Combined use of antibody-drug conjugate and immune checkpoint inhibitor

Abstract

Provided is a use of an antibody-drug conjugate alone or in combination in the preparation of drugs for preventing and / or treating cancer. Specifically, provided is a use of an antibody-drug conjugate or a pharmaceutically acceptable salt, metabolite or solvent compound thereof alone or in combination with an immune checkpoint inhibitor in the preparation of drugs for preventing and / or treating cancer.

Description

Combination therapy of antibody-drug conjugates and immune checkpoint inhibitors Technical Field

[0001] This application belongs 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 immune checkpoint inhibitor, 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. The monoclonal antibody serves as a carrier for the efficient and targeted delivery of small-molecule cytotoxic drugs to target tumor cells. Tumor-specific antibodies enable ADCs to selectively deliver small-molecule cytotoxic drugs, minimizing off-target effects while retaining their anti-tumor properties, effectively improving the benefit-risk ratio of anti-tumor therapy. B7 homology 3 protein (B7-H3, also known as CD276, herein referred to as "B7-H3" or "B7H3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily and a member of the B7 immune co-stimulatory and co-inhibitory family. It is overexpressed in a variety of solid tumors, including lung cancer, prostate cancer, esophageal cancer, head and neck squamous cell carcinoma, osteosarcoma, bladder cancer, and melanoma, but has limited expression in normal tissues. Therefore, B7-H3 is an ideal target for ADCs.

[0003] Immune checkpoint inhibitors (ICIs) block the binding of immune checkpoints to their ligands, relieving checkpoint-induced immune suppression and thereby reactivating immune cells to exert anti-tumor effects. Currently, several ICIs have achieved remarkable results in clinical anti-tumor applications, representing a breakthrough in cancer treatment. Inhibitors targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been successfully used in the clinical treatment of various malignancies. PD-1 / PD-L1 antibodies have a broad anti-cancer spectrum and demonstrate robust and long-lasting efficacy in some cancer patients. Ten PD-1 monoclonal antibodies and three PD-L1 monoclonal antibodies have been approved for the clinical treatment of 11 cancer types, including non-small cell lung cancer, melanoma, head and neck cancer, colorectal cancer, and gastric cancer. Although ICIs have significant anti-tumor activity in many types of malignant tumors, their response rate is low in most tumors, and new regimens need to be developed to improve the response rate of ICIs treatment.

[0004] Classic osteosarcoma (hereafter referred to as osteosarcoma) is a common malignant bone tumor, accounting for 35% of all malignant bone tumors. Classic osteosarcoma is more common in adolescents, with a median age of onset of 20 years. It is the most common primary malignant bone tumor in children and adolescents. Approximately 10% to 15% of newly diagnosed osteosarcoma patients develop distant metastases. The 5-year survival rate for patients with localized osteosarcoma is approximately 60%, while that for patients with advanced (recurrent or metastatic) osteosarcoma is only approximately 20%. The standard first-line chemotherapy regimen for osteosarcoma consists of methotrexate, doxorubicin, cisplatin, and ifosfamide. Patients with osteosarcoma who are not candidates for radical surgery lack effective treatment options after standard chemotherapy fails. No drugs or other treatments have demonstrated a significant survival benefit for these patients. Currently, there are no approved second-line treatment options, and existing treatments are associated with significant hematologic toxicity and adverse reactions. Therefore, improving the efficacy of second-line osteosarcoma treatment and prolonging patient survival are among the goals of current clinical research, and new treatments are urgently needed to meet these patient needs.

[0005] The preferred combination therapy of the present invention exhibits higher effects than any single treatment, and while improving efficacy, has lower side effects of combined medication, thereby maximizing the survival benefits of patients receiving immunotherapy.

[0006] Summary of the Invention

[0007] The present disclosure provides a use of an antibody-drug conjugate and an immune checkpoint inhibitor in combination in the preparation of a drug for treating cancer. The structure of the antibody-drug conjugate is shown in formula (I):

[0008] 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 4.1.

[0009] Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof.

[0010] In some embodiments, the anti-B7H3 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.

[0011] 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.

[0012] Among them, the CDR sequences mentioned above are shown in the following table:

[0013] Table 1 Heavy chain and light chain CDR sequences

[0014] Note: CDR sequences are derived from those shown in the Kabat definition.

[0015] Preferably, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.

[0016] In some alternative embodiments, the anti-B7H3 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.

[0017] In some optional embodiments, the anti-B7H3 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.

[0018] In other alternative embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a light chain constant region of kappa or lambda.

[0019] Furthermore, it is preferred that the heavy chain variable region sequence of the anti-B7H3 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.

[0020] The sequences of the heavy and light chain variable regions of the aforementioned anti-B7H3 antibodies or antigen-binding fragments thereof are shown below:

[0021] Heavy chain variable region sequence

[0022] Light chain variable region sequence

[0023] 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.

[0024] Furthermore, it is preferred that the heavy chain sequence of the anti-B7H3 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.

[0025] The sequences of the heavy and light chains of the aforementioned anti-B7H3 antibodies or antigen-binding fragments thereof are shown below:

[0026] Heavy chain (IgG1) amino acid sequence: (SEQ ID NO: 09)

[0027] Light chain (λ) amino acid sequence: (SEQ ID NO: 10)

[0028] In some embodiments, the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof targeting PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, B7-H4, preferably antibodies or antigen-binding fragments thereof targeting PD-1 or PD-L1.

[0029] In some embodiments, the immune checkpoint inhibitor is selected from Toripalimab, Sintilimab, Camrelizumab, Dostarlimab, Tislelizumab, Zimberelimab, Penpulimab, Serplulimab, Pucotenlimab, Pembrolizumab, olizumab), Nivolumab, Sugemalimab, Envafolimab, Adebrelimab, Atezolizumab, Durvalumab, Ipilimumab, Candonilimab, with Camrelizumab and Adebrelimab being preferred.

[0030] The sequences of the heavy and light chains of the aforementioned carrelizumab are as follows:

[0031] Heavy chain amino acid sequence: (SEQ ID NO: 11)

[0032] Light chain amino acid sequence: (SEQ ID NO: 12)

[0033] The sequences of the heavy and light chains of the aforementioned Adebelimumab are shown below:

[0034] Heavy chain amino acid sequence: (SEQ ID NO: 13)

[0035] Light chain amino acid sequence: (SEQ ID NO: 14)

[0036] Dotalizumab is a PD-1 blocking IgG4 humanized monoclonal antibody, marketed as JEMPERLI. The main structure and function of dotalizumab have been described in WO 2014 / 179664, WO 2018 / 085468 and WO 2018 / 129559.

[0037] The heavy and light chain sequences of dotalizumab are as follows:

[0038] Heavy chain amino acid sequence: (SEQ ID NO: 15)

[0039] Light chain amino acid sequence: (SEQ ID NO: 16)

[0040] In some embodiments, dotarizumab or a biosimilar thereof is administered to a patient in need thereof at a dose of 500 mg once every three weeks (Q3W).

[0041] In some embodiments, patients in need thereof are administered 500 mg of dotarizumab or a biosimilar thereof once every three weeks (Q3W) for 4-6 cycles, followed by 1000 mg of dotarizumab or a biosimilar thereof once every 6 weeks (Q6W).

[0042] Pembrolizumab is a PD-1 blocking IgG4 humanized monoclonal antibody, sold under the trade name KEYTRUDA.

[0043] The heavy and light chain sequences of pembrolizumab are as follows:

[0044] Heavy chain amino acid sequence: (SEQ ID NO: 17)

[0045] Light chain amino acid sequence: (SEQ ID NO: 18)

[0046] In some embodiments, pembrolizumab or a biosimilar thereof is administered to a patient in need thereof at a dose of 200 mg once every three weeks (Q3W); or, at a dose of 400 mg once every six weeks (Q6W).

[0047] Imfinzi is a PD-L1 blocking IgG1 monoclonal antibody marketed under the trade name IMFINZI.

[0048] The heavy and light chain sequences of durvalumab are as follows:

[0049] Heavy chain amino acid sequence: (SEQ ID NO: 19)

[0050] Light chain amino acid sequence: (SEQ ID NO: 20)

[0051] In some embodiments, durvalumab or a biosimilar thereof is administered to patients in need thereof who are ≥30 kg at a dose of 1500 mg once every three weeks (Q3W).

[0052] In some embodiments, durvalumab or a biosimilar thereof is administered to patients in need thereof who are <30 kg at a dose of 20 mg / kg once every three weeks (Q3W).

[0053] In some embodiments, durvalumab or a biosimilar thereof is administered to patients in need thereof ≥ 30 kg at a dose of 1120 mg once every three weeks (Q3W).

[0054] In some embodiments, durvalumab or a biosimilar thereof is administered to patients in need thereof weighing <30 kg at a dose of 15 mg / kg once every three weeks (Q3W).

[0055] On the other hand, the present invention discloses the use of the antibody-drug conjugate and the immune checkpoint inhibitor in combination with a platinum drug in the preparation of a drug for treating cancer.

[0056] In an optional embodiment, the platinum drug is selected from the group consisting of: carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, dicycloplatin, preferably carboplatin and / or cisplatin.

[0057] In an alternative embodiment, the antibody drug conjugate and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.

[0058] In an optional embodiment, the antibody-drug conjugate, the immune checkpoint inhibitor, and the platinum drug are contained in different preparations as active ingredients, and are administered simultaneously or at different times.

[0059] In another aspect, the antibody drug conjugate and the immune checkpoint inhibitor are contained in a single formulation as active ingredients and administered.

[0060] In another aspect, the antibody drug conjugate, the immune checkpoint inhibitor, and the platinum drug are contained in a single preparation as active ingredients and administered.

[0061] 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 4.0 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 kg, 5.8mg / 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, 9.0m g / kg, 9.2mg / kg, 9.4mg / kg, 9.6mg / kg, 9.8mg / kg, 10.0mg / kg, 10.2mg / kg, 10.4mg / kg, 10.6 mg / kg, 10.8mg / kg, 11.0mg / kg, 11.2mg / kg, 11.4mg / kg, 11.6mg / kg, 11.8mg / kg or 12.0mg / kg.

[0062] 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.

[0063] In a preferred embodiment, the antibody drug conjugate is administered at a starting dose of 6.0 mg / kg or 8.0 mg / kg, with a dosing frequency of once every three weeks.

[0064] In an optional embodiment, the dose of the immune checkpoint inhibitor is 10 mg to 2000 mg, preferably 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265mg, 270mg, 275mg, 280mg, 285mg, 290mg, 295mg, 300mg, 310mg, 320mg, 325mg, 330mg, 340mg, 350mg, 360mg, 370mg, 375mg, 380mg, 390mg, 400mg, 450mg, 500mg , 550mg, 600mg, 650mg, 700mg, 750mg, 800mg, 850mg, 900mg, 950mg, 1000mg, 1100mg, 1120mg, 1150mg, 1200mg, 1250mg, 1300mg, 1350mg, 1400mg, 1450mg, 1500mg.

[0065] In an optional embodiment, the dose of the immune checkpoint inhibitor 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, 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. / kg, 4.8mg / kg, 5.0mg / kg, 5.2mg / kg, 5.4mg / kg, 5.6mg / kg, 5.8mg / 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, 12.0mg / kg, 12.2mg / kg, 12.4mg / kg, 12.6mg / kg, 12.8mg / kg, 13.0mg / kg, 13.2mg / kg, 13.4mg / kg, 13.6mg / kg, 13.8mg / kg, 14.0mg / kg, 14.2mg / kg, 14.4mg / kg, 14.6mg / kg, 14.8mg / kg, 15.0mg / kg, 15 .2mg / kg, 15.4mg / kg, 15.6mg / kg, 15.8mg / kg, 16.0mg / kg, 16.2mg / kg, 16.4mg / kg, 16.6mg / kg, 16.8mg / kg, 17.0mg / kg, 17.2mg / kg, 17.4mg / kg, 17.6mg / kg, 17.8mg / kg, 18.0mg / kg, 18.2mg / kg, 18.4mg / kg, 18.6mg / kg, 18.8mg / kg, 19.0mg / kg, 19.2mg / kg, 19.4mg / kg, 19.6mg / kg, 19.8mg / kg, 20.0mg / kg, 20.2mg / kg, 20.4mg / kg, 20.6mg / kg, 20.8mg / kg, 30.0mg / kg. .

[0066] In an optional embodiment, the immune checkpoint inhibitor is administered once a week, once every two weeks, once every three weeks, or once every four weeks.

[0067] In a preferred embodiment, the dose of the immune checkpoint inhibitor is 20 mg / kg, and the administration frequency is once every three weeks.

[0068] 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.

[0069] 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.

[0070] In an optional embodiment, the platinum drug is administered for a total of 4 to 6 cycles.

[0071] In a preferred embodiment, the dosage of platinum drugs is: cisplatin 75 mg / m 2 Or carboplatin AUC 5mg / ml / min intravenous drip, the dosage frequency is once every three weeks.

[0072] In an optional embodiment, the cancer is selected from at least one of the following: lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine 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, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.

[0073] Furthermore, the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma.

[0074] In an alternative embodiment, the cancer is an advanced solid cancer that has failed or is intolerant to first-line treatment or has no effective standard treatment.

[0075] In alternative embodiments, the cancer is a recurrent, metastatic and / or drug-resistant cancer.

[0076] In an optional embodiment, the cancer is an advanced solid tumor such as small cell lung cancer, non-small cell lung squamous cell carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, etc.

[0077] In an optional embodiment, the cancer is extensive-stage small cell lung cancer (SCLC) that has failed or is intolerant to at least one line of treatment, locally advanced or metastatic non-small cell lung squamous cell carcinoma (NSCLC) that has progressed after or is intolerant to at least one line of treatment, unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that has progressed after or is intolerant to at least one line of treatment, locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed after or is intolerant to at least one line of treatment, or other advanced solid tumors that have failed adequate standard treatment or have no effective standard treatment.

[0078] In an alternative embodiment, the osteosarcoma is advanced osteosarcoma.

[0079] In an optional embodiment, advanced osteosarcoma is advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 lines of treatment.

[0080] The present disclosure also provides a pharmaceutical composition comprising the above-mentioned antibody-drug conjugate and immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0081] In some embodiments, the pharmaceutical composition further comprises the platinum drug, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0082] The present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate and an immune checkpoint inhibitor in combination to a subject in need thereof, wherein the combined administration can be simultaneous or at different time points.

[0083] The present disclosure also provides a method for treating cancer, comprising administering the above-mentioned antibody-drug conjugate, an immune checkpoint inhibitor, and a platinum drug in combination to a subject in need thereof, wherein the combined administration can be simultaneous or at different time points.

[0084] In an optional embodiment, the cancer is selected from at least one of the following: lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine 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, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tissue tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.

[0085] In an optional embodiment, the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma.

[0086] In an alternative embodiment, the cancer is an advanced solid cancer that has failed or is intolerant to first-line treatment or has no effective standard treatment.

[0087] In alternative embodiments, the cancer is a recurrent, metastatic and / or drug-resistant cancer.

[0088] In an optional embodiment, the cancer is an advanced solid tumor such as small cell lung cancer, non-small cell lung squamous cell carcinoma, esophageal squamous cell carcinoma, nasopharyngeal carcinoma, etc.

[0089] In an optional embodiment, the cancer is extensive-stage small cell lung cancer (SCLC) that has failed or is intolerant to at least one line of treatment, locally advanced or metastatic non-small cell lung squamous cell carcinoma (NSCLC) that has progressed after or is intolerant to at least one line of treatment, unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that has progressed after or is intolerant to at least one line of treatment, locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed after or is intolerant to at least one line of treatment, or other advanced solid tumors that have failed adequate standard treatment or have no effective standard treatment.

[0090] In an alternative embodiment, the osteosarcoma is advanced osteosarcoma.

[0091] In an optional embodiment, advanced osteosarcoma is advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 lines of treatment.

[0092] Another aspect of the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H3 antibody-drug conjugate is used in combination with the aforementioned anti-PD-1 antibody or an antigen-binding fragment thereof.

[0093] Another aspect of the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H3 antibody-drug conjugate is used in combination with the aforementioned anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0094] Another aspect of the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H3 antibody-drug conjugate is used in combination with the aforementioned anti-PD-1 antibody or antigen-binding fragment thereof and the aforementioned platinum drug.

[0095] Another aspect of the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in treating cancer, wherein the anti-B7H3 antibody-drug conjugate is used in combination with the aforementioned anti-PD-L1 antibody or antigen-binding fragment thereof and the aforementioned platinum drug.

[0096] 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.

[0097] Administration by simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration all fall within the scope of combined administration described herein. "Simultaneously" herein refers to administering at least one dose of an anti-PD-1 / PD-L1 antibody or antigen-binding fragment thereof and an anti-B7H3 antibody-drug conjugate within a certain time period, optionally within 3 days, 2 days, or 1 day, wherein both or more drugs exhibit pharmacological effects. "Sequential" administration includes administering an anti-PD-1 / PD-L1 antibody or antigen-binding fragment thereof and an anti-B7H3 antibody-drug conjugate separately within different dosing cycles. The time period can be within one dosing cycle, optionally within 4 weeks, 3 weeks, 2 weeks, or 1 week. This period includes treatments in which the anti-PD-1 / PD-L1 antibody or antigen-binding fragment thereof and the anti-B7H3 antibody-drug conjugate are administered by the same route of administration or by different routes of administration.

[0098] the term

[0099] 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.

[0100] The present disclosure incorporates all the contents of application WO2020063673 into the present application.

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] The term "immune checkpoint inhibitor" refers to agents that inhibit the immunosuppressive system to activate tumor immunity.

[0108] The term "anti-PD-1 antibody or an antigen-binding fragment thereof" refers to an antibody that specifically binds to PD-1 (programmed cell death-1; CD279; PDCD1) and has the activity of reducing, inhibiting, and / or interfering with signal transduction caused by the interaction between PD-1 and PD-L1 or PD-L2 as a binding partner. The anti-PD-1 antibody used in the present disclosure is not particularly limited as long as its clinical efficacy and safety have been demonstrated.

[0109] The term "anti-PD-L1 antibody or antigen-binding fragment thereof" refers to an antibody that specifically binds to PD-L1 (programmed cell death ligand 1; CD274; B7-H1) and has the activity of reducing, inhibiting, and / or interfering with signal transduction caused by the interaction between PD-L1 and PD-1 or B7.1 (CD80) as a binding partner. The anti-PD-L1 antibody used in the present disclosure is not particularly limited as long as its clinical efficacy and safety have been demonstrated.

[0110] 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.

[0111] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] Figure 1. Efficacy of drug A combined with drug B on the subcutaneous xenograft tumor model of human lung cancer cell line Calu-6.

[0113] Figure 2. Efficacy of drug A combined with drug C on the subcutaneous xenograft tumor model of human lung cancer cell line Calu-6.

[0114] Figure 3. Efficacy of drug A combined with drug B on the subcutaneous xenograft tumor model of human osteosarcoma cell line SJSA-1.

[0115] Figure 4. Efficacy of drug A combined with drug C on the subcutaneous xenograft tumor model of human osteosarcoma cell line SJSA-1.

[0116] Figure 5 shows the changes in body weight of mice in each group in Example 4. DETAILED DESCRIPTION

[0117] 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.

[0118] Example 1. Preparation of anti-B7H3 antibody drug conjugates

[0119] According to the production method described in WO2020063673, h1702DS (anti-B7H3 antibody) and an isotecan analog were used to prepare the anti-B7H3 antibody-drug conjugate shown in the following structure. The average value calculated by the HIC method was n = 4.1, i.e., FADC-2. The h1702DS heavy chain sequence is shown in SEQ ID NO: 09, and the light chain sequence is shown in SEQ ID NO: 10.

[0120] Example 2. Efficacy of individual / combination drugs in the PBMC humanized NCG mouse homograft model of the human lung cancer cell line Calu-6.

[0121] 1. Experimental Materials

[0122] 1.1 Human lung cancer cell Calu-6 CDX model information

[0123] Calu-6 cells were cultured in DMEM supplemented with 10% fetal bovine serum and 1% penicillin-streptomycin in a 37°C, 5% CO2 incubator. After confluence, the cells were subcultured and collected in the logarithmic growth phase.

[0124] 1.2 PBMC information

[0125] PBMCs were purchased from Maishun Biotechnology Co., Ltd. in Zhejiang Free Trade Zone, batch P121090306C.

[0126] 1.3 Experimental animals

[0127] NCG mice, female, weighing 17–19 g, were purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0128] 1.4 Test drugs

[0129] 1) Drug A: Prepared using the method described in WO2020063673, the drug was prepared with normal saline.

[0130] 2) Drug B: Camrelizumab for injection, the heavy and light chain sequences are shown in SEQ ID NO: 11 and SEQ ID NO: 12, respectively. Provided by Suzhou Shengdia Biopharmaceutical Co., Ltd., batch number 202201004F. The drug was prepared in normal saline.

[0131] 3) Drug C: Adebelimumab injection, the heavy and light chain sequences are shown in SEQ ID NO: 13 and SEQ ID NO: 14, respectively. Provided by Suzhou Shengdia Biopharmaceutical Co., Ltd., batch number 202304004C. The drug was prepared in normal saline.

[0132] 1.5 Experimental Instruments

[0133] Table 1. Instruments used in the experiment

[0134] 1.6 Experimental reagents and consumables

[0135] Table 2. Reagents and consumables used in the experiment

[0136] 2. Experimental Methods

[0137] PBMC cells were taken out of liquid nitrogen, slowly shaken in a 37℃ water bath to thaw, centrifuged, resuspended in PBS and inoculated. 8 days after PBMC cell inoculation, 0.1mL Calu-6 cell suspension (containing 5×10 6 The tumors were subcutaneously inoculated on the right side of the back of NCG mice. The tumor growth was observed and the animals were randomly divided into groups according to the tumor volume and weight. The average tumor volume at the time of grouping was 145 mm 3 The day of grouping was defined as day 0, or PG-D0. All animals began dosing on the day of grouping, and the remaining animals were euthanized at the end of the experiment. Specific dosing and dosing schedules are shown in Table 3. Tumor volume was measured, mouse body weight was weighed, and data were recorded.

[0138] Table 3. Dosage and grouping

[0139] 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%.

[0140] The experimental indicators are to examine the effect of drugs on tumor growth, and the specific indicators are relative tumor proliferation rate T / C (%) or tumor inhibition rate TGI (%). Tumor volume measurement: Use vernier calipers to measure twice a week, and the tumor volume calculation formula is V = 0.5a × b 2 , a and b represent the long diameter and wide diameter of the tumor, respectively.

[0141] 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%.

[0142] 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%.

[0143] At the end of the experiment (PG-D21), all animals were euthanized by CO2 asphyxiation according to group order. After euthanasia, the tumor masses were removed, weighed, and photographed.

[0144] 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 9, and p < 0.05 was considered significant.

[0145] 3. Experimental Results

[0146] The growth inhibitory effects of drug A, drug B, and drug C alone or in combination on subcutaneous xenograft tumors of human lung cancer cells Calu-6 are shown in Table 4 and Figures 1 and 2. In the figures, the data for the Vehicle group, the Drug A_1 mg / kg group, and the Drug A_2 mg / kg group are experimental data from the same group.

[0147] Table 4. Evaluation of the antitumor efficacy of drug A, drug B, and drug C alone or in combination in the Calu-6 xenograft tumor model

[0148] a. Mean ± SEM;

[0149] b. Statistical analysis was performed using Dunnett's multiple comparisons test in a one-way ANOVA. Additionally, statistical analysis was performed using a t-test. The p-values ​​for the 2 mg / kg plus 3 mg / kg group compared with the 2 mg / kg and 3 mg / kg groups, respectively, were 0.0364 and <0.0001. The p-value for the 2 mg / kg plus 20 mg / kg group compared with the 20 mg / kg group was <0.0001.

[0150] In a PBMC-humanized Calu-6 xenograft tumor model, monotherapy with drug A at 1 mg / kg and drug A at 2 mg / kg resulted in tumor inhibition rates of 51.25% and 74.82%, respectively, demonstrating significant and dose-dependent tumor inhibition. Monotherapy with drug B at 3 mg / kg and drug C at 20 mg / kg resulted in tumor inhibition rates of 0.97% and -4.55%, respectively, demonstrating no significant tumor inhibition. Combination therapy with drug A at 1 mg / kg and drug A at 2 mg / kg and drug B at 3 mg / kg resulted in tumor inhibition rates of 58.63% and 89.93%, respectively. The combination of drug A at 2 mg / kg and drug B at 3 mg / kg significantly enhanced tumor inhibition compared to the monotherapy groups with drug A at 2 mg / kg and drug B at 3 mg / kg, demonstrating statistically significant differences (p < 0.05). The combination of Drug A (2 mg / kg) and Drug C (20 mg / kg) resulted in an 80.34% tumor inhibition rate. The combined treatment group exhibited significantly greater tumor inhibition than the Drug C (20 mg / kg) monotherapy group (p<0.05), and also significantly improved over the Drug A (2 mg / kg) monotherapy group. Furthermore, no treatment-related deaths or other adverse events occurred in the mice, demonstrating that tumor-bearing mice tolerated both Drug A monotherapy and the combination therapy with Drugs B and C well.

[0151] During the experiment, the mean body weight of the animals in the Vehicle group remained relatively stable. At the end of the experiment (day 21), the mean body weight change in this group was 8.97%. The mean body weight changes in the tumor-bearing mice treated with Drug A at 1 mg / kg and Drug A at 2 mg / kg were 8.27% and 6.22%, respectively. The mean body weight changes in the tumor-bearing mice treated with Drug B at 3 mg / kg and in combination with Drug A at 1 mg / kg and Drug A at 2 mg / kg were -3.79%, 1.73%, and -1.53%, respectively. The mean body weight changes in the tumor-bearing mice treated with Drug C at 20 mg / kg and in combination with Drug C at 2 mg / kg were 6.58% and 1.84%, respectively. Notably, GvHD induced by humanized PBMC inoculation was the primary cause of the animals' weight loss. No other treatment-related deaths or other abnormalities occurred in the mice, indicating that the tumor-bearing mice tolerated the test drug A alone and in combination with Drugs B and C well.

[0152] In summary, tumor-bearing mice were tolerant to drug A monotherapy or combined treatment with drugs B and C. The anti-tumor efficacy of the drug A_2mg / kg and drug B_3mg / kg combination treatment group was significantly better than that of each single drug treatment group. The anti-tumor efficacy of the drug A_2mg / kg and drug C_20mg / kg combination treatment group was significantly better than that of the drug C_20mg / kg monotherapy group, and better than the drug A_2mg / kg monotherapy group.

[0153] Example 3. Clinical Trial of Anti-B7H3 Antibody Drug Conjugate Combined with Immune Checkpoint Inhibitors ± Platinum Drugs for the Treatment of Advanced Solid Tumors

[0154] This trial is used to evaluate the safety, tolerability, and efficacy of various combination therapy regimens in patients with advanced solid tumors. Study endpoints include, but are not limited to: the MTD or maximum applicable dose (MAD) of the anti-B7H3 antibody-drug conjugate administered intravenously in the combination therapy regimen, the objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) assessed by the investigator according to the RECIST 1.1 criteria, the pharmacokinetic characteristics of the anti-B7H3 antibody-drug conjugate administered intravenously in the combination therapy regimen, and the immunogenicity of the anti-B7H3 antibody-drug conjugate in the combination therapy regimen.

[0155] 1. Name of investigational drug:

[0156] (1) Anti-B7H3 Antibody Drug Conjugates

[0157] Dosage form: Injection (lyophilized powder), Specification: 100 mg / bottle, packaged in 20 mL borosilicate glass tube injection bottle, Manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.

[0158] (2) Immune checkpoint inhibitors

[0159] Adebelimumab, dosage form: injection, specification: 600mg (12ml) / bottle, packaged in borosilicate glass controlled injection bottles, manufacturer: Suzhou Shengdia Biotechnology Co., Ltd.

[0160] (3) Platinum drugs

[0161] Carboplatin, dosage form: injection, specifications: 50mg (10mL) / 100mg (10mL), ampoule packaging, manufacturer: Qilu Pharmaceutical Co., Ltd.

[0162] Cisplatin, dosage form: injection, specification: 6ml: 30mg, controlled antibiotic bottled, manufacturer: Jiangsu Hausen Pharmaceutical Co., Ltd.

[0163] 2. Target group:

[0164] Patients with advanced solid tumors who have failed or are intolerant to first-line treatment or have no effective standard treatment, specifically as follows: (1) extensive-stage small cell lung cancer (SCLC) that has failed or is intolerant to at least one first-line treatment; (2) extensive-stage small cell lung cancer (SCLC) that has not received treatment; (3) locally advanced or metastatic non-small cell lung squamous cell carcinoma (NSCLC) that has progressed after at least one first-line treatment or is intolerant; (4) locally advanced or metastatic non-small cell lung squamous cell carcinoma (NSCLC) that has not received treatment in the advanced stage; (5) (6) Unresectable locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that has not been treated in the advanced stage; (7) Locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed after at least one line of treatment or is intolerant; (8) Locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that has not been treated in the advanced stage; (9) Patients with advanced solid tumors who have failed other adequate standard treatments or have no effective standard treatment and who are assessed by the investigator to be likely to benefit from the study treatment.

[0165] 3. Dosage regimen:

[0166] In this study, every 3 weeks (21 days) was a treatment cycle (C).

[0167] Cohort 1a:

[0168] The recommended dosing priority is to administer adebelimumab first, followed by the anti-B7H3 antibody-drug conjugate at least 30 minutes after the first administration. The entire dosing regimen (adebelimumab + anti-B7H3 antibody-drug conjugate) should be completed within 72 hours, starting from the first dose of the combination therapy and ending with the last dose.

[0169] Adebelimumab: 20 mg / kg, total dose calculated based on pre-dose body weight, administered by intravenous drip every 3 weeks until objective disease progression (excluding donated drugs) or other protocol-specified criteria for discontinuation of study treatment are met. Anti-B7H3 antibody-drug conjugate: Administered at a starting dose of 8.0 mg / kg by intravenous drip every 3 weeks until objective disease progression (excluding donated drugs) or other protocol-specified criteria for discontinuation of study treatment are met.

[0170] Cohort 1b:

[0171] The recommended dosing priority is: administer adebelimumab first, followed by an anti-B7H3 antibody-drug conjugate at least 30 minutes after the completion of the dosing; then administer cisplatin / carboplatin at least 60 minutes after the completion of the anti-B7H3 antibody-drug conjugate. The entire dosing regimen (adebelimumab + anti-B7H3 antibody-drug conjugate + cisplatin / carboplatin) should be completed within 72 hours, starting from the first dose of the combination therapy and ending with the last dose.

[0172] Adebelimumab: 20 mg / kg, total dose calculated based on pre-dose weight, intravenous drip, every 3 weeks, until objective disease progression (excluding donated drugs) or other protocol-specified termination criteria are met. Anti-B7H3 antibody-drug conjugate: Administered at a starting dose of 6.0 mg / kg, intravenous drip, every 3 weeks, until objective disease progression (excluding donated drugs) or other protocol-specified termination criteria are met.

[0173] Cisplatin / Carboplatin: Cisplatin 75 mg / m² or carboplatin AUC 5 mg / ml / min intravenously every 3 weeks for 4-6 cycles. Investigators may choose cisplatin or carboplatin based on the patient's specific condition. Interchangeability of cisplatin and carboplatin is permitted during treatment due to tolerability issues, but patients should be fully informed of the risk of cross-sensitivity. If a patient cannot tolerate the drug due to safety reasons, treatment should be discontinued.

[0174] Example 4. Evaluation of the in vivo inhibitory effect of drug A combined with drug B or drug C on human osteosarcoma cell transplanted tumors in mice

[0175] 1. Experimental Materials

[0176] The human osteosarcoma cell line SJSA-1 was purchased from Guangzhou Geneo Biotechnology Co., Ltd. and cultured as a monolayer in vitro in DMEM medium supplemented with 10% fetal bovine serum in a 37°C, 5% CO2 incubator. Cells were routinely digested and passaged twice weekly using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, cells were harvested, counted, and plated.

[0177] NOG-dKO mice, female, weighing 16-22 g, were purchased from Zhejiang Weitong Lihua Laboratory Animal Technology Co., Ltd.

[0178] 2. Experimental Methods

[0179] PBMC cells (human peripheral blood mononuclear cells) were resuspended in PBS and the density was adjusted to 5.0×10 7 cells / mL, injected into the tail vein, and each mouse was inoculated with 0.1 mL (5.0×10 6 cells / mice);

[0180] One week after seeding PBMC cells, SJSA-1 cells were resuspended in PBS and the density was adjusted to 1.0×10 8 The resuspended cells were mixed with an equal volume of Matrigel and inoculated subcutaneously on the right back of each mouse, with 0.1 mL (5.0 × 10 6 cells / mice);

[0181] When the average tumor volume grows to 50-100 mm 3 Mice were divided into groups (D0) and dosed (D0). Drugs were administered via tail vein injection (iv, drug A) or intraperitoneal injection (ip, drug B or drug C), either single dose (drug A) or twice weekly (biweekly, drug B or drug C). The dose volume was 10 mL / kg. The solvent group received the same volume of "saline." Specific dosages and dosing schedules are shown in Table 1. Tumor volume was measured, mice were weighed, and data were recorded.

[0182] The experimental indicators are to examine the effect of drugs on tumor growth, and the specific indicators are T / C% or tumor inhibition rate TGI (%).

[0183] The tumor diameter was measured with a vernier caliper, and the tumor volume (V) was calculated as follows:

[0184] V=1 / 2×a×b 2 Where a and b represent the long and short diameters of the tumor, respectively.

[0185] T / C(%)=(TT i ) / (CC i)×100, where T and C are the tumor volumes of the drug-treated group and the control group at the end of the experiment, T i and C i The tumor volumes of the drug-treated group and the control group at the beginning of the experiment.

[0186] Tumor inhibition rate (TGI) (%) = 100-T / C ​​(%).

[0187] When the tumor regressed, the tumor inhibition rate (TGI) (%) = 100-(T-Ti) / Ti×100.

[0188] If the tumor is smaller than its starting size, T <T i or C <C i If the tumor disappears completely, it is defined as complete tumor regression (CR).

[0189] The experiment ends, the experimental endpoint is reached, or the average tumor volume reaches 2,000 mm 3 , the mice were euthanized, and the tumors were dissected and photographed.

[0190] Experimental data were analyzed and graphed using GraphPad Prism 9. Two-way ANOVA was used to analyze tumor volume data at different time points within each group and assess intergroup differences. A P value < 0.05 was considered statistically significant.

[0191] Table 5. Dosing regimen of drug A combined with drug B or drug C in the human osteosarcoma SJSA-1 model

[0192] 3. Experimental Results

[0193] The growth inhibitory effect of drug A combined with drug B on the SJSA-1 model is shown in Table 6 and Figure 3, and the weight changes of mice in each group are shown in Figure 5; the growth inhibitory effect of drug A combined with drug C on the SJSA-1 model is shown in Table 7 and Figure 4, and the weight changes of mice in each group are shown in Figure 5.

[0194] Table 6. Growth inhibitory effects of drug A combined with drug B on the SJSA-1 model

[0195] Note:

[0196] P value Day 22: The value obtained by analyzing the tumor volume of each animal in different groups with the vehicle group as the control;

[0197] # : Compared with the drug A + drug B combination group, two-way ANOVA was used for analysis. ## P<0.01,### P<0.001.

[0198] At the end of the experiment (Day 22), the average tumor volumes of the drug A, drug B, and drug A + drug B groups were 1,763 mm 3 、1,900mm 3 and 907mm 3 , the tumor inhibition rates were 31.26%, 25.67% and 66.08%, respectively; compared with the solvent group, each drug group had a significant tumor inhibition effect (P values ​​were 0.0040, 0.0176 and <0.001, respectively); the drug A + drug B combination treatment group (G5) showed statistically significant differences compared with the respective single drug groups (G2 and G3) (P<0.01 and P<0.001), reflecting a strong tumor inhibition effect.

[0199] Table 7. Growth inhibitory effects of drug A combined with drug C on the SJSA-1 model

[0200] Note:

[0201] P value Day 22: The value obtained by analyzing the tumor volume of each animal in different groups with the vehicle group as the control;

[0202] # : Compared with the drug A + drug C combination group, two-way ANOVA was used for analysis. ### P<0.001.

[0203] At the end of the experiment (Day 22), the average tumor volumes of the drug A, drug C, and drug A + drug C groups were 1,763 mm 3 、1,911mm 3 and 558mm 3 , the tumor inhibition rates were 31.26%, 25.25% and 80.26%, respectively; compared with the solvent group, each drug group had a significant tumor inhibition effect (P values ​​were 0.0051, 0.0234 and <0.001, respectively); the drug A + drug C combination treatment group (G6) showed statistically significant differences compared with the respective single drug groups (G2 and G4) (P < 0.001), reflecting a stronger tumor inhibition effect.

[0204] During the entire experiment, SJSA-1 tumor-bearing mice showed good tolerance to drug A, drug B, drug C, drug A combined with drug B, and drug A combined with drug C.

[0205] Overall, in the human osteosarcoma cell SJSA-1 mouse model, the combination of drug A + drug B and drug A + drug C had better tumor inhibitory effects than each drug alone.

[0206] Example 5. Clinical trial of anti-B7H3 antibody drug conjugate combined with immune checkpoint inhibitors for the treatment of advanced osteosarcoma

[0207] To evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of an injectable anti-B7H3 antibody-drug conjugate combination therapy in subjects with advanced osteosarcoma.

[0208] To determine a safe and potentially effective dose, an expanded study in the target population will be conducted to obtain further safety, PK and efficacy of the combination therapy and to determine the target dose of the combination therapy.

[0209] 1. Name of investigational drug:

[0210] (1) Anti-B7H3 Antibody Drug Conjugates

[0211] Dosage form: Injection (lyophilized powder), Specification: 100 mg / bottle, packaged in 20 mL borosilicate glass tube injection bottle, Manufacturer: Shanghai Hansoh Biopharmaceutical Technology Co., Ltd.

[0212] (2) Immune checkpoint inhibitors

[0213] Adebelimumab, dosage form: injection, specification: 600mg (12ml) / bottle, packaged in borosilicate glass controlled injection bottles, manufacturer: Suzhou Shengdia Biotechnology Co., Ltd.

[0214] 2. Target group:

[0215] Queue 2

[0216] Dose escalation / expansion population: Patients with advanced osteosarcoma who have progressed after standard treatment and meet the following conditions:

[0217] ① Advanced osteosarcoma definition: a. The primary tumor or locally recurrent tumor cannot be radically cured by surgery or other local treatments (e.g., stereotactic radiosurgery, argon-helium cryoablation, focused ultrasound, etc.), or the patient refuses surgery or other local treatments. b. Distant metastasis has occurred, and the metastatic tumor cannot be radically cured by surgery or other local treatments (e.g., stereotactic radiosurgery, argon-helium cryoablation, focused ultrasound, etc.), or the patient refuses surgery or other local treatments.

[0218] ② Progression after standard treatment, defined as receipt of two or more of the following standard treatment drugs: methotrexate, anthracyclines, cisplatin, or ifosfamide. Subjects who have previously received only first-line treatment (≥2 standard treatment drugs) and whose disease progression occurred within 6 months after the end of treatment are eligible for inclusion in the study. For patients whose disease progression occurred more than 6 months after the end of treatment, the investigators will need to conduct a risk-benefit assessment to determine whether the subject should be included in the treatment study.

[0219] ③The total number of previous treatment lines does not exceed 2 lines.

[0220] Note:

[0221] For subjects who are enrolled due to intolerance to the last treatment, the investigator is required to record the reason or explanation for intolerance to the current treatment.

[0222] When the cumulative dosage of anthracyclines reaches a certain dosage, it can be considered as intolerable. The maximum lifetime cumulative dosage of commonly used anthracyclines is shown in Appendix XIII.

[0223] If a subject refuses first-line standard treatment during the dose escalation phase, enrollment will be allowed after the investigator reaches an agreement with the sponsor and the ethics committee agrees.

[0224] 3. Dosage regimen

[0225] The pre-set starting dose of the anti-B7H3 antibody-drug conjugate combination for all two-drug combination cohorts (cohort 2a) was 10.0 mg / kg Q3W. In cohort 2a, the combination drug dose was fixed, and only the anti-B7H3 antibody-drug conjugate dose was adjusted.

[0226] The recommended dosing priority is to administer adebelimumab first, followed by the anti-B7H3 antibody-drug conjugate at least 30 minutes after the first administration. The entire dosing regimen (adebelimumab + anti-B7H3 antibody-drug conjugate) should be completed within 72 hours, starting from the first dose of the combination therapy and ending with the last dose.

[0227] Adebelimumab: 20 mg / kg, intravenous drip, Q3W, until objective disease progression (except continued treatment after disease progression) or meeting other criteria for termination of study treatment specified in the protocol.

[0228] Anti-B7H3 antibody-drug conjugate: Administer the drug at a preset dose of 10 mg / kg by intravenous drip every 3 weeks until objective disease progression (except for continued treatment after disease progression) or meet other criteria for termination of study treatment as specified in the protocol.

[0229] Although the specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes can be made to the details based on all the teachings published, and these changes are all within the scope of protection of the present invention. The entire invention is given by the appended claims and any equivalents thereof.

Claims

1. Use of an antibody-drug conjugate and an immune checkpoint inhibitor in combination in 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-B7H3 antibody or an antigen-binding fragment thereof.

2. The use according to claim 1, wherein the anti-B7H3 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-B7H3 antibody or antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof.

4. According to the use described in claim 3, the anti-B7H3 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-B7H3 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-B7H3 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-B7H3 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 use according to any one of claims 1 to 6, wherein the immune checkpoint inhibitor is selected from antibodies or antigen-binding fragments thereof targeting PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, B7-H4, preferably antibodies or antigen-binding fragments thereof targeting PD-1 and PD-L1.

8. The method of any one of claims 1 to 7, wherein the immune checkpoint inhibitor is selected from Toripalimab, Sintilimab, Camrelizumab, Dostarlimab, Tislelizumab, Zimberelimab, Penpulimab, Serplulimab, Pucotenlimab, Pembrolizumab, Nivolumab, and nivolumab. umab), Sugemalimab, Envafolimab, Adebrelimab, Atezolizumab, Durvalumab, Ipilimumab, Candonilimab, preferably Camrelizumab, Adebrelimab, Dostarlimab, Pembrolizumab, Durvalumab.

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 any one of claims 1 to 10, wherein the antibody drug conjugate and the immune checkpoint inhibitor are contained in different preparations as active ingredients, respectively, and are administered simultaneously or at different times.

12. The use according to any one of claims 1 to 10, wherein the antibody drug conjugate and the immune checkpoint inhibitor are contained in a single formulation as active ingredients and administered.

13. The use according to claim 9 or 10, wherein the dosage of the platinum drug is calculated by the area under the curve (AUC) and is 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 claim 9 or 10, 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.

15. The use according to any one of claims 1 to 14, 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.

16. The use according to any one of claims 1 to 15, wherein the dosage of the immune checkpoint inhibitor is 10 mg to 2000 mg, preferably 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1120 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, and the frequency of administration is once a week, once every two weeks, once every three weeks or once every four weeks.

17. The use according to any one of claims 1 to 16, wherein the dosage of the immune checkpoint inhibitor 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.

18. The method of claim 1 , wherein the cancer is selected from at least one of lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine 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, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.

19. The use according to claim 18, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma.

20. The use according to any one of claims 1 to 17, wherein the cancer is an advanced solid cancer that has failed or is intolerant to first-line treatment or has no effective standard treatment.

21. The method according to claim 19, wherein the osteosarcoma is advanced osteosarcoma, preferably advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 treatment lines.

22. A pharmaceutical composition comprising an antibody drug conjugate as defined in any one of claims 1 to 21 and an immune checkpoint inhibitor, and one or more pharmaceutically acceptable carriers, excipients, and diluents.

23. A method for treating cancer, the method comprising administering to a subject in need thereof a combination of an antibody drug conjugate as defined in any one of claims 1 to 21, an immune checkpoint inhibitor as defined in any one of claims 1 to 21, and optionally a platinum drug as defined in any one of claims 9-20, wherein the combined administration may be simultaneous or at different time points.

24. The method of claim 23, wherein the cancer is selected from at least one of the following: lung cancer, stomach cancer, liver cancer, kidney cancer, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, bladder cancer, esophageal cancer, nasopharyngeal cancer, salivary gland cancer, head and neck cancer, skin cancer, pharyngeal cancer, laryngeal cancer, gallbladder cancer, bile duct cancer, thyroid cancer, uterine cancer, vulvar cancer, penis cancer, testicular cancer, urothelial cancer, urethral cancer, colon cancer, rectal cancer, colorectal cancer, esophageal gastric junction cancer, gastrointestinal stromal tumor, squamous cell carcinoma, peritoneal cancer, leukemia, malignant lymphoma, plasmacytoma, myeloma, neuroepithelial tumor, nerve sheath tumor, mesothelioma, Paget's disease and sarcoma.

25. The method according to claim 24, wherein the lung cancer is selected from non-small cell lung cancer and small cell lung cancer, the esophageal cancer is esophageal squamous cell carcinoma, and the sarcoma is osteosarcoma.

26. The method of claim 23, wherein the cancer is an advanced solid cancer that has failed or is intolerant to first-line treatment or has no effective standard treatment.

27. The method according to claim 25, wherein the osteosarcoma is advanced osteosarcoma, preferably advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed 2 treatment lines.

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