered independently in separate formulations, including administration simultaneously or at different time points for combined synergistic effect. In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0086] The term "treating" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0087] The term "effective amount" or "therapeutically effective amount" of a combination of therapeutic agents is an amount sufficient to provide a significant improvement compared to baseline clinically observable signs and symptoms of the cancer being treated by the combination. BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1: Growth inhibition of human HT29-hB7h4 subcutaneous xenograft tumors by single-agent or combination therapy

[0089] Figure 2: Growth inhibition of OVCAR3 xenograft tumor model in mice by single-drug or combination therapy DETAILED DESCRIPTION

[0090] The present application will be explained in more detail below with reference to the embodiments. The embodiments of the present application are only used to illustrate the technical solutions of the present application and are not intended to limit the essence and scope of the present application.

[0091] Example 1. Preparation of anti-B7H4 antibody drug conjugates

[0092] According to the production method described in WO2020244657, hu2F7 (an anti-B7H4 antibody) and an isotecan analog were used to prepare the anti-B7H4 antibody-drug conjugate shown in the following structure. The average value calculated by the HIC method was: y = 6.1. The hu2F7 heavy chain sequence is shown in SEQ ID NO: 09, and the light chain sequence is shown in SEQ ID NO: 10.

[0093] Example 2. In vivo pharmacodynamic study of anti-B7H4 antibody drug conjugates as monotherapy or in combination therapy in a human HT29-hB7h4 subcutaneous xenograft mouse model

[0094] 1. Test drug

[0095] Drug A: Prepared by the method in Example 1, using physiological saline.

[0096] Drug B: Bevacizumab for injection, provided by Suzhou Shengdia Biopharmaceutical Co., Ltd., and prepared with normal saline.

[0097] Drug C: Cisplatin API, purchased from MCE, product number HY-17394, ultrapure water was used for drug preparation.

[0098] 2. Experimental instruments and reagents

[0099] 2.1 Instruments

[0100] CO2 incubator (HERAcell-240i, Thermo Fisher Scientific); precision balance (SECURA225D-1CN, Sartorius AG, Germany); standard balance (HZ2002A, Changzhou Tianzhiping Instrument Equipment Co., Ltd.); biological safety cabinet (BSC1300-II-A2, Shandong Xinhua Medical Equipment Co., Ltd.); digital caliper ((0-150) mm / 0.01 mm, Mitutoyo, Japan); pipettes (20-200 μL; 100-1000 μL, Eppendorf)

[0101] 2.2 Reagents

[0102] RPMI 1640 was purchased from Gibco with a catalog number of 22400-071; FBS was purchased from Gibco with a catalog number of 10091148; PBS was purchased from Gibco with a catalog number of 10010023; trypsin was purchased from Gibco with a catalog number of 25200056; Puromycin Dihydrochloride was purchased from Gibco with a catalog number of A1113803; and Matrigel was purchased from Corning with a catalog number of 354234.

[0103] 3. Experimental operation and data processing

[0104] 3.1 Animals

[0105] BALB / c nude mice, 8-10 weeks old, female, were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd.

[0106] 3.2 Cell culture and cell suspension preparation

[0107] a. Remove a strain of HT29-hB7h4 cells from the cell bank and resuscitate the cells in RPMI 1640 medium (RPMI 1640 + 10% FBS + 5 μg / mL Puromycin). Place the revived cells in a cell culture flask (label the flask with the cell type, date, and culturer's name) and culture in a CO2 incubator (37°C, 5% CO2).

[0108] b. Subculture the cells 2-3 times per week and continue to culture in a CO2 incubator. Repeat this process until the cell count meets the in vivo efficacy requirement.

[0109] c. Collect the cultured cells, count them using an automatic cell counter, and resuspend the cells in PBS according to the counting results to prepare a cell suspension (density 10×10 7 / mL), add an equal volume of Matrigel to the cell suspension, mix evenly, and place in an ice box for use.

[0110] 3.3 Cell seeding

[0111] a, Nude mice were marked with disposable ear tags for both mice and rats before inoculation.

[0112] b. Mix the cell suspension thoroughly during inoculation, draw out 0.2-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0113] c. Secure the nude mouse with your left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0114] d. The experimental nude mice were inoculated sequentially (0.1 mL of cell suspension per mouse).

[0115] 3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0116] a. Tumors were measured and their sizes were calculated on days 4-7 after inoculation, depending on tumor growth.

[0117] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0118] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0119] c. Based on the grouping results, the test drugs were administered (administration method: tail vein injection; administration volume: 10 mL / kg; administration frequency: single administration of drug A; twice a week of drug B; once a week of drug C; administration cycle: 21 days; vehicle: normal saline). The specific dosage and administration schedule are shown in Table 1.

[0120] Table 1. Dosage and grouping

[0121] a. Dosing volume: 10 μL / g of mouse body weight. Stop dosing if body weight decreases by more than 15% and resume dosing when body weight recovers to within 10%.

[0122] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0123] e, Animals were euthanized after the experiment.

[0124] f. Experimental indicators are to examine the effect of drugs on tumor growth. The specific indicators are relative tumor proliferation rate T / C (%) or tumor inhibition rate TGI (%).

[0125] Calculation of TGI (%): If the tumor did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the time of grouping for that treatment group) / (average tumor volume at the end of treatment for the vehicle control group - average tumor volume at the time of grouping for the vehicle control group)] × 100%. If the tumor regressed, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the time of grouping for that treatment group) / average tumor volume at the time of grouping for that treatment group] × 100%.

[0126] Calculation of T / C (%): T / C (%) = average tumor volume of a treatment group at the end of drug administration / average tumor volume of the vehicle control group at the end of treatment × 100%.

[0127] At the end of the experiment, all animals were euthanized by CO2 asphyxiation in the order of their groups. After euthanasia, the tumor masses were removed, weighed, and photographed.

[0128] All data are expressed as mean ± SEM. Tumor volume data for each group at different time points were statistically analyzed using Dunnett's multiple comparisons test in two-way ANOVA to assess intergroup differences. Tumor volume differences between groups were analyzed using Dunnett's multiple comparisons test in one-way ANOVA. Differences in tumor volume between the two groups were analyzed using the t-test. All data were analyzed using GraphPad Prism 10, and p < 0.05 was considered significant.

[0129] 4. Experimental results and conclusions

[0130] The growth inhibitory effects of drug A, drug B, and drug C alone or in combination on human HT29-hB7h4 subcutaneous xenograft tumors are shown in Table 2 and Figure 1 .

[0131] Table 2. Evaluation of the antitumor efficacy of single-drug or combination therapy in the HT29-hB7h4 xenograft tumor model

[0132] a. Mean ± SEM;

[0133] b. Compared with the Vehicle group, Dunnett's multiple comparisons test in one-way ANOVA was used for statistical analysis.

[0134] In the HT29-hB7h4 xenograft tumor model, data from D0-D30 showed that the drug A monotherapy group, as well as the drug A combination and triple-drug combination groups with drug B and / or drug C, showed significant differences compared to the vehicle group. Throughout the experiment, no animals experienced weight loss leading to drug discontinuation, and no animals experienced morbidity or mortality.

[0135] Comparing the tumor inhibition effects of the drug groups based on tumor volume on day 30 after drug administration, the drug A + drug B group showed superior tumor inhibition to the single-drug treatment groups, while the drug A + drug C group also showed superior tumor inhibition to the single-drug treatment groups. The drug A + drug B + drug C group had the most excellent tumor inhibition effect, superior to the drug A alone group, significantly superior to the drug B and drug C alone groups, and also significantly superior to the drug B + drug C group.

[0136] In summary, drug A alone, in combination with drug B and / or drug C, and in combination with a triplet all demonstrated favorable tumor-suppressing effects. Both the drug A + drug B and drug A + drug C groups were superior to the monotherapy groups, suggesting that the combination of drug A with drug B or drug C had a synergistic effect. The drug A + drug B + drug C group demonstrated the most robust tumor-suppressing effect, surpassing the monotherapy and combination groups.

[0137] Example 3. In vivo pharmacodynamic study of anti-B7H4 antibody drug conjugates as monotherapy or in combination therapy in a human OVCAR3 subcutaneous xenograft mouse model

[0138] 1. Test drug

[0139] Drug A: Prepared by the method in Example 1, using physiological saline.

[0140] Drug B: Bevacizumab for injection, provided by Suzhou Shengdia Biopharmaceutical Co., Ltd., and prepared with normal saline.

[0141] Drug C: Cisplatin API, purchased from MCE, product number HY-17394, ultrapure water was used for drug preparation.

[0142] 2. Experimental instruments and reagents

[0143] 2.1 Instruments

[0144] CO2 incubator (HERAcell-240i, Thermo Fisher Scientific); precision balance (SECURA225D-1CN, Sartorius AG, Germany); standard balance (HZ2002A, Changzhou Tianzhiping Instrument Equipment Co., Ltd.); biological safety cabinet (BSC1300-II-A2, Shandong Xinhua Medical Equipment Co., Ltd.); digital caliper ((0-150) mm / 0.01 mm, Mitutoyo, Japan); pipettes (20-200 μL; 100-1000 μL, Eppendorf)

[0145] 2.2 Reagents

[0146] RPMI 1640 was purchased from Gibco, catalog number 22400-071; FBS was purchased from Gibco, catalog number 10091148; PBS was purchased from Gibco, catalog number 10010023; trypsin was purchased from Gibco, catalog number 25200056; Matrigel was purchased from Corning, catalog number 354234.

[0147] 3. Experimental operation and data processing

[0148] 3.1 Animals

[0149] NOD SCID mice, 6-8 weeks old, female, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0150] 3.2 Cell culture and cell suspension preparation

[0151] a. Remove one strain of OVCAR3 cells from the cell bank and resuscitate them in RPMI 1640 medium. Place the revived cells in a cell culture flask (label the flask with the cell type, date, and name of the culturer) and culture them in a CO2 incubator (37°C, 5% CO2).

[0152] b. Subculture the cells once a week and continue to culture them in a CO2 incubator. Repeat this process until the cell number meets the in vivo efficacy requirement.

[0153] c. Collect the cultured cells, count them using an automatic cell counter, and resuspend the cells in PBS according to the counting results to prepare a cell suspension (density 10×10 7 / mL), add an equal volume of Matrigel to the cell suspension, mix evenly, and place in an ice box for use.

[0154] 3.3 Cell seeding

[0155] a, Mice were marked with disposable universal ear tags for rats and mice before inoculation;

[0156] b. Mix the cell suspension thoroughly during inoculation, draw out 0.2-1 mL of cell suspension with a 1 mL syringe, remove any bubbles, and place the syringe on an ice pack until ready to use.

[0157] c. Restrain the NOD SCID mouse with the left hand and disinfect the right side of the nude mouse's back near the right shoulder (inoculation site) with a 75% alcohol cotton ball. Start inoculation 30 seconds later.

[0158] d, The experimental NOD SCID mice were inoculated sequentially (0.2 mL of cell suspension per mouse).

[0159] 3.4 Tumor measurement, grouping, and drug administration in tumor-bearing mice

[0160] a. Tumors were measured and their size was calculated on days 20-30 after inoculation, depending on tumor growth.

[0161] Tumor volume calculation: Tumor volume (mm 3 ) = length (mm) × width (mm) × width (mm) / 2

[0162] b, Tumor-bearing mice were randomly divided into groups according to their weight and tumor size;

[0163] c. Based on the grouping results, the test drugs were administered (administration method: tail vein injection and intraperitoneal injection; administration volume: 10 mL / kg; administration frequency: single administration of drug A; twice a week of drug B; once a week of drug C; administration cycle: 21 days; vehicle: normal saline). The specific dosage and administration schedule are shown in Table 3.

[0164] Table 3. Dosage and grouping

[0165] a. Dosing volume: 10 μL / g of mouse body weight. Stop dosing if body weight decreases by more than 15% and resume dosing when body weight recovers to within 10%.

[0166] d, Tumors were measured and weighed twice a week after the start of the test drug administration.

[0167] e, Animals were euthanized after the experiment.

[0168] f. Experimental indicators were used to examine the effects of the drug on tumor growth, specifically the relative tumor proliferation rate (T / C) (%) or tumor inhibition rate (TGI) (%). Tumor volume measurement: Tumor volume was measured twice weekly using a vernier caliper. The formula for calculating tumor volume was V = 0.5a × b², where a and b represent the length and width of the tumor, respectively.

[0169] Calculation of TGI (%): If the tumor did not regress, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the time of grouping for that treatment group) / (average tumor volume at the end of treatment for the vehicle control group - average tumor volume at the time of grouping for the vehicle control group)] × 100%. If the tumor regressed, TGI (%) = [1 - (average tumor volume at the end of dosing for a given treatment group - average tumor volume at the time of grouping for that treatment group) / average tumor volume at the time of grouping for that treatment group] × 100%.

[0170] Calculation of T / C (%): T / C (%) = average tumor volume of a treatment group at the end of drug administration / average tumor volume of the vehicle control group at the end of treatment × 100%.

[0171] At the end of the experiment, all animals were euthanized by CO2 asphyxiation in the order of their groups. After euthanasia, the tumor masses were removed, weighed, and photographed.

[0172] All data are expressed as mean ± SEM. Tumor volume data at different time points within each group were statistically analyzed using Dunnett's multiple comparisons test in a two-way ANOVA to assess intergroup differences. Differences in tumor volume between the two groups were analyzed using the t-test. All data were analyzed using GraphPad Prism 10, and p < 0.05 was considered significant.

[0173] 4. Experimental results and conclusions

[0174] The results of drug A, drug B and drug C alone or in combination for the treatment of mouse OVCAR3 xenograft tumor model are shown in Table 4 and Figure 2.

[0175] Table 4. Evaluation of the antitumor efficacy of drug A alone or in combination therapy in the OVCAR3 xenograft tumor model

[0176] a. Mean ± SEM;

[0177] b. Compared with the Vehicle group, statistical analysis was performed using Dunnett's multiple comparisons test in Two-way ANOVA.

[0178] In the ovarian cancer cell line OVCAR3 tumor-bearing model, data from D0-D21 showed that the monotherapy groups, the two-drug combination groups, and the triple-drug combination groups of Drug A, Drug B, and Drug C all showed significant differences compared to the vehicle group. Throughout the experiment, no animals experienced weight loss leading to drug discontinuation, and no animals experienced morbidity or mortality.

[0179] Comparison of tumor inhibition between the drug groups based on tumor volume on day 21 after drug administration showed that the tumor inhibition effect of the Drug A + Drug B group was significantly better than that of the Drug A and Drug B groups alone; and the tumor inhibition effect of the Drug A + Drug C group was significantly better than that of the Drug A and Drug C groups alone. The tumor inhibition effect of the Drug A + Drug B + Drug C group was the most excellent, significantly better than that of each single-drug group, and also significantly better than that of the Drug B + Drug C group.

[0180] In summary, Drug A, Drug B, and Drug C all demonstrated excellent tumor-suppressing effects in the monotherapy, dual-drug, and triple-drug treatment groups. Both the Drug A + Drug B and Drug A + Drug C groups were significantly superior to the monotherapy groups, suggesting a synergistic effect between Drug A and either Drug B or Drug C. The Drug A + Drug B + Drug C group demonstrated the most superior tumor-suppressing effect, significantly superior to the monotherapy and dual-drug combination groups.

[0181] Example 4. Clinical Trial of Anti-B7H4 Antibody Drug Conjugate Combined with Anti-VEGF Antibody ± Platinum Drugs for the Treatment of Advanced Solid Tumors

[0182] 1. Research Objectives

[0183] Main research objectives:

[0184] To evaluate the safety and tolerability of anti-B7H4 antibody-drug conjugate combination therapy in subjects with advanced solid tumors.

[0185] Secondary study objectives:

[0186] 1. Evaluate the PK characteristics of anti-B7H4 antibody-drug conjugate combination therapy in subjects with advanced solid tumors;

[0187] 2. Evaluate the efficacy of anti-B7H4 antibody-drug conjugate combination therapy in subjects with advanced solid tumors;

[0188] 3. Evaluate the immunogenicity of anti-B7H4 antibody-drug conjugate combination therapy in subjects with advanced solid tumors.

[0189] Exploratory research objectives:

[0190] 1. Explore the relationship between exposure and effect of anti-B7H4 antibody-drug conjugates;

[0191] 2. Explore biomarkers that predict or influence the efficacy of anti-B7H4 antibody-drug conjugate combination therapy.

[0192] 2. Name of investigational drug:

[0193] (1) Anti-B7H4 Antibody-Drug Conjugates

[0194] Dosage form: Sterile powder for injection, Specification: 50 mg / bottle, Manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.

[0195] (2) Anti-VEGF antibodies

[0196] Bevacizumab, dosage form: sterile solution for injection, specification: 100 mg (4 mL) / vial, manufacturer: Suzhou Shengdia Biopharmaceutical Co., Ltd.

[0197] (3) Platinum drugs

[0198] Carboplatin, Appearance: White or off-white freeze-dried loose blocks or powder, Manufacturer: Qilu Pharmaceutical Co., Ltd.

[0199] Cisplatin, Appearance: Light yellow-green to light yellow to slightly viscous clear liquid, Manufacturer: Jiangsu Hausen Pharmaceutical Co., Ltd.

[0200] 3. Target group:

[0201] Patients with pathologically confirmed advanced solid tumors, specifically as follows:

[0202] (1) Patients with platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. (2) Patients with advanced endometrial cancer who have failed adequate standard treatment or have no effective standard treatment. (3) Patients with advanced endometrial cancer who have progressed after first-line platinum-containing chemotherapy. (4) Patients with platinum-resistant recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. (5) Patients with previously untreated platinum-sensitive recurrent epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. (6) Patients with previously untreated advanced endometrial cancer. (7) Patients with recurrent / metastatic / locally advanced inoperable endometrial cancer.

[0203] 4. Dosage regimen:

[0204] In this study, every 3 weeks (21 days) was a treatment cycle (C).

[0205] The study is designed to have two combination therapy cohorts, each consisting of a dose-finding phase and a dose-expansion phase:

[0206] Cohort 3 (3A / 3B): anti-B7H4 antibody-drug conjugate combined with bevacizumab.

[0207] Cohort 4 (4A / 4B): anti-B7H4 antibody-drug conjugate combined with bevacizumab and platinum.

[0208] For the dual therapy cohort (i.e., cohort 3), the starting dose of the anti-B7H4 antibody drug conjugate was 4.8 mg / kg, with a total of two dose groups (3.8 mg / kg and 4.8 mg / kg). If the starting dose was not tolerated, it was decremented to 3.8 mg / kg. For the triple therapy cohort (i.e., cohort 4), the starting dose of the anti-B7H4 antibody drug conjugate was 3.8 mg / kg, with a total of three dose groups (2.8 mg / kg, 3.8 mg / kg, and 4.8 mg / kg). If the starting dose was not tolerated, it was decremented to the 2.8 mg / kg dose level.

[0209] Cohort 3A: Anti-B7H4 antibody drug conjugate every 3 weeks, according to the dose level of the group, until disease progression or other discontinuation criteria are met. Bevacizumab 15mg / kg every 3 weeks, until disease progression or other discontinuation criteria are met

[0210] Cohort 4A: Anti-B7H4 antibody-drug conjugate administered every 3 weeks, at the entry dose level, until disease progression or other discontinuation criteria are met. Bevacizumab 15 mg / kg every 3 weeks, continued until disease progression or other discontinuation criteria are met. Cisplatin 75 mg / m² or carboplatin AUC 5 mg / ml / min every 3 weeks is recommended for up to 6 cycles.

[0211] Cohort 3B: Anti-B7H4 antibody-drug conjugate every 3 weeks, expanded dose / recommended dose, continued until disease progression or other discontinuation criteria are met. Bevacizumab 15 mg / kg every 3 weeks, continued until disease progression or other discontinuation criteria are met.

[0212] Cohort 4B: Anti-B7H4 antibody-drug conjugate every 3 weeks, expanded dose / recommended dose, continued until disease progression or other discontinuation criteria are met. Bevacizumab 15 mg / kg every 3 weeks, continued until disease progression or other discontinuation criteria are met. Cisplatin or carboplatin, select the corresponding recommended dose and number of cycles according to the indication (see Table 5)

[0213] Table 5 Recommended platinum doses and cycles for each indication during the dose expansion phase

[0214] 5. Study endpoints:

[0215] Primary study endpoint:

[0216] The maximum tolerated dose (MTD) or maximum applicable dose (MAD) of anti-B7H4 antibody-drug conjugate combination therapy.

[0217] Secondary study endpoints:

[0218] 1. Safety of anti-B7H4 antibody-drug conjugate combination therapy: incidence of adverse events (AEs); incidence of serious adverse events (SAEs); proportion of subjects with dose adjustments and treatment discontinuations due to AEs; changes in physical examination, ophthalmological examination, vital signs, body weight, laboratory tests (blood count, urine count, blood biochemistry, coagulation function), ECG, echocardiogram, and ECOGPs;

[0219] 2. PK characteristics of anti-B7H4 antibody-drug conjugate combination therapy;

[0220] 3. Effectiveness of anti-B7H4 antibody-drug conjugate combination therapy: Investigator-assessed objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and progression-free survival (PFS) according to RECIST v1.1 criteria; overall survival (OS);

[0221] 4. Immunogenicity of anti-B7H4 antibody-drug conjugates: anti-drug antibody (ADA) detection rate and ADA titer.

[0222] Exploratory study endpoints:

[0223] 1. The relationship between exposure and effect of anti-B7H4 antibody-drug conjugates;

[0224] 2. Explore biomarkers that predict or influence the efficacy of anti-B7H4 antibody-drug conjugate combination therapy.

[0225] 6. Research results:

[0226] As of November 20, 2024, a total of 6 patients received anti-B7H4 antibody-drug conjugate (4.8 mg / kg, every 3 weeks) combined with bevacizumab (15 mg / kg, every 3 weeks). Among them, 5 patients (83.3%) had ovarian cancer and 1 patient (16.7%) had fallopian tube cancer. The number of previous lines of anti-cancer drug treatment was: 0 patients received first-line treatment, 1 patient received second-line treatment, 3 patients received third-line treatment, and 2 patients received fourth-line treatment or higher. The median number of lines of treatment (range) was 3.0 (3, 4).

[0227] The drug had definite anti-tumor efficacy in 5 subjects with platinum-resistant ovarian cancer whose efficacy could be evaluated. The efficacy data are shown in Table 6. There were 2 PRs (all confirmed), 3 SDs, ORR = 40%, and DCR = 100%.

[0228] Table 6. Efficacy data for subjects with platinum-resistant ovarian cancer

[0229] In summary, the anti-B7H4 antibody-drug conjugate (4.8 mg / kg, Q3W) combined with bevacizumab (15 mg / kg, Q3W) has a definite and superior antitumor efficacy against platinum-resistant ovarian cancer, with predictable and manageable safety events.

[0230] Example 5. Clinical Trial of PARP Inhibitor Combined with Anti-B7H4 Antibody Drug Conjugate and Bevacizumab for the Treatment of Advanced Solid Tumors

[0231] 1. Research Objectives

[0232] Main research objectives:

[0233] To evaluate the safety and tolerability of PARP inhibitor combination therapy in subjects with advanced solid tumors.

[0234] Secondary study objectives:

[0235] 1. Evaluate the PK characteristics of PARP inhibitor combination therapy in subjects with advanced solid tumors;

[0236] 2. Evaluate other safety indicators of PARP inhibitor combination therapy in subjects with advanced solid tumors;

[0237] 3. Evaluate the efficacy of PARP inhibitor combination therapy in subjects with advanced solid tumors;

[0238] 4. Evaluate the PK characteristics of anti-B7H4 antibody-drug conjugate combination therapy in patients with advanced solid tumors;

[0239] 5. Evaluate the immunogenicity of anti-B7H4 antibody-drug conjugates in combination therapy.

[0240] Exploratory research objectives:

[0241] 1. The relationship between exposure and effect;

[0242] 2. Explore biomarkers that predict or influence the efficacy of combination therapy with anti-PARP inhibitors.

[0243] 2. Name of investigational drug:

[0244] (1) Anti-B7H4 Antibody-Drug Conjugates

[0245] Dosage form: Injection (lyophilized powder), Specification: 50 mg / bottle, Manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.

[0246] (2) Poly adenosinediphosphate ribose polymerase (PARP) inhibitors

[0247] 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide was prepared using the method disclosed in WO2022223025.

[0248] Dosage form: tablets, specifications: 10mg, 40mg, manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.

[0249] (3) Anti-VEGF antibodies

[0250] Bevacizumab injection, dosage form: sterile solution for injection, specification: 100 mg (4 mL) / bottle, manufacturer: Suzhou Shengdia Biotechnology Co., Ltd.

[0251] (4) Platinum drugs

[0252] Carboplatin injection, properties: Carboplatin for injection is white or off-white freeze-dried loose blocks or powder, manufacturer: Qilu Pharmaceutical Co., Ltd.

[0253] Cisplatin injection, properties: light yellow-green to light yellow to slightly viscous clear liquid, manufacturer: Jiangsu Hausen Pharmaceutical Group Co., Ltd.

[0254] 3. Target group:

[0255] Patients with platinum-sensitive recurrent ovarian cancer:

[0256] ① Histologically confirmed high-grade (poorly differentiated) serous or high-grade (poorly differentiated) endometrioid epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0257] ②Disease progression or recurrence after 2-3 lines of treatment, and disease progression or recurrence is ≥ 6 months from the completion of the last platinum-containing chemotherapy.

[0258] ③ No systemic anti-tumor treatment has been received since the most recent progression or recurrence.

[0259] ④Previously received at least one PARP inhibitor treatment.

[0260] ⑤ The researcher assesses that the patient is not suitable for tumor reduction surgery (e.g., surgical resection cannot achieve satisfactory tumor reduction), or the subject refuses tumor reduction surgery.

[0261] Newly diagnosed advanced ovarian cancer not receiving systemic anticancer therapy:

[0262] ① Patients with histologically or cytologically confirmed or with predominantly high-grade (poorly differentiated) serous or high-grade (poorly differentiated) endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, and FIGO stage III or IV. Patients with histologically classified as carcinosarcoma, undifferentiated, or mucinous cell carcinoma or clear cell carcinoma in epithelial ovarian cancer are not permitted.

[0263] ② The subject has completed or plans to undergo initial tumor cytoreductive surgery, or plans to undergo intermediate tumor cytoreductive surgery.

[0264] ③No previous treatment with PARP inhibitors.

[0265] ④The patients have not received any systemic anti-tumor treatment for advanced ovarian cancer in the past.

[0266] 4. Dosage regimen:

[0267] The dose-finding phase of this study has the following cohorts:

[0268] Cohort 5A: anti-B7H4 antibody-drug conjugate combined with a PARP inhibitor and bevacizumab.

[0269] In this dose-finding process, an anti-B7H4 antibody-drug conjugate was used in combination with bevacizumab and a platinum drug in the induction phase, and an anti-B7H4 antibody-drug conjugate was used in combination with bevacizumab and a PARP inhibitor in the sequential maintenance phase.

[0270] During the induction therapy phase, the day of the subject's first medication is recorded as C1D1 (the first day of the first cycle), and the day of each subsequent medication is the D1 of the next treatment cycle. The medication interval window period is 21±3 days; after completing the induction therapy phase and before entering maintenance therapy, the subject needs to undergo a tumor imaging assessment. If the disease has not progressed, they can enter the maintenance therapy phase. The first dose of PARP inhibitors in the maintenance therapy phase should be within 3 to 6 weeks after the last dose of platinum in the induction therapy phase. The date of the first PARP inhibitor drug treatment in the maintenance therapy phase is defined as D1 of the current visit, and every 21 days thereafter is a treatment cycle. The following is the dosing regimen for various drugs in this cohort:

[0271] The starting dose of the PARP inhibitor is 40 mg QD, with three pre-defined dose groups (20 mg, 40 mg, and 80 mg QD). If the starting dose is not tolerated, the dose is reduced to 20 mg QD. PARP inhibitor treatment should be started 3 to 6 weeks after the completion of platinum-based chemotherapy in the induction phase. Each 21-day treatment cycle is completed, and the drug should be taken orally once daily. Subjects should fast from 2 hours before to 1 hour after PARP inhibitor administration.

[0272] The starting dose of the anti-B7H4 antibody drug conjugate is 3.8 mg / kg every 3 weeks, with a total of three dose groups (2.8 mg / kg, 3.8 mg / kg, and 4.8 mg / kg every 3 weeks). If the starting dose is not tolerated, the dose will be reduced to 2.8 mg / kg every 3 weeks. Subjects will receive intravenous administration of the anti-B7H4 antibody drug conjugate starting on C1D1 (+3 days). Starting from C2, the interval between the first intravenous dose and the previous first intravenous dose will be 21 (±3) days.

[0273] Platinum-based: Subjects with platinum-sensitive recurrent ovarian cancer will receive either cisplatin 75 mg / m² every 3 weeks or carboplatin AUC 5 mg / mL / min every 3 weeks, at the investigator's option. Six cycles of platinum-based chemotherapy are recommended for subjects with platinum-sensitive recurrent ovarian cancer, while subjects with newly diagnosed advanced ovarian cancer will receive 6 to 8 cycles. Subjects will receive intravenous platinum-based chemotherapy starting on C1D1 (+3 days). Starting on C2, each subsequent dose will be administered with an interval of 21 (±3) days between the first dose and the previous dose. Investigators may choose cisplatin or carboplatin based on the subject's individual needs. Cisplatin and carboplatin may be used interchangeably during treatment due to tolerability issues, but subjects should be fully informed of the risk of cross-sensitivity. If a subject cannot tolerate the drug due to safety concerns, treatment will be discontinued.

[0274] Bevacizumab: All subjects in the dose-escalation phase will receive bevacizumab. Subjects will receive 15 mg / kg intravenously every three weeks. Newly diagnosed ovarian cancer subjects will receive bevacizumab starting on Day 1 (+3 days) and continuing for up to 15 months. Subjects with platinum-sensitive recurrent ovarian cancer will receive bevacizumab starting on Day 1 (+3 days) and continuing until objective disease progression (unless continued after disease progression) or other discontinuation criteria are met.

[0275] In this cohort, intravenous medications are recommended after PARP inhibitor administration. Intravenous medications are recommended to be administered in the following order: bevacizumab first (if applicable), followed by anti-B7H4 antibody-drug conjugates, and finally platinum (if applicable). All drugs are administered continuously until the completion of the pre-specified treatment course, objective disease progression (except for continued treatment after disease progression), or other discontinuation criteria are met.

[0276] 5. Study endpoints:

[0277] Primary study endpoint:

[0278] The maximum tolerated dose (MTD) or maximum applicable dose (MAD) of PARP inhibitor combination therapy.

[0279] Secondary study endpoints:

[0280] 1. PK characteristics of PARP inhibitor combination therapy;

[0281] 2. Safety of PARP inhibitor combination therapy;

[0282] 3. Effectiveness of PARP inhibitor combination therapy (investigator assessment):

[0283] a. Investigator-assessed objective response rate (ORR), disease control rate (DCR), and duration of response (DoR) according to RECIST v1.1 for subjects with target lesions at baseline (all solid tumors except prostate cancer);

[0284] b. Investigator-assessed progression-free survival (PFS) according to RECIST v1.1 (all solid tumors except prostate cancer);

[0285] c. Overall survival (OS);

[0286] d. Investigator-assessed ORR according to RECIST v1.1 and GCIG CA-125 criteria (ovarian cancer only);

[0287] e. Investigator-assessed ORR, DCR, DoR, and radiographic progression-free survival (rPFS) according to RECIST v1.1 (soft tissue) and PCWG3 criteria (bone lesions) (prostate cancer only);

[0288] f. Proportion of subjects with a CA-125 decrease of ≥50% from baseline and time to CA-125 progression (ovarian cancer only);

[0289] g.PSA50 response rate and time to PSA progression (prostate cancer only).

[0290] 6. PK characteristics of combined anti-B7H4 antibody-drug conjugate therapy in patients with advanced solid tumors.

[0291] Exploratory study endpoints:

[0292] 1. Explore the relationship between exposure and effect;

[0293] 2. Explore biomarkers that predict or influence the efficacy of PARP inhibitor combination therapy.

Claims

1. Use of an antibody-drug conjugate and an anti-VEGF antibody in combination for the preparation of a drug for treating cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I): in: n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, and n is a decimal or an integer; Pc is an anti-B7H4 antibody or an antigen-binding fragment thereof.

2. The use according to claim 1, wherein the anti-B7H4 antibody or antigen-binding fragment thereof comprises: heavy chain HCDR1, HCDR2, HCDR3 as shown in the amino acid sequences of SEQ ID NOs: 01, 02 and 03, respectively, and light chain LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NOs: 04, 05 and 06, respectively.

3. The use according to claim 1 or 2, wherein the anti-B7H4 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.

4. The use according to claim 3, wherein the anti-B7H4 antibody or its antigen-binding fragment comprises a heavy chain constant region of human IgG1, IgG2, IgG3 or IgG4 isotype, and a light chain constant region comprising κ or λ; preferably, the anti-B7H4 antibody or its antigen-binding fragment comprises a heavy chain constant region of IgG1 or IgG4 isotype.

5. The use according to claim 3, wherein the heavy chain variable region sequence of the anti-B7H4 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 07 or a variant thereof, and the light chain variable region sequence is as shown in SEQ ID NO: 08 or a variant thereof.

6. The use according to any one of claims 1 to 5, wherein the heavy chain sequence of the anti-B7H4 antibody or antigen-binding fragment thereof is as shown in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is as shown in SEQ ID NO: 10 or a variant thereof.

7. The method according to any one of claims 1 to 6, wherein the anti-VEGF antibody is selected from the group consisting of Bevacizumab, Ranibizumab, Sevacizumab, Suvemcitug, Varisacumab, CMAB-801, and LYN-00101.

8. The use according to any one of claims 1 to 7, wherein the antibody drug conjugate and the anti-VEGF antibody are contained in different preparations as active ingredients, respectively, and are administered simultaneously, concurrently, sequentially, continuously, alternately or separately.

9. The use according to any one of claims 1 to 8, further combined with a platinum drug.

10. The use according to claim 9, wherein the platinum drug is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, dicycloplatin; preferably carboplatin and / or cisplatin.

11. The use according to claim 9 or 10, wherein the antibody-drug conjugate, anti-VEGF antibody, and platinum drug are contained in different preparations as active ingredients, respectively, and are administered simultaneously, concurrently, sequentially, continuously, alternately, or separately.

12. The method according to any one of claims 9 to 11, wherein the dosage of the platinum drug is 10 mg / m 2 Up to 500 mg / m 2 , preferably 10 mg / m 2 Up to 200 mg / m 2 , more preferably 25 mg / m 2 , 50mg / m 2 , 75mg / m 2 , 100mg / m 2 , 125mg / m 2 , 150mg / m 2 , 175mg / m 2 or 200 mg / m 2 The dosing frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

13. The use according to any one of claims 9 to 11, wherein the dosage of the platinum drug is calculated as the area under the curve (AUC) and is selected from 1 to 10 mg / ml / min, preferably 3 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, 8 mg / ml / min, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

14. The use according to any one of claims 1 to 8, further combined with a poly (ADP-ribose) polymerase inhibitor.

15. The use according to claim 14, wherein the poly(ADP-ribose) polymerase inhibitor is selected from one or more of Olaparib, Fluzoparib, Niraparib, Pamiparib, Rucaparib, Talazoparib, Veliparib, Senaparib, CEP-8983, BGB-290 or 1'-((7-ethyl-6-carbonyl-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)-N-methyl-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-6-carboxamide.

16. The use according to claim 14 or 15, wherein the antibody-drug conjugate, anti-VEGF antibody, and poly(ADP-ribose) polymerase inhibitor are contained in different preparations as active ingredients, respectively, and are administered simultaneously, concurrently, sequentially, continuously, alternately, or separately.

17. The use according to any one of claims 14 to 16, wherein the poly(ADP-ribose) polymerase inhibitor is administered at a dose of 1 mg / kg to 500 mg / m 2 , preferably 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg, 50mg / kg, 55mg / kg, 60mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, 100mg / kg, 110mg / kg, 120mg / kg, 130mg / kg, 140mg / kg, 150mg / kg, 160mg / kg, 170mg / kg, 180mg / kg, 190mg / kg, 2 00mg / kg, 210mg / kg, 220mg / kg, 230mg / kg, 240mg / kg, 250mg / kg, 260mg / kg, 270mg / kg, 280mg / kg, 290mg / kg, 300mg / kg, 320mg / kg, 340mg / kg, 350mg / kg, 360mg / kg, 380mg / kg, 400mg / kg, 420mg / kg, 440mg / kg, 450mg / kg, 460mg / kg, 480mg / kg or 500mg / kg; the dosage frequency is once a day, twice a day, three times a day, once every two days or once every three days.

18. The use according to any one of claims 1 to 17, wherein the dosage of the antibody drug conjugate is 0.1 mg / kg to 12.0 mg / kg, preferably 1.0 mg / kg to 12.0 mg / kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

19. The use according to any one of claims 1 to 18, wherein the dose of the anti-VEGF antibody is 1.0 mg / kg to 100 mg / kg, preferably 1.0 mg / kg to 40 mg / kg, more preferably 1.0 mg / kg to 30 mg / kg, and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks.

20. The use according to any one of claims 1 to 19, wherein the cancer is an advanced solid tumor for which adequate standard treatment has failed or for which there is no effective standard treatment.

21. The method of claim 1 , wherein the cancer is selected from at least one of the following: ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, Paget's disease, and sarcoma.

22. The use according to claim 21, wherein the fallopian tube cancer is selected from platinum-resistant fallopian tube cancer and platinum-sensitive recurrent fallopian tube cancer.

23. The use according to claim 21, wherein the ovarian cancer is selected from epithelial ovarian cancer and platinum-sensitive recurrent ovarian cancer; the uterine cancer is selected from endometrial cancer; and the peritoneal cancer is selected from primary peritoneal cancer.

24. The use according to claim 23, wherein the epithelial ovarian cancer is selected from platinum-resistant epithelial ovarian cancer and platinum-sensitive recurrent epithelial ovarian cancer; the endometrial cancer is selected from advanced endometrial cancer that has failed adequate standard treatment or has no effective standard treatment, and recurrent / metastatic endometrial cancer; and the primary peritoneal cancer is selected from platinum-resistant primary peritoneal cancer and platinum-sensitive recurrent primary peritoneal cancer.

25. A method for treating or preventing cancer, comprising administering to a subject in need thereof an antibody drug conjugate as claimed in any one of claims 1 to 19, an anti-VEGF antibody as defined in any one of claims 1 to 19, and optionally a platinum drug as defined in any one of claims 9 to 13, wherein the combined administration can be simultaneous, concurrent, sequential, continuous, alternating or separate administration.

26. A method for treating or preventing cancer, comprising administering to a subject in need thereof an antibody-drug conjugate according to any one of claims 1 to 19, an anti-VEGF antibody as defined in any one of claims 1 to 19, and a platinum drug as defined in any one of claims 9 to 13 in combination during an induction therapy phase, wherein the combined administration may be simultaneous, concurrent, sequential, continuous, alternating, or separate administration; and administering to a subject in need thereof an antibody-drug conjugate according to any one of claims 1 to 19, an anti-VEGF antibody as defined in any one of claims 1 to 19, and a poly(ADP-ribose) polymerase inhibitor as defined in any one of claims 14 to 17 in combination during a maintenance therapy phase after the induction therapy, wherein the combined administration may be simultaneous, concurrent, sequential, continuous, alternating, or separate administration.

27. The method of claim 25 or 26, wherein the cancer is an advanced solid tumor for which adequate standard therapy has failed or for which there is no effective standard therapy.

28. The method of claim 25 or 26, wherein the cancer is selected from at least one of the following: ovarian cancer, fallopian tube cancer, peritoneal cancer, uterine cancer, head and neck cancer, lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, bladder cancer, esophageal cancer, salivary gland cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, vulvar cancer, penile cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, Paget's disease, and sarcoma.

29. The method according to claim 28, wherein the fallopian tube cancer is selected from platinum-resistant fallopian tube cancer and platinum-sensitive recurrent fallopian tube cancer.

30. The method of claim 28, wherein the ovarian cancer is selected from epithelial ovarian cancer and platinum-sensitive recurrent ovarian cancer; the uterine cancer is selected from endometrial cancer; and the peritoneal cancer is selected from primary peritoneal cancer.

31. The method of claim 30, wherein the epithelial ovarian cancer is selected from platinum-resistant epithelial ovarian cancer, platinum-sensitive recurrent epithelial ovarian cancer, high-grade serous ovarian cancer, and high-grade endometrioid epithelial ovarian cancer; the endometrial cancer is selected from advanced endometrial cancer that has failed adequate standard treatment or has no effective standard treatment, and recurrent / metastatic endometrial cancer; and the primary peritoneal cancer is selected from platinum-resistant primary peritoneal cancer and platinum-sensitive recurrent primary peritoneal cancer.

32. A pharmaceutical combination comprising the antibody drug conjugate of any one of claims 1 to 19 and a pharmaceutically acceptable excipient thereof, the anti-VEGF antibody defined in any one of claims 1 to 19 and a pharmaceutically acceptable excipient thereof; and optionally, a platinum drug defined in any one of claims 9 to 13 and a pharmaceutically acceptable excipient thereof.

33. A pharmaceutical combination comprising the antibody-drug conjugate of any one of claims 1 to 19 and a pharmaceutically acceptable excipient thereof, the anti-VEGF antibody defined in any one of claims 1 to 19 and a pharmaceutically acceptable excipient thereof, and the poly(ADP-ribose) polymerase inhibitor defined in any one of claims 14 to 17 and a pharmaceutically acceptable excipient thereof.

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