Combined use of antibody-drug conjugates and immune checkpoint inhibitors

Abstract

The use of antibody-drug conjugates alone or in combination in the preparation of drugs for the prevention and / or treatment of cancer is provided. Specifically, the use of antibody-drug conjugates, or pharmaceutically acceptable salts, metabolites, or solvent compounds thereof, alone or in combination with immune checkpoint inhibitors, is provided in the preparation of drugs for the prevention and / or treatment of cancer.

Description

[Technical Field]

[0001] This application relates to the pharmaceutical field and to the use of antibody-drug conjugates alone or in combination in the preparation of pharmaceuticals for the prevention and / or treatment of cancer. Specifically, the present invention provides the use of antibody-drug conjugates or pharmaceutically acceptable salts, metabolites, or solvates thereof, alone or in combination with immune checkpoint inhibitors, in the preparation of pharmaceuticals for the prevention and / or treatment of cancer. [Background technology]

[0002] Antibody-drug conjugates (ADCs) are a class of targeted biological agents in which a monoclonal antibody is used as a carrier to efficiently deliver a small molecule cytotoxic drug to a target tumor cell in a targeted manner, with the cytotoxic drug being linked to the monoclonal antibody via a linker. Tumor-specific antibodies enable ADC drugs to selectively deliver small molecule cytotoxic drugs while reducing their off-target effects and preserving their antitumor properties, thereby effectively improving the benefit-to-risk ratio of antitumor therapy. B7 homologous protein 3 (also known as B7-H3, CD276, and referred to herein as "B7-H3" or "B7H3") is a type I transmembrane glycoprotein of the immunoglobulin superfamily and a member of the B7 immunocostimulatory and co-inhibitory family. This protein is overexpressed in various solid tumors such as lung cancer, prostate cancer, esophageal cancer, head and neck squamous cell carcinoma, osteosarcoma, and melanoma, but its expression is limited in normal tissues, making B7-H3 an ideal target for ADC drugs.

[0003] Immune checkpoint inhibitors (ICIs) block the binding of immune checkpoints to their ligands, thereby reducing immunosuppression caused by immune checkpoints and reactivating immune cells to exert antitumor effects. Currently, several ICIs are achieving remarkable efficacy in antitumor clinical applications, representing a breakthrough in tumor therapy. Inhibitors targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), programmed death-1 receptor (PD-1), and programmed death-ligand 1 (PD-L1) have been successfully used in the clinical treatment of various malignancies. Among these, PD-1 / PD-L1 antibody drugs have a broad antitumor spectrum and have shown sustained and potent efficacy in some tumor patients. Ten PD-1 monoclonal antibodies and three PD-L1 monoclonal antibodies have been approved for the clinical treatment of 11 types of cancer, including non-small cell lung cancer, melanoma, head and neck cancer, colorectal cancer, and gastric cancer. While ICIs exhibit significant antitumor activity in multiple types of malignancies, their response rates in most tumors are relatively low, and there is a need to develop new regimens to improve the response rate to ICI therapy.

[0004] Conventional osteosarcoma (hereinafter referred to as osteosarcoma) is a common malignant bone tumor, accounting for 35% of all malignant bone tumors. Conventional osteosarcoma frequently occurs in adolescence, with a median age of onset of 20 years, and is the most common primary malignant bone tumor in children and adolescents. Approximately 10% to 15% of newly diagnosed osteosarcoma patients present with distant metastases, and the 5-year survival rate for patients with localized osteosarcoma is about 60%, compared to only about 20% for patients with advanced (recurrent or metastatic) osteosarcoma. The standard first-line chemotherapy regimen for osteosarcoma is a regimen containing methotrexate, doxorubicin, cisplatin, and ifosfamide. For osteosarcoma patients who cannot undergo curative surgical treatment, there is a lack of effective treatment options after the failure of standard chemotherapy, and there are still no drugs or other treatment options that can show a significant survival benefit to such patients. Currently, no second-line treatment regimens are approved, and existing treatments have relatively high hematological toxicity and numerous adverse reactions. Therefore, improving the effectiveness of second-line treatment for osteosarcoma and extending patient survival are among the goals of current clinical research, and new treatment methods are urgently needed to meet patients' treatment needs.

[0005] The preferred combination therapy of the present invention exhibits higher efficacy than each treatment used individually, improving effectiveness while minimizing the side effects associated with the combination therapy and promoting the maximization of survival benefits for patients receiving immunotherapy. [Overview of the project]

[0006] This disclosure relates to the use of a combination of an antibody-drug conjugate and an immune checkpoint inhibitor in the preparation of a drug for treating cancer, wherein the structure of the antibody-drug conjugate is given by formula (I): [ka] It provides the use of combinations as shown.

[0007] In the formula, 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 (which may be an integer or a decimal), and still more preferably 4.1.

[0008] Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof.

[0009] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises heavy chain HCDR1, HCDR2, and HCDR3 represented by the amino acid sequences of SEQ ID NOs: 01, 02, and 03, respectively, and light chain LCDR1, LCDR2, and LCDR3 represented by the amino acid sequences of SEQ ID NOs: 04, 05, and 06, respectively.

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

[0011] Each of the CDR sequences described above is as shown in the following table.

[0012] [Table 1]

[0013] Preferably, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from humanized antibodies or fragments thereof.

[0014] In some optional embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof described in the present application is selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.

[0015] In some optional embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof described in the present application comprises a heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4 isotype, and preferably comprises a heavy chain constant region of IgG1 or IgG4 isotype.

[0016] In other optional embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a κ or λ light chain constant region.

[0017] Further, preferably, 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.

[0018] The heavy chain and light chain variable regions of the aforementioned anti-B7H3 antibody or antigen-binding fragment thereof are as follows: Heavy chain variable region sequence ##STR## SEQ ID NO: 07 Light chain variable region sequence ##STR## SEQ ID NO: 08 Note: The sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, the sequences shown in italics are FR sequences, the underlined sequences are CDR sequences, and the CDR sequences are derived from Kabat's definition rules.

[0019] Further, preferably, 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.

[0020] The heavy chain and light chain sequences of the aforementioned anti-B7H3 antibody or antigen-binding fragment thereof are as follows: Heavy chain (IgG1) amino acid sequence: (SEQ ID NO: 09) ##STR## Light chain (λ) amino acid sequence: (SEQ ID NO: 10) [ka]

[0021] In some embodiments, the immune checkpoint inhibitor is selected from antibodies that target PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, or B7-H4, or their antigen-binding fragments. Preferably, it is an antibody that targets PD-1 or PD-L1, or its antigen-binding fragment.

[0022] In some embodiments, immune checkpoint inhibitors include tripalimab, sintilimab, camlezumab, dostarlimab, tislerizumab, zimberelimab, penpulimab, serplulimab, pucotenlimab, and pembrolizumab. The following are selected from lizumab, nivolumab, sugemalimab, envafolimab, adebrelimab, atezolizumab, durvalumab, ipilimumab, and cadnilimab antibodies, preferably camrelizumab and adebrelimab.

[0023] The heavy and light chain sequences of camrelizumab are as follows: Heavy chain amino acid sequence: (SEQ ID NO: 11) [ka] Light chain amino acid sequence: (SEQ ID NO: 12) [ka]

[0024] The heavy and light chain sequences of adebrelimab, as mentioned above, are as follows: Heavy chain amino acid sequence: (SEQ ID NO: 13) [ka] Light chain amino acid sequence: (SEQ ID NO: 14) [ka]

[0025] Dostallimab is a PD-1 blocking IgG4 humanized monoclonal antibody, trade name JEMPERLI, and its main structure and function are described in International Publication No. 2014 / 179664, International Publication No. 2018 / 085468, and International Publication No. 2018 / 129559.

[0026] The heavy and light chain sequences of dostallimab are as follows: Heavy chain amino acid sequence: (SEQ ID NO: 15) [ka] Light chain amino acid sequence: (SEQ ID NO: 16) [ka]

[0027] In some embodiments, dostallimab or its biosimilar is administered to patients in need at a dose of 500 mg once every three weeks (Q3W).

[0028] In some embodiments, dostallimab or its biosimilar is administered to patients in need at a dose of 500 mg once every three weeks (Q3W) for four to six cycles, followed by a dose of 1000 mg of dostallimab or its biosimilar once every six weeks (Q6W).

[0029] Pembrolizumab is a PD-1 blocking IgG4 humanized monoclonal antibody, and its trade name is KEYTRUDA.

[0030] The heavy and light chain sequences of pembrolizumab are as follows: Heavy chain amino acid sequence: (SEQ ID NO: 17) [ka] Light chain amino acid sequence: (SEQ ID NO: 18) [ka]

[0031] In some embodiments, pembrolizumab or its biosimilar is administered to patients in need at a dose of 200 mg once every three weeks (Q3W); or it is administered at a dose of 400 mg once every six weeks (Q6W).

[0032] Durvalumab is a PD-L1 blocking IgG1 monoclonal antibody, and its trade name is IMFINZI.

[0033] The heavy and light chain sequences of durvalumab are as follows: Heavy chain amino acid sequence: (SEQ ID NO: 19) [ka] Light chain amino acid sequence: (SEQ ID NO: 20) [ka]

[0034] In some embodiments, durvalumab or its biosimilar is administered to patients requiring a body weight of ≥30 kg at a dose of 1500 mg once every three weeks (Q3W).

[0035] In some embodiments, durvalumab or its biosimilar is administered to patients requiring a body weight of <30 kg at a dose of 20 mg / kg once every three weeks (Q3W).

[0036] In some embodiments, durvalumab or its biosimilar is administered to patients requiring a body weight of ≥30 kg at a dose of 1120 mg once every three weeks (Q3W).

[0037] In some embodiments, durvalumab or its biosimilar is administered to patients requiring a body weight of <30 kg at a dose of 15 mg / kg once every three weeks (Q3W).

[0038] In another aspect, the disclosure relates to the use of antibody-drug conjugates and immune checkpoint inhibitors further combined with platinum agents in the preparation of pharmaceuticals for the treatment of cancer.

[0039] In optional embodiments, the platinum agent is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, and dicycloplatin, preferably carboplatin and / or cisplatin.

[0040] In an optional embodiment, the antibody-drug conjugate and the immune checkpoint inhibitor are each included as active ingredients in different formulations and may or may not be administered simultaneously.

[0041] In an optional embodiment, the antibody-drug conjugate, immune checkpoint inhibitor, and platinum-based drug are each included as active ingredients in different formulations, and may or may not be administered simultaneously.

[0042] In another embodiment, the antibody-drug conjugate and the immune checkpoint inhibitor are included as active ingredients in a single formulation and administered.

[0043] In another embodiment, antibody-drug conjugates, immune checkpoint inhibitors, and platinum-based drugs are included as active ingredients in a single formulation and administered.

[0044] In optional embodiments, 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, and 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. , 5.6mg / 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, 9.0 The dosages are mg / 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.

[0045] In an optional embodiment, the administration frequency of the antibody-drug conjugate is once a week, once every two weeks, once every three weeks, or once every four weeks.

[0046] In preferred embodiments, the antibody-drug conjugate is administered according to an initial dose of 6.0 mg / kg or 8.0 mg / kg, with a frequency of once every three weeks.

[0047] In optional embodiments, 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 The dosages are 260mg, 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, or 1500mg.

[0048] In optional embodiments, 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, and 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. 4.2mg / kg, 4.4mg / kg, 4.6mg / 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 / k g, 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 g / 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, 19.6 mg / kg, 19.8 mg / kg, 20.0 mg / kg, 20.2 mg / kg, 20.4 mg / kg, 20.6 mg / kg, 20.8 mg / kg, or 30.0 mg / kg.

[0049] In an optional embodiment, the administration frequency of the immune checkpoint inhibitor is once weekly, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0050] In a preferred embodiment, the dose of the immune checkpoint inhibitor is 20 mg / kg, and the administration frequency is once every 3 weeks.

[0051] In an optional embodiment, the administration dose of the platinum agent is calculated by 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, or 9 mg / ml / min, and the administration frequency is once weekly, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0052] In an optional embodiment, the administration dose of the platinum agent is 10 mg / m 2 ~500 mg / m 2 , preferably 10 mg / m 2 ~200 mg / m 2 , more preferably 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 , 100 mg / m 2 , 125 mg / m 2 , 150 mg / m 2 , 175 mg / m 2 , or 200 mg / m 2 , and the administration frequency is once weekly, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0053] In an optional embodiment, the platinum agent is administered for a total of 4 to 6 cycles.

[0054] In a preferred embodiment, the dose of the platinum drug is cisplatin 75 mg / m² administered intravenously. 2 Alternatively, carboplatin AUC 5 mg / ml / min is administered once every three weeks.

[0055] In an optional embodiment, cancer is selected from at least one of the following: lung cancer, gastric 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, adenocarcinoma of the esophageal junction, 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.

[0056] Furthermore, lung cancer is selected from non-small cell lung cancer and small cell lung cancer, esophageal cancer is esophageal squamous cell carcinoma, and sarcoma is osteosarcoma.

[0057] In an optional embodiment, the cancer is an advanced solid tumor that has either failed primary treatment, is intolerant to primary treatment, or does not have an effective standard treatment. JPEG2026536558000018.jpg425 (advanced solid cancer).

[0058] In an optional embodiment, the cancer is recurrent, metastatic, and / or drug-resistant cancer.

[0059] In an optional embodiment, the cancer is an advanced-stage solid tumor such as small cell lung cancer, non-small cell squamous cell lung cancer, esophageal squamous cell carcinoma, and nasopharyngeal carcinoma.

[0060] In the optional embodiment, the cancer is advanced small cell lung cancer that has failed or cannot tolerate at least primary treatment. JPEG2026536558000019.jpg432, patients with extensive-stage small cell lung cancer (SCLC), locally advanced or metastatic non-small cell squamous cell lung cancer (NSCLC) that has progressed or is intolerant to at least first-line treatment, unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that has progressed or is intolerant to at least first-line treatment, locally advanced, recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed or is intolerant to at least first-line treatment, or other advanced-stage solid tumors for which appropriate standard treatment has been unsuccessful or for which there is no effective standard treatment.

[0061] In the optional embodiment, the osteosarcoma is advanced-stage osteosarcoma.

[0062] In the optional embodiment, advanced osteosarcoma ( JPEG2026536558000020.jpg521, advanced osteosarcoma) is a type of advanced osteosarcoma that progresses after standard treatment. JPEG2026536558000021.jpg525 (progressive osteosarcoma), and the total number of previous treatment lines does not exceed 2.

[0063] This disclosure further provides pharmaceutical compositions comprising the above-mentioned antibody-drug conjugates and immune checkpoint inhibitors, as well as one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0064] In some embodiments, the pharmaceutical composition further comprises a platinum agent and one or more pharmaceutically acceptable carriers, excipients, and diluents.

[0065] This disclosure further provides a method for treating cancer, which comprises administering the above-mentioned antibody-drug conjugate and immune checkpoint inhibitor in combination to a target subject of interest, and this combination administration may be simultaneous or at different time points.

[0066] This disclosure further provides a method for treating cancer, which involves administering a combination of the above-mentioned antibody-drug conjugate, immune checkpoint inhibitor, and platinum-based drug to a target subject, and this combination administration may be simultaneous or at different time points.

[0067] In an optional embodiment, cancer is selected from at least one of the following: lung cancer, gastric 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, adenocarcinoma of the esophageal junction, 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.

[0068] In the optional embodiment, lung cancer is selected from non-small cell lung cancer and small cell lung cancer, esophageal cancer is esophageal squamous cell carcinoma, and sarcoma is osteosarcoma.

[0069] In an optional embodiment, the cancer is an advanced solid tumor that has either failed or is intolerant to first-line treatment, or for which there is no effective standard treatment.

[0070] In an optional embodiment, the cancer is recurrent, metastatic, and / or drug-resistant cancer.

[0071] In an optional embodiment, the cancer is an advanced-stage solid tumor such as small cell lung cancer, non-small cell squamous cell lung cancer, esophageal squamous cell carcinoma, and nasopharyngeal carcinoma.

[0072] In optional embodiments, the cancer is a patient with advanced small cell lung cancer (SCLC) that has failed or cannot tolerate at least first-line treatment, locally advanced or metastatic non-small cell squamous cell lung cancer (NSCLC) that has progressed or is intolerant to at least first-line treatment, unresectable locally advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that has progressed or is intolerant to at least first-line treatment, locally advanced, recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed or is intolerant to at least first-line treatment, or another advanced solid tumor for which appropriate standard treatment has failed or for which there is no effective standard treatment.

[0073] In the optional embodiment, the osteosarcoma is advanced-stage osteosarcoma.

[0074] In the optional embodiment, advanced osteosarcoma is defined as advanced osteosarcoma that has progressed after standard treatment, and the total number of previous treatment lines does not exceed two.

[0075] In another aspect, the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in the treatment of cancer, the anti-B7H3 antibody-drug conjugate being used in combination with the aforementioned anti-PD-1 antibody or its antigen-binding fragment.

[0076] In another embodiment, the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in the treatment of cancer, the anti-B7H3 antibody-drug conjugate being used in combination with the aforementioned anti-PD-L1 antibody or its antigen-binding fragment.

[0077] In another embodiment, the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in the treatment of cancer, the anti-B7H3 antibody-drug conjugate being used in combination with the aforementioned anti-PD-1 antibody or its antigen-binding fragment and the aforementioned platinum agent.

[0078] In another embodiment, the present disclosure provides the aforementioned anti-B7H3 antibody-drug conjugate for use in the treatment of cancer, the anti-B7H3 antibody-drug conjugate being used in combination with the aforementioned anti-PD-L1 antibody or its antigen-binding fragment and the aforementioned platinum agent.

[0079] In this disclosure, the so-called “combination” refers to a mode of administration that includes various situations in which two or more drugs are administered sequentially or simultaneously.

[0080] All administration methods, including simultaneous administration, co-administration of separate formulations, or successive administration of separate formulations, belong to the combination administrations described herein. In this specification, "simultaneous" means that at least one dose of anti-PD-1 / PD-L1 antibody or its antigen-binding fragment and an anti-B7H3 antibody-drug conjugate are administered within a specific period, optionally within 3 days, 2 days, or 1 day, and both substances exhibit pharmacological effects. "Successive" administration includes situations in which the anti-PD-1 / PD-L1 antibody or its antigen-binding fragment and the anti-B7H3 antibody-drug conjugate are administered in different administration cycles. This period may optionally be within 4 weeks, 3 weeks, 2 weeks, or 1 week within a single administration cycle. Such periods include treatment in which an anti-PD-1 / PD-L1 antibody or its antigen-binding fragment and an anti-B7H3 antibody-drug conjugate are administered via the same route of administration or via different routes of administration.

[0081] term To facilitate understanding of this disclosure, certain technical and scientific terms are defined below. Unless expressly defined herein, all other technical and scientific terms used herein have the meanings generally understood by those skilled in the art to which this disclosure pertains.

[0082] This disclosure incorporates the entire contents of International Publication No. 2020063673 into this application.

[0083] The term “antibody-drug conjugate” refers to an antibody that is linked to a biologically active drug via a stable linking unit. In this disclosure, “antibody-drug conjugate” refers to a monoclonal antibody or antibody fragment that is linked to a biologically active toxic drug via a stable linking unit.

[0084] The term "antibody" refers to immunoglobulin, a tetrameric structure composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. Immunoglobulins differ in the amino acid composition and sequence of their heavy chain constant regions, and therefore their antigenicity also differs. Thus, immunoglobulins can be classified into five classes, also called immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being the μ, δ, γ, α, and ε chains, respectively. The same class of Ig can be further classified into different subclasses depending on the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds; for example, IgG can be classified into IgG1, IgG2, IgG3, and IgG4. The light chains can be classified into κ or λ chains depending on the differences in their constant regions. In each of the five classes of Ig, Ig may have either a κ or γ chain.

[0085] The sequences of approximately 110 amino acids near the N-terminus of the antibody's heavy and light chains are highly different and constitute the variable region (Fv region); the sequences of the remaining amino acids near the C-terminus are relatively stable and constitute the constant region. The variable region includes three hypervariable regions (HVRs) and four framework regions (FRs) with relatively conserved sequences. The three hypervariable regions determine the antibody's specificity and are also called 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, with the order of arrangement from amino-terminus to carboxyl-terminus being FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0086] In this disclosure, all amino acid sequences of the aforementioned CDRs are presented in accordance with Kabat's definition rules. However, the CDR of antibodies has been defined in various ways, such as Chothia's definition 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's definition based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, USD Department of Health and Human Services, National Institutes of Health (1987)), AbM's definition (University of Bath), Contact's definition (University College London), the International ImMunoGeneTics Database (IMGT) (World Wide Web imgt.cines.fr / ), and North's definition based on affinity propagation clustering using numerous crystal structures. Those skilled in the art will know that CDRs can be defined by their respective definitions. Unless otherwise specified, those skilled in the art should understand that the terms “CDR” and “complementarity-determining region” in reference to a given antibody or region thereof (e.g., variable region) should be understood to encompass the complementarity-determining region as defined by any of the known schemes described in the present invention. While the claimed scope of protection of the present invention is based on sequences shown according to Kabat's definition rules, amino acid sequences corresponding to other CDR definition rules should also be included within the scope of protection of the present invention.

[0087] 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 full-length antibodies can be used to perform the antigen-binding function of an antibody. Examples of binding fragments contained in "antigen-binding fragments" include: (i) a monovalent fragment consisting of a Fab fragment, VL, VH, CL, and CH1 domains; (ii) a bivalent fragment F(ab')2 containing two Fab fragments linked by a disulfide crosslink on a hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of the antibody; (v) a single-domain or dAb fragment (Ward et al., (1989) Nature 341:544-546) (consisting of a VH domain); and (vi) an isolated complementarity-determining region (CDR), or (vii) optionally, a combination of two or more isolated CDRs linked by a synthetic linker.

[0088] The term “drug load” refers to the average number of cytotoxic agents loaded onto each ligand in the formula (I) molecule, and may also be expressed as a ratio of drug amount to antibody amount. The drug load may range from 0 to 12, preferably 1 to 10, cytotoxic agents (D) bound to each antibody (Pc). In embodiments of this disclosure, the drug load is represented as n, and may also be referred to as the DAR value, and is exemplary the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. The average drug amount per ADC molecule after the conjugation reaction can be determined by conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assay, and HPLC.

[0089] The term "immune checkpoint inhibitor" refers to drugs that inhibit the immunosuppressive system in order to activate tumor immunity.

[0090] The term "anti-PD-1 antibody or its antigen-binding fragment" refers to an antibody that specifically binds to PD-1 (programmed cell death 1; CD279; PDCD1) and has the activity to reduce, inhibit, and / or interfere with signaling induced by the interaction between PD-1 and PD-L1 or PD-L2 as its binding counterpart. The anti-PD-1 antibodies used in this disclosure are not particularly limited, as long as their clinical efficacy and safety have been demonstrated.

[0091] The term "anti-PD-L1 antibody or its antigen-binding fragment" refers to an antibody that specifically binds to PD-L1 (programmed cell death ligand 1; CD274; B7-H1) and has the activity to reduce, inhibit, and / or interfere with signal transduction caused by the interaction between PD-L1 and PD-1 or B7.1 (CD80) as its binding counterpart. The anti-PD-L1 antibodies used in this disclosure are not particularly limited, as long as their clinical efficacy and safety have been demonstrated.

[0092] The term “pharmaceutical composition” means a product comprising one or more active ingredients (e.g., antibodies, ADCs) in a selective amount, and any product directly or indirectly produced by combining one or more active ingredients in a selective amount. Different active ingredients in a pharmaceutical composition may be administered independently in separate formulations, including combined synergistic enhancements by administration at simultaneous or different time points. In this disclosure, “pharmaceutical composition” and “formulation” are not mutually exclusive.

[0093] The term “treatment” means administering to a patient an internal or external therapeutic agent, for example, a composition comprising any of the conjugated compounds of the Disclosure, where the patient has one or more disease symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, the therapeutic agent is administered to a patient or group to be treated in an amount effective to alleviate one or more disease symptoms, resulting in regression of such symptoms or inhibition of the onset of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate any particular disease symptom (also referred to as the “therapeutic effective dose”) may vary depending on a variety of factors, including the patient’s disease state, age and weight, and the drug’s ability to produce the desired efficacy in the patient. Whether disease symptoms have been alleviated may be assessed by any clinical trial method commonly used by a physician or other healthcare professional to assess the severity or progression of symptoms. Embodiments of the present disclosure (e.g., a treatment method or product) may not be effective in alleviating each target disease symptom, but it should be determined that they should alleviate the target disease symptoms in a statistically significant number of patients according to any statistical test method known in the art, such as Student's t-test, chi-squared test, Mann and Whitney U test, Kruskal-Wallis test (H test), Yonkhiel-Tapstra test, and Wilcoxon test. [Brief explanation of the drawing]

[0094] [Figure 1] This study demonstrates the efficacy of drug A in combination with drug B in a subcutaneous xenograft tumor model using the human lung cancer cell line Calu-6. [Figure 2] This study demonstrates the efficacy of drug A in combination with drug C in a subcutaneous xenograft tumor model using the human lung cancer cell line Calu-6. [Figure 3] This study demonstrates the efficacy of drug A in combination with drug B in a subcutaneous xenograft tumor model using the human osteosarcoma cell line SJSA-1. [Figure 4] This study demonstrates the efficacy of drug A in combination with drug C in a subcutaneous xenograft tumor model using the human osteosarcoma cell line SJSA-1. [Figure 5]The changes in mouse body weight in each group of Example 4 are shown.

[0095] Specific Embodiments This application is described in more detail below in conjunction with the examples provided, and the examples provided are used solely to illustrate the technical solutions of this application and are not intended to limit the materials and scope of this application. [Examples]

[0096] Example 1. Preparation of anti-B7H3 antibody-drug conjugate According to the manufacturing method described in International Publication No. 2020063673, an anti-B7H3 antibody-drug conjugate represented by the following structure was prepared using H1702DS (anti-B7H3 antibody) and an exatecan analog, and the mean values ​​calculated by the HIC method were as follows: N=4.1, i.e., FADC-2. Here, the heavy chain sequence of H1702DS is shown in 09 and the light chain sequence is shown in 10. [ka]

[0097] Example 2. Pharmacodynamic effects of monotherapy and combination therapy of human lung cancer cell line Calu-6 to PBMC-humanized NCG mouse allograft models. 1. Experimental materials 1.1 Information on the human lung cancer cell Calu-6 CDX model Calu-6 cells were cultured in a 37°C incubator containing 5% CO2 in DMEM culture medium containing 10% fetal bovine serum and 1% penicillin-streptomycin dual antibiotics. After growing the cells to confluence, they were subcultured in flasks, and Calu-6 cells in the logarithmic growth phase were collected, counted, and inoculated.

[0098] 1.2 PBMC Information PBMC was purchased from Zhejiang Free Trade Zone Maishun Biotechnology Co., Ltd. in batch P121090306C.

[0099] 1.3 Laboratory Animals NCG mice, female, weighing 17-19g, were purchased from Jiangsu Jicui Yaokang Biotechnology Co.,Ltd.

[0100] 1.4 Test drug 1) Drug A: Prepared according to the method described in International Publication No. 2020063673, using physiological saline for drug preparation. 2) Drug B: Camrelizumab for injection, with heavy and light chain sequences as shown in Sequence ID No. 11 and Sequence ID No. 12, respectively. Physiological saline, batch number 202201004F, provided by Suzhou Shengdiya Biopharmaceutical Co., Ltd., was used for drug preparation. 3) Drug C: Adebrelimab for injection, with heavy and light chain sequences as shown in SEQ ID NOs. 13 and 14, respectively. Physiological saline, batch number 202304004C, provided by Suzhou Shengdiya Biopharmaceutical Co., Ltd., was used for drug preparation.

[0101] 1.5 Laboratory Equipment

[0102] [Table 2]

[0103] 1.6 Laboratory Reagents and Consumables

[0104] [Table 3]

[0105] 2. Experimental Method PBMC cells were removed from liquid nitrogen, thawed by gently shaking in a 37°C water bath, then centrifuged, resuspended in PBS, and then inoculated. Eight days after PBMC cell inoculation, 0.1 mL (5 × 10) of Calu-6 cell suspension was administered. 6 A solution containing cells was subcutaneously inoculated into the right back of NCG mice. Tumor growth was observed, and random grouping was performed according to tumor volume and animal body weight. At the time of grouping, the average tumor volume was 145 mm². 3 The day of group division was defined as day 0, i.e., PG-D0. Administration to all animals began on the day of group division, and the remaining animals were euthanized at the end of the experiment. The specific dosages and administration regimens are shown in Table 3. Tumor volume and mouse body weight were measured, and the data were recorded.

[0106] [Table 4]

[0107] The experimental indicator was to investigate the effect of the drug on tumor growth, and the specific indicators were the relative tumor growth rate T / C (%) or the tumor growth inhibition rate TGI (%). Tumor volume measurement: Measurements were taken twice a week using calipers, and the tumor volume calculation formula was V = 0.5a × b 2 (In the formula, a and b represent the diameter in the longitudinal direction and the diameter in the width direction of the tumor.)

[0108] TGI (%) calculation: If there is no tumor volume, TGI (%) = [1 - (average tumor volume of the treatment group at the end of administration - average tumor volume of the treatment group at the time of group assignment) / (average tumor volume of the vehicle control group at the end of treatment - average tumor volume of the vehicle control group at the time of group assignment)] × 100%. If there is tumor regression, TGI (%) = [1 - (average tumor volume of the treatment group at the end of administration - average tumor volume of the treatment group at the time of group assignment) / average tumor volume of the treatment group at the time of group assignment] × 100%.

[0109] Calculation of T / C(%): T / C(%) = mean tumor volume of the treatment group at the end of treatment / mean tumor volume of the vehicle control group at the end of treatment × 100%.

[0110] At the end of the experiment (PG-D21), all animals were euthanized sequentially by CO2 asphyxiation, group by group. After euthanasia, the tumor masses were removed, weighed, and photographed.

[0111] All data are expressed as mean ± SEM. Statistical analysis was performed using Dunnett's multiple comparison test in two-dimensional ANOVA to evaluate differences between groups based on tumor volume data for each group at different time points. Differences in tumor volume between groups were analyzed using Dunnett's multiple comparison test in one-way ANOVA. Differences in tumor volume between two groups were analyzed using t-tests. GraphPad Prism 9 was used for all data analysis, and p<0.05 was considered statistically significant.

[0112] 3. Experimental Results Table 4 and Figures 1 and 2 show the inhibitory effects of drugs A, B, and C, individually or in combination, on the proliferation of subcutaneous xenograft tumors of human lung cancer cells Calu-6. In the figures, the data for the vehicle group, drug A_1 mg / kg group, and drug A_2 mg / kg group are experimental data from the same group.

[0113] [Table 5]

[0114] In a PBMC humanized human lung cancer cell line Calu-6 xenograft tumor model, monotherapy with drug A_1 mg / kg and drug A_2 mg / kg showed tumor inhibition rates of 51.25% and 74.82%, respectively, demonstrating a significant and dose-dependent tumor inhibition effect. Monotherapy with drug B_3 mg / kg and drug C_20 mg / kg showed tumor inhibition rates of 0.97% and -4.55%, respectively, and did not show a clear tumor inhibition effect. Treatment with drug A_1 mg / kg and drug A_2 mg / kg in combination with drug B_3 mg / kg showed tumor inhibition rates of 58.63% and 89.93%, respectively. The treatment group with drug A_2 mg / kg in combination with drug B_3 mg / kg showed a significantly improved tumor inhibition effect compared to the drug A_2 mg / kg monotherapy group and the drug B_3 mg / kg monotherapy group, and the difference was statistically significant (p<0.05). The tumor inhibition rate of treatment with drug A_2mg / kg in combination with drug C_20mg / kg was 80.34%. The tumor inhibition effect was significantly better in the combination treatment group than in the drug C_20mg / kg monotherapy group (p<0.05), and better than in the drug A_2mg / kg monotherapy group. In addition, the mice did not exhibit treatment-related death or other abnormal symptoms, indicating that tumor-bearing mice may be well-tolerated to drug A alone and in combination with drugs B and C.

[0115] During the experiment, the mean body weight of the animals in the vehicle group remained relatively stable, and at the experimental endpoint (day 21), the mean percentage change in body weight of animals in this group was 8.97%. The mean percentage change in body weight of tumor-bearing mice in the drug A_1 mg / kg monotherapy group and the drug A_2 mg / kg monotherapy group was 8.27% and 6.22%, respectively. The mean percentage change in body weight of the drug B_3 mg / kg monotherapy group and the drug A_1 mg / kg and drug A_2 mg / kg combination therapy group was -3.79%, 1.73%, and -1.53%, respectively. The mean percentage change in body weight of tumor-bearing mice in the drug C_20 mg / kg monotherapy group and the drug A_2 mg / kg combination therapy group was 6.58% and 1.84%, respectively. Of particular note is that GvHD caused by humanization of PBMC inoculation was the main cause of weight loss in the animals. In addition, the mice did not experience treatment-related death or other abnormal symptoms, indicating that tumor-bearing mice may be well-tolerated to treatment with test drug A, as well as its combination with drugs B and C.

[0116] In summary, tumor-bearing mice were tolerant to both drug A monotherapy and combination therapy with drugs B and C. The antitumor effect of drug A at 2 mg / kg in combination with drug B at 3 mg / kg was significantly better than that of each monotherapy group. The antitumor effect of drug A at 2 mg / kg in combination with drug C at 20 mg / kg was significantly better than that of drug C monotherapy at 20 mg / kg, and also better than that of drug A monotherapy at 2 mg / kg.

[0117] Example 3. Clinical trial of an anti-B7H3 antibody-drug conjugate combined with an immune checkpoint inhibitor ± platinum agent for the treatment of advanced solid tumors. This study is used to evaluate the safety, tolerability, and efficacy of each combination therapy regimen in patients with advanced solid tumors. Study endpoints include, but are not limited to, the MTD or maximum applicable dose (MAD) of intravenous administration of the anti-B7H3 antibody-drug conjugate in the combination therapy regimen, objective response rate (ORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and overall survival (OS) as assessed by the investigator according to RECIST 1.1 standards, the pharmacokinetic characteristics of intravenous administration of the anti-B7H3 antibody-drug conjugate in the combination therapy regimen, and the immunogenicity of the anti-B7H3 antibody-drug conjugate in the combination therapy regimen.

[0118] 1. Name of the test drug: (1) Anti-B7H3 antibody-drug conjugate Dosage form: Injectable (lyophilized powder), Specifications: 100 mg / vial packaged in a 20 mL borosilicate glass injection vial, Manufacturer: Shanghai Hansoh Biomedical Technology Co., Ltd. (2) Immune checkpoint inhibitors Adebrelimab, Dosage Form: Injectable, Specifications: 600 mg (12 ml) per vial, packaged in a borosilicate glass injection vial, Manufacturer: Suzhou Shengdiya Biopharmaceutical Co.,Ltd. (3) Platinum drugs Carboplatin, Dosage form: Injectable, Specifications: 50 mg (10 mL) / 100 mg (10 mL), Ampoule packaging, Manufacturer: Qilu Pharmaceutical Co., Ltd. Cisplatin, Dosage Form: Injectable, Specifications: 6ml:30mg, Packaged in a controlled antibiotic vial, Manufacturer: Jiangsu Hansoh Pharmaceutical Group Co.,Ltd.

[0119] 2. Target group: Patients with advanced solid tumors who have had unsuccessful or intolerant first-line treatment, or for whom there is no effective standard treatment, specifically: (1) advanced small cell lung cancer (SCLC) for which first-line treatment has been unsuccessful or intolerant; (2) untreated advanced small cell lung cancer (SCLC); (3) locally advanced or metastatic non-small cell squamous cell lung cancer (NSCLC) that has progressed or is intolerant to first-line treatment; (4) locally advanced or metastatic non-small cell squamous cell lung cancer (NSCLC) that is in an advanced stage and untreated; (5) patients with advanced or metastatic non-small cell squamous cell lung cancer that has progressed or is intolerant to first-line treatment. (6) Unresectable locally advanced recurrent or metastatic esophageal squamous cell carcinoma (ESCC) that is intolerant to the treatment; (7) Locally advanced, recurrent or metastatic nasopharyngeal carcinoma (NPC) that has progressed after at least one first-line treatment or is intolerant to it; (8) Locally advanced recurrent or metastatic nasopharyngeal carcinoma (NPC) that is untreated at an advanced stage; and (9) Patients with other advanced solid tumors for which appropriate standard treatment has been unsuccessful or for which there is no effective standard treatment, and for whom the investigator has assessed that there is a possibility of benefiting from the investigational treatment.

[0120] 3. Dosage regimen: In this study, every three weeks (21 days) constituted one treatment cycle (C).

[0121] Cohort 1a: Recommended administration priority: Adebrelimab should be administered first, followed at least 30 minutes after completion of that administration by the anti-B7H3 antibody-drug conjugate treatment. The entire administration regimen (adebrelimab + anti-B7H3 antibody-drug conjugate) must be completed within 72 hours, calculated from the start of administration of the first drug in the combination therapy to the completion of administration of the last drug.

[0122] Adebrelimab: 20 mg / kg. The total dose is calculated according to the subject's pre-administration weight measurement and administered intravenously by Q3W until objective disease progression (excluding drug donation) or other criteria for termination of the study treatment specified in the protocol are reached. Anti-B7H3 antibody-drug conjugate: Administered intravenously by Q3W at an initial dose of 8.0 mg / kg until objective disease progression (excluding drug donation) or other criteria for termination of the study treatment specified in the protocol are reached.

[0123] Cohort 1b: Recommended administration order: Adebrelimab should be administered first, followed by the anti-B7H3 antibody-drug conjugate treatment at least 30 minutes after completion of the adebrelimab administration; followed by the cisplatin / carboplatin treatment at least 60 minutes after completion of the anti-B7H3 antibody-drug conjugate administration. The entire administration regimen (adebrelimab + anti-B7H3 antibody-drug conjugate + cisplatin / carboplatin) must be completed within 72 hours, calculated from the start of administration of the first drug in the combination therapy to the completion of administration of the last drug.

[0124] Adebrelimab: 20 mg / kg. The total dose is calculated according to the subject's pre-administration weight measurement and administered intravenously by Q3W until objective disease progression (excluding drug donation) or other criteria for termination of the study treatment specified in the protocol are reached. Anti-B7H3 antibody-drug conjugate: Administered intravenously by Q3W at an initial dose of 6.0 mg / kg until objective disease progression (excluding drug donation) or other criteria for termination of the study treatment specified in the protocol are reached.

[0125] Cisplatin / Carboplatin: Administered intravenously over a total of 4–6 cycles, with Q3W doses of 75 mg / m2 of cisplatin or 5 mg / ml / min of carboplatin AUC. The principal investigator may select cisplatin or carboplatin according to the patient's specific condition. During treatment, switching between cisplatin and carboplatin is permissible due to tolerability issues, but patients should be fully informed about the risk of cross-allergy. If a patient does not tolerate a drug for safety reasons, treatment with that drug should be terminated.

[0126] Example 4. Evaluation of the in vivo inhibitory effect of drug A in combination with drug B or drug C against human osteosarcoma tumors transplanted into mice. 1. Experimental materials The human osteosarcoma cell line SJSA-1 was purchased from Guangzhou Jennio Biotech Co., Ltd. and cultured in vitro in a monolayer. The culture conditions were DMEM medium + 10% fetal bovine serum in a cell incubator containing 5% CO2 at 37°C. Conventional digestion and subculturing were performed twice a week using trypsin-EDTA. When cell confluence reached 80%-90% and the required volume was reached, the cells were harvested, counted, and inoculated.

[0127] NOG-dKO mice, female, weighing 16-22g were purchased from Zhejiang Vital River Laboratory Animal Technology Co.,Ltd.

[0128] 2. Experimental Method PBMC cells (human peripheral blood mononuclear cells) were resuspended in PBS and 5.0 × 10⁶ 7 Adjust the cell density to 5.0 × 10¹⁴ cells / mL, inject through the tail vein, and administer 0.1 mL (5.0 × 10¹⁴) to each mouse. 6 Cells (mouse) were inoculated.

[0129] One week after inoculation of PBMC cells, SJSA-1 cells were resuspended in PBS and 1.0 × 10⁶ cells were added. 8The cells were adjusted to a density of cells / mL, resuspended, mixed with an equal volume of Matrigel, and subcutaneously inoculated into the right back of each mouse. Each mouse received 0.1 mL (5.0 × 10⁶) of the solution. 6 Cells (mouse) were inoculated;

[0130] Average tumor volume is 50-100 mm 3 When the tumors proliferated, the mice were divided into groups (D0) and administered drugs (D0). Mice were administered a single dose (Drug A) or twice weekly (BIW, Drug B or Drug C) by tail vein injection (iv, Drug A) or intraperitoneal injection (ip, Drug B or Drug C); the administration volume was 10 mL / kg; the vehicle group was administered the same volume of "vehicle" (physiological saline); specific doses and administration regimens are shown in Table 1. Tumor volume and mouse body weight were measured and the data were recorded.

[0131] The experimental indicator was to test the effect of the drug on tumor growth, and the specific indicator was T / C% or tumor growth inhibition rate TGI(%).

[0132] The tumor diameter was measured with calipers, and the formula for calculating the tumor volume (V) was as follows: V = 1 / 2 × a × b 2 (In the formula, a and b represent the long and short diameters of the tumor, respectively.) T / C(%)=(TT i ) / (CC i ) × 100 (wherein T and C are the tumor volumes of the treatment group and the control group at the end of the experiment, T i and C i (These are the tumor volumes of the treatment group and the control group at the start of the experiment.) Tumor growth inhibition rate (TGI) (%) = 100-T / C ​​(%). When tumor regression occurs, the tumor growth inhibition rate (TGI) (%) = 100 - (T - Ti) / Ti × 100.

[0133] When a tumor shrinks relative to its initial volume, that is, T <T i or C <C iIf the tumor does not completely disappear, it is defined as partial regression (PR); if the tumor completely disappears, it is defined as complete regression (CR).

[0134] At the end of the experiment, when the experimental endpoint was reached, or when the average tumor volume reached 2,000 mm³ 3 When the tumors reached a certain stage, the mice were euthanized, then dissected to recover the tumors, and photographed.

[0135] Experimental data were analyzed and plotted using GraphPad Prism 9. Statistical analysis was performed using two-way ANOVA based on tumor volume data for each group at different time points to assess differences between groups. Statistical significance was defined as p<0.05.

[0136] [Table 6]

[0137] 3. Experimental Results Table 6 and Figure 3 show the inhibitory effect of drug A in combination with drug B on the SJSA-1 model, and Figure 5 shows the changes in body weight of mice in each group; Table 7 and Figure 4 show the inhibitory effect of drug A in combination with drug C on the SJSA-1 model, and Figure 5 shows the changes in body weight of mice in each group.

[0138] [Table 7]

[0139] At the end of the experiment (day 22), the average tumor volume for drug A, drug B, and drug A + drug B groups was 1,763 mm², respectively. 3 , 1,900mm 3 , and 907mm 3The tumor inhibition rates were 31.26%, 25.67%, and 66.08%, respectively; all treatment groups showed a significant tumor inhibition effect compared to the vehicle group (P values ​​were 0.0040, 0.0176, and <0.001, respectively); the combination treatment group of drug A + drug B (G5) showed a statistically significant difference compared to the respective monotherapy groups (G2 and G3) (P<0.01 and P<0.001), demonstrating a relatively strong tumor inhibition effect.

[0140] [Table 8]

[0141] At the end of the experiment (day 22), the average tumor volume for drug A, drug C, and drug A + drug C groups was 1,763 mm², respectively. 3 , 1,911mm 3 , and 558mm 3 The tumor inhibition rates were 31.26%, 25.25%, and 80.26%, respectively; all treatment groups showed a significant tumor inhibition effect compared to the vehicle group (P values ​​were 0.0051, 0.0234, and <0.001, respectively); the combination treatment group of drug A + drug C (G6) showed a statistically significant difference compared to the respective monotherapy groups (G2 and G4) (P < 0.001), demonstrating a relatively strong tumor inhibition effect.

[0142] Throughout the experiment, SJSA-1 tumor-bearing mice exhibited relatively good tolerance to drug A, drug B, drug C, and drug A in combination with drug B, and drug A in combination with drug C.

[0143] Overall, in the human osteosarcoma cell SJSA-1 mouse model, treatment with drug A + drug B and treatment with drug A + drug C showed better tumor inhibitory effects than each monotherapy.

[0144] Example 5. Clinical trial of an anti-B7H3 antibody-drug conjugate combined with an immune checkpoint inhibitor for the treatment of advanced osteosarcoma. The objective is to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of anti-B7H3 antibody-drug conjugates for combination injection therapy regimens in patients with advanced osteosarcoma.

[0145] Expanded trials in the target population will be conducted at doses determined to be safe and potentially effective, to obtain further safety, pharmacokinetic (PK), and efficacy of the combination therapy regimen, and to determine the target dose of the combination therapy regimen.

[0146] Name of the test drug: (1) Anti-B7H3 antibody-drug conjugate Dosage form: Injectable (lyophilized powder), Specifications: 100 mg / vial packaged in a 20 mL borosilicate glass injection vial, Manufacturer: Shanghai Hansoh Biomedical Technology Co., Ltd. (2) Immune checkpoint inhibitors Adebrelimab, Dosage Form: Injectable, Specifications: 600 mg (12 ml) per vial, packaged in a borosilicate glass injection vial, Manufacturer: Suzhou Shengdiya Biopharmaceutical Co.,Ltd.

[0147] 2. Target group: Cohort 2 Dose escalation / expansion group: Progressive osteosarcoma that has progressed after standard treatment and also meets the following conditions: 1) Definition of progressive osteosarcoma: a. The primary tumor or locally recurrent tumor cannot be cured by surgery or other local treatment means (e.g., stereotactic radiotherapy, argon helium knife, focused ultrasound knife, etc.), or the patient refuses surgery or other local treatment. b. Distant metastasis has already occurred, and the metastatic tumor cannot be cured by surgery or other local treatment means (e.g., stereotactic radiotherapy, argon helium knife, focused ultrasound knife, etc.), or the patient refuses surgery or other local treatment. 2) Progression after standard treatment, where standard treatment is defined as receiving two or more of the following standard therapies: methotrexate, anthracycline, cisplatin, or ifosfamide. If a subject is still receiving only first-line treatment (≥2 standard therapies) and disease progression occurs within 6 months of the end of treatment, the subject may be included in the trial; for patients whose disease progression occurs after 6 months, the principal investigator must determine whether the subject should be included in the treatment trial through a risk-benefit assessment. 3) The total number of previous treatment lines does not exceed 2. Note: For subjects enrolled due to intolerance to the last treatment, the principal investigator must document or provide an explanation for the reason for the intolerance to the current treatment. An intolerance may be counted when the cumulative dose of anthracyclines reaches a certain dose, and the maximum lifetime cumulative dose of commonly used anthracyclines is shown in Appendix 13. If a patient refuses to receive standard primary care during the dose escalation period, enrollment may be permitted after the principal investigator and sponsor have communicated and reached an agreement, and after approval by the ethics committee.

[0148] 3. Dosage regimen For all two-drug combination cohorts (Cohort 2a), the pre-set starting dose of the anti-B7H3 antibody-drug conjugate is 10.0 mg / kg Q3W. In Cohort 2a, the dose of the combination drug is fixed, and only the dose of the anti-B7H3 antibody-drug conjugate is adjusted.

[0149] Recommended administration priority: Adebrelimab should be administered first, followed at least 30 minutes after completion of that administration by the anti-B7H3 antibody-drug conjugate treatment. The entire administration regimen (adebrelimab + anti-B7H3 antibody-drug conjugate) must be completed within 72 hours, calculated from the start of administration of the first drug in the combination therapy to the completion of administration of the last drug.

[0150] Adebrelimab: 20 mg / kg by Q3W intravenous infusion until objective disease progression (excluding continued treatment after disease progression) or until other criteria for termination of the study treatment specified in the protocol are met.

[0151] Anti-B7H3 antibody-drug conjugate: Administered intravenously by Q3W at a pre-set dose of 10 mg / kg until objective disease progression (excluding continued treatment after disease progression) or until other criteria for termination of the study treatment specified in the protocol are met.

[0152] While specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and changes may be made to the details in accordance with all previously disclosed teachings, and that all such changes will remain within the scope of the protection of the present invention. The entirety of the present invention is defined by the appended claims and any equivalents thereof.

Claims

1. The use of a combination of an antibody-drug conjugate and an immune checkpoint inhibitor in the preparation of a drug for the treatment of cancer, wherein the structure of the antibody-drug conjugate is formula (I): 【Chemistry 1】 As shown, in the formula, 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 its antigen-binding fragment.

2. The use according to claim 1, wherein the anti-B7H3 antibody or its antigen-binding fragment comprises heavy chain HCDR1, HCDR2, and HCDR3 represented by the amino acid sequences of SEQ ID NOs. 01, 02, and 03, respectively, and light chain LCDR1, LCDR2, and LCDR3 represented by 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 its antigen-binding fragment is selected from a humanized antibody or its fragment.

4. The use according to claim 3, wherein the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain constant region of a human IgG1, IgG2, IgG3, or IgG4 isotype and a κ or λ light chain constant region; preferably, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain constant region of an IgG1 or IgG4 isotype.

5. The use according to claim 3, wherein the heavy chain variable region sequence of the anti-B7H3 antibody or its antigen-binding fragment 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.

6. The use according to any one of claims 1 to 5, wherein the heavy chain sequence of the anti-B7H3 antibody or its antigen-binding fragment 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.

7. The use according to any one of claims 1 to 6, wherein the immune checkpoint inhibitor is selected from antibodies that target PD-1, PD-L1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, A2aR, B7-H3, and B7-H4, or antigen-binding fragments thereof, and preferably selected from antibodies that target PD-1 and PD-L1, or antigen-binding fragments thereof.

8. The aforementioned immune checkpoint inhibitors include tripalimab, cintilimab, camrelizumab, dostarlimab, tislerizumab, zimberelimab, penpulimab, serplulimab, pucotenlimab, pembrolizumab, nivolumab, sugemalimab, and Use according to any one of claims 1 to 7, selected from Envafolimab, Adebrelimab, Atezolizumab, Durvalumab, Ipilimumab, and Cadonilimab antibody, preferably Camrelizumab, Adebrelimab, Dostarlimab, Pembrolizumab, and Durvalumab.

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

10. The use according to claim 9, wherein the platinum agent is selected from carboplatin, cisplatin, oxaliplatin, nedaplatin, lobaplatin, satraplatin, cycloplatin, miboplatin, enloplatin, iproplatin, and 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 each included as active ingredients in different formulations and are administered simultaneously or not simultaneously.

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

13. The use according to claim 9 or 10, wherein the dose of the platinum agent 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, or 8 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.

14. The administration dose of the platinum drug is 10 mg / m ２ to 500 mg / m ２ , preferably 10 mg / m ２ to 200 mg / m ２ , more preferably 25 mg / m ２ , 50 mg / m ２ , 75 mg / m ２ , 100 mg / m ２ , 125 mg / m ２ , 150 mg / m ２ , 175 mg / m ２ , or 200 mg / m ２ , and the administration frequency is once weekly, once every 2 weeks, once every 3 weeks, or once every 4 weeks, the use according to claim 9 or 10.

15. The use according to any one of claims 1 to 14, wherein 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, and the frequency of administration 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 dose 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, or 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 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, and the frequency of administration is once a week, once every two weeks, once every three weeks, or once every four weeks.

18. The use according to any one of claims 1 to 17, 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, penile cancer, testicular cancer, urothelial carcinoma, urethral cancer, colon cancer, rectal cancer, colorectal cancer, adenocarcinoma of the esophageal junction, 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.

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 tumor that has been unsuccessful in primary treatment, is intolerant to such treatment, or does not have an 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 has previously received a total of two or fewer lines of treatment.

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

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

24. The method according to 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, penile cancer, testicular cancer, urothelial carcinoma, urethral cancer, colon cancer, rectal cancer, colorectal cancer, adenocarcinoma of the esophageal junction, 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.

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 according to claim 23, wherein the cancer is an advanced solid tumor that has either failed or is intolerant to primary treatment, or for which there is 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 has previously received a total of two or fewer lines of treatment.

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