Methods of treating cancer with anti-B7H3 antibody-drug conjugates

Abstract

The invention relates to application of a combination of an anti-B7H3 antibody-drug conjugate and selulimab in preparation of a drug for treating cancer. The invention also relates to application of a pharmaceutical composition and a pharmaceutical kit comprising the combination in treatment of cancer.

Description

Technical Field

[0001] The present invention belongs to the field of molecular immunology and tumor treatment technology. It relates to a method or use of administering an anti-B7H3 antibody-drug conjugate in combination with other therapeutic agents to treat cancer, wherein the other therapeutic agent is selected from an anti-PD-1 antibody or an antigen-binding fragment thereof or / and a chemotherapeutic drug, and the present invention also relates to a pharmaceutical composition and a pharmaceutical kit for the use of the combination in treating cancer. Background Art

[0002] Malignant tumors have become a major public health problem worldwide, causing nearly 10 million deaths in 2020. The number of cancer patients and deaths from cancer has continued to rise worldwide, resulting in the continuous expansion of the overall scale of the cancer treatment market and the increasing demand for new therapeutic drugs and new treatment methods.

[0003] Monoclonal antibody drugs have the advantages of strong targeting, high specificity and low incidence of adverse reactions. Antibody-drug conjugate (ADC) is a representative product among them. Because ADC has the characteristics of both the effectiveness of small molecule drugs and the targeting of antibody drugs, it can not only reduce the toxic side effects of cytotoxic drugs, but also improve the therapeutic effect of drugs. At present, 15 ADC drugs have been approved for marketing worldwide, targeting breast cancer, lung cancer and gastrointestinal cancer. From the perspective of clinical effects, ADC drugs have a low response rate to solid tumors, such as It is an ADC drug targeting Trop-2. In the treatment of triple-negative breast cancer (TNBC), the ORR response rate is 27%-35%. It is an ADC drug targeting TF, with an ORR response rate of 24% in the treatment of recurrent or malignant cervical cancer. At the same time, because ADC is coupled with cytotoxic compounds as payload, there are toxicities in clinical applications, such as hematological adverse reactions, including pancytopenia, neutropenia, thrombocytopenia, etc., in addition to peripheral neuropathy, hepatotoxicity, pulmonary toxicity, cardiotoxicity, etc., which lead to clinical dosage restrictions and poor treatment effects in some indications. From this point of view, ADC drugs need to explore more treatment methods (such as combined use with drugs with different mechanisms of action) to further improve the treatment effect.

[0004] Immune checkpoints, as immunosuppressive pathways, are critical for maintaining autoimmune tolerance and regulating the duration and extent of immune responses in peripheral tissues. However, these pathways can be "hijacked" by tumors and continuously activated, inhibiting anti-tumor immunity and promoting tumorigenesis (Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4): 252–264.), Haanen JB, Robert C. Immune Checkpoint Inhibitors. Prog Tumor Res. 2015; 42: 55–66.). Programmed cell death 1 (PD-1) is currently the most widely used target of immune checkpoint inhibitors (ICIs), approved for clinical treatment of a variety of tumors. However, due to the heterogeneity of tumors and the complexity of the tumor microenvironment, the overall efficacy of immune checkpoint inhibitors is low (Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res. 2014; 20(19): 5064–5074., Restifo NP, Smyth MJ, Snyder A. Acquired resistance to immunotherapy and future challenges. Nat Rev Cancer. 2016; 16(2): 121–126.), for most cancer types, only 20%-30% of patients have an immune response.

[0005] Small molecule cytotoxic drugs have been used clinically for many years and are the first-line treatment for many diseases. Although they are effective in the early stages of treatment, they are highly toxic, and patients have poor tolerance to long-term administration and are prone to drug resistance. Summary of the invention

[0006] In view of the deficiencies of immune checkpoint inhibitors and small molecule toxins in treating cancer, the present disclosure provides a method of combining an antibody-drug conjugate with other therapeutic agents to achieve excellent anti-tumor effects in the treatment of cancer in animals, humans and other individuals, such as enhanced efficacy, increased durability of therapeutic response and / or reduced dose-dependent toxicity.

[0007] In a first aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject:

[0008] (a) an anti-B7H3 antibody-drug conjugate, comprising an anti-B7H3 antibody or an antigen-binding fragment thereof and a camptothecin drug, wherein the anti-B7H3 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0009] The heavy chain variable region comprises:

[0010] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0011] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0012] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0013] The light chain variable region comprises:

[0014] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0015] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0016] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0017] The CDRs are determined by the Kabat definition scheme;

[0018] and (b) other therapeutic agents selected from the group consisting of: anti-PD-1 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs.

[0019] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof of the anti-B7H3 antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.2%, at least 99.5%, at least 99.7%, at least 99.9% sequence identity to the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprising an amino acid sequence having at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.2%, at least 99.5%, at least 99.7%, at least 99.9% sequence identity to the amino acid sequence of SEQ ID NO:8.

[0020] In some embodiments, the heavy chain variable region of the anti-B7H3 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO:7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:8.

[0021] In some embodiments, the anti-B7H3 antibody comprises the heavy chain shown in SEQ ID NO:9, and the light chain shown in SEQ ID NO:10.

[0022] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment is the antibody numbered 1D1, 1D1-01, 2E3 or 2E3-02 in WO2022170971; more preferably, the anti-B7H3 antibody is the antibody numbered 1D1-01 or 2E3-02; and further preferably, the anti-B7H3 antibody is the antibody numbered 2E3-02.

[0023] In a second aspect, the present disclosure provides a method for treating cancer, the method comprising administering to a subject:

[0024] a) an anti-B7H3 antibody-drug conjugate, wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the following formula, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing:

[0025] Tb-(LD)q,

[0026] in:

[0027] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof; preferably, Tb is the anti-B7H3 antibody or an antigen-binding fragment thereof described in the first aspect; L is a linker and has the following structure:

[0028]

[0029] The 1st bit is connected to Tb, and the 2nd bit is connected to D;

[0030] D is a biologically active molecular fragment, such as camptothecin drugs;

[0031] q is selected from any value between 0.1 and 16.0,

[0032] and (b) other therapeutic agents selected from the group consisting of: anti-PD-1 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs.

[0033] In some embodiments, the method for treating cancer is characterized in that the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the structure of the following formula I, or a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing:

[0034]

[0035] in:

[0036] S is the sulfur atom on Tb;

[0037] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0038] q is selected from any value between 0.1-16.0, preferably q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and more preferably q is 2, 4, 6 or 8.

[0039] In other embodiments, the antibody-drug conjugate may also be selected from:

[0040]

[0041]

[0042] wherein Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0043] S is the sulfur atom on Tb;

[0044] q is the drug-antibody coupling ratio, selected from any value between 0.1-16.0; preferably 1-10; preferably, q is 1, 2, 3, 4, 5, 6, 7 or 8; more preferably, q is 2, 4, 6 or 8.

[0045] In some embodiments, the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the structure shown in Formula II below, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing,

[0046]

[0047] Here, S is the sulfur atom on Tb.

[0048] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment and the monoclonal antibody or its antigen-binding fragment include: Fab, Fab', F(ab')2, Fd, Fv (e.g., scFv), dAb, complementarity determining region fragment, non-human antibody, humanized antibody, chimeric antibody, fully human antibody, Probody, monoclonal antibody, bispecific antibody or multispecific antibody.

[0049] In some embodiments, Tb is an antibody or antigen-binding fragment thereof having B7H3-2Ig and / or B7H3-4Ig.

[0050] In some embodiments, Tb is an antibody or an antigen-binding fragment thereof having a higher B7H3-4Ig binding activity than a B7H3-2Ig binding activity.

[0051] In some embodiments, Tb is a non-human antibody, a humanized antibody, a chimeric antibody, or a fully human antibody.

[0052] In some embodiments, Tb is a monoclonal antibody, a bispecific antibody, or a multispecific antibody.

[0053] In some embodiments, Tb is a monoclonal antibody or an antigen-binding fragment thereof.

[0054] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is an antibody numbered 1D1, 1D1-01, 2E3, 2E3-02 in WO2022170971, enoblituzumab, mirzotamab, omburtamab, an antibody numbered M30-H1-L4 in CN 103687945B, Antibodies numbered mAb-C-DUBA in 109069633A, and see CN112521512, WO2021027674, WO2021021543, WO2021006619, CN111662384, CN111454357, WO2020151384, WO2020140094, WO2020103100, WO2020102779, WO2020063673, WO2020047257, WO2020041626, CN110684790, CN110642948, WO20192 25787, WO2019226017, US20190338030, CN110305213, WO2018209346, WO2018177393, US9150656, WO2016106004, WO2016044383, WO2016033225, WO2015181267, US20120294796, WO2011109400, CN101104639, WO2004093894, WO2002010187 or WO2001018021.

[0055] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is an antibody numbered 1D1, 1D1-01, 2E3 or 2E3-02 in WO2022170971; more preferably, the anti-B7H3 antibody is an antibody numbered 1D1-01 or 2E3-02; and further preferably, the B7H3 antibody is an antibody numbered 2E3-02.

[0056] In some embodiments, the anti-B7H3 antibody is a 2E3-02 antibody comprising a heavy chain as shown in SEQ ID NO:9, and a light chain as shown in SEQ ID NO:10.

[0057] In some embodiments, the antibody or antigen-binding fragment further comprises a framework region derived from a human or murine immunoglobulin.

[0058] In some embodiments, the additional therapeutic agent is an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0059] In some embodiments, the other therapeutic agents are anti-PD-1 antibodies or antigen-binding fragments thereof and chemotherapeutic drugs.

[0060] In some embodiments, the additional therapeutic agent satisfies one or more of the following conditions:

[0061] i. The anti-PD-1 antibody or antigen-binding fragment thereof is selected from serplulimab (HLX10 or Hans-like);

[0062] ii. The chemotherapy drug is selected from platinum drugs; preferably, the platinum drug is selected from cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, Iproplatin, dicycloplatin or a combination of the foregoing.

[0063] In some embodiments, the method comprises administering to the subject an anti-B7H3 antibody-drug conjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0064] In some embodiments, the method comprises administering to the subject an anti-B7H3 antibody-drug conjugate, an anti-PD-1 antibody or an antigen-binding fragment thereof, and a platinum drug.

[0065] In some embodiments, the platinum drug is selected from carboplatin.

[0066] In some embodiments, the platinum drug is selected from cisplatin.

[0067] In some embodiments, the method of treating cancer comprises administering to a subject:

[0068] (a) an anti-B7H3 antibody-drug conjugate, wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the structure of the following formula I, or a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing:

[0069]

[0070] Wherein: S is a sulfur atom on Tb; Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof; q is selected from any value between 0.1 and 16.0, preferably q is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, more preferably q is 2, 4, 6 or 8, and more preferably q is 8;

[0071] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0072] The heavy chain variable region (VH) comprises:

[0073] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0074] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0075] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0076] The light chain variable region (VL) comprises:

[0077] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0078] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0079] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0080] The CDRs are determined by the Kabat definition scheme;

[0081] and (b) an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody is serplulimab (HLX10 or HANS-like).

[0082] In some embodiments, the method of treating cancer further comprises administering to the subject: (c) a platinum drug. In some embodiments, the platinum drug is selected from carboplatin. In some embodiments, the platinum drug is selected from cisplatin.

[0083] In some embodiments, the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing is administered at a dose of 0.1-15 mg / kg body weight of the individual.

[0084] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose ranging from 0.1-10 mg / kg, 0.2-8 mg / kg, 0.3-6 mg / kg, 0.4-4 mg / kg, or 0.5-3 mg / kg;

[0085] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of: 0.4 mg / kg,

[0086] 0.5mg / kg, 0.6mg / kg, 0.8mg / kg, 1.0mg / kg, 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg,

[0087] 2.2mg / kg, 2.4mg / kg, 2.6mg / kg, 2.8mg / kg, 3.0mg / kg, 4.0mg / kg, 5.0mg / kg.

[0088] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.2 mg / kg.

[0089] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.4 mg / kg.

[0090] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.6 mg / kg.

[0091] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.8 mg / kg.

[0092] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.0 mg / kg.

[0093] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.2 mg / kg.

[0094] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.4 mg / kg.

[0095] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to the subject at a dose of about 2.6 mg / kg.

[0096] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to the subject at a dose of about 2.8 mg / kg.

[0097] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 3.0 mg / kg.

[0098] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose ranging from about 50 mg to about 650 mg or in a dose of 1-10 mg / kg.

[0099] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose ranging from 100-600 mg, 100-500 mg, 100-400 mg, 200-600 mg, 200-500 mg, 200-400 mg, 150-450 mg, 150-250 mg, 250-350 mg, 350-450 mg, 450-550 mg, 550-650 mg.

[0100] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose ranging from 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, and 600 mg.

[0101] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose of about 100 mg.

[0102] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose of about 200 mg.

[0103] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose of about 400 mg.

[0104] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose of about 600 mg.

[0105] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject at a dose of: 1.0 mg / kg,

[0106] 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.4mg / kg, 2.8mg / kg, 3.0mg / kg, 3.5mg / kg, 4.0mg / kg, 4.5mg / kg, 5.0mg / kg.

[0107] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 2.0 mg / kg.

[0108] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 4.0 mg / kg.

[0109] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 4.5 mg / kg.

[0110] In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject at a dose of about 6.0 mg / kg.

[0111] In some embodiments, the platinum drug is:

[0112] i. Range of about 50-150 mg / m 2 The dose is administered to the subject;

[0113] Preferably, the platinum drug is administered to the subject at a dose of 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 or 150 mg / m 2 ;

[0114] or

[0115] ii. The dose for each administration is calculated by the area under the curve (AUC), selected from 1-10 mg / ml / min;

[0116] Preferably, the platinum drug is administered to the subject at a dose of 3 mg / mL / min, 4 mg / mL / min, 5 mg / mL / min, 6 mg / mL / min or 7 mg / mL / min.

[0117] In some embodiments, the platinum drug is administered to the subject at a dose of 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 or 150 mg / m 2 .

[0118] In some embodiments, the platinum drug is about 75 mg / m 2 The dose is administered to the subject.

[0119] In some embodiments, the platinum drug is about 80 mg / m 2 The dose is administered to the subject.

[0120] In some embodiments, the dose of carboplatin administered each time is calculated as the area under the curve (AUC) and is selected from 1-10 mg / ml / min, preferably 1 mg / ml / min, 2 mg / ml / min, 2.5 mg / ml / min, 3 mg / ml / min, 3.75 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min, 7 mg / ml / min, 8 mg / ml / min. In some embodiments, the dose of carboplatin administered each time is 3 mg / ml / min, 4 mg / ml / min, 5 mg / ml / min, 6 mg / ml / min or 7 mg / ml / min.

[0121] In some embodiments, the dose of cisplatin administered each time is selected from 50-150 mg / m 2 , preferably from 50 mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 and 150 mg / m 2 .

[0122] In some embodiments, the administration cycle of the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibody or antigen-binding fragment thereof, and platinum drug is 7-42 days.

[0123] In some embodiments, the administration cycle of the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibody or its antigen-binding fragment, and platinum drug is 14 days, 21 days, 28 days, 35 days or 42 days.

[0124] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered once a day, once a week, once every two weeks, once every three weeks, twice every three weeks, once every four weeks, once a month, once every five weeks, or once every six weeks.

[0125] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered for a period of one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months or longer, optionally, the duration of each administration cycle is the same or different, and the intervals between each administration cycle are the same or different.

[0126] In some embodiments, the PD-1 antibody or antigen-binding fragment thereof is administered once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, or once every six weeks.

[0127] In some embodiments, the administration cycle of the PD-1 antibody or antigen-binding fragment thereof is one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months or longer. Optionally, the duration of each administration cycle is the same or different, and the interval between each administration cycle is the same or different.

[0128] In some embodiments, the platinum drug (eg, carboplatin or cisplatin) is administered once a day, once a week, once every two weeks, once every three weeks, once every four weeks, once a month, once every five weeks, or once every six weeks.

[0129] In some embodiments, the platinum drug (e.g., carboplatin or cisplatin) is administered for a period of one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months or longer, optionally, the duration of each administration cycle is the same or different, and the intervals between each administration cycle are the same or different.

[0130] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered simultaneously.

[0131] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered separately.

[0132] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered sequentially.

[0133] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered first, followed by administration of the other therapeutic agent.

[0134] In some embodiments, the cancer is selected from a solid tumor.

[0135] In some embodiments, the cancer is selected from the group consisting of nasopharyngeal carcinoma, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma.

[0136] In some embodiments, the cancer is selected from the group consisting of: nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer.

[0137] In some embodiments, the cancer is selected from non-small cell lung cancer.

[0138] In some embodiments, the non-small cell lung cancer (NSCLC) is selected from the group consisting of: NSCLC squamous cell carcinoma, NSCLC adenocarcinoma, pulmonary lymphoepithelioma-like carcinoma, and large cell lung cancer.

[0139] In some embodiments, the nasopharyngeal carcinoma is selected from keratinizing squamous cell carcinoma of the nasopharynx, non-keratinizing nasopharyngeal carcinoma (including differentiated or undifferentiated types), basaloid squamous cell carcinoma of the nasopharynx, nasopharyngeal carcinoma in situ, invasive nasopharyngeal carcinoma (including but not limited to squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, vesicular cell carcinoma or undifferentiated nasopharyngeal carcinoma).

[0140] In some embodiments, the non-keratinizing nasopharyngeal carcinoma comprises a differentiated type or an undifferentiated type.

[0141] In some embodiments, the invasive nasopharyngeal carcinoma includes but is not limited to squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, vesicular cell carcinoma, or undifferentiated nasopharyngeal carcinoma.

[0142] In some embodiments, the subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has failed previous treatment with a platinum-containing regimen.

[0143] In some embodiments, the subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has not received systemic treatment.

[0144] In some embodiments, the subject is a patient with small cell lung cancer who has not received systemic treatment.

[0145] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is negative for epidermal growth factor receptor (EGFR) sensitive mutations, negative for anaplastic lymphoma kinase (ALK), and / or negative for c-ros oncogene (ROS1) and who has previously failed treatment with a platinum-containing regimen.

[0146] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is negative for epidermal growth factor receptor (EGFR) sensitive mutations and negative for anaplastic lymphoma kinase (ALK) / c-ros oncogene (ROS1) and has previously failed platinum-containing regimens.

[0147] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is EGFR sensitive mutation-negative, ALK-negative and / or c-ros oncogene (ROS1)-negative and has not received systemic treatment.

[0148] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is EGFR sensitive mutation-negative and ALK / c-ros oncogene (ROS1)-negative and has not received systemic treatment.

[0149] In some embodiments, the anti-B7H3 antibody-drug conjugate and other therapeutic agent are present in a unit dosage form.

[0150] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are present in the same dosage unit.

[0151] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are present in different formulation units.

[0152] In some embodiments, the administration route can be oral administration, parenteral administration, or transdermal administration. The parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection.

[0153] In some embodiments, the anti-B7H3 antibody-drug conjugate and other therapeutic agent are administered by intravenous injection.

[0154] In some embodiments, the anti-B7H3 antibody-drug conjugate or its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate of the foregoing is administered by injection. Before injection, the anti-B7H3 antibody-drug conjugate or its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate of the foregoing needs to be configured into an injectable form. The preferred injection form is an injection solution or a lyophilized powder, which comprises the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate of the foregoing, and optionally a buffer, a stabilizer, The invention relates to a pharmaceutical composition comprising the following: a stabilizer, a pH regulator and a surfactant; wherein the buffering agent may be selected from one or more of acetate, citrate, succinate and phosphate; the stabilizer may be selected from sugar or amino acid, preferably disaccharide, such as sucrose, lactose, trehalose or maltose; the pH regulator may be selected from one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide; the surfactant may be selected from polyoxyethylene hydrogenated castor oil, glycerol fatty acid ester and polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is polysorbate 20, 40, 60 or 80, most preferably polysorbate 20.

[0155] In some embodiments, one or more therapeutic effects of the subject are improved relative to baseline after administration of the anti-B7H3 antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof, wherein the one or more therapeutic effects are selected from: tumor size derived from the cancer, objective response rate (ORR), depth of response (DpR), disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), and overall survival (OS).

[0156] In some embodiments, the size of the subject's tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor prior to administration of the anti-B7H3 antibody-drug conjugate and the anti-PD-1 antibody or antigen-binding fragment thereof.

[0157] In a third aspect, the present disclosure further provides a pharmaceutical composition comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents, wherein the other therapeutic agents are selected from anti-PD-1 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs, and the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs are as described herein.

[0158] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, diluents or carriers.

[0159] In some embodiments, the pharmaceutical composition comprises an anti-B7H3 antibody-drug conjugate and other therapeutic agents; wherein the other therapeutic agents are selected from: i. slulizumab; or, ii. slulizumab and platinum drugs;

[0160] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof:

[0161]

[0162] wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8;

[0163] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0164] The heavy chain variable region (VH) comprises:

[0165] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0166] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0167] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0168] The light chain variable region (VL) comprises:

[0169] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0170] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0171] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0172] The CDRs were determined by the Kabat definition scheme.

[0173] In a fourth aspect, the present disclosure further provides a kit comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents, wherein the other therapeutic agents are selected from anti-PD-1 antibodies or antigen-binding fragments thereof, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs, and the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibodies or antigen-binding fragments thereof, and chemotherapeutic drugs are as described herein.

[0174] In some embodiments, the kit comprises an anti-B7H3 antibody-drug conjugate and other therapeutic agents; wherein the other therapeutic agents are selected from: i. slulizumab; or, ii. slulizumab and platinum drugs;

[0175] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof:

[0176]

[0177] wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8;

[0178] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0179] The heavy chain variable region (VH) comprises:

[0180] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0181] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0182] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0183] The light chain variable region (VL) comprises:

[0184] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0185] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0186] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0187] The CDRs were determined by the Kabat definition scheme.

[0188] In a fifth aspect, the present disclosure provides the use of anti-B7H3 antibody-drug conjugates in combination with other therapeutic agents in the preparation of drugs for treating cancer.

[0189] In some embodiments, the cancer is a solid tumor.

[0190] In some embodiments, the cancer is selected from the group consisting of nasopharyngeal carcinoma, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma.

[0191] In some embodiments, the cancer is selected from the group consisting of: nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer.

[0192] In some embodiments, the non-small cell lung cancer is selected from the group consisting of: NSCLC squamous cell carcinoma, NSCLC adenocarcinoma, pulmonary lymphoepithelioma-like carcinoma, and large cell lung cancer.

[0193] In some embodiments, the nasopharyngeal carcinoma is selected from the group consisting of keratinizing squamous cell carcinoma of the nasopharynx, non-keratinizing nasopharyngeal carcinoma, basaloid squamous cell carcinoma of the nasopharynx, nasopharyngeal carcinoma in situ, and invasive nasopharyngeal carcinoma.

[0194] In some embodiments, there is also provided use of the combination of the anti-B7H3 antibody-drug conjugate described above and an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a drug for treating cancer.

[0195] In some embodiments, there is also provided an anti-B7H3 antibody-drug conjugate and slulizumab for use in the preparation of a drug for treating cancer, wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I or a pharmaceutically acceptable salt thereof:

[0196]

[0197] wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8;

[0198] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0199] The heavy chain variable region (VH) comprises:

[0200] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0201] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0202] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0203] The light chain variable region (VL) comprises:

[0204] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0205] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0206] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0207] The CDRs were determined by the Kabat definition scheme.

[0208] In some embodiments, there is also provided the use of the aforementioned anti-B7H3 antibody-drug conjugate and anti-PD-1 antibody or its antigen-binding fragment, or the combination of anti-PD-1 antibody or its antigen-binding fragment and chemotherapeutic drug in the preparation of a drug for treating cancer.

[0209] In some embodiments, there is also provided an anti-B7H3 antibody-drug conjugate, slulizumab and a platinum drug for use in the preparation of a drug for treating cancer, wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I or a pharmaceutically acceptable salt thereof:

[0210]

[0211] wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8;

[0212] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0213] The heavy chain variable region (VH) comprises:

[0214] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0215] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0216] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0217] The light chain variable region (VL) comprises:

[0218] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0219] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0220] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0221] The CDRs were determined by the Kabat definition scheme.

[0222] In some embodiments, the platinum drug is cisplatin. In some embodiments, the platinum drug is carboplatin.

[0223] In some embodiments, the combination therapy of anti-B7H3 antibody-drug conjugate and immune checkpoint inhibitor has a significant inhibitory effect on tumors. In a mouse tumor-bearing model, compared with single drug, the combined administration of anti-B7H3 antibody-drug conjugate and anti-PD-1 antibody can synergistically inhibit tumor growth and produce a significant anti-tumor effect.

[0224] In some embodiments, the present disclosure further verifies the inhibitory effect of anti-B7H3 antibody-drug conjugates and anti-PD-1 antibodies, or anti-PD-1 antibodies or antigen-binding fragments thereof and chemotherapeutic drugs on tumors through experiments. The verification method is not limited to animal tumor models, but also includes in vitro cell models, human clinical trials, etc.; the tumor type is not limited to colorectal cancer, but can also be other tumors, including but not limited to nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer, esophageal squamous cell carcinoma, prostate cancer, head and neck squamous cell carcinoma, etc. DETAILED DESCRIPTION OF THE INVENTION

[0226] Unless otherwise defined, all terms used herein have the same meaning as those generally understood by those of ordinary skill in the art. For relevant definitions and terms, see, for example, Current Protocols in Molecular Biology (Ausubel). Meanwhile, for a better understanding of the present disclosure, definitions and explanations of relevant terms are provided below.

[0227] All documents mentioned herein are incorporated herein by reference in their entirety.

[0228] The natural sequence B7H3 antibody herein can be isolated from nature, or prepared by recombinant DNA technology, chemical synthesis or a combination thereof.

[0229] As used herein, the term "antibody" is interpreted in the broadest sense and includes intact monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (eg, bispecific antibodies) formed from at least two intact antibodies, so long as they have the desired biological activity.

[0230] As used herein, the term "monoclonal antibody" refers to an antibody that comes from a group of substantially homogeneous antibodies, i.e., the antibodies that make up the group are identical except for a small amount of natural mutations that may be present. Monoclonal antibodies have high specificity for one determinant (epitope) of an antigen, whereas polyclonal antibodies, in contrast, contain different antibodies for different determinants (epitopes). In addition to their specificity, monoclonal antibodies have the advantage that they can be synthesized without contamination by other antibodies. The modifier "monoclonal" here indicates that the antibody is characterized by being from a substantially homogeneous group of antibodies and should not be construed as requiring production by a particular method.

[0231] Herein, monoclonal antibodies also specifically include chimeric antibodies, i.e., a portion of the heavy chain and / or light chain is identical or homologous to a certain type, class or subclass of antibody, and the remaining portion is identical or homologous to another type, class or subclass of antibody, as long as they have the desired biological activity (see, e.g., US 4,816,567; and Morrison et al., 1984, PNAS, 81: 6851-6855). Chimeric antibodies that can be used in the present invention include primatized antibodies, which contain variable region antigen binding sequences from non-human primates (e.g., monkeys, orangutans, etc.) and human constant region sequences.

[0232] The term "antibody fragment" refers to a portion of an antibody, preferably the antigen binding region or variable region. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; and single-chain antibody molecules.

[0233] In the present disclosure, the term "drug" refers to a substance that inhibits or prevents the function of cells and / or causes cell death or destruction.

[0234] The antibody-drug conjugate of the present invention may be in the form of a pharmaceutically acceptable salt, or in the form of a stereoisomer, or in the form of a metabolite, or in the form of a solvate, and the salt, stereoisomer or metabolite may also be in the form of a solvate.

[0235] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compound and are biologically or otherwise desirable for use as a drug. In many cases, the antibody-drug conjugates of the present invention can form acid addition salts and / or base addition salts by virtue of the presence of amino and / or carboxyl groups or similar groups therein.

[0236] Pharmaceutically acceptable acid addition salts may be salts formed with inorganic or organic acids. The inorganic acid includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. The organic acid includes, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

[0237] Pharmaceutically acceptable base addition salts may be salts formed with inorganic bases or organic bases. The salts formed with inorganic bases include, for example, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts and aluminum salts, and ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts are particularly preferred. The organic bases include, for example, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like. Specific examples of organic bases are isopropylamine, trimethylamine, diethylamine, N-ethylethylamine, tripropylamine and ethanolamine.

[0238] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficient amount of a basic compound with a suitable acid affording a pharmaceutically acceptable anion.

[0239] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds with one or more asymmetric centers, racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers can be produced. Specific individual molecules can also exist as geometric isomers (cis / trans). Unless otherwise stated, when the stereochemistry of a disclosed compound is not clearly stated in the nomenclature or structure and has one or more asymmetric centers, it should be understood that all possible stereoisomers of the compound are represented.

[0240] The term "solvate" refers to a solvate formed by the association of one or more solvent molecules with an antibody-drug conjugate of any formula (I) or a pharmaceutically acceptable salt or isomer thereof. The term solvate includes hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates and the like).

[0241] Also included within the scope of the present disclosure are metabolites of the compounds of the present invention, i.e., substances formed in vivo upon administration of the compounds of the present invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the present invention, including compounds prepared by contacting the compounds of the present invention with a lactating animal for a period of time sufficient to produce a metabolic product thereof.

[0242] As used herein, the term "treatment" refers to a method implemented to obtain a beneficial or desired clinical outcome. For purposes of the present invention, a beneficial or desired clinical outcome includes, but is not limited to, alleviating symptoms, reducing the scope of the disease, stabilizing (i.e., no longer worsening) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease, and alleviating symptoms (whether partially or completely), whether detectable or undetectable. In addition, "treatment" may also refer to extending survival compared to the expected survival (if not receiving treatment).

[0243] As used herein, the term "progression of disease" or "disease progression" refers to an increase of at least 20% in the sum of the diameters of target lesions, with reference to the minimum value of the sum of the diameters of all target lesions in the entire study (including the baseline sum if it is the minimum value in the study), and an absolute increase of at least 5 mm in the sum of the diameters; or the appearance of one or more new lesions.

[0244] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of anti-B7H3 antibody-drug conjugate (anti-B7H3-ADC) and / or anti-PD-1 antibody or its antigen-binding fragment and / or chemotherapeutic drug that is effective in preventing or alleviating the disease or condition to be treated when the anti-B7H3 antibody-drug conjugate (anti-B7H3-ADC) and / or anti-PD-1 body or its antigen-binding fragment and / or chemotherapeutic drug is administered to cells, tissues or subjects. A therapeutically effective dose further refers to an amount of anti-B7H3 antibody-drug conjugate (anti-B7H3-ADC) and / or anti-PD-1 body or its antigen-binding fragment and / or chemotherapeutic drug sufficient to cause symptom relief, such as treatment, cure, or alleviation of a related medical condition, or increase in the rate of treatment, cure, or alleviation of the symptoms. The effective amount for a specific subject may vary depending on a variety of factors, such as the disease to be treated, the patient's overall health, the method, route and dosage of administration, and the severity of side effects. The effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects. A therapeutically effective amount will alleviate symptoms generally by at least 10%; usually by at least 20%; at least about 30%; at least 40% or at least 50%.

[0245] As used herein, the terms "individual", "subject" or "patient" refer to any animal that is the target of treatment, observation or experiment, including (but not limited to) non-human primates, rodents, etc. Typically, the terms "subject" and "patient" are used interchangeably herein when referring to a human individual. The mammal can be one or more selected from humans, bovine animals (e.g., cows), porcine animals (e.g., pigs), ovine animals (e.g., sheep), caprine animals (e.g., goats), equines (e.g., horses), canines (e.g., domestic dogs), felines (e.g., domestic cats), lagomorphs (e.g., rabbits), rodents (e.g., rats or mice), etc. In a specific embodiment, the subject is a human.

[0246] As used herein, the terms "complete remission (CR)", "partial remission (PR)", "stable disease (SD)", "progressive disease (PD)", "objective response rate (ORR)", and "disease control rate (DCR)" are defined as follows:

[0247] When the disease is a solid tumor, the efficacy of the solid tumor is evaluated as "complete remission (CR)", "partial remission (PR)", "stable disease (SD)", "progressive disease (PD)", "objective response rate (ORR)", "disease control rate (DCR)" according to the following criteria (see New response evaluation criteria insolid tumors: Revised RECIST guideline (version 1.1), EA Eisenhauer et al., "EUROPEAN JOURNAL OF CANCER", 45 (2009), pp. 228-247). The evaluation of target lesions is as follows:

[0248] Complete remission (CR): All target lesions disappear, the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm, and there are no new lesions.

[0249] Partial response (PR): The sum of the diameters of target lesions (short diameter of lymph nodes) is reduced by at least 30% compared with the baseline level. There is no significant progression of non-target lesions and no new lesions.

[0250] Stable disease (SD): The target lesions have not decreased to the level of PR, nor have they increased to the level of PD, but are somewhere in between. The minimum value of the sum of diameters can be used as a reference for research.

[0251] Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire trial study is used as a reference, and the relative increase in the sum of diameters is at least 20% (if the baseline measurement value is the smallest, the baseline value is used as a reference); in addition, the absolute value of the sum of the measured target lesion diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0252] Objective response rate (ORR): refers to the proportion of patients whose tumors shrink to a certain extent, including cases of CR and PR. The subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are based on RECIST 1.1.

[0253] Disease control rate (DCR) was defined as the percentage of patients with complete remission (CR), partial remission (PR) and stable disease (SD).

[0254] PFS and OS can be measured according to the standards set by the National Cancer Institute and the US Food and Drug Administration for new drug approval. See Johnson et al., J. Clin. Oncol. 21(7): 1404-1411 (2003).

[0255] Progression-free survival (PFS) refers to the time from registration to disease progression or death. PFS is generally measured using the Kaplan-Meier method and the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 standard. Generally speaking, progression-free survival refers to the state in which the patient remains alive and the cancer does not worsen.

[0256] "Overall survival" (OS) refers to the time from patient enrollment to death or censoring the last known survival date. OS includes the extension of life expectancy compared to untreated or untreated individuals or patients. Overall survival refers to the state in which a patient remains alive for a specified period of time, such as one year, five years, etc. from the time of diagnosis or treatment. In a patient population, overall survival is measured as median overall survival (mOS).

[0257] Depth of response (DpR): Depth of response refers to the degree of reduction in tumor volume or disease during treatment, specifically the percentage of maximum tumor reduction achieved during treatment compared with baseline. If CR occurs, the DpR is 100. It is usually measured based on imaging or clinical evaluation.

[0258] Duration of response (DoR): Duration of response refers to the duration of tumor remission after treatment, specifically the time from the first confirmed complete response (CR) or confirmed partial response (PR) to the first disease progression of the subject who achieved confirmed complete response (CR) or confirmed partial response (PR).

[0259] Time to remission (TTR): Time to remission refers to the time from the start of treatment to the patient's first remission (CR or PR) status. BRIEF DESCRIPTION OF THE DRAWINGS

[0260] Figure 1 : Results of efficacy test of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug on MC38-B model.

[0261] Figure 2 : Body weight status of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug in MC38-B model.

[0262] Figure 3 : Results of efficacy test of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug on MC38-B recurrence model.

[0263] Figure 4 : Body weight changes in the MC38-B relapse model after the combination of antibody-drug conjugate (ADC1) and anti-PD-1 drug. DETAILED DESCRIPTION

[0264] Sequence information

[0265] The sequence information involved in this application is described in the following table:

[0266]

[0267]

[0268] The present disclosure is further described below by describing specific implementations, but this is not intended to limit the present disclosure. Those skilled in the art may make various modifications or improvements based on the teachings of the present disclosure without departing from the basic concept and scope of the present disclosure.

[0269] Example 1: Production of anti-B7H3 antibody-drug conjugates

[0270]

[0271] The production method described in 4.1.7.1 was implemented with reference to International Publication No. WO2022170971A1, and an anti-B7H3 ADC composition (hereinafter referred to as "ADC1") was produced using a humanized anti-B7H3 antibody (2E3-02).

[0272] Example 2: Efficacy test of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug on MC38-B transplanted tumor

[0273] 1. Experimental Materials

[0274] Test compounds: ADC1, Anti-PD-1, ADC1+Anti-PD-1, and saline as negative control. Anti-PD-1 is a mouse Anti-mouse PD-1 antibody expressed in cells constructed based on the heavy chain and light chain of antibody C in patent WO2017132827A1.

[0275] Experimental cells: MC38-B7H3 cells (hereinafter referred to as MC38-B, MC38 cells transfected with human B7H3 recombinant protein);

[0276] Experimental animals: C57BL / 6J mice, female, 5-6 weeks old, purchased from Jicui Pharmaceutical Biotechnology Co., Ltd.

[0277] 2. Experimental Plan

[0278] Cell treatment

[0279] MC38-B cells were cultured in 15 cm diameter culture dishes using 1640 medium containing 10% FBS. When the confluence reached about 80-90%, they were digested with trypsin-EDTA, washed twice with PBS, and then centrifuged and resuspended in pre-cooled PBS. The cells were counted using a cell counter and diluted with PBS to a cell concentration of 5 × 10 7 / ml.

[0280] 2.2. Tumor cell transplantation

[0281] C57BL / 6J mice were adapted to the laboratory environment for 2-5 days and MC38-B cells were subcutaneously inoculated in the right ribs. The inoculated cell volume was 5×10 6 / mouse, the inoculation volume was 0.1mL, and the tumor was grown to 150mm 3 When about , conduct the experiment.

[0282] 2.3. Animal administration and testing

[0283] 2.3.1 Combination drug trial plan

[0284] The tumor-bearing nude mice were given drugs according to the following regimen:

[0285] Table 1 Dosage regimen

[0286]

[0287] Note: There are 5 animals in each group, and the administration volume is 10mL / kg.

[0288] 2.3.2 Relapse model test plan

[0289] MC38-B cells were re-inoculated on Day 29 of experimental group 3 (i.e., ADC1+Anti-PD-1 combination therapy), which was recorded as Day 0.

[0290] The control group (normal saline group) was composed of newly enrolled blank mice according to the animal weight and age, and MC38-B cells were inoculated according to the scheme in 2.2.

[0291] The above two groups only measured the tumor size and did not receive any medication.

[0292] 2.4. Tumor volume and body weight determination:

[0293] Tumor volume and body weight were measured twice a week, and T / C% and TGI (%) were calculated using the following formula: relative tumor proliferation rate T / C (%) =

[0294] TRTV / CRTV×100% (TRTV: average RTV of the treatment group; CRTV: average RTV of the control group; RTV=Vt / V0, V0 is the tumor volume of the animal when grouped, and Vt is the tumor volume of the animal after treatment); relative tumor inhibition rate TGI%=(1-T / C)×100% (T and C are the relative tumor volumes (RTV) of the treatment group and the control group at a specific time point, respectively.

[0295] The formula for calculating tumor volume (V) is: V = 1 / 2 × L long × L short 2 , where Llong and Lshort represent the long diameter and short diameter of the tumor, respectively.

[0296] 3. Experimental results

[0297] 3.1 Results of combined drug therapy experiments

[0298] The specific results are shown in Table 2 and Figure 1 and Figure 2 . The test results showed that the tumor inhibition rates of test group 1, test group 2 and test group 3 on Day 25 of administration were 52.58%, 15.05% and 99.49%, respectively. Among them, the TGI of the single-drug groups (test group 1 and test group 2) were less than 60%, with no significant drug effect. The combination group (test group 3) had a very significant tumor inhibition effect, with a TGI of 99.49%, and tumor regression had occurred. At the same time, after the fifth administration (Day 17), the tumor volume test time was extended to Day 60, and the tumor continued to regress. The above data show that compared with the single-drug group, the combined administration group produced a significant synergistic effect. At the same time, during the administration period, the body weight of animals in each group increased steadily, indicating that there was no obvious toxicity in both single-drug and combined administration.

[0299] Table 2 MC38-B transplant tumor model data

[0300]

[0301]

[0302] 3.2 Tumor measurement results of the recurrence model

[0303] The detailed results are shown in Table 3 and Figure 3 and Figure 4 The tumor measurement results showed that after the tumor was re-inoculated in the experimental group 3, the TGI on Day 21 reached 99.29%, and the tumor still regressed. However, the tumor volume of the mice in the control group was too large (>1000mm 3), the experiment was terminated early for animal ethics reasons. The above data show that the combination of ADC1 and Anti-PD-1 can effectively inhibit tumor regeneration. In terms of body weight, there was no significant decrease in animals in each group.

[0304] Table 3 Recurrence model data

[0305]

[0306] Example 3: Clinical trial of anti-B7H3 antibody-drug conjugate combined with immunotherapy for various advanced solid tumors

[0307] The anti-B7H3 antibody drug conjugate is a multicenter, open-label, Phase I study to evaluate the safety, efficacy and pharmacokinetics of the anti-B7H3 antibody drug conjugate of the present invention with slulizumab in combination with or without platinum drugs in selected patients with advanced solid tumors.

[0308] The selection criteria for the subjects were:

[0309] The inclusion criteria are:

[0310] 1) The participants were informed of the trial conditions before the start of the trial and voluntarily signed their names and dates on the Informed Consent Form (ICF).

[0311] 2) Aged ≥18 and ≤75 years old.

[0312] 3) Enrolled population (using the 8th edition of the International Union Against Cancer [UICC] and American Joint Committee on Cancer [AJCC] staging system):

[0313] Dose escalation: Histologically or cytologically confirmed advanced solid tumors that have progressed on or are intolerant to standard therapy, or for which no standard therapy is available.

[0314] Queue expansion:

[0315] Queue A:

[0316] a) Metastatic (stage IVB) or recurrent NPC confirmed by histology or cytology;

[0317] b) previously received platinum-containing chemotherapy;

[0318] c) Patients were allowed to have received previous anti-PD-(L)1 treatment.

[0319] d) Disease progression or intolerance was documented during or after the last systemic treatment.

[0320] Queue B:

[0321] a) Metastatic (stage IVB) or recurrent NPC confirmed by histology or cytology;

[0322] b) No previous systemic treatment for the current disease. Patients can be enrolled if they have received chemoradiotherapy with curative intent before the diagnosis of metastatic or recurrent disease and there is a treatment-free interval of at least 6 months from the last chemoradiotherapy to the diagnosis of metastatic or recurrent disease.

[0323] Cohort C:

[0324] a) Histologically or cytologically confirmed extensive-stage SCLC (AJCC 8th Edition stage IV [any T, any N, Mla / b / c], or T3-4 cannot be included in a tolerable radiotherapy plan due to multiple lung nodules or large tumor / nodule volume);

[0325] b) No previous systemic treatment for the current disease. Patients can be enrolled if they have received chemoradiotherapy with curative intent in the past for limited-stage disease and there is a treatment-free interval of at least 6 months from the last chemoradiotherapy to the diagnosis of extensive-stage SCLC.

[0326] Queue D:

[0327] a) Patients with locally advanced (stage IIIB / IIIC) or metastatic (stage IV) NSCLC confirmed by histology or cytology and not suitable for radical surgery or radiotherapy;

[0328] b) No known epidermal growth factor receptor (EGFR) sensitive mutations, anaplastic lymphoma kinase (ALK) and c-ros oncogene (ROS1) fusions. Patients with adenocarcinoma or mixed adenocarcinoma components must undergo corresponding gene testing. Patients with other pathological types such as squamous cell carcinoma do not need to undergo corresponding gene testing;

[0329] c) previously received up to two lines of systemic treatment including platinum-containing chemotherapy;

[0330] d) Patients who had received previous anti-PD-(L)1 treatment were allowed.

[0331] e) Disease progression or intolerance was documented during or after the last systemic treatment.

[0332] Queue E:

[0333] a) Patients with locally advanced (stage IIIB / IIIC) or metastatic (stage IV) NSCLC confirmed by histology or cytology and not suitable for radical surgery or radiotherapy;

[0334] b) No known epidermal growth factor receptor (EGFR) sensitive mutations, anaplastic lymphoma kinase (ALK) and c-ros oncogene (ROS1) fusions. Patients with adenocarcinoma or mixed adenocarcinoma components must undergo corresponding gene testing. Patients with other pathological types such as squamous cell carcinoma do not need to undergo corresponding gene testing;

[0335] c) No previous systemic treatment for the current disease. If the patient has previously received treatment for the purpose of cure (not limited to surgery or adjuvant therapy), a treatment-free interval of at least 6 months is required.

[0336] Queue F:

[0337] a) Advanced solid tumors confirmed by histology or cytology (except for tumor types in cohorts A–E);

[0338] b) previously received at most two lines of systemic treatment for the current disease or no standard treatment options are available;

[0339] c) Disease progression or intolerance documented during or after the last systemic treatment.

[0340] 4) According to RECIST v1.1, there is at least one extracranial measurable lesion. Lesions that have received radiotherapy or other local treatments in the past cannot be used as target lesions unless the lesions have clearly progressed.

[0341] 5) Archived or fresh tumor tissue samples can be provided. Patients who are unable to provide tumor samples or have insufficient samples can be enrolled based on their specific circumstances after discussion with the sponsor.

[0342] 6) Eastern Cooperative Oncology Group performance status (ECOGPS) is 0 or 1.

[0343] 7) The body organ and bone marrow function meet the requirements within 7 days before the first dose, as defined below:

[0344] a) Hemoglobin (Hb) ≥ 9.0 g / dL (no blood transfusion or erythropoietin treatment within 14 days before the first dose);

[0345] b) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (no granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose);

[0346] c) Platelet count (PLT) ≥100×10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose);

[0347] d) TBIL ≤1.5×ULN in the absence of obvious liver metastasis, or ≤3×ULN in the presence of liver metastasis;

[0348] e) ALT and AST ≤ 3×ULN in the absence of obvious liver metastasis, or ≤ 5×ULN in the presence of liver metastasis;

[0349] f) serum albumin ≥3.0 g / dL;

[0350] g) Creatinine clearance ≥50 mL / min (calculated according to the Cockcroft-Gault formula);

[0351] h) Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for patients receiving anticoagulant therapy, who must have a stable anticoagulant therapy regimen, and whose APTT and INR must be within the appropriate therapeutic range deemed by the investigator.

[0352] 8) Female patients of childbearing potential must agree to take effective contraceptive measures from the time of screening to the entire study period and at least 6 months after the last dose of the study drug. Male patients must agree to take effective contraceptive measures from the time of screening to the entire study period and at least 6 months after the last dose of the study drug.

[0353] 9) Expected survival period ≥ 3 months.

[0354] 10) Able and willing to comply with the visits and procedures specified in the study protocol.

[0355] Exclusion criteria were:

[0356] 1) Combined SCLC.

[0357] 2) Suitable for local radical treatment.

[0358] 3) Patients who have received previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs).

[0359] 4) Patients who have received previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors.

[0360] 5) Patients who have experienced immune-related adverse events (irAEs) of CTCAE ≥ 3 in the past during treatment with anti-PD-(L)1 or other immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, and other treatments targeting tumor immune mechanisms, excluding endocrine diseases such as hyperglycemia and hypothyroidism that have recovered to ≤ 2.

[0361] 6) Toxicity of previous anticancer therapy has not been alleviated, defined as toxicity that has not been alleviated to NCI CTCAE ≤ grade 1, baseline level, or level specified in the inclusion / exclusion criteria (except for alopecia and pigmentation). Patients with chronic grade 2 toxicity who are asymptomatic or adequately controlled with stable medication may be eligible for inclusion after discussion with the sponsor.

[0362] 7) Enrolled in another clinical study at the same time, unless it is an observational (non-interventional) clinical study or in the follow-up period of an interventional study.

[0363] 8) Insufficient washout period of previous anticancer treatment before the first dose of study drug, defined as follows:

[0364] a) Chemotherapy or small molecule targeted therapy < 2 weeks or 5 half-lives, whichever is shorter

[0365] b) Antibody treatment < 3 weeks;

[0366] c) hormone therapy < 3 weeks;

[0367] d) Chinese herbal medicine treatment with anti-tumor indications for less than 2 weeks;

[0368] e) brain radiotherapy < 2 weeks;

[0369] f) Palliative radiotherapy < 2 weeks, radical radiotherapy < 4 weeks.

[0370] 9) Patients who have undergone major surgery (excluding diagnostic surgery) or severe trauma within 4 weeks before the first dose of study drug, or are in the recovery period and the investigator determines that it will affect the study, or are expected to undergo major surgery during the study.

[0371] 10) Patients who have received allogeneic stem cell or solid organ transplantation in the past.

[0372] 11) Patients with active autoimmune diseases requiring systemic treatment (i.e., use of corticosteroids or immunosuppressive drugs) within 2 years before the first administration of study drug, or patients with autoimmune diseases that the investigator judges to be likely to relapse or are planned to be treated.

[0373] 12) Patients who have received systemic steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive treatment within 2 weeks before the first dose of study drug, except for the following:

[0374] a) Intranasal, inhaled, topical steroids, or local steroid injections (such as intra-articular injections);

[0375] b) physiologic doses of systemic steroids as replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency);

[0376] c) Steroids as prophylaxis for hypersensitivity reactions (such as allergy to CT contrast agents) or chemotherapy-induced nausea and vomiting (CINV).

[0377] 13) Received any live vaccine within 4 weeks before the first dose of study drug, or planned to receive live vaccine during the study.

[0378] 14) Leptomeningeal metastasis or carcinomatous meningitis.

[0379] 15) Brain metastasis or spinal cord compression, excluding the following:

[0380] a) Patients with asymptomatic brain metastases who do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are allowed to enroll;

[0381] b) Patients with treated brain metastases are allowed to enroll if their brain metastases are stable (brain imaging at least 4 weeks before the first dose shows stable lesions, no new neurological symptoms, and no immediate need for local or systemic treatment within 2 weeks before the first dose), and there is no evidence of new or enlarged brain metastases.

[0382] 16) Suffering from uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0383] a) History of symptomatic congestive heart failure (New York Heart Association [NYHA] class II to IV) or any arterial thromboembolic event (such as myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months before the first dose;

[0384] b) Underwent percutaneous coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) within 6 months before the first dose;

[0385] c) uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and / or diastolic blood pressure (DBP) >100 mmHg after antihypertensive treatment;

[0386] d) severe arrhythmia requiring treatment;

[0387] e) The QT interval corrected by the Fridericia formula (QTcF) is prolonged to >450ms (male) or 470ms (female).

[0388] 17) Clinically significant pulmonary diseases, including but not limited to:

[0389] a) A history of (non-infectious) interstitial lung disease (ILD) / interstitial pneumonia requiring steroid treatment, or current ILD / interstitial pneumonia;

[0390] b) Pulmonary embolism occurred within 3 months before the first dose;

[0391] c) previous pneumonectomy;

[0392] d) Other moderate to severe lung diseases that may interfere with the detection or treatment of drug-related pulmonary toxicity and seriously affect respiratory function.

[0393] 18) Diagnosed with Gilbert's syndrome.

[0394] 19) Patients with uncontrolled third space effusion (such as pleural effusion, ascites, pericardial effusion) who require repeated drainage.

[0395] 20) Patients with a history of gastrointestinal perforation and / or fistula within 6 months before the first dose, or active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation.

[0396] 21) The tumor tissue obviously invades the organs adjacent to the lesion (major arteries or trachea), resulting in a higher risk of bleeding or fistula; there is a history of intratracheal stent implantation.

[0397] 22) Severe infection (NCI CTCAE ≥ 3) occurred within 4 weeks before the first dose, such as severe pneumonia, bacteremia, infectious complications requiring hospitalization, or active infection within 2 weeks before the first dose, requiring systemic treatment. Patients receiving prophylactic anti-infective treatment (such as prevention of urinary tract infection or exacerbation of chronic obstructive pulmonary disease) may be eligible for inclusion after discussion with the sponsor.

[0398] 23) Known human immunodeficiency virus (HIV) infection.

[0399] 24) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive hepatitis B core antibody (HBcAb) and / or hepatitis B surface antigen (HBsAg), and HBV deoxyribonucleic acid (DNA) level>200IU / mL or 1000copies / mL. HBV-infected patients should receive antiviral treatment according to local treatment guidelines and be willing to receive antiviral treatment throughout the study period; active HCV is defined as positive hepatitis C antibody and HCV ribonucleic acid (RNA) level higher than the ULN of the research center.

[0400] 25) Any other primary malignant tumor within 3 years before the first dose of study drug, except for adequately resected non-melanoma skin cancer, cured in situ disease, or other cured solid tumors.

[0401] 26) History of severe hypersensitivity reaction to study drugs, inactive ingredients in preparations, or other monoclonal antibodies.

[0402] 27) Lactating women, or women whose pregnancy has been confirmed by a pregnancy test within 7 days before the first dose.

[0403] 28) The researcher believes that there are any diseases / medical conditions, organ system dysfunction or social conditions that may interfere with the patient's ability to sign the informed consent, adversely affect the patient's ability to cooperate and participate in the study, or affect the interpretation of the study results, including but not limited to certain severe and / or uncontrolled medical conditions (such as acute or chronic pancreatitis, immunodeficiency, etc.), mental illness, substance / alcohol abuse, etc.

[0404] Treatment regimen: Subjects who met all inclusion criteria and did not meet any of the exclusion criteria received anti-B7H3 antibody drug conjugates (lyophilized injections prepared according to conventional methods in the art, with a dose of 1.2, 1.6, 1.8, 2.0, or 2.4 mg / kg) and slulizumab (3.0 mg / kg or 4.5 mg / kg) with or without cisplatin (70 mg / m 2 ), intravenous drip, with a treatment cycle of every three weeks (with or without cisplatin) or every two weeks (without cisplatin). Efficacy evaluation is performed every time until disease progression, intolerable toxicity or voluntary withdrawal occurs. The endpoints of the study include safety and tolerability, MTD and RDE, ORR, DCR, pharmacokinetics, immunogenicity, efficacy-related biomarkers, etc.

[0405] Treatment Effect:

[0406] In the dose escalation phase of this clinical study, a total of 14 patients with advanced solid tumors who had failed standard treatment were enrolled, of which 8 subjects were evaluable for efficacy, and the remaining 6 subjects were not evaluated for efficacy because they had not yet reached the tumor evaluation window period. According to the RECIST v1.1 tumor efficacy evaluation standard, among these 8 subjects who could be evaluated for efficacy, 2 subjects achieved the best efficacy evaluation of confirmed partial remission (PR); 2 subjects achieved the best efficacy of PR; 4 subjects achieved the best efficacy of stable disease (SD). The specific efficacy of these 8 subjects who could be evaluated for efficacy is shown in Example 5 below.

[0407] Example 4: Specific efficacy of anti-B7H3 antibody-drug conjugate combined with slulizumab in patients with various advanced solid tumors

[0408] 1. Subject 101001: male, 68 years old, pathologically diagnosed with non-small cell lung cancer-adenocarcinoma, lymph node metastasis, brain metastasis. The target lesions were located in the right lower lobe and subcarinal lymph nodes. After 18 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the right lower lobe lesion was reduced from 30mm to 11mm, a reduction of 63.3%, and the lymph node lesion was reduced from 23mm to 11mm, a reduction of 52.2%. The overall best efficacy evaluation reached a confirmed PR.

[0409] 2. Subject 101002: male, 52 years old, pathologically diagnosed with non-small cell lung cancer-squamous cell carcinoma and pleural metastasis. The target lesions were located in the left lower lobe, right hilar lymph nodes, and left hilar lymph nodes. After 18 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left lower lobe lesions shrank from 34mm to 28mm, a decrease of 17.6%, the right hilar lymph nodes shrank from 22mm to 18mm, a decrease of 9.1%, and the left hilar lymph nodes shrank from 20mm to 16mm, a decrease of 20%. The overall best efficacy evaluation reached SD.

[0410] 3. Subject 101004: Male, 46 years old, pathologically diagnosed with small cell lung cancer, lymph node metastasis, pleural metastasis, pleural effusion, and pericardial effusion. The target lesions were located in the left hilar lesions, prevascular space lymph nodes, and subcarinal lymph nodes. After 12 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left hilar lesions shrank from 93mm to 51mm, a decrease of 45.2%, the prevascular space lymph nodes shrank from 21mm to 8mm, a decrease of 61.9%, and the subcarinal lymph nodes shrank from 24mm to 14mm, a decrease of 41.7%. The overall best efficacy evaluation reached PR.

[0411] 4. Subject 101006: male, 69 years old, pathologically diagnosed with non-small cell lung cancer-adenocarcinoma, lymph node metastasis, brain metastasis, and bone metastasis. The target lesion was located in the left lower lobe of the lung. After 12 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left lower lobe lesion was reduced from 38mm to 29mm, a reduction of 23.7%. The overall best efficacy evaluation reached SD.

[0412] 5. Subject 111001: female, 47 years old, pathologically diagnosed with nasopharyngeal carcinoma and lymph node metastasis. The target lesion was located at the left skull base. After 12 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left skull base lesion stabilized from 45.4mm to 45.5mm. The overall best efficacy evaluation reached SD.

[0413] 6. Subject 101007: female, 59 years old, pathologically diagnosed with small cell lung cancer, lymph node metastasis, brain metastasis, pleural metastasis, and peritoneal metastasis. The target lesions were located in the left lower lobe lesions, left upper lobe lesions, celiac trunk and left gastric artery lymph node lesions. After 12 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left lower lobe lesions shrank from 67mm to 35mm, a decrease of 47.8%, the left upper lobe lesions shrank from 19mm to 8mm, a decrease of 57.9%, the celiac trunk lymph nodes shrank from 20mm to 6mm, a decrease of 70%, and the left gastric artery lymph nodes shrank from 19mm to 7mm, a decrease of 63.1%. The overall best efficacy evaluation reached a confirmed PR.

[0414] 7. Subject 102001: female, 57 years old, pathologically diagnosed with small cell lung cancer, brain metastasis, pleural effusion. The target lesions were located in the left hilum and left lower lobe. After 6 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the left hilum lesion shrank from 30.1mm to 24mm, a decrease of 20.2%, and the left lower lobe lesion shrank from 18mm to 16mm, a decrease of 11.1%. The overall best efficacy assessment reached SD.

[0415] 8. Subject 108001: female, 48 years old, pathologically diagnosed with nasopharyngeal carcinoma and liver metastasis. The target lesion was located in the right liver. After 6 weeks of anti-B7H3 antibody-drug conjugate combined with slulizumab treatment, the right liver lesion shrank from 16mm to 11mm, a reduction of 31.2%. The overall best efficacy evaluation reached PR.

[0416] In summary, the combined treatment regimen of the anti-B7H3 antibody-drug conjugate of the present invention and slulizumab preliminarily showed certain efficacy in patients with various advanced solid tumors, and the tumor condition gradually improved.

[0417] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention. In addition, the technical solutions between the various embodiments can be combined with each other, but it must be based on the ability of ordinary technicians in the field to implement; when the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the protection scope required by the present invention.

Claims

1. Use of an anti-B7H3 antibody-drug conjugate and slulizumab in the preparation of a drug for treating cancer, characterized in that: The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof: wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8; The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region (VH) comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and The light chain variable region (VL) comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; The CDRs were determined by the Kabat definition scheme.

2. Use of an anti-B7H3 antibody-drug conjugate, slulizumab and a platinum drug in the preparation of a drug for treating cancer, characterized in that: The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof: wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8; The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region (VH) comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and The light chain variable region (VL) comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; The CDRs were determined by the Kabat definition scheme.

3. The use according to claim 1 or 2, characterized in that: The platinum drug is cisplatin.

4. The use according to claim 1 or 2, characterized in that: The cancer is a solid tumor.

5. The use according to claim 1 or 2, characterized in that: The cancer is selected from the group consisting of nasopharyngeal carcinoma, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma.

6. The use according to claim 5, characterized in that The cancer is selected from the group consisting of nasopharyngeal carcinoma, non-small cell lung cancer, and small cell lung cancer.

7. The use according to claim 5, characterized in that The non-small cell lung cancer is selected from: NSCLC squamous cell carcinoma, NSCLC adenocarcinoma, pulmonary lymphoepithelioma-like carcinoma, and large cell lung cancer.

8. The use according to claim 5, characterized in that The nasopharyngeal carcinoma is selected from: keratinizing squamous cell carcinoma of the nasopharynx, non-keratinizing nasopharyngeal carcinoma, basaloid squamous cell carcinoma of the nasopharynx, nasopharyngeal carcinoma in situ, and invasive nasopharyngeal carcinoma.

9. The use according to claim 1 or 2, wherein the heavy chain variable region (VH) comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO:

8.

10. The use according to claim 1 or 2, wherein the anti-B7H3 antibody comprises a heavy chain with an amino acid sequence of SEQ ID NO: 9 and a light chain with an amino acid sequence of SEQ ID NO:

10.

11. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises an anti-B7H3 antibody-drug conjugate and other therapeutic agents; wherein the other therapeutic agents are selected from: i. slulizumab; or, ii. slulizumab and platinum drugs; The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof: wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8; The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region (VH) comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and The light chain variable region (VL) comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; The CDRs are determined by the Kabat definition scheme; Preferably, the pharmaceutical composition is a pharmaceutical composition for treating cancer, the cancer being as defined in any one of claims 1 and 4-8.

12. The pharmaceutical composition according to claim 11, characterized in that The heavy chain variable region (VH) comprises the amino acid sequence of SEQ ID NO:7, and the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO:

8.

13. The pharmaceutical composition according to claim 11 or 12, characterized in that The anti-B7H3 antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO:9 and a light chain having an amino acid sequence of SEQ ID NO:

10.

14. A kit, characterized in that: Comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents; wherein the other therapeutic agent is selected from: i. slulizumab; or, ii. slulizumab and platinum drugs; The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula I, or a pharmaceutically acceptable salt thereof: wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8; The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region (VH) comprises: (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and The light chain variable region (VL) comprises: (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6; The CDRs are determined by the Kabat definition scheme; Preferably, the kit is a kit for treating cancer, the cancer being as defined in any one of claims 1 and 4-8.

15. The kit according to claim 14, characterized in that The heavy chain variable region (VH) comprises the amino acid sequence of SEQ ID NO:7, and the light chain variable region (VL) comprises the amino acid sequence of SEQ ID NO:

8.

16. The kit according to claim 14 or 15, characterized in that The anti-B7H3 antibody comprises a heavy chain having an amino acid sequence of SEQ ID NO:9 and a light chain having an amino acid sequence of SEQ ID NO:10.

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