Use of antibody-drug conjugate in combination with vegfr TKI and / or anthracycline for treating cancer

Abstract

The present invention provides a combination of therapeutic agents for preventing and / or treating neoplastic diseases. Specifically, the present invention provides an antibody-drug conjugate in combination with VEGFR TKI and / or in combination with anthracycline in the preparation of a drug for preventing and / or treating cancer.

Description

Use of antibody drug conjugate in combination with VEGFR TKI and / or anthracycline for treating cancer TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and relates to the use of an antibody drug conjugate in combination with a VEGFR TKI and / or in combination with an anthracycline for the manufacture of a medicament for treating cancer. The relevant combination has the potential to achieve clinical benefits that are difficult to achieve with a single drug. BACKGROUND

[0002] Soft tissue sarcoma is a malignant tumor originating from mesodermal connective tissue, accounting for 0.72% to 1.05% of human malignant tumors, and the annual incidence in China is about 2.91 / 100,000. About 75% of STS lesions are located in the extremities, and the most common metastatic site is the lung. According to the tissue origin and different morphology and biological behavior, there are more than 50 subtypes of STS, among which the most common subtypes include undifferentiated pleomorphic sarcoma, liposarcoma, leiomyosarcoma and synovial sarcoma, etc. In the past decade, there has been no progress in the systemic treatment of advanced first-line STS - the initial treatment of advanced STS still receives anthracycline-based chemotherapy, and the OS of the initial patients is about 12 months. Some STS subtypes such as liposarcoma and alveolar soft part sarcoma have poor response to chemotherapy and poor prognosis. In the past decade, no new drug has been approved for the first-line treatment of STS in China, and the existing treatment for advanced unresectable soft tissue sarcoma has limited benefits. For STS with low incidence and high malignancy, new drugs are urgently needed to improve clinical treatment.

[0003] B7-H3 mRNA is widely expressed in almost all human immune and non-immune tissues and organs, but its protein expression in normal tissues is very limited, with a certain low level of expression in breast, prostate, testis, liver, lung, placenta and some lymphoid organs. The difference between the wide expression of B7-H3 mRNA and the limited distribution of protein indicates a complex post-transcriptional regulation mechanism between them. More and more studies have reported that B7-H3 protein can be abnormally highly expressed in various tumor cells / tissues. A study of 132 soft tissue sarcoma tissue samples by immunohistochemical staining (IHC) showed that the positive rate of B7-H3 in soft tissue sarcoma was 91.5% (122 / 132). In addition, many studies have also shown that the high expression of B7-H3 is closely related to the biological characteristics of tumors, disease progression and patient prognosis.

[0004] Vascular endothelial growth factor (VEGF)-VEGFR family is the most studied pro-angiogenic regulatory factor, which induces endothelial cell differentiation and angiogenesis. VEGFR, as the main receptor of VEGF, is mainly distributed in endothelial cells such as vascular endothelial cells and lymphatic endothelial cells. After binding with VEGF, it can activate the tyrosine kinase in the intracellular domain of VEGFR, phosphorylate the tyrosine residue, thereby activating the intracellular signal transduction pathway, inducing tumor angiogenesis and promoting tumor growth. VEGFR-TKI can inhibit tumor angiogenesis by inhibiting the phosphorylation of its target receptor tyrosine kinase, and has an anti-tumor effect. The anti-angiogenic characteristics of VEGFR-TKI make it have the potential mechanism of combination with various anti-tumor drugs.

[0005] As the cornerstone of first-line treatment for advanced soft tissue sarcoma, anthracyclines mainly interfere with topoisomerase II to rejoin the broken DNA double strands, thereby hindering the process of DNA replication, transcription and RNA synthesis, and then playing a role in killing tumor cells.

[0006] Although there are some drugs that have shown anti-tumor effect in soft tissue sarcoma, the existing treatment has limited benefit, and new treatment regimens need to be explored to more effectively exert anti-tumor effect, so as to bring better clinical efficacy to patients with soft tissue sarcoma. SUMMARY

[0007] The application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with a VEGFR-TKI and / or an anthracycline in the preparation of a drug for preventing or treating cancer.

[0008] In a first aspect, the application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with a VEGFR-TKI in the preparation of a drug for preventing or treating cancer.

[0009] In a second aspect, the application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with an anthracycline in the preparation of a drug for preventing or treating cancer.

[0010] In a third aspect, the application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with a VEGFR-TKI and an anthracycline in the preparation of a drug for preventing or treating cancer.

[0011] In a fourth aspect, the present application provides use of a combination of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof and a VEGFR-TKI in the manufacture of a medicament for treating cancer.

[0012] In a fifth aspect, the present application provides use of a combination of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof and an anthracycline in the manufacture of a medicament for treating cancer.

[0013] In a sixth aspect, the present application provides use of a combination of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, a VEGFR-TKI and an anthracycline in the manufacture of a medicament for treating cancer.

[0014] In a seventh aspect, the present application provides use of a pharmaceutical composition in the manufacture of a medicament for treating cancer; wherein the pharmaceutical composition comprises: (1) a B7H3 antibody drug conjugate or a pharmaceutically acceptable salt thereof and a VEGFR-TKI; (2) a B7H3 antibody drug conjugate or a pharmaceutically acceptable salt thereof and an anthracycline; (1) a B7H3 antibody drug conjugate or a pharmaceutically acceptable salt thereof, a VEGFR-TKI and an anthracycline.

[0015] In an eighth aspect, the present application provides use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof for treating a subject having cancer, wherein the subject is also administered: (1) a VEGFR-TKI; (2) an anthracycline; or (3) a VEGFR-TKI and an anthracycline.

[0016] In some embodiments, the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof has a structure as shown in Formula (I):

[0017] wherein:

[0018] n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a decimal number or an integer;

[0019] Pc is an anti-B7H3 antibody or an antigen binding fragment thereof.

[0020] In some embodiments, the anti-B7H3 antibody or an antigen binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), the VH comprises HCDR1, HCDR2 and HCDR3 in the sequence set forth in SEQ ID NO: 07, and the VL comprises LCDR1, LCDR2 and LCDR3 in the sequence set forth in SEQ ID NO: 08.

[0021] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, HCDR3 as set forth in SEQ ID NOs: 01, 02, and 03, respectively, and LCDR1, LCDR2, and LCDR3 as set forth in SEQ ID NOs: 04, 05, and 06, respectively.

[0022] In the present application, the amino acid sequences of the aforementioned CDRs are shown according to the Kabat definition. However, it is well known to those skilled in the art that the CDRs of an antibody can be defined by various methods in the art. Although the scope of the present application is based on the sequences shown according to the Kabat definition, the amino acid sequences according to other definitions of CDRs should also fall within the scope of the present application.

[0023] In which, the aforementioned CDR sequences are shown in the following table:

[0024] Table 1. CDR sequences of each heavy chain and light chain

[0025] Note: The CDR sequences are derived from the sequences shown according to the Kabat definition.

[0026] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is selected from a humanized antibody or fragment thereof.

[0027] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4 isotype, and a light chain constant region comprising kappa or lambda; preferably, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain constant region of IgG1 or IgG4 isotype.

[0028] In some embodiments, the heavy chain variable region VH 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 VL sequence is the sequence shown in SEQ ID NO: 08 or a variant thereof.

[0029] The sequences of the aforementioned heavy and light chain variable regions of the anti-B7H3 antibody or antigen-binding fragment thereof are shown as follows:

[0030] Heavy chain variable region VH sequence

[0031] Light chain variable region VL sequence

[0032] Note: The order is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, the italicized sequence in the sequence is FR sequence, and the underlined sequence is CDR sequence, wherein the CDR sequence is derived from the Kabat definition rule.

[0033] In some embodiments, the heavy chain sequence of the anti-B7H3 antibody or antigen binding fragment thereof is a sequence as set forth in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is a sequence as set forth in SEQ ID NO: 10 or a variant thereof.

[0034] The sequences of the heavy and light chains of the foregoing anti-B7H3 antibody or antigen binding fragment thereof are as follows:

[0035] Heavy chain (IgG1) amino acid sequence: (SEQ ID NO: 09)

[0036] Light chain (lambda) amino acid sequence: (SEQ ID NO: 10)

[0037] In some embodiments, the (1) VEGFR-TKI, and / or (2) anthracycline is selected from any combination of the following:

[0038] (a) VEGFR-TKI;

[0039] (b) anthracycline;

[0040] (c) VEGFR-TKI and anthracycline.

[0041] In some embodiments, the VEGFR TKI is selected from Anlotinib, Sorafenib, Sunitinib, Axitinib, Pazopanib, Regorafenib, Cabozantinib, Lenvatinib, Apatinib, Fruquintinib, Nintedanib, Vorolanib, Surufatinib, Donafenib, Tivozanib, Zabofloxacin, Vandetanib, Famitinib, Lucitanib, Cediranib, Simmitinib, Sitravatinib, Chiauranib, Telatinib, Ningetinib, Dovitinib, CEP-11981, ZSP-1603, ODM-203, Pamufetinib, FH-2001, Orantinib, preferably, the VEGFR TKI is selected from Anlotinib.

[0042] In some embodiments, the anthracycline is selected from Epirubicin, Daunorubicin, Doxorubicin, Aclarubicin, Idarubicin, Mitoxantrone, Valrubicin; preferably, the anthracycline is selected from Epirubicin.

[0043] In some embodiments, the (1) VEGFR-TKI, and / or (2) anthracycline is selected from any combination of:

[0044] (a) Anlotinib;

[0045] (b) Epirubicin;

[0046] (c) Anlotinib and Epirubicin.

[0047] The present application provides use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with Anlotinib in the manufacture of a medicament for preventing or treating cancer.

[0048] The application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate compound thereof in combination with epirubicin in the preparation of a drug for preventing or treating cancer.

[0049] The application provides a use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate compound thereof in combination with anlotinib and epirubicin in the preparation of a drug for preventing or treating cancer.

[0050] In some embodiments, the effective administration amount of the VEGFR TKI is 1-30 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg, more preferably 12 mg; and the administration frequency is once a day, once every two days, once every three days, preferably once a day.

[0051] In some embodiments, the effective administration amount of the VEGFR TKI is 12 mg; and the administration frequency is once a day.

[0052] In some embodiments, the effective administration amount of the anthracycline drug is 10-150 mg / m 2 , preferably 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 65 mg / m 2 , 70 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 85 mg / m 2 , 90 mg / m 2 , 95 mg / m 2 , 100 mg / m 2 , 105 mg / m 2 or 110 mg / m 2 , more preferably 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 ; and the administration frequency is once a week, once every two weeks, once every three weeks or once every four weeks, preferably once every two weeks, once every three weeks, more preferably once every three weeks.

[0053] In some embodiments, the effective administration amount of the anthracycline is 75 mg / m 2 with a dosing frequency of once every three weeks. In some embodiments, the effective administration amount of the anthracycline is 50 mg / m 2 with a dosing frequency of once every three weeks. In some embodiments, the effective administration amount of the anthracycline is 25 mg / m 2 with a dosing frequency of once every three weeks.

[0054] In some embodiments, the effective administration amount of the anlotinib is 1-30 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg, more preferably 12 mg, with a dosing frequency of once a day, once every two days, once every three days, preferably once a day.

[0055] In some embodiments, the effective administration amount of the anlotinib is 12 mg, with a dosing frequency of once a day.

[0056] In some embodiments, the effective administration amount of the epirubicin is 10-150 mg / m 2 , preferably 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 65 mg / m 2 , 70 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 85 mg / m 2 , 90 mg / m 2 , 95 mg / m 2 , 100 mg / m 2 , 105 mg / m 2 or 110 mg / m 2 , more preferably 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 , with a dosing frequency of once a week, once every two weeks, once every three weeks or once every four weeks, preferably once every two weeks, once every three weeks, more preferably once every three weeks.

[0057] In some embodiments, the effective administered amount of the epirubicin is 75 mg / m 2 ; with a dosing frequency of once every three weeks. In some embodiments, the effective administered amount of the epirubicin is 50 mg / m 2 ; with a dosing frequency of once every three weeks. In some embodiments, the effective administered amount of the epirubicin is 25 mg / m 2 ; with a dosing frequency of once every three weeks.

[0058] In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 1.0 mg / kg to 16.0 mg / kg, preferably 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 11 mg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg, or 12 mg / kg, more preferably 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, or 12 mg / kg, more preferably 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg; the dosing frequency is once every week, once every two weeks, once every three weeks, or once every four weeks, preferably once every two weeks, once every three weeks, more preferably once every three weeks.

[0059] In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 12.0 mg / kg; and the dosing frequency is once every three weeks. In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 10.0 mg / kg; and the dosing frequency is once every three weeks. In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 8.0 mg / kg; and the dosing frequency is once every three weeks. In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 6.0 mg / kg; and the dosing frequency is once every three weeks. In some embodiments, the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is 4.0 mg / kg; and the dosing frequency is once every three weeks.

[0060] In some embodiments, the cancer is a sarcoma, preferably the sarcoma is selected from soft tissue sarcoma.

[0061] In some embodiments, the soft tissue sarcoma is advanced soft tissue sarcoma, preferably advanced stage, treatment naive, unresectable soft tissue sarcoma, or advanced unresectable soft tissue sarcoma that has failed at least one chemotherapy regimen comprising an anthracycline.

[0062] In some embodiments, the use or method of any of the foregoing employs any of the following dosing regimens:

[0063] (1) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every two weeks, every three weeks, 8 mg, 10 mg, 12 mg of anlotinib is administered every day;

[0064] (2) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every two weeks, every three weeks, 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 of epirubicin is administered every two weeks, every three weeks;

[0065] (3) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every two weeks, every three weeks, 8 mg, 10 mg, 12 mg of anlotinib per day, 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 of epirubicin every two weeks, every three weeks.

[0066] In some embodiments, the use or method of any of the foregoing, employs any of the following dosing regimens:

[0067] (1) 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 12 mg of anlotinib per day;

[0068] (2) 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 50 mg / m 2 , 75 mg / m 2 of epirubicin every three weeks;

[0069] (3) 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 12 mg of anlotinib per day, 50 mg / m 2 , 75 mg / m 2 of epirubicin every three weeks.

[0070] In some embodiments, the use or method of any of the foregoing, employs any of the following dosing regimens:

[0071] (1-1) 10.0 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 12 mg of anlotinib per day;

[0072] (1-2) 8.0 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 12 mg of anlotinib per day;

[0073] (1-3) 12 mg / kg of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every three weeks, 12 mg of anlotinib per day.

[0074] In some embodiments, the use or method of any of the foregoing employs any of the following dosing regimens:

[0075] (2-1) 10.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 75 mg / m 2 of epirubicin is administered every three weeks;

[0076] (2-2) 12 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 75 mg / m 2 of epirubicin is administered every three weeks;

[0077] (2-3) 8.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 75 mg / m 2 of epirubicin is administered every three weeks;

[0078] (2-4) 10.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 50 mg / m 2 of epirubicin is administered every three weeks.

[0079] In some embodiments, the use or method of any of the foregoing employs any of the following dosing regimens:

[0080] (3-1) 8.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 12 mg of anlotinib is administered every day, 75 mg / m 2 of epirubicin is administered every three weeks;

[0081] (3-2) 10.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 12 mg of anlotinib is administered every day, 75 mg / m 2 of epirubicin is administered every three weeks;

[0082] (3-3) 6.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, is administered every three weeks, 12 mg of anlotinib is administered every day, 75 mg / m 2 of epirubicin is administered every three weeks;

[0083] (3-4) 8.0 mg / kg of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every three weeks, 12 mg of anlotinib is administered every day, 50 mg / m2 of epirubicin is administered every three weeks. 2 (3-5) 6.0 mg / kg of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every three weeks, 12 mg of anlotinib is administered every day, 50 mg / m2 of epirubicin is administered every three weeks.

[0084] (3-5) 6.0 mg / kg of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every three weeks, 12 mg of anlotinib is administered every day, 50 mg / m2 of epirubicin is administered every three weeks. 2 (3-5) 6.0 mg / kg of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every three weeks, 12 mg of anlotinib is administered every day, 50 mg / m2 of epirubicin is administered every three weeks.

[0085] In some embodiments, the cancer is a sarcoma, preferably the sarcoma is selected from soft tissue sarcoma.

[0086] In some embodiments, the soft tissue sarcoma is advanced soft tissue sarcoma, preferably advanced stage, treatment-naive, unresectable soft tissue sarcoma, or advanced unresectable soft tissue sarcoma that has failed at least 1 prior chemotherapy regimen comprising anthracycline.

[0087] The present application provides a pharmaceutical combination, characterized in comprising: 1) an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, and 2) a VEGFR-TKI and / or an anthracycline; the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof has a structure as shown in formula (1):

[0088] wherein:

[0089] Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0090] n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a fraction or an integer;

[0091] the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, the VEGFR-TKI, the anthracycline are respectively defined as above;

[0092] The pharmaceutical combination is used for preventing and / or treating cancer, preferably the cancer is a sarcoma, more preferably the sarcoma is selected from soft tissue sarcoma.

[0093] The present application provides a method for preventing and / or treating cancer, the method comprising administering to a subject an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof having a structure as shown in formula (1):

[0094] wherein:

[0095] Pc is an anti-B7H3 antibody or antigen binding fragment thereof;

[0096] n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a decimal or an integer;

[0097] Preferably, the method further comprises administering a VEGFR-TKI and / or an anthracycline

[0098] Preferably, the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, the VEGFR-TKI, the anthracycline are each as defined above.

[0099] Preferably, the subject is a cancer patient, preferably the cancer is a sarcoma, more preferably the sarcoma is selected from soft tissue sarcoma.

[0100] In some embodiments, the soft tissue sarcoma is an advanced stage, treatment naive, unresectable soft tissue sarcoma, or an advanced unresectable soft tissue sarcoma that has failed at least one chemotherapy regimen comprising an anthracycline.

[0101] The anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof of the present application, in combination with a VEGFR TKI and / or in combination with an anthracycline, has significantly stronger tumor inhibition than single agent, showing good synergistic effect. No new toxicity is observed in the combination administration group, and has biological activity and therapeutic potential for the treatment of advanced soft tissue sarcoma.

[0102] DETAILED DESCRIPTION

[0103] I. Terminology

[0104] For the purposes of the present application, certain technical and scientific terms are specifically defined below. Unless otherwise clearly indicated, all other technical and scientific terms used herein have the meanings that are commonly understood by one of ordinary skill in the art in the field of the application.

[0105] When a list is provided, unless otherwise indicated, each individual element of the list and every combination of the list is individually contemplated as a separate embodiment. For example, a list of embodiments presented as“A, B, or C” would be understood as including the embodiments“A,”“B,”“C,”“A or B,”“A or C,”“B or C,” or“A, B, or C.”

[0106] The term“and / or,” such as“A and / or B” should be understood to mean“A and B,” or“A or B,” and should be used to provide explicit support for both usages.

[0107] "About" means within the acceptable error range of a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. In the context of a particular measurement, result, or embodiment, "about" means within one standard deviation or up to 5% of the stated value (whichever is greater) according to the practice in the art.

[0108] The three letter and one letter codes for amino acid residues are in accord with the IUPAC-IUBMB standards as described in J. Biol. Chem. 243, p. 3558 (1968).

[0109] The term "antibody" as used herein refers to an immunoglobulin, which is a four polypeptide chain structure connected by interchain disulfide bonds, consisting of two identical heavy chains and two identical light chains. The antigenicity of immunoglobulins differs according to the amino acid composition and the order of arrangement of the constant region of the heavy chain. Accordingly, immunoglobulins can be classified into five types, or isotypes, i.e., IgM, IgD, IgG, IgA, and IgE, and the corresponding heavy chains are μ chain, δ chain, γ chain, α chain, and ε chain, respectively. The same type of Ig can be further classified into different subclasses according to the differences in the amino acid composition of the hinge region and the number and position of disulfide bonds in the heavy chain, e.g., IgG can be classified into IgG1, IgG2, IgG3, and IgG4. The light chain is classified into κ chain or λ chain according to the constant region. Each of the five types of Ig can have either κ chain or λ chain.

[0110] In the present application, the antibody light chain variable region described herein can further comprise a light chain constant region comprising human or murine κ, λ chain, or a variant thereof.

[0111] In the present application, the antibody heavy chain variable region described herein can further comprise a heavy chain constant region comprising human or murine IgG1, IgG2, IgG 3, IgG 4, or a variant thereof.

[0112] The sequences of about 110 amino acids in the N-terminal of both the heavy and light chains are highly variable and form the variable region (V region); the remaining amino acid sequences in the C-terminal are relatively stable and form the constant region (C region). The variable region includes three hypervariable regions (HVR) and four relatively conserved framework regions (FR). The three hypervariable regions determine the specificity of the antibody, also known as the complementarity-determining region (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) is composed of three CDR regions and four FR regions, arranged in the order of FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 from the amino terminal to the carboxyl terminal. The three CDR regions of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3. The CDR amino acid residues of the VL region and the VH region of the antibody or antigen binding fragment described in the present application are in accordance with the known Kabat numbering rules and Kabat or ABM definition rules (http: / / bioinf.org.uk / abs / ).

[0113] The term "recombinant human antibody" includes human antibodies that are prepared, expressed, created or isolated by recombinant means, such techniques and methods being well known in the art, such as:

[0114] 1. an antibody isolated from a transgenic, transchromosomal animal (e.g., a mouse) that has been genetically modified to produce a human immunoglobulin gene repertoire or a hybridoma generated from such an animal;

[0115] 2. an antibody isolated from a host cell, such as a transfectoma, that is transformed to express the antibody;

[0116] 3. an antibody isolated from a recombinant, combinatorial human antibody library; and

[0117] 4. an antibody prepared, expressed, created or isolated by a method comprising splicing of human immunoglobulin gene sequences to other DNA sequences.

[0118] Such recombinant human antibodies comprise variable and constant regions, which regions are encoded by specific human germline immunoglobulin sequences, but also include rearrangements and mutations that occur subsequently, such as during maturation of the antibody.

[0119] The term "humanized antibody" (also referred to as CDR-grafted antibody) refers to an antibody in which the CDR sequences of a mouse are grafted into the variable region framework of a human antibody. Humanized antibodies can overcome the disadvantage of chimeric antibodies, which induce a strong immune response due to the presence of a large number of mouse protein components. To avoid a decrease in immunogenicity while causing a decrease in activity, the human antibody variable region can be subjected to minimal back mutations to maintain the activity.

[0120] The term "antigen binding fragment" refers to an antigen binding fragment of an antibody and antibody analogs, which generally include at least a portion of the antigen binding or variable region (e.g., one or more CDRs) of the parental antibody. The antibody fragment retains at least certain binding specificities of the parental antibody. Generally, the antibody fragment retains at least 10% of the binding activity of the parental antibody when expressed on a molar basis. Preferably, the antibody fragment retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the binding affinity of the parental antibody to the target. Examples of antigen binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, linear antibodies, single chain antibodies, nanobodies, domain antibodies, and multi-specific antibodies. Engineered antibody variants are reviewed in Holliger and Hudson, 2005, Nat. Biotechnol. 23:1126-11.

[0121] The term "Fab" consists of one light chain and the CH1 and variable region of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0122] The term "Fc" region contains the two heavy chain fragments that include the CH1 and CH2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0123] The term "Fab' fragment" contains one light chain and a portion of one heavy chain that includes the VH domain and CH1 domain and the region between the CH1 and CH2 domains, whereby an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab')2 molecule.

[0124] The term "F(ab')2 fragment" contains two light chains and two heavy chains that include portions of the constant region between the CH1 and CH2 domains, whereby an interchain disulfide bond is formed between the two heavy chains. Thus, the F(ab')2 fragment consists of two Fab' fragments held together by a disulfide bond between the two heavy chains.

[0125] The term "Fv region" comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0126] The term "multispecific antibody" is used in its broadest sense to include antibodies having polyepitopic specificity. These multispecific antibodies include, but are not limited to, antibodies comprising a heavy chain variable region, VH, and a light chain variable region, VL, wherein the VH-VL unit has polyepitopic specificity; antibodies having two or more VL and VH regions, each VH-VL unit binds to a different target or a different epitope of the same target; antibodies having two or more single variable domains, each single variable domain binds to a different target or a different epitope of the same target; full length antibodies, antibody fragments, diabodies, bispecific diabodies and triabodies, antibody fragments covalently or noncovalently linked together, and the like.

[0127] The term "domain antibody fragment" is an immunologically functional immunoglobulin fragment containing only a heavy chain variable region or a light chain variable region chain. In some cases, two or more VH regions are covalently linked with a peptide linker to form a bivalent domain antibody fragment. The two VH regions of a bivalent domain antibody fragment can target the same or different antigens.

[0128] The term "single-arm antibody" as described herein refers to an antigen-binding fragment comprising a Fab fragment and a Fc fragment, typically the Fab fragment comprises a heavy chain (e.g., VH and CH1) and a light chain (e.g., VL and CL), and the Fc fragment comprises a constant region (e.g., CH2 and CH3). The Fab fragment and the Fc fragment can be connected by a linker or not. The single-arm antibody of the present application can be prepared or synthesized by various methods, for example, the sequence encoding the Fab heavy chain and the sequence encoding the Fc are constructed into the same vector, and the sequence encoding the Fab light chain is constructed into another vector, and the two vectors are transformed into host cells respectively to obtain the single-arm antibody.

[0129] The term "antigen binding site" as used herein refers to the three-dimensional space recognized by an antibody or antigen binding fragment of the present application.

[0130] The term "epitope" refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes can be formed both by contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically preserved when the protein is subjected to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost upon denaturing solvents. Epitopes usually consist of at least 3-15 amino acids in a unique spatial conformation. Methods of determining what epitope is bound by a given antibody are well known in the art, including immunoblot and immunoprecipitation assay analysis, etc. Methods of determining the spatial conformation of an epitope include techniques known in the art and described herein, such as X-ray crystallography and two-dimensional nuclear magnetic resonance, etc.

[0131] The terms "inhibition" or "blockade" are used interchangeably and encompass both partial and complete inhibition / blockade. Inhibition / blockade of a ligand preferably reduces or alters the normal level or type of activity that occurs upon ligand binding in the absence of inhibition or blockade. Inhibition and blockade are also intended to encompass any measurable reduction in ligand binding affinity upon contact with an antibody as compared to the ligand not in contact with the antibody.

[0132] The term "inhibition of growth" (e.g., with respect to a cell) is intended to encompass any measurable reduction of cell growth.

[0133] The terms "induction of an immune response" and "enhancement of an immune response" are used interchangeably and refer to the stimulation (i.e., active or adaptive) of an immune response to a particular antigen. The term "induction" with respect to the induction of CDC or ADCC refers to the stimulation of a particular direct cell killing mechanism.

[0134] "ADCC", antibody-dependent cell-mediated cytotoxicity, as described herein, refers to the lysis of a target cell by a Fc receptor-expressing cell, via recognition of the Fc portion of the antibody bound to the target cell. The ADCC effector function of an antibody can be enhanced or reduced or eliminated by modification of the Fc portion of IgG. Such modifications refer to mutations in the constant region of the heavy chain of the antibody.

[0135] Methods for producing and purifying antibodies and antigen binding fragments are well known in the art and can be found in Current Protocols in Immunology, John Wiley & Sons, Inc., NY, 5-8 and 15 chapters. For example, mice can be immunized with a human antigen or fragment thereof, the resulting antibodies can be renatured, purified, and can be subjected to amino acid sequencing using conventional methods. Antigen binding fragments can likewise be prepared using conventional methods. The antibodies or antigen binding fragments of the invention are genetically engineered to add one or more human FR regions to the CDR regions of a non-human source. Human FR germline sequences can be obtained from the website of ImMunoGeneTics (IMGT) at http: / / imgt.cines.fr or from the journal Immunoglobulin, 2001 ISBN 012441351.

[0136] The engineered antibodies or antigen binding fragments of the present application can be produced and purified using conventional methods. The cDNA sequence of the corresponding antibody can be cloned and recombined into a GS expression vector. The recombinant immunoglobulin expression vector can be stably transfected into CHO cells. As a more preferred prior art, mammalian expression systems result in glycosylation of the antibody, particularly in the Fc portion of the antibody. CThe height of the N-terminal region is conserved. Stable clones are obtained by expressing antibodies that specifically bind to the human antigen. Positive clones are expanded in serum-free media in a bioreactor to produce the antibody. The culture fluid in which the antibody is secreted can be purified, collected using conventional techniques. The antibody can be filtered and concentrated using conventional methods. Soluble mixtures and polymers can also be removed using conventional methods, such as molecular sieves, ion exchange. The resulting product is immediately frozen, such as at -70°C, or lyophilized.

[0137] An "antibody drug conjugate (ADC)" is a compound that links an antibody or an antibody fragment to a cytotoxic drug or a small molecule drug with cell-killing activity through a stable chemical linker. The ADC takes advantage of the specificity of the antibody to bind to specific or highly expressed antigens on tumor cells and the high efficiency of the cytotoxic drug, avoiding toxic side effects on normal cells. Compared with traditional chemotherapy drugs, the ADC can precisely bind to tumor cells and reduce the impact on normal cells.

[0138] In the anti-B7H3 antibody drug conjugate of the present disclosure, "n" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody drug conjugate molecule, which can also be expressed as the ratio of the amount of drug to the amount of antibody, and is the average number of drugs per ADC molecule after the conjugation reaction is identified by hydrophobic chromatography (HIC) mass spectrometry.

[0139] The term "pharmaceutical composition" is a product comprising one or more active ingredients (e.g., an antibody, a small molecule drug), and any product which results, directly or indirectly, from combining one or more active ingredients in a specified amount. Different active ingredients in a pharmaceutical composition can be administered independently in separate formulations, including simultaneous or sequential administration at different times, in combination. In the present disclosure, "pharmaceutical composition" and "formulation" are not mutually exclusive.

[0140] The term "in combination" or "in conjunction" is a mode of administration, which means that at least one dose of the bispecific antibody or bispecific antibody pharmaceutical composition and at least one dose of the additional therapeutic agent are administered within a certain time period, wherein both substances show a pharmacological effect. The time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, more preferably within 12 hours. The bispecific antibody or bispecific antibody pharmaceutical composition and the additional therapeutic agent can be administered simultaneously or sequentially. Such a time period includes treatments wherein the bispecific antibody or bispecific antibody pharmaceutical composition and the additional therapeutic agent are administered by the same or different routes of administration. The mode of administration in combination according to the present application is selected from the group consisting of simultaneous administration, separate formulation and co-administration, or separate formulation and sequential administration.

[0141] The terms "administering," "administered," and "treatment" when applied to an animal, human, test subject, cell, tissue, organ, or biological fluid, mean the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, test subject, cell, tissue, organ, or biological fluid. "Administering," "administered," and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of a cell includes contact of the agent with the cell, as well as contact of the agent with a fluid that is in contact with the cell. "Administering," "administered," and "treatment" also mean treatment by an agent, diagnostic, binding composition, or by another cell in vitro and ex vivo, for example. "Treatment" when applied to a human, veterinary, or research subject, means therapeutic treatment, prophylactic or preventative measures, research, and diagnostic applications.

[0142] The term "treatment" means the administration of an internal or external therapeutic agent, such as an antibody of any one of the present application, to a patient having one or more symptoms of a disease, where the therapeutic agent is known to have a therapeutic effect on those symptoms. Generally, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population, whether by inducing regression of such symptoms or inhibiting progression of such symptoms to any clinically measurable extent. The amount of therapeutic agent effective to alleviate any particular symptom of a disease (also referred to as "therapeutically effective amount") can vary according to factors such as the disease state, age, and weight of the patient, and the ability of the drug to elicit a desired effect in the patient. Whether a disease symptom has been alleviated can be assessed by any clinically measured method generally used by a physician or other professional health care provider to assess the severity or progression of the symptom. Embodiments of the present application (e.g., a method of treatment or article of manufacture) can not be effective in alleviating the target disease symptom in every patient, but should alleviate the target disease symptom in a statistically significant number of patients as determined by any statistical test known in the art, such as the Student's t-test, the chi-square test, the U-test according to Mann and Whitney, the Kruskal-Wallis test (H-test), the Jonckheere-Terpstra test, and the Wilcoxon test.

[0143] The term "preventing" a disease or disorder means preventing the occurrence of the disorder in a subject.

[0144] The term "diagnosing" refers to a method of determining whether a subject has a given disease or disorder or is likely to develop a given disease or disorder in the future or is likely to respond to treatment of a previously diagnosed disease or disorder (i.e., stratifying a patient population according to likelihood of responding to treatment). Diagnosing is typically performed by a physician based on general guidelines for the disease to be diagnosed or other criteria indicating that the subject is likely to respond to a particular treatment.

[0145] The terms "subject" and "patient" mean a mammal, and especially a primate, and especially a human.

[0146] The term "consisting essentially of or variations thereof as used throughout this specification and claims, indicate the inclusion of all components or elements of the listed groups as well as any other components or elements not specifically listed, so long as such components or elements do not materially alter the basic and novel properties of the specified dosage regimen, method or composition.

[0147] The term "naturally occurring" as applied to a subject matter as described herein refers to the fact that the subject matter can be found in nature. For example, a polypeptide sequence or a polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified in the laboratory is naturally occurring.

[0148] The term "effective amount" includes an amount that is sufficient to ameliorate or prevent the symptoms or conditions of a medical disorder. An effective amount also means an amount that is sufficient to allow or promote diagnosis. An effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the overall health status of the patient, the method route and dose of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxic effects.

[0149] "Optional" or "optionally" means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally comprising 1-3 antibody heavy chain variable regions" means that antibody heavy chain variable regions of a particular sequence can or can not be present.

[0150] The term "overall survival (OS)" refers to the time from randomization to death from any cause. Subjects who are alive at the time of the last follow-up have OS censored at the time of the last follow-up. Subjects who are lost to follow-up have OS censored at the time of the last confirmed survival prior to loss of follow-up. OS censored is defined as the time from randomization to censoring.

[0151] The term "Objective response rate (ORR)" refers to the proportion of patients who have tumor shrinkage to a certain extent and maintain for a certain time, including CR and PR cases. The tumor objective response is assessed using the Response Evaluation Criteria in Solid Tumors (RECIST 1.1 criteria). Subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete remission (CR), partial remission (PR), stable (SD), and progression (PD) according to the RECIST 1.1 criteria.

[0152] The term "complete response (CR)" means disappearance of all target lesions, with a decrease in the sum of the shortest diameters of all pathologic lymph nodes (including target nodes and non-target nodes) to <10 mm.

[0153] The term "partial response (PR)" means at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of the diameters.

[0154] The term "progressive disease (PD)" means at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this refers to the smallest sum

[0155] The term "stable disease (SD)" means neither sufficient shrinkage of target lesions to qualify for PR nor sufficient increase in the size of target lesions to qualify for PD, taking as reference the smallest sum of diameters while on study.

[0156] The term "progression-free survival (PFS)" means the time from randomization to the first recorded date of objective tumor progression or death from any cause, whichever comes first. PFS analysis includes tumor assessments during study treatment and follow-up, according to RECIST 1.1 criteria. If a patient has more than one indicator of PD, such as relapse, appearance of new lesions, or death, the first occurrence is used for PFS analysis. If a patient switches to other treatment or anti-tumor therapy directed at target lesions is also considered tumor progression and censored data.

[0157] The term "time to treatment failure (TTF)" means randomization to disease progression or death or discontinuation of study due to toxicity, including patient withdrawal of informed consent. DETAILED DESCRIPTION

[0158] The present application is further described in connection with the following examples, which are not meant to limit the scope of the application. Unless otherwise indicated, the experimental procedures in the examples of the present application were carried out in accordance with conventional conditions, such as those described in Current Protocols in Immunology, John Wiley & Sons, Inc., New York, NY, 1994, or as recommended by the manufacturer of the materials or reagents used. Unless otherwise indicated, the reagents used in the examples of the present application were commercially available and used according to the manufacturer's instructions.

[0159] Example 1. Preparation of Anti-B7H3 Antibody Drug Conjugate

[0160] According to the production method described in WO2020063673, h1702DS (anti-B7H3 antibody) was used with exatekin analogue to prepare anti-B7H3 antibody-drug conjugate as shown in the following structure, HIC method average: n = 4.1, that is, FADC-2. Among them, the heavy chain sequence of h1702DS is shown in SEQ ID NO: 09, and the light chain sequence is shown in SEQ ID NO: 10.

[0161] Example 2. Evaluation of the in vivo inhibitory effect of drug A combined with B and / or drug C on human soft tissue sarcoma cell mouse transplanted tumors

[0162] 1. Experimental materials

[0163] Drug A: Anti-B7-H3 antibody drug conjugate, dissolved with Saline for drug preparation, from Shanghai Hansoh Biomedical Technology Co., Ltd.;

[0164] Drug B: Anlotinib, purchased from Selleck;

[0165] Drug C: Epirubicin, purchased from MCE;

[0166] Human soft tissue sarcoma cell line HT1080 was purchased from the Chinese Academy of Sciences Cell Bank, cultured in monolayer in vitro, and the culture conditions were DMEM medium plus 10% fetal bovine serum, cultured in a 37°C 5% CO2 cell incubator. When the cell saturation degree was 80%-90%, the number reached the requirement, the cells were collected, counted, and inoculated.

[0167] BALB / c nude mice, female, body weight 18-24g, purchased from Zhejiang Vantoll Life Experimental Animal Technology Co., Ltd.

[0168] 2. Experimental method

[0169] HT1080 cells were resuspended in PBS, the density was adjusted to 2.0×10 7 cells / mL, inoculated subcutaneously on the right side of each mouse, 0.1 mL (2.0×10 6 cells / mouse) per mouse.

[0170] The HT1080 model was allowed to grow to an average tumor volume of 50-100mm 3Time point group (D0), dosing (D0). Mice were dosed (i.v. with Drug A or Drug C or p.o. with Drug B) at a single dose (Drug A) or once a week (QW, Drug C) or once a day (QD, Drug B); the volume of dosing was 10 mL / kg; the solvent group was given the same volume of "solvent" (Saline); the specific dosing dose and dosing schedule are shown in Table 1. The tumor volume was measured, the mice were weighed, and the data were recorded.

[0171] The experimental index was to investigate the effect of the drug on tumor growth, and the specific index was T / C% or tumor inhibition rate TGI (%).

[0172] The tumor diameter was measured with a vernier caliper, and the tumor volume (V) was calculated according to the following formula:

[0173] V = 1 / 2 × a × b 2 wherein a and b represent the long diameter and the short diameter of the tumor, respectively.

[0174] T / C (%) = (T-T i ) / (C-C i ) × 100 wherein T and C are the tumor volumes of the dosing group and the control group at the end of the experiment, T i and C i are the tumor volumes of the dosing group and the control group at the beginning of the experiment.

[0175] Tumor inhibition rate (TGI) (%) = 100 - T / C (%).

[0176] When the tumor regressed, the tumor inhibition rate (TGI) (%) = 100 - (T-T i ) / T i × 100.

[0177] If the tumor volume was smaller than the initial volume, i.e., T < T i or C < C i , it was defined as partial regression of tumor (PR); if the tumor completely disappeared, it was defined as complete regression of tumor (CR).

[0178] At the end of the experiment, when the experimental endpoint was reached or the average tumor volume reached 2,000 mm 3 , the mice were euthanized, and the tumors were dissected and photographed.

[0179] Experimental data were analyzed and plotted using GraphPad Prism 9. Based on the tumor volume and body weight change rate data at different time points of each group, the differences between groups were evaluated using Two-way ANOVA for statistical analysis; the differences in tumor volume between groups on the endpoint day were analyzed using One-way ANOVA method; the tumor volume between two groups was analyzed for difference using t-test. P<0.05 was defined as statistically significant difference.

[0180] Table 2. Dosing regimen of drug A combined with drug B and / or drug C in human soft tissue sarcoma model

[0181] Experimental data were analyzed and plotted using GraphPad Prism 9. Based on the tumor volume and body weight change rate data at different time points of each group, the differences between groups were evaluated using Two-way ANOVA for statistical analysis; the differences in tumor volume between groups on the endpoint day were analyzed using One-way ANOVA method; the tumor volume between two groups was analyzed for difference using t-test. P<0.05 was defined as statistically significant difference.

[0182] 3. Experimental results

[0183] The growth inhibition effect of drug A combined with drug B and drug A combined with drug C on HT1080 model is shown in Table 3 and Figure 1, and the body weight change of each group of mice is shown in Figure 2.

[0184] Table 3. Growth inhibition effect of drug A combined with drug B and / or drug C on HT1080 model

[0185] Note:

[0186] P value Day 13: the values obtained by analyzing the tumor volume of each animal in different groups with the solvent group as control;

[0187] # : compared with the drug A+drug B combination group, analyzed using Two-way ANOVA, # P<0.05, ### P<0.001;

[0188] $ : compared with the drug A+drug C combination group, analyzed using Two-way ANOVA, $ P<0.05, $$$ P<0.001.

[0189] At the end of the experiment (Day 13), the average tumor volumes of drug A, drug B, drug C, drug A+drug B, and drug A+drug C groups were 2,386 mm3 , 450 mm 3 , 773 mm 3 , 1,447 mm 3 , 48 mm 3 and 43 mm 3 The tumor inhibition rates were 84.12%, 70.11%, 40.83%, 144.24% and 149.98%, respectively; compared with the solvent group, each administration group had a significant tumor inhibition effect (P<0.0001); the drug A+drug B combination therapy group (G5) had a statistically significant difference compared with the respective single-drug groups (G2 and G3) (P<0.05 and P<0.001), and the drug A+drug C combination therapy group (G6) had a statistically significant difference compared with the respective single-drug groups (G2 and G4) (P<0.05 and P<0.001), which showed a strong tumor inhibition effect.

[0190] During the entire experiment, the HT1080 tumor-bearing mice had good tolerance to drug A, drug B, drug C, and drug A combined with drug B and drug A combined with drug C.

[0191] Overall, in the mouse model of human soft tissue sarcoma cells HT1080, the drug A+drug B combination therapy and the drug A+drug C combination therapy had better tumor inhibition effect than the respective single-drug.

[0192] Example 3. Ib phase clinical study on safety, tolerability, pharmacokinetics and effectiveness of anti-B7H3 antibody drug conjugate combination therapy in patients with advanced soft tissue sarcoma

[0193] 1. Purpose of the study

[0194] To evaluate the safety, tolerability, pharmacokinetics (PK) and effectiveness of anti-B7H3 antibody drug conjugate combination therapy in subjects with advanced soft tissue sarcoma.

[0195] To evaluate the safety, tolerability, PK characteristics and effectiveness of anti-B7H3 antibody drug conjugate under different combination regimens; to determine the safety and potential effectiveness of the dose, and to obtain further safety, PK and effectiveness of each combination therapy regimen in the target population, and to determine the target dose of the combination therapy regimen.

[0196] 2. Study drug

[0197] (1) Anti-B7H3 antibody drug conjugate

[0198] Dosage form: injection (lyophilized powder), specification: 100 mg / bottle, packaged with 20 mL of borosilicate glass tube injection bottles, manufacturer: Shanghai Hansoh Biomedical Technology Co., Ltd.

[0199] (2) Anlotinib hydrochloride capsules

[0200] Anlotinib hydrochloride capsules, dosage form: capsules, specifications: 12, 10, 8 mg, manufacturer: Zhejiang Hisun Pharmaceutical Co., Ltd.

[0201] (3) Epirubicin hydrochloride for injection

[0202] Epirubicin hydrochloride for injection, dosage form: injection (lyophilized powder), specifications: 10, 50 mg, westlin bottle. 10 bottles / box and 1 bottle / box, manufacturer: Pfizer Pharmaceutical (Wuxi) Co., Ltd.

[0203] 3. Dosing regimen

[0204] This study is a 3-week (21-day) cycle (C) for each treatment.

[0205] Starting dose: The study includes an escalation design of two-drug combination and three-drug combination as a whole, considering that there may be toxic additive effects of combination drugs, different starting doses of anti-B7H3 antibody drug conjugate will be used for combination escalation under different combination regimens.

[0206] The preset anti-B7H3 antibody drug conjugate combination starting dose of all two-drug combination cohorts (cohort 1a, 1b) is 10.0 mg / kg Q3W, and the preset anti-B7H3 antibody drug conjugate combination starting dose of three-drug combination cohort (cohort 1c) is 8.0 mg / kg Q3W. In cohort 1a, the dose of the combination drug is fixed, and only the dose of anti-B7H3 antibody drug conjugate is adjusted. In cohorts 1b and 1c, only the dose of anti-B7H3 antibody drug conjugate is escalated, and the dose of anti-B7H3 antibody drug conjugate or epirubicin is explored according to the drug-relatedness of DLT events.

[0207] Cohort 1a:

[0208] Recommended priority order of administration: Anlotinib is given orally first, and anti-B7H3 antibody drug conjugate treatment is given at least 30 minutes after the completion of administration.

[0209] Anlotinib: 12 mg, once a day, taken orally before breakfast. Continuous medication for 2 weeks, 1 week off, i.e. 3 weeks (21 days) for a course of treatment.

[0210] Anti-B7H3 antibody drug conjugate: administered according to the preset dose of 10.0 mg / kg, intravenous infusion, once every three weeks (Q3W).

[0211] Cohort 1b:

[0212] Recommended administration priority: Epirubicin is given first, and the anti-B7H3 antibody drug conjugate treatment is given at least 30 min after the administration is completed. The entire administration regimen (epirubicin + anti-B7H3 antibody drug conjugate) requires completion within 72 h, counting from the start of the first drug administration of this combination therapy to the completion of the last drug administration.

[0213] Epirubicin: 75 mg / m 2 , Q3W, for a total of 6 cycles of administration.

[0214] Anti-B7H3 antibody drug conjugate: administration is performed according to the preset dose of 10.0 mg / kg, intravenous infusion, once every three weeks (Q3W).

[0215] Cohort 1c:

[0216] Recommended administration priority: Anlotinib is given orally first, and the epirubicin is given at least 30 min after the administration is completed, and the anti-B7H3 antibody drug conjugate treatment is given at least 30 min after the administration is completed. The entire administration regimen (anlotinib + epirubicin + anti-B7H3 antibody drug conjugate) requires completion within 72 h, counting from the start of the first drug administration of this combination therapy to the completion of the last drug administration.

[0217] Anlotinib: 12 mg, once a day, orally before breakfast. Continuous medication for 2 weeks, drug withdrawal for 1 week, i.e. 3 weeks (21 days) for a course of treatment.

[0218] Epirubicin: 75 mg / m 2 , Q3W, for a total of 6 cycles of administration.

[0219] Anti-B7H3 antibody drug conjugate: administration is performed according to the preset dose of 8.0 mg / kg, intravenous infusion, once every three weeks (Q3W).

[0220] 4. Inclusion criteria

[0221] The subjects must meet the following inclusion criteria to be enrolled in this study:

[0222] 1. Male or female who is 18 years of age or older (≥18 years of age).

[0223] 2. Tumor diagnosis and history of prior anti-tumor treatment:

[0224] All enrolled subjects must be pathologically diagnosed with advanced bone and soft tissue sarcoma (key immunohistochemistry / tumor cell phenotype results required for clear diagnosis), with the following specific requirements:

[0225] Cohort 1:

[0226] Dose-escalation population: Patients with advanced unresectable soft tissue sarcoma who have failed at least 1 prior chemotherapy regimen (must include an anthracycline) (except alveolar soft part sarcoma and clear cell sarcoma, which can be included in the cohort of patients who have failed prior sunitinib treatment), and all patients enrolled have received a total of no more than 2 prior lines of therapy. Patients enrolled in Cohorts 1b and 1c have a cumulative dose of anthracyclines of no more than half of the maximum cumulative lifetime dose.

[0227] Expansion population: Patients with advanced stage, treatment-naive, unresectable soft tissue sarcoma.

[0228] Table 4. Study enrollment population

[0229] 3. According to RECIST 1.1, subjects have at least 1 target lesion. The requirements for target lesions are: measurable lesions that have not been irradiated or that have clearly progressed following local therapy, with a longest diameter of >10 mm at baseline (if lymph nodes, a longest short diameter of >15 mm is required); brain and / or bone lesions are not accepted as target lesions.

[0230] 4. Provision of tumor tissue sample (subjects who fail screening for other reasons can not provide a tumor tissue sample): All subjects are required to provide a fresh tumor tissue sample (sample type is a tumor tissue block or a formalin-fixed, paraffin-embedded [FFPE] tumor tissue section) at screening for retrospective testing of B7-H3 by IHC at a central laboratory; if fresh sample is not available, a newly prepared FFPE section from a FFPE tumor tissue block within 2 years can be accepted.

[0231] 5. Eastern Cooperative Oncology Group (ECOG) performance status score (PS) of 0 to 1 and no deterioration within 2 weeks prior to first dose.

[0232] 6. Minimum expected survival of >12 weeks.

[0233] 7. Female subjects of childbearing potential willing to use an appropriate method of contraception (see Appendix XII) and not breast-feeding from the time of signing the informed consent form until 6 months after the last dose of study treatment (whichever is later) and male subjects willing to use a barrier method of contraception (i.e., condom) from the time of signing the informed consent form until 6 months after the last dose of study treatment (whichever is later).

[0234] 8. Female subjects with a negative serum pregnancy test result within 7 days prior to first dose or meet one of the following criteria that demonstrate no risk of pregnancy:

[0235] Postmenopausal is defined as age >60 years and amenorrhea for at least 12 months after cessation of all exogenous hormonal replacement therapies;

[0236] A woman less than 60 years of age is considered postmenopausal if she has been amenorrhic for 12 months or more after stopping all exogenous hormone therapy and has luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels within the laboratory postmenopausal reference range;

[0237] Has undergone irreversible sterilization procedures including hysterectomy, bilateral oophorectomy, or bilateral tubal ligation, but not bilateral tubal occlusion.

[0238] 9. Willing to participate in the clinical trial, understand the study procedures and be able to sign the informed consent form in writing.

[0239] While the specific embodiments of the application have been described in detail, those skilled in the art will appreciate that various modifications and alterations to this application can be made in light of the teachings set forth herein. It is intended that the appended claims be construed to include all such modifications and alterations with respect to all equivalents. The entire contents of the specification for this application is hereby incorporated by reference.

Claims

Use of an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof in combination with (1) a VEGFR-TKI, and / or (2) an anthracycline in the manufacture of a medicament for preventing and / or treating sarcoma; wherein The structure of the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is shown as formula (I): wherein: n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a decimal or an integer; Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof. The use according to claim 1, wherein the anti-B7H3 antibody or an antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: (1) the VH comprises HCDR1, HCDR2 and HCDR3 in the sequence set forth in SEQ ID NO: 07, and the VL comprises LCDR1, LCDR2 and LCDR3 in the sequence set forth in SEQ ID NO: 08; or, (2) the VH comprises HCDR1, HCDR2, HCDR3 as set forth in the amino acid sequences of SEQ ID NOs: 01, 02 and 03, respectively, and the VL comprises LCDR1, LCDR2 and LCDR3 as set forth in the amino acid sequences of SEQ ID NOs: 04, 05 and 06, respectively. The use according to claim 1 or 2, wherein the anti-B7H3 antibody or an antigen-binding fragment thereof is selected from a humanized antibody or a fragment thereof; Preferably, the VH sequence of the anti-B7H3 antibody or an antigen-binding fragment thereof is a sequence as set forth in SEQ ID NO: 07 or a variant thereof, and the VL sequence is a sequence as set forth in SEQ ID NO: 08 or a variant thereof; More preferably, the heavy chain sequence of the anti-B7H3 antibody or an antigen-binding fragment thereof is a sequence as set forth in SEQ ID NO: 09 or a variant thereof, and the light chain sequence is a sequence as set forth in SEQ ID NO: 10 or a variant thereof. Use according to any one of claims 1 to 3, characterized in that The (1) VEGFR-TKI, and / or (2) anthracycline is selected from any combination of the following: (a) a VEGFR-TKI; (b) an anthracycline; (c) a VEGFR-TKI and an anthracycline. Use according to any one of claims 1 to 4, characterized in that The VEGFR-TKI is selected from the group consisting of Anlotinib, Sorafenib, Sunitinib, Axitinib, Pazopanib, Regorafenib, Cabozantinib, Lenvatinib, Apatinib, Fruquintinib, Nintedanib, Vorolanib, Surufatinib, Donafenib, Tivozanib, Zabofloxacin, Vandetanib, Famitinib, Lucitanib, Cediranib, Simmitinib, Sitravatinib, Chiauranib, Telatinib, Ningetinib, Dovitinib, CEP-11981, ZSP-1603, ODM-203, Pamufetinib, FH-2001, Orantinib, preferably, the VEGFR-TKI is selected from the group consisting of Anlotinib. Use according to any one of claims 1 to 5, characterized in that The anthracycline is selected from the group consisting of Epirubicin, Daunorubicin, Doxorubicin, Aclarubicin, Idarubicin, Mitoxantrone, Valrubicin; preferably, the anthracycline is selected from the group consisting of Epirubicin. Use according to claim 4, characterized in that The (1) VEGFR-TKI, and / or (2) anthracycline is selected from any combination of the following: (a) Anlotinib; (b) Epirubicin; (c) Anlotinib and Epirubicin. The use according to any one of claims 1-7, wherein the effective amount of the VEGFR-TKI is 1-30 mg, preferably 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg or 20 mg, more preferably 12 mg. The VEGFR-TKI is administered once a day, once every two days, once every three days, preferably once a day. The VEGFR-TKI is administered once a day, once every two days, once every three days, preferably once a day. Use according to any one of claims 1-8, wherein the effective amount of anthracycline is 10-150 mg / m 2 , preferably 25 mg / m 2 , 30 mg / m 2 , 35 mg / m 2 , 40 mg / m 2 , 45 mg / m 2 , 50 mg / m 2 , 55 mg / m 2 , 60 mg / m 2 , 65 mg / m 2 , 70 mg / m 2 , 75 mg / m 2 , 80 mg / m 2 , 85 mg / m 2 , 90 mg / m 2 , 95 mg / m 2 , 100 mg / m 2 , 105 mg / m 2 or 110 mg / m 2 , more preferably 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 ; and the frequency of administration is once a week, once in two weeks, once in three weeks or once in four weeks, preferably once in two weeks, once in three weeks, more preferably once in three weeks. The use according to any one of claims 1-9, wherein the dose of the anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite or solvate thereof, is 1.0 mg / kg to 16.0 mg / kg, preferably 4.0 mg / kg, 4.1 mg / kg, 4.2 mg / kg, 4.3 mg / kg, 4.4 mg / kg, 4.5 mg / kg, 4.6 mg / kg, 4.7 mg / kg, 4.8 mg / kg, 4.9 mg / kg, 5 mg / kg, 5.1 mg / kg, 5.2 mg / kg, 5.3 mg / kg, 5.4 mg / kg, 5.5 mg / kg, 5.6 mg / kg, 5.7 mg / kg, 5.8 mg / kg, 5.9 mg / kg, 6.0 mg / kg, 6.1 mg / kg, 6.2 mg / kg, 6.3 mg / kg, 6.4 mg / kg, 6.5 mg / kg, 6.6 mg / kg, 6.7 mg / kg, 6.8 mg / kg, 6.9 mg / kg, 7 mg / kg, 7.1 mg / kg, 7.2 mg / kg, 7.3 mg / kg, 7.4 mg / kg, 7.5 mg / kg, 7.6 mg / kg, 7.7 mg / kg, 7.8 mg / kg, 7.9 mg / kg, 8 mg / kg, 8.1 mg / kg, 8.2 mg / kg, 8.3 mg / kg, 8.4 mg / kg, 8.5 mg / kg, 8.6 mg / kg, 8.7 mg / kg, 8.8 mg / kg, 8.9 mg / kg, 9 mg / kg, 9.1 mg / kg, 9.2 mg / kg, 9.3 mg / kg, 9.4 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 9.7 mg / kg, 9.8 mg / kg, 9.9 mg / kg, 10 mg / kg, 10.1 mg / kg, 10.2 mg / kg, 10.3 mg / kg, 10.4 mg / kg, 10.5 mg / kg, 10.6 mg / kg, 10.7 mg / kg, 10.8 mg / kg, 10.9 mg / kg, 11 mg / kg, 11.1 mg / kg, 11.2 mg / kg, 11.3 mg / kg, 11.4 mg / kg, 11.5 mg / kg, 11.6 mg / kg, 11.7 mg / kg, 11.8 mg / kg, 11.9 mg / kg or 12 mg / kg, more preferably 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg; the dosing frequency is once every one week, once every two weeks, once every three weeks or once every four weeks, preferably once every two weeks, once every three weeks, more preferably once every three weeks. The use according to any one of claims 1-10, wherein a pharmaceutical combination of any one of the following is administered: (1) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every two weeks, 8 mg, 10 mg, 12 mg of anlotinib is administered every day, every three weeks; (2) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, every two weeks, every three weeks, 25 mg / m 2 of doxorubicin every two weeks, every three weeks, 2 75 mg / m 2 of doxorubicin every two weeks, every three weeks. (3) 4.0 mg / kg, 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, 8 mg, 10 mg, 12 mg of anlotinib every day, 25 mg / m 2 , 50 mg / m 2 , 75 mg / m 2 of epirubicin every two weeks, every three weeks. The use according to claim 11, wherein the pharmaceutical combination of any one of the following is administered: (1) 8.0 mg / kg, 10.0 mg / kg, 12 mg / kg of the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof is administered every three weeks, 12 mg of anlotinib is administered every day; (2) Administer 8.0 mg / kg, 10.0 mg / kg, or 12 mg / kg of anti-B7H3 antibody-drug conjugate or its pharmaceutically acceptable salts, metabolites, or solvent compounds every three weeks, or 50 mg / kg every three weeks. 2 75mg / m 2 The surface is softer than the star; (3) 6.0 mg / kg, 8.0 mg / kg, 10.0 mg / kg of an anti-B7H3 antibody drug conjugate, or a pharmaceutically acceptable salt, metabolite, or solvate thereof, 12 mg of anlotinib per day, 50 mg / m 2 of doxorubicin every three weeks. 2 of doxorubicin every three weeks. Use according to any one of claims 1 to 12, wherein The sarcoma is soft tissue sarcoma; preferably is advanced soft tissue sarcoma, more preferably is advanced stage treatment-naive, unresectable soft tissue sarcoma, or advanced unresectable soft tissue sarcoma that has failed at least one chemotherapy regimen comprising an anthracycline. A pharmaceutical combination, characterized in that comprising: 1) an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite, or solvate thereof, and 2) a VEGFR-TKI and / or an anthracycline; the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite, or solvate thereof having a structure as shown in formula (1): wherein: Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof; n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a fraction or an integer; Preferably, the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, the VEGFR-TKI, the anthracycline are each as defined in any one of claims 1-12; Preferably, the pharmaceutical composition is for preventing and / or treating sarcoma, preferably as defined in claim 13. A method of preventing and / or treating sarcoma, the method comprising administering to a subject an anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite, or solvate thereof of a structure as shown in Formula (1): wherein: Pc is an anti-B7H3 antibody or an antigen-binding fragment thereof; n is 1 to 10, preferably 2 to 8, more preferably 3 to 8, n is a fraction or an integer; Preferably, the method further comprises administering a VEGFR-TKI and / or an anthracycline Preferably, the anti-B7H3 antibody drug conjugate or a pharmaceutically acceptable salt, metabolite or solvate thereof, the VEGFR-TKI, the anthracycline are each as defined in any one of claims 1-12; Preferably, the subject is a sarcoma patient, preferably as defined in claim 13.

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