Method for treating cancer by anti-b7h3 antibody-drug conjugate

Abstract

A method or use of administering an anti-B7H3 antibody-drug conjugate in combination with other therapeutic agents for treating cancer. The other therapeutic agents are selected from anti-PD-1 antibodies or antigen-binding fragments or / and chemotherapeutic drugs thereof. Also provided is a use of the combination in a pharmaceutical composition and a pharmaceutical kit for treating cancer.

Description

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

[0001] This application claims priority to Chinese Patent Application No. 2023115012636 filed on November 13, 2023, and Chinese Patent Application No. 2024110769786 filed on August 7, 2024. This application incorporates the entirety of the aforementioned Chinese patent applications. Technical Field

[0002] The present invention belongs to the fields of molecular immunology and tumor therapy. It relates to methods or uses of administering an anti-B7H3 antibody-drug conjugate in combination with other therapeutic agents for treating cancer, wherein the other therapeutic agents are selected from anti-PD-1 antibodies or antigen-binding fragments thereof and / or chemotherapeutic agents. The present invention also relates to pharmaceutical compositions and pharmaceutical kits for the use of such combinations in treating cancer. Background Art

[0003] Malignant tumors have become a major global public health issue, causing nearly 10 million deaths in 2020. The number of cancer patients and deaths worldwide continues to rise, leading to the continuous expansion of the overall cancer treatment market and increasing demand for new therapeutic drugs and new treatment methods.

[0004] Monoclonal antibody drugs have the advantages of strong targeting, high specificity and low incidence of adverse reactions, and antibody-drug conjugates (ADCs) are representative products among them. Since ADCs have the characteristics of both the effectiveness of small molecule drugs and the targeting of antibody drugs, they can not only reduce the toxic side effects of cytotoxic drugs, but also improve the therapeutic effect of drugs. Currently, 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, with an ORR response rate of 27%-35% in the treatment of triple-negative breast cancer (TNBC). 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 to a cytotoxic compound 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 limit the clinical dosage and have poor therapeutic effects in some indications. Therefore, ADC drugs need to explore more treatment methods (such as combined use with drugs with different mechanisms of action) to further improve the therapeutic effect.

[0005] Immune checkpoints, as immunosuppressive pathways, are crucial 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) and its ligand (PD-L1) are currently the most widely used targets of immune checkpoint inhibitors (ICIs), approved for the 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-1therapy. 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 cancers, only 20%-30% of patients have an immune response.

[0006] Small molecule cytotoxic drugs have been used clinically for many years and are the first-line treatment for a variety of diseases. Although they are effective in the early stages of treatment, they are highly toxic, poorly tolerated by patients with long-term administration, and are prone to drug resistance.

[0007] Summary of the Invention

[0008] In response to the shortcomings of immune checkpoint inhibitors and small molecule toxins in treating cancer, the present disclosure provides a method for combining antibody-drug conjugates 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.

[0009] In a first aspect, the present disclosure provides a method for treating cancer, comprising administering to a subject, for example, administering to a subject in need thereof, an effective amount of:

[0010] (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:

[0011] The heavy chain variable region comprises:

[0012] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0013] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0014] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0015] The light chain variable region comprises:

[0016] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0017] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0018] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0019] The CDRs were determined by the Kabat definition scheme;

[0020] and (b) other therapeutic agents selected from: anti-PD-1 antibodies or antigen-binding fragments thereof, chemotherapeutic drugs, or one or two of the foregoing.

[0021] 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, wherein the heavy chain variable region comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence having at least 85% sequence identity to the amino acid sequence shown in SEQ ID NO:8.

[0022] In some embodiments, the amino acid sequence of the heavy chain variable region is an amino acid sequence that is 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%, or at least 99.9% identical to SEQ ID NO:7, and the amino acid sequence of the light chain variable region is an amino acid sequence that is 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%, or at least 99.9% identical to SEQ ID NO:8.

[0023] In some embodiments, the heavy chain variable region of the anti-B7H3 antibody or antigen-binding fragment thereof comprises the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:8.

[0024] In some embodiments, the amino acid sequence of the heavy chain variable region of the anti-B7H3 antibody or antigen-binding fragment thereof is shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:8.

[0025] In some embodiments, the anti-B7H3 antibody comprises the heavy chain set forth in SEQ ID NO:9, and the light chain set forth in SEQ ID NO:10.

[0026] In some embodiments, the anti-B7H3 antibody comprises a heavy chain having an amino acid sequence that is 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% identical to SEQ ID NO:9, and a light chain having an amino acid sequence that is 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% identical to SEQ ID NO:10.

[0027] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof is the antibody numbered 2E3-02 in WO2022170971.

[0028] In a second aspect, the present disclosure provides a method for treating cancer, comprising administering to a subject, for example, administering to a subject in need thereof, an effective amount of:

[0029] 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 thereof:

[0030] Tb-(LD)q,

[0031] in:

[0032] 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 having the following structure:

[0033] The 1st position is connected to Tb, and the 2nd position is connected to D;

[0034] D is a bioactive molecular fragment, such as camptothecin drugs;

[0035] 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 and 10; more preferably, q is 2, 4, 6 or 8;

[0036] and (b) other therapeutic agents selected from: anti-PD-1 antibodies or antigen-binding fragments thereof, chemotherapeutic drugs, or one or two of the foregoing.

[0037] In some embodiments, the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the structure of Formula I below, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0038] in:

[0039] S is the sulfur atom on Tb;

[0040] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0041] 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, more preferably q is 2, 4, 6 or 8.

[0042] In other embodiments, the antibody-drug conjugate may also be selected from:

[0043] wherein Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0044] S is the sulfur atom on Tb;

[0045] 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.

[0046] In some embodiments, the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having the structure of Formula II below, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof.

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

[0048] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof and monoclonal antibody or antigen-binding fragment thereof 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 antigen-binding fragment thereof having higher binding activity for B7H3-4Ig than for B7H3-2Ig.

[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 the antibody numbered 2E3-02 in WO2022170971.

[0056] In some embodiments, the anti-B7H3 antibody is the 2E3-02 antibody, which comprises the heavy chain shown in SEQ ID NO:9 and the light chain 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 additional therapeutic agent is an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug.

[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 the group consisting of AK103 (HX008), Treprinumab, Sintilimab, Camrelizumab, Tislelizumab, Nivolumab (Opdivo or Nivolumab), Keytruda (Pembrolizumab), Nofazinlimab, Serplulimab (HLX10 or Hans), Geptanolimab, Lipustobart, BAT-1306, Finotonlimab, Rulonilimab, SG001, Zimberelimab, Spartalizumab, Cemiplimab, STI-A1110, or one or more of the foregoing; the anti-PD-1 antibody may also be Bio X Cell BE0146 antibody;

[0062] ii. The chemotherapy drug is selected from a platinum drug; preferably, the platinum chemotherapy drug is selected from cisplatin, carboplatin, cyclothiaplatin, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, iproplatin, dicycloplatin, or a combination thereof;

[0063] iii. the anti-PD-1 antibody is not slulizumab;

[0064] iv. The anti-PD-1 antibody is not Keytruda or Pembrolizumab;

[0065] v. The anti-PD-1 antibody is not Treprinumab.

[0066] In some preferred embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from: pembrolizumab (Keytruda or Pembrolizumab), serplulimab (HLX10 or Hans), treprinumab or Bio X Cell BE0146 antibody.

[0067] In some preferred embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof is selected from: pembrolizumab (Keytruda or Pembrolizumab), serplulimab (HLX10 or Hans-like).

[0068] In some embodiments, when the anti-PD-1 antibody is slulizumab, the anti-B7H3 antibody-drug conjugate is not an antibody-drug conjugate of Formula I or a pharmaceutically acceptable salt thereof:

[0069] wherein S is a sulfur atom on Tb, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, and q is 8;

[0070] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0071] The heavy chain variable region (VH) comprises:

[0072] (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1;

[0073] (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and

[0074] (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and

[0075] The light chain variable region (VL) comprises:

[0076] (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 4;

[0077] (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and

[0078] (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 6;

[0079] The CDRs were determined according to the Kabat definition scheme.

[0080] In some embodiments, the method comprises administering to the subject an anti-B7H3 antibody-drug conjugate and an anti-PD-1 antibody or antigen-binding fragment thereof.

[0081] 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.

[0082] In some embodiments, the platinum drug is selected from carboplatin.

[0083] In some embodiments, the platinum drug is selected from cisplatin.

[0084] In some embodiments, the method of treating cancer comprises administering to a subject:

[0085] (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 thereof:

[0086] 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, and 10, more preferably q is 2, 4, 6, or 8, and more preferably q is 8;

[0087] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0088] The heavy chain variable region (VH) comprises:

[0089] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0090] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0091] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0092] The light chain variable region (VL) comprises:

[0093] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0094] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0095] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0096] The CDRs were determined by the Kabat definition scheme;

[0097] 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).

[0098] 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.

[0099] In some embodiments, the method of treating cancer comprises administering to a subject:

[0100] (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 thereof:

[0101] 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, and 10, more preferably q is 2, 4, 6, or 8, and more preferably q is 8;

[0102] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0103] The heavy chain variable region (VH) comprises:

[0104] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0105] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0106] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0107] The light chain variable region (VL) comprises:

[0108] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0109] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0110] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0111] The CDRs were determined by the Kabat definition scheme;

[0112] and (b) an anti-PD-1 antibody or an antigen-binding fragment thereof, wherein the anti-PD-1 antibody is pembrolizumab (Keytruda or Pembrolizumab).

[0113] 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.

[0114] In some embodiments, the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof, is administered at a dose of 0.1-15 mg / kg body weight of the individual.

[0115] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose in the following ranges: 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;

[0116] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 4.0 mg / kg, or 5.0 mg / kg.

[0117] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.2 mg / kg.

[0118] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.4 mg / kg.

[0119] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.6 mg / kg.

[0120] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 1.8 mg / kg.

[0121] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.0 mg / kg.

[0122] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.2 mg / kg.

[0123] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.4 mg / kg.

[0124] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.6 mg / kg.

[0125] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 2.8 mg / kg.

[0126] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of about 3.0 mg / kg.

[0127] 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.

[0128] 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.

[0129] 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, or 600 mg.

[0130] 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.

[0131] 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.

[0132] 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.

[0133] 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.

[0134] 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, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, or 5.0 mg / kg.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] In some embodiments, the platinum drug is:

[0140] i. Range of approximately 50-150 mg / m 2 The dose is administered to the subject;

[0141] Preferably, the platinum drug is administered to the subject at a dose of 50 mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 or 150 mg / m 2 ;

[0142] or

[0143] ii. The dose for each administration is calculated as the area under the curve (AUC), selected from 1-10 mg / ml / min;

[0144] Preferably, the platinum drug is administered to the subject at the following dosage (ie, injection rate): 3 mg / mL / min, 4 mg / mL / min, 5 mg / mL / min, 6 mg / mL / min or 7 mg / mL / min.

[0145] In some embodiments, the platinum drug is administered to the subject at a dose of 50 mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 or 150 mg / m 2 .

[0146] In some embodiments, the platinum drug is about 70 mg / m 2 The dose is administered to the subject.

[0147] In some embodiments, the platinum drug is about 75 mg / m 2 The dose is administered to the subject.

[0148] In some embodiments, the platinum drug is about 80 mg / m 2 The dose is administered to the subject.

[0149] 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, and 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.

[0150] In some embodiments, the dose of cisplatin administered each time is selected from 50-150 mg / m 2 , preferably from 50 mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 and 150 mg / m 2 .

[0151] In some embodiments, the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or antigen-binding fragment thereof, and the platinum drug are administered for a period of 7 to 42 days. Preferably, the administration period is 21 to 42 days.

[0152] In some embodiments, the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibody or antigen-binding fragment thereof, and platinum drug are administered for a period of 14 days, 21 days, 28 days, 35 days, or 42 days.

[0153] 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.

[0154] 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 with each administration period being the same or different, and the intervals between each administration period being the same or different.

[0155] 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.

[0156] In some embodiments, the PD-1 antibody or antigen-binding fragment thereof 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.

[0157] 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.

[0158] 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.

[0159] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered simultaneously.

[0160] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered separately.

[0161] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are administered sequentially.

[0162] In some embodiments, the anti-B7H3 antibody-drug conjugate is administered first, followed by administration of the other therapeutic agent.

[0163] In some embodiments, the cancer is selected from solid tumors.

[0164] 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.

[0165] In some embodiments, the cancer is selected from the group consisting of nasopharyngeal carcinoma, non-small cell lung cancer, and small cell lung cancer.

[0166] In some embodiments, the cancer is selected from non-small cell lung cancer.

[0167] 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.

[0168] In some embodiments, the non-small cell lung cancer (NSCLC) is selected from: driver gene positive or driver gene negative.

[0169] 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).

[0170] In some embodiments, the non-keratinizing nasopharyngeal carcinoma comprises a differentiated type or an undifferentiated type.

[0171] 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.

[0172] In some embodiments, the subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has previously failed treatment with a platinum-containing regimen.

[0173] In some embodiments, the subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has not received systemic treatment.

[0174] In some embodiments, the subject is a patient with small cell lung cancer who has not received systemic treatment.

[0175] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer that 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 has previously failed treatment with a platinum-containing regimen.

[0176] 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 treatment with a platinum-containing regimen.

[0177] In some embodiments, the subject is a patient with EGFR sensitizing mutation-negative, ALK-negative and / or c-ros proto-oncogene (ROS1)-negative locally advanced or metastatic non-small cell lung cancer who has not received systemic treatment.

[0178] In some embodiments, the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is negative for EGFR sensitive mutations and negative for ALK / c-ros proto-oncogene (ROS1) and has not received systemic treatment.

[0179] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are present in a unit dosage form.

[0180] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are present in the same dosage unit.

[0181] In some embodiments, the anti-B7H3 antibody-drug conjugate and the other therapeutic agent are present in different dosage units.

[0182] 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.

[0183] In some embodiments, the anti-B7H3 antibody-drug conjugate and other therapeutic agent are administered by intravenous injection.

[0184] In some embodiments, the anti-B7H3 antibody-drug conjugate or its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate thereof is administered by injection. Before injection, the anti-B7H3 antibody-drug conjugate or its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate thereof needs to be prepared into an injectable form. The preferred injection form is an injection solution or a lyophilized powder, which contains the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer or metabolite or solvate thereof, and optionally a buffer, a stabilizer, The present invention also comprises a stabilizer, a pH regulator and a surfactant; wherein the buffering agent can be selected from one or more of acetate, citrate, succinate and phosphate; the stabilizer can be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose or maltose; the pH regulator can be selected from one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide; the surfactant can 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.

[0185] In some embodiments, the subject experiences improvement relative to baseline in one or more therapeutic effects following 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 the group consisting of: 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).

[0186] 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.

[0187] 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 one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, and the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or an antigen-binding fragment thereof, and the chemotherapeutic drug are as described herein.

[0188] In some embodiments, the pharmaceutical composition is a pharmaceutical composition for treating cancer, and the cancer is as described above.

[0189] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0190] In some embodiments, the pharmaceutical composition comprises an anti-B7H3 antibody-drug conjugate and another therapeutic agent; wherein the other therapeutic agent is selected from: i. slulizumab; or, ii. slulizumab and a platinum drug;

[0191] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[0192] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0193] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0194] The heavy chain variable region (VH) comprises:

[0195] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0196] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0197] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0198] The light chain variable region (VL) comprises:

[0199] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0200] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0201] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0202] The CDRs were determined according to the Kabat definition scheme.

[0203] In some embodiments, the pharmaceutical composition comprises an anti-B7H3 antibody-drug conjugate and another therapeutic agent; wherein the other therapeutic agent is selected from: i. pembrolizumab (Keytruda or Pembrolizumab); or, ii. pembrolizumab (Keytruda or Pembrolizumab) and a platinum drug;

[0204] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[0205] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0206] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0207] The heavy chain variable region (VH) comprises:

[0208] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0209] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0210] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0211] The light chain variable region (VL) comprises:

[0212] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0213] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0214] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0215] The CDRs were determined according to the Kabat definition scheme.

[0216] 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 one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, and the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or an antigen-binding fragment thereof, and the chemotherapeutic drug are as described herein.

[0217] In some embodiments, the kit is a kit for treating cancer, and the cancer is as described above.

[0218] 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 a platinum drug;

[0219] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[0220] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0221] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0222] The heavy chain variable region (VH) comprises:

[0223] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0224] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0225] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0226] The light chain variable region (VL) comprises:

[0227] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0228] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0229] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0230] The CDRs were determined according to the Kabat definition scheme.

[0231] In some embodiments, the kit comprises an anti-B7H3 antibody-drug conjugate and another therapeutic agent; wherein the other therapeutic agent is selected from: i. pembrolizumab (Keytruda or Pembrolizumab); or, ii. pembrolizumab (Keytruda or Pembrolizumab) and a platinum drug;

[0232] The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt thereof:

[0233] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0234] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0235] The heavy chain variable region (VH) comprises:

[0236] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0237] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0238] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0239] The light chain variable region (VL) comprises:

[0240] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0241] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0242] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0243] The CDRs were determined according to the Kabat definition scheme.

[0244] In some embodiments, the kit comprises kit A and kit B, wherein kit A comprises the anti-B7H3 antibody-drug conjugate as an active ingredient, and kit B comprises the other therapeutic agent as an active ingredient.

[0245] In a fifth aspect, the present disclosure further provides use of the kit described in the fourth aspect in preparing a drug for treating cancer.

[0246] In a sixth aspect, the present disclosure provides a drug combination comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents, wherein the other therapeutic agents are selected from one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, and the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or an antigen-binding fragment thereof, and the chemotherapeutic drug are as described above.

[0247] In a seventh aspect, the present disclosure provides use of a combination of an anti-B7H3 antibody-drug conjugate and other therapeutic agents in the preparation of a medicament for treating cancer.

[0248] In some embodiments, there is also provided use of the aforementioned anti-B7H3 antibody-drug conjugate in combination with an anti-PD-1 antibody or an antigen-binding fragment thereof in the preparation of a drug for treating cancer.

[0249] In some embodiments, the present invention also provides a use of the aforementioned anti-B7H3 antibody-drug conjugate and anti-PD-1 antibody or antigen-binding fragment thereof and chemotherapy drug in combination for the preparation of a drug for treating cancer.

[0250] In one aspect, the present disclosure also provides the above kit or pharmaceutical combination for treating cancer.

[0251] In yet another aspect, provided is a use of an anti-B7H3 antibody-drug conjugate in preparing a drug for treating cancer, wherein the anti-B7H3 antibody-drug conjugate is administered in combination with other therapeutic agents, and the anti-B7H3 antibody-drug conjugate is as described above.

[0252] In yet another aspect, an anti-B7H3 antibody-drug conjugate for treating cancer is provided. The anti-B7H3 antibody-drug conjugate is as described above and is administered in combination with other therapeutic agents.

[0253] In some embodiments, an anti-B7H3 antibody-drug conjugate is provided for use in combination with serplulimab (HLX10 or Hans-like) for treating cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0254] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0255] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0256] The heavy chain variable region (VH) comprises:

[0257] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0258] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0259] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0260] The light chain variable region (VL) comprises:

[0261] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0262] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0263] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0264] The CDRs were determined according to the Kabat definition scheme.

[0265] In some embodiments, an anti-B7H3 antibody-drug conjugate is provided for use in combination with serplulimab (HLX10 or Hans-like) and a platinum drug for the treatment of cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0266] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0267] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0268] The heavy chain variable region (VH) comprises:

[0269] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0270] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0271] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0272] The light chain variable region (VL) comprises:

[0273] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0274] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0275] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0276] The CDRs were determined according to the Kabat definition scheme.

[0277] In some embodiments, a PD-1 antibody is provided for use in combination with an anti-B7H3 antibody-drug conjugate for treating cancer; wherein the PD-1 antibody is slulizumab, and the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0278] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0279] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0280] The heavy chain variable region (VH) comprises:

[0281] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0282] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0283] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0284] The light chain variable region (VL) comprises:

[0285] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0286] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0287] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0288] The CDRs were determined according to the Kabat definition scheme.

[0289] In some embodiments, a PD-1 antibody is provided for use in combination with an anti-B7H3 antibody-drug conjugate and a platinum drug for treating cancer; wherein the PD-1 antibody is slulizumab, and the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0290] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0291] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0292] The heavy chain variable region (VH) comprises:

[0293] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0294] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0295] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0296] The light chain variable region (VL) comprises:

[0297] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0298] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0299] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0300] The CDRs were determined according to the Kabat definition scheme.

[0301] In some embodiments, a combination of an anti-B7H3 antibody-drug conjugate and serplulimab (HLX10 or Hans-like) is provided for the treatment of cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0302] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0303] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0304] The heavy chain variable region (VH) comprises:

[0305] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0306] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0307] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0308] The light chain variable region (VL) comprises:

[0309] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0310] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0311] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0312] The CDRs were determined according to the Kabat definition scheme.

[0313] In some embodiments, an anti-B7H3 antibody-drug conjugate is provided for use in combination with pembrolizumab (Keytruda or Pembrolizumab) for treating cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0314] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0315] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0316] The heavy chain variable region (VH) comprises:

[0317] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0318] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0319] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0320] The light chain variable region (VL) comprises:

[0321] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0322] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0323] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0324] The CDRs were determined according to the Kabat definition scheme.

[0325] In some embodiments, an anti-B7H3 antibody-drug conjugate is provided for use in combination with pembrolizumab (Keytruda or Pembrolizumab) and a platinum drug for the treatment of cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0326] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0327] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0328] The heavy chain variable region (VH) comprises:

[0329] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0330] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0331] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0332] The light chain variable region (VL) comprises:

[0333] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0334] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0335] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0336] The CDRs were determined according to the Kabat definition scheme.

[0337] In some embodiments, a PD-1 antibody is provided for use in combination with an anti-B7H3 antibody-drug conjugate for treating cancer; wherein the PD-1 antibody is pembrolizumab (Keytruda or Pembrolizumab), and the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0338] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0339] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0340] The heavy chain variable region (VH) comprises:

[0341] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0342] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0343] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0344] The light chain variable region (VL) comprises:

[0345] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0346] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0347] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0348] The CDRs were determined according to the Kabat definition scheme.

[0349] In some embodiments, a PD-1 antibody is provided for use in combination with an anti-B7H3 antibody-drug conjugate and a platinum drug for the treatment of cancer; wherein the PD-1 antibody is pembrolizumab (Keytruda or Pembrolizumab), and the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0350] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0351] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0352] The heavy chain variable region (VH) comprises:

[0353] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0354] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0355] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0356] The light chain variable region (VL) comprises:

[0357] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0358] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0359] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0360] The CDRs were determined according to the Kabat definition scheme.

[0361] In some embodiments, a combination of an anti-B7H3 antibody-drug conjugate and pembrolizumab (Keytruda or Pembrolizumab) is provided for the treatment of cancer; wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate represented by the structure of Formula I, or a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof:

[0362] wherein S is a sulfur atom on Tb, and 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, and 10, more preferably q is 2, 4, 6, or 8, and even more preferably q is 8;

[0363] The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0364] The heavy chain variable region (VH) comprises:

[0365] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0366] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0367] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0368] The light chain variable region (VL) comprises:

[0369] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0370] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0371] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0372] The CDRs were determined according to the Kabat definition scheme.

[0373] In some embodiments, the combination of anti-B7H3 antibody-drug conjugates and immune checkpoint inhibitors has a significant inhibitory effect on tumors. In a mouse tumor-bearing model, compared with single drugs, the combined administration of anti-B7H3 antibody-drug conjugates and anti-PD-1 antibodies can synergistically inhibit tumor growth and produce a significant anti-tumor effect.

[0374] In some embodiments, the present disclosure further demonstrates the tumor-suppressing effects of anti-B7H3 antibody-drug conjugates in combination with anti-PD-1 antibodies and / or chemotherapeutic agents through experimental validation. Validation is not limited to animal tumor models, but also includes in vitro cell models and human clinical trials. Tumor types are not limited to colorectal cancer, but can also include other tumors, including but not limited to nasopharyngeal carcinoma, non-small cell lung cancer, small cell lung cancer, esophageal squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma.

[0375] Detailed Description of the Invention

[0376] Unless otherwise defined, all terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. For relevant definitions and terms, see, for example, Current Protocols in Molecular Biology (Ausubel). For a better understanding of this disclosure, definitions and explanations of relevant terms are provided below.

[0377] All documents mentioned herein are incorporated by reference in their entirety.

[0378] The native sequence B7H3 antibody herein can be isolated from nature, or prepared by recombinant DNA technology, chemical synthesis, or a combination thereof.

[0379] As used herein, the term "antibody" is interpreted in the broadest sense to include intact monoclonal antibodies, polyclonal antibodies, and multispecific antibodies (eg, bispecific antibodies) formed from at least two intact antibodies, so long as they possess the desired biological activity.

[0380] As used herein, the term "monoclonal antibody" refers to an antibody that is derived from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for a small number of naturally occurring mutations that may be present. Monoclonal antibodies have high specificity for a single determinant (epitope) of an antigen, whereas polyclonal antibodies, in contrast, comprise different antibodies directed against different determinants (epitopes). In addition to their specificity, monoclonal antibodies have the advantage of being synthesized without contamination by other antibodies. The modifier "monoclonal" herein indicates that the antibody is characterized by being derived from a substantially homogeneous population of antibodies and should not be construed as requiring production by a specific method.

[0381] 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, for example, 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.

[0382] In this context, "plurality" includes more than one selection, such as two, three, four or more. In certain embodiments, "plurality" means at least two.

[0383] The term "antibody fragment" refers to a portion of an antibody, preferably the antigen binding or variable region. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; and single-chain antibody molecules.

[0384] 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.

[0385] The antibody-drug conjugates of the present invention may be in the form of pharmaceutically acceptable salts, stereoisomers, metabolites, or solvates, and the salts, stereoisomers, or metabolites may also be in the form of solvates.

[0386] 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 pharmaceutical. 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.

[0387] Pharmaceutically acceptable acid addition salts may be salts formed with inorganic or organic acids. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. The organic acids include, 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.

[0388] 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, with ammonium salts, potassium salts, sodium salts, calcium salts and magnesium salts being particularly preferred. The organic bases include, for example, primary, secondary 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.

[0389] 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.

[0390] 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 indicated in its nomenclature or structure and it has one or more asymmetric centers, it should be understood that all possible stereoisomers of the compound are represented.

[0391] 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).

[0392] Also included within the scope of this disclosure are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, and the like of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting the compounds of the invention with a lactating animal for a period of time sufficient to produce a metabolic product thereof.

[0393] 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, beneficial or desired clinical outcomes include, but are not limited to, alleviating symptoms, reducing the focus 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" can also refer to extending survival compared to the expected survival (if not receiving treatment).

[0394] 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 in the sum of the diameters of at least 5 mm; or the appearance of one or more new lesions.

[0395] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an anti-B7H3 antibody-drug conjugate (anti-B7H3-ADC) and / or an anti-PD-1 antibody or its antigen-binding fragment and / or a chemotherapeutic agent that, when administered to a cell, tissue, or subject, effectively prevents or alleviates the disease or condition being treated. A therapeutically effective dose further refers to an amount of an anti-B7H3 antibody-drug conjugate (anti-B7H3-ADC) and / or an anti-PD-1 antibody or its antigen-binding fragment and / or a chemotherapeutic agent sufficient to cause symptom alleviation, such as treatment, cure, or alleviation of a related medical condition, or to increase the rate of treatment, cure, or alleviation of the symptoms. The effective amount for a particular subject may vary depending on a variety of factors, such as the disease being treated, the patient's overall health, the 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%.

[0396] 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, and the like. 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, bovines (e.g., cows), porcines (e.g., pigs), ovines (e.g., sheep), caprines (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), and the like. In certain embodiments, the subject is a human.

[0397] As used herein, the terms "complete response (CR)", "partial response (PR)", "stable disease (SD)", "progressive disease (PD)", "objective response rate (ORR)", and "disease control rate (DCR)" are defined as follows:

[0398] When the disease is a solid tumor, the efficacy of the solid tumor is evaluated according to the following criteria (see New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), EAEisenhauer et al., EUROPEAN JOURNAL OF CANCER, 45 (2009), pp. 228-247) as "complete response (CR)", "partial response (PR)", "stable disease (SD)", "progressive disease (PD)", "objective response rate (ORR)", and "disease control rate (DCR)". The evaluation of target lesions is as follows:

[0399] 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.

[0400] Partial response (PR): The sum of the diameters of target lesions (short diameter of lymph nodes) is reduced by at least 30% compared to the baseline level. There is no significant progression of non-target lesions and no new lesions.

[0401] Stable disease (SD): The target lesion has not decreased to the level of PR, nor increased to the level of PD, but is somewhere in between. The minimum sum of the diameters can be used as a reference for research.

[0402] 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 diameter is at least 20% (if the baseline measurement value is the minimum, 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 as disease progression).

[0403] Objective response rate (ORR) refers to the proportion of patients whose tumors shrink to a certain degree, including both complete response (CR) and partial response (PR). Subjects must have measurable tumor lesions at baseline, and efficacy assessment criteria are based on RECIST 1.1.

[0404] Disease control rate (DCR) was defined as the percentage of patients with complete remission (CR), partial remission (PR) and stable disease (SD) among the total number of patients analyzed.

[0405] 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 approvals. See Johnson et al., J. Clin. Oncol. 21(7): 1404-1411 (2003).

[0406] Progression-free survival (PFS) is the time from enrollment 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 period in which a patient remains alive without their cancer worsening.

[0407] "Overall survival" (OS) refers to the time from patient enrollment to death or censoring the last known alive 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).

[0408] Depth of Response (DpR): Depth of response refers to the degree of reduction in tumor volume or disease during treatment. Specifically, it refers to the percentage of maximum tumor reduction achieved during treatment compared to baseline. If CR occurs, the DpR is 100. It is usually measured based on imaging or clinical assessment.

[0409] 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).

[0410] Time to response (TTR): Time to response refers to the time from the start of treatment to the patient's first remission (CR or PR) status. BRIEF DESCRIPTION OF THE DRAWINGS

[0411] Figure 1: Efficacy test results of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug in MC38-B model

[0412] Figure 2: Body weight of the MC38-B model treated with an antibody-drug conjugate (ADC1) combined with an anti-PD-1 drug.

[0413] Figure 3: Efficacy test results of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug in MC38-B recurrent model

[0414] Figure 4: Body weight changes in the MC38-B relapse model treated with antibody-drug conjugate (ADC1) combined with anti-PD-1 drugs DETAILED DESCRIPTION

[0415] Sequence information

[0416] The sequence information involved in this application is described in the following table:

[0417] The present disclosure is further described below by describing specific embodiments, but this is not intended to limit the present disclosure. Those skilled in the art can make various modifications or improvements based on the teachings of the present disclosure without departing from the basic idea and scope of the present disclosure.

[0418] Example 1: Production of anti-B7H3 antibody-drug conjugates

[0419] 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).

[0420] Example 2: Efficacy test of antibody-drug conjugate (ADC1) combined with anti-PD-1 drug on MC38-B transplanted tumors

[0421] 1. Experimental Materials

[0422] Test compounds: ADC1, Anti-PD-1, and ADC1 + Anti-PD-1. Normal saline was used as a negative control. Anti-PD-1 is a cell-expressed murine anti-mouse PD-1 antibody constructed based on the heavy and light chain sequences of Antibody C in patent WO2017132827A1.

[0423] Experimental cells: MC38-B7H3 cells (hereinafter referred to as MC38-B, MC38 cells transfected with human B7H3 recombinant protein);

[0424] Experimental animals: C57BL / 6J female mice, 5-6 weeks old, were purchased from Jicui Yaokang Biotechnology Co., Ltd.

[0425] 2. Experimental Plan

[0426] Cell treatment

[0427] 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.

[0428] 2.2. Tumor cell transplantation

[0429] C57BL / 6J mice were acclimated to the laboratory environment for 2-5 days and MC38-B cells were subcutaneously inoculated in the right rib cage at a dose of 5 × 10 6 / mouse, the inoculation volume was 0.1mL, and the tumor was grown to 150mm 3 When about , conduct the experiment.

[0430] 2.3. Animal Dosing and Testing

[0431] 2.3.1 Combination drug trial plan

[0432] The tumor-bearing nude mice were dosed according to the following regimen:

[0433] Table 1 Dosage regimen Note: Each group had 5 animals and the administration volume was 10 mL / kg.

[0434] 2.3.2 Recurrence Model Experimental Plan

[0435] 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.

[0436] The control group (normal saline group) consisted of newly enrolled blank mice according to their weight and age, and were inoculated with MC38-B cells according to the protocol described in 2.2.

[0437] The above two groups only measured tumor size and did not receive any medication.

[0438] 2.4. Tumor volume and body weight determination:

[0439] Tumor volume and body weight were measured twice a week, and T / C% and TGI (%) were calculated using the following formulas: relative tumor proliferation rate (T / C%) = TRTV / CRTV × 100% (TRTV: mean RTV of the treatment group; CRTV: mean RTV of the control group; RTV = Vt / V0, where V0 is the tumor volume of the animal at the time of grouping 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 and control groups, respectively, at a specific time point).

[0440] The formula for calculating tumor volume (V) is: V = 1 / 2 × L length × L short 2 , where Llong and Lshort represent the long diameter and short diameter of the tumor, respectively.

[0441] 3. Experimental Results

[0442] 3.1 Results of combined drug treatment experiments

[0443] Specific results are shown in Table 2 and Figures 1 and 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 combination administration group produced a significant synergistic effect. At the same time, during the administration period, the weight of animals in each group increased steadily, indicating that there was no obvious toxicity in both single-drug and combined administration.

[0444] Table 2 MC38-B transplant tumor model data

[0445] 3.2 Tumor measurement results of the recurrence model

[0446] The specific results are shown in Table 3 and Figures 3 and 4. The tumor measurement results showed that after the tumor was re-inoculated in the experimental group 3, the TGI reached 99.29% on Day 21, and the tumor still regressed. However, the tumor volume of the mice in the control group was too large (>1000mm 3 The trial was terminated early for animal ethics reasons. These data demonstrate that the combination of ADC1 and Anti-PD-1 effectively inhibits tumor regeneration. No significant weight loss was observed in any of the animal groups.

[0447] Table 3 Recurrence model data

[0448] Example 3: Activity Study of Anti-B7H3 Antibody-Drug Conjugate Combined with Keytruda in Tumor Cell and Human PBMC Co-culture Experiment

[0449] The in vitro activity of ADC1 in combination with Keytruda was evaluated using NCI-H1975-Lux cells co-cultured with human PBMC cells.

[0450] Frozen human PBMCs were quickly thawed in a 37°C water bath and the cell density was adjusted to 2×10 6 / ml, add medium containing SEB to the cell suspension to make the final concentration of SEB 100ng / ml, and culture for 72h at 37℃, 5% CO2 to stimulate and activate PBMC. After stimulation, resuspend PBMC cells by centrifugation and adjust the cell density to 2×10 5 / ml.

[0451] NCI-H1975-Lux cells (constructed by Sino-US Crown Biotechnology Co., Ltd.) were cultured in RPMI 1640 + 10% FBS medium at 37°C, 5% CO2. Cells in the logarithmic growth phase were harvested and counted to ensure that cell viability was above 90%. The cell density was adjusted to 10,000 cells / 100 μl / well and plated overnight. 50 μl of PBMC suspension was added to the adherent NCI-H1975-Lux cell wells for co-culture. According to the experimental design, 0.3 μM and 0.6 μM ADC1, 10 μg / ml Keytruda-treated cells, and the corresponding control group 10 μg / ml hIgG4 isotype (isotype control) were added. The cells were cultured for 72 hours at 37°C, 5% CO2.

[0452] After incubation, the 96-well plate was placed at room temperature for 30 minutes. 50 μL of Reagent (from Promega, catalog number E2520), and the chemiluminescence value was detected after incubation for 20 minutes to obtain the ratio of each group to the luminescence value of NCI-H1975-Lux cells co-cultured with human PBMC cells without any addition.

[0453] The results are shown in Table 4. It can be seen that ADC1+Keytruda has a lower luminescence value ratio than ADC1+hIgG4 isotype, and Keytruda and hIgG4 isotype both have stronger tumor inhibitory effects, and the tumor inhibitory effect increases with increasing ADC concentration.

[0454] Table 4 In vitro test results

[0455] Example 4: In vivo activity test of antibody-drug conjugate (ADC) and anti-PD1 antibody combination

[0456] 1. Experimental Materials

[0457] Test compound: ADC1, anti-mouse PD-1 antibody (anti-mPD-1, BioXcell, BE0146), physiological saline as solvent control.

[0458] Experimental cells: B-hB7-H3 CT26.WT cells overexpressing human B7-H3 were constructed by Biocytogen (Beijing) Pharmaceutical Technology Co., Ltd.

[0459] Experimental animals: Female BALB / c mice, 6-8 weeks old, were provided by Biocytogen.

[0460] 2. Experimental Plan

[0461] Cell treatment

[0462] B-hB7-H3 CT26.WT cells were cultured in RPMI 1640 + 10% FBS at 37°C in a 5% CO2 incubator. Twice a week, cells were routinely digested and passaged using trypsin containing EDTA. Cells were washed twice with PBS, centrifuged, and resuspended in pre-chilled PBS. Counted cells using a cell counter, the cell suspension was adjusted to the appropriate concentration, and then plated.

[0463] 2.2. Tumor cell inoculation

[0464] BALB / c mice were acclimated to the laboratory environment for 3-5 days, and cells were plated at 1×10 6 Each mouse was subcutaneously inoculated with 0.1 mL PBS on the right side of the back. The average tumor volume reached about 80-120 mm. 3 The group dosing started at 14:00.

[0465] 2.3. Animal Dosing and Testing

[0466] The tumor-bearing nude mice were dosed according to the following schedule in Table 5:

[0467] Table 5. Dosage regimen

[0468] 2.4. Tumor volume and body weight determination

[0469] The day of the first administration was designated as day 0, and the administration was repeated four times in total. Tumor diameter and body weight were measured regularly. Tumor volume, relative tumor growth rate, and relative tumor inhibition rate were calculated, and a tumor growth curve was drawn. The calculation formulas were:

[0470] The formula for calculating tumor volume (V) is: V = 1 / 2 × Llong × Lshort2, where Llong and Lshort represent the long diameter and short diameter of the tumor, respectively.

[0471] Relative tumor growth inhibition rate TGI (%) = [(1-(average tumor volume of the dosing group on a certain day - average tumor volume of the dosing group at the time of dosing)) / (average tumor volume of the vehicle control group on a certain day - average tumor volume of the vehicle control group at the time of dosing)] × 100%.

[0472] Relative tumor growth rate (T / C) (%): Calculated as follows: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the vehicle control group). RTV, relative tumor volume, is calculated as RTV = Vt / V0, where V0 is the mean tumor volume measured at the time of group dosing (i.e., D0), and Vt is the mean tumor volume at a single measurement. TRTV and CRTV data are collected on the same day.

[0473] 3. Experimental Results

[0474] The test results showed that the antibody-drug conjugates of the present disclosure combined with anti-PD1 showed a relatively significant tumor inhibition effect. During the administration period, the animals in each group showed no significant weight loss or obvious drug toxicity. Specific results are shown in Table 6.

[0475] Table 6. Tumor volume data of B-hB7-H3 CT26.WT model

[0476] Example 5: Clinical trial of anti-B7H3 antibody-drug conjugates combined with immunotherapy for various advanced solid tumors

[0477] This clinical trial 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 in combination with slulizumab with or without platinum drugs in selected patients with advanced solid tumors.

[0478] The selection criteria for the subjects were:

[0479] The inclusion criteria are:

[0480] 1) Participants were informed of the trial details before the start of the trial and voluntarily signed their name and date on the Informed Consent Form (ICF).

[0481] 2) Aged ≥18 and ≤75 years old.

[0482] 3) Enrolled population (staging using the 8th edition of the Union for International Cancer Control [UICC] and American Joint Committee on Cancer [AJCC] staging systems):

[0483] Dose escalation: Patients with histologically or cytologically confirmed advanced solid tumors that have progressed on or are intolerant to standard therapy, or for whom no standard therapy is available.

[0484] Queue expansion:

[0485] Queue A:

[0486] a) Patients with metastatic (stage IVB) or recurrent NPC confirmed by histology or cytology;

[0487] b) previously received platinum-containing chemotherapy;

[0488] c) Patients were allowed to have received previous anti-PD-(L)1 treatment.

[0489] d) Disease progression or intolerance was documented during or after the last systemic treatment.

[0490] Queue B:

[0491] a) Patients with metastatic (stage IVB) or recurrent NPC confirmed by histology or cytology;

[0492] b) Patients who have not received previous systemic treatment for the current disease 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.

[0493] Queue C:

[0494] a) Histologically or cytologically confirmed extensive-stage SCLC (AJCC 8th Edition stage IV [any T, any N, M1a / b / c], or T3-4 cannot be included in a tolerable radiotherapy plan due to multiple lung nodules or the tumor / nodule volume is too large);

[0495] b) No previous systemic treatment for the current disease. Patients can be enrolled if they have previously received chemoradiotherapy with curative intent for limited-stage disease and there was a treatment-free interval of at least 6 months from the last chemoradiotherapy to the diagnosis of extensive-stage SCLC.

[0496] Queue D:

[0497] 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;

[0498] 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 genetic testing. Patients with other pathological types such as squamous cell carcinoma do not need to undergo corresponding genetic testing;

[0499] c) previously received up to two lines of systemic treatment including platinum-containing chemotherapy;

[0500] d) Patients were allowed to have received previous anti-PD-(L)1 treatment.

[0501] e) Disease progression or intolerance was documented during or after the last systemic treatment.

[0502] Queue E:

[0503] 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;

[0504] 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 genetic testing. Patients with other pathological types such as squamous cell carcinoma do not need to undergo corresponding genetic testing;

[0505] c) No previous systemic treatment for the current disease. If the patient has previously received curative treatment (not limited to surgery or adjuvant therapy), a treatment-free interval of at least 6 months is required.

[0506] Queue F:

[0507] a) Patients with advanced solid tumors confirmed by histology or cytology (except for tumor types in cohorts A–E);

[0508] b) previously received at most two lines of systemic treatment for the current disease or no standard treatment options are available;

[0509] c) Disease progression or intolerance was documented during or after the last systemic therapy.

[0510] 4) At least one measurable extracranial lesion according to RECIST v1.1. Lesions that have previously received radiotherapy or other local treatments cannot be used as target lesions unless the lesions have clearly progressed.

[0511] 5) Archived or fresh tumor tissue samples can be provided. Patients who are unable to provide tumor samples or have insufficient samples may be enrolled on a case-by-case basis after discussion with the sponsor.

[0512] 6) Eastern Cooperative Oncology Group performance status (ECOGPS) is 0 or 1.

[0513] 7) The body organ and bone marrow function meet the requirements within 7 days before the first dose, as defined below:

[0514] a) Hemoglobin (Hb) ≥ 9.0 g / dL (no blood transfusion or erythropoietin treatment within 14 days before the first dose);

[0515] b) Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L (not received granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose);

[0516] c) Platelet count (PLT) ≥100×10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose);

[0517] d) TBIL ≤ 1.5 × ULN in the absence of obvious liver metastasis, or ≤ 3 × ULN in the presence of liver metastasis;

[0518] e) ALT and AST ≤ 3 × ULN in the absence of obvious liver metastasis, or ≤ 5 × ULN in the presence of liver metastasis;

[0519] f) serum albumin ≥3.0 g / dL;

[0520] g) Creatinine clearance ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula);

[0521] h) Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for patients receiving anticoagulant therapy. These patients must have a stable anticoagulant therapy regimen, and the APTT and INR must be within the appropriate therapeutic range determined by the investigator.

[0522] 8) Female patients of childbearing potential must agree to take highly effective contraceptive measures from the time of screening throughout the study and for at least 6 months after the last dose of the study drug. Male patients must agree to take highly effective contraceptive measures from the time of screening throughout the study and for at least 6 months after the last dose of the study drug.

[0523] 9) Expected survival period ≥ 3 months.

[0524] 10) Able and willing to comply with the visits and procedures specified in the study protocol.

[0525] Exclusion criteria were:

[0526] 1) Combined SCLC.

[0527] 2) Suitable for local radical treatment.

[0528] 3) Previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs).

[0529] 4) Patients have previously received treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors.

[0530] 5) Patients have previously experienced immune-related adverse events (irAEs) of CTCAE ≥ 3 during treatment with anti-PD-(L)1 or other immune checkpoint inhibitors, immune checkpoint agonists, immune cell therapy, and other therapies targeting tumor immune mechanisms, excluding endocrine diseases such as hyperglycemia and hypothyroidism that have recovered to ≤ 2.

[0531] 6) Toxicity from previous anticancer therapy has not been alleviated, defined as toxicity that has not been alleviated to NCI CTCAE ≤ grade 1, baseline level, or the level specified in the inclusion / exclusion criteria (excluding alopecia and hyperpigmentation). Patients with chronic grade 2 toxicity who are asymptomatic or adequately controlled with stable medication may be eligible for enrollment after discussion with the sponsor.

[0532] 7) The patient is concurrently enrolled in another clinical study, unless it is an observational (non-interventional) clinical study or is in the follow-up period of an interventional study.

[0533] 8) Insufficient washout period for previous anticancer treatment before the first dose of study drug, defined as follows:

[0534] a) Chemotherapy or small molecule targeted therapy < 2 weeks or 5 half-lives, whichever is shorter

[0535] b) Antibody treatment < 3 weeks;

[0536] c) hormone treatment for <3 weeks;

[0537] d) Treatment with Chinese herbal medicine for anti-tumor indications for less than 2 weeks;

[0538] e) brain radiotherapy for <2 weeks;

[0539] f) Palliative radiotherapy < 2 weeks, radical radiotherapy < 4 weeks.

[0540] 9) Underwent major surgery (excluding diagnostic surgery) or severe trauma within 4 weeks before the first dose of study drug, or is in the recovery period and the investigator judges that it will affect the study, or is expected to undergo major surgery during the study.

[0541] 10) Previous allogeneic stem cell or solid organ transplantation.

[0542] 11) Active autoimmune disease requiring systemic treatment (i.e., use of corticosteroids or immunosuppressive drugs) within 2 years before the first dose of study drug, or autoimmune disease that the investigator judges to be likely to relapse or is planned for treatment.

[0543] 12) 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:

[0544] a) Intranasal, inhaled, topical steroids, or local steroid injections (such as intra-articular injections);

[0545] b) physiologic doses of systemic steroids as replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency);

[0546] c) Steroids as prophylaxis for hypersensitivity reactions (such as allergy to CT contrast agents) or chemotherapy-induced nausea and vomiting (CINV).

[0547] 13) Received any live vaccine within 4 weeks before the first dose of study drug, or planned to receive live vaccine during the study.

[0548] 14) Leptomeningeal metastasis or carcinomatous meningitis.

[0549] 15) Brain metastasis or spinal cord compression, excluding the following:

[0550] a) Patients with asymptomatic brain metastases who do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are allowed to enroll;

[0551] b) Patients with treated brain metastases are allowed to enroll if their metastatic disease is stable (brain imaging for at least 4 weeks before the first dose shows stable lesions, no new neurological symptoms, and no need for immediate local or systemic treatment within 2 weeks before the first dose), and there is no evidence of new or enlarged brain metastases.

[0552] 16) Suffering from uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0553] 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;

[0554] b) Received percutaneous transluminal angioplasty (PTCA) or coronary artery bypass grafting (CABG) within 6 months before the first dose;

[0555] c) uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and / or diastolic blood pressure (DBP) >100 mmHg after antihypertensive treatment;

[0556] d) severe arrhythmia requiring treatment;

[0557] e) The QT interval corrected by the Fridericia formula (QTcF) is prolonged to >450ms (male) or 470ms (female).

[0558] 17) Clinically significant pulmonary diseases, including but not limited to:

[0559] a) A history of (non-infectious) interstitial lung disease (ILD) / interstitial pneumonia requiring steroid treatment, or current ILD / interstitial pneumonia;

[0560] b) Pulmonary embolism occurred within 3 months before the first dose;

[0561] c) previous pneumonectomy;

[0562] 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.

[0563] 18) Diagnosed with Gilbert syndrome.

[0564] 19) Patients with uncontrolled third space effusion (such as pleural effusion, ascites, pericardial effusion) who require repeated drainage.

[0565] 20) 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.

[0566] 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 endotracheal stent implantation.

[0567] 22) Severe infection (NCI CTCAE ≥ Grade 3) within 4 weeks before the first dose, such as severe pneumonia, bacteremia, infectious complications requiring hospitalization, or active infection requiring systemic treatment within 2 weeks before the first dose. Patients receiving prophylactic anti-infective treatment (such as prevention of urinary tract infection or exacerbation of chronic obstructive pulmonary disease) may be eligible for enrollment after discussion with the sponsor.

[0568] 23) Known human immunodeficiency virus (HIV) infection.

[0569] 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) levels >200 IU / mL or 1000 copies / 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) levels higher than the study center's ULN.

[0570] 25) Suffering from 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.

[0571] 26) History of severe hypersensitivity reaction to the study drug, inactive ingredients in the preparation, or other monoclonal antibodies.

[0572] 27) Lactating women, or women whose pregnancy has been confirmed by a pregnancy test within 7 days before the first dose.

[0573] 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.

[0574] Treatment regimen: Subjects who met all inclusion criteria and did not meet any exclusion criteria received anti-B7H3 antibody drug conjugate (lyophilized injection 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 ) was administered intravenously, with treatment cycles of three weeks (with or without cisplatin) or two weeks (without cisplatin). Efficacy was evaluated until disease progression, unacceptable toxicity, or voluntary withdrawal. Endpoints included safety and tolerability, mean time to treatment (MTD) and progression-free death (RDE), overall response rate (ORR), daily response rate (DCR), pharmacokinetics, immunogenicity, and efficacy-related biomarkers.

[0575] Treatment effects:

[0576] In the dose-escalation phase of this clinical study, 14 patients with advanced solid tumors who had failed standard therapy were enrolled. Eight of these subjects were evaluable for efficacy, while the remaining six subjects were not evaluated for efficacy because they had not yet reached the tumor assessment window. According to RECIST v1.1, among these eight evaluable subjects, two achieved a confirmed partial response (PR) as their best efficacy assessment; two achieved a PR as their best efficacy assessment; and four achieved stable disease (SD) as their best efficacy assessment. The specific efficacy responses for these eight evaluable subjects are described in Example 6 below.

[0577] Example 6: Specific efficacy of anti-B7H3 antibody-drug conjugate combined with slulizumab in patients with various advanced solid tumors

[0578] 1. Subject 101001: A 68-year-old male patient was pathologically diagnosed with non-small cell lung cancer (NSCLC) adenocarcinoma with lymph node and brain metastases. The target lesions were located in the right lower lobe and subcarinal lymph nodes. After 18 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the right lower lobe lesion shrank from 30 mm to 11 mm, a 63.3% reduction, and the subcarinal lymph node lesion shrank from 23 mm to 11 mm, a 52.2% reduction. The overall best response assessment achieved a confirmed PR.

[0579] 2. Subject 101002: A 52-year-old male patient was pathologically diagnosed with non-small cell lung cancer (NSCLC)-squamous cell carcinoma and pleural metastasis. Target lesions were located in the left lower lobe, right hilar lymph nodes, and left hilar lymph nodes. After 18 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the left lower lobe lesion shrank from 34 mm to 28 mm, a 17.6% reduction; the right hilar lymph node shrank from 22 mm to 18 mm, a 9.1% reduction; and the left hilar lymph node shrank from 20 mm to 16 mm, a 20% reduction. The overall best response assessment achieved SD.

[0580] 3. Subject 101004, a 46-year-old male, was pathologically diagnosed with small cell lung cancer (SCLC) with lymph node and pleural metastases, pleural effusion, and pericardial effusion. The target lesions were located in the left hilar lesion, prevascular space lymph nodes, and subcarinal lymph nodes. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the left hilar lesion shrank from 93 mm to 51 mm, a 45.2% reduction; the prevascular space lymph nodes shrank from 21 mm to 8 mm, a 61.9% reduction; and the subcarinal lymph nodes shrank from 24 mm to 14 mm, a 41.7% reduction. The overall best response rate was achieved.

[0581] 4. Subject 101006: A 69-year-old male patient was pathologically diagnosed with non-small cell lung cancer (NSCLC) adenocarcinoma with lymph node, brain, and bone metastases. The target lesion was located in the left lower lobe of the lung. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the lesion in the left lower lobe shrank from 38 mm to 29 mm, a 23.7% reduction. The overall best response assessment achieved SD.

[0582] 5. Subject 111001: A 47-year-old female patient was pathologically diagnosed with nasopharyngeal carcinoma and lymph node metastasis. The target lesion was located at the left skull base. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the left skull base lesion stabilized from 45.4 mm to 45.5 mm. The overall best response assessment achieved SD.

[0583] 6. Subject 101007, a 59-year-old female, was pathologically diagnosed with small cell lung cancer (SCLC) with lymph node, brain, pleural, and peritoneal metastases. Target lesions were located in the left lower lobe, left upper lobe, and lymph nodes surrounding the celiac axis and the left gastric artery. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the left lower lobe lesion shrank from 67 mm to 35 mm, a 47.8% reduction; the left upper lobe lesion shrank from 19 mm to 8 mm, a 57.9% reduction; the lymph nodes surrounding the celiac axis shrank from 20 mm to 6 mm, a 70% reduction; and the lymph nodes surrounding the left gastric artery shrank from 19 mm to 7 mm, a 63.1% reduction. The overall best response assessment achieved a confirmed PR.

[0584] 7. Subject 102001: A 57-year-old female patient was pathologically diagnosed with small cell lung cancer (SCLC) with brain metastases and pleural effusion. The target lesions were located in the left hilum and left lower lobe. After six weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the left hilum lesion shrank from 30.1 mm to 24 mm, a 20.2% reduction, and the left lower lobe lesion shrank from 18 mm to 16 mm, an 11.1% reduction. The overall best response assessment achieved SD.

[0585] 8. Subject 108001: A 48-year-old female patient was pathologically diagnosed with nasopharyngeal carcinoma (NPC) with liver metastasis. The target lesion was located in the right liver. After six weeks of treatment with an anti-B7H3 antibody-drug conjugate combined with slulizumab, the right liver lesion shrank from 16 mm to 11 mm, a 31.2% reduction. The overall best response rate was achieved.

[0586] In summary, the combination therapy of the anti-B7H3 antibody-drug conjugate of the present invention and slulizumab has preliminarily shown certain efficacy in patients with various advanced solid tumors, and the tumor condition has gradually improved.

[0587] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention. In addition, the technical solutions of the various embodiments may be combined with each other, but this must be based on the fact that they can be implemented by a person of ordinary skill in the art. If the combination of technical solutions is mutually inconsistent or cannot be implemented, it shall be deemed that such combination of technical solutions does not exist and is not within the scope of protection claimed by the present invention.

Claims

1. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of: (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: The heavy chain variable region (VH) comprises: (i) CDR-H1, which comprises the amino acid sequence shown in SEQ ID NO: 1; (ii) CDR-H2, which comprises the amino acid sequence shown in SEQ ID NO: 2; and (iii) CDR-H3, which comprises the amino acid sequence shown in SEQ ID NO: 3; and The light chain variable region (VL) comprises: (iv) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO:4; (v) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO:5; and (vi) CDR-L3, which comprises the amino acid sequence shown in SEQ ID NO:6; The CDRs are determined by the Kabat definition scheme; and (b) other therapeutic agents selected from: one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug.

2. The method of claim 1, wherein: The heavy chain variable region comprises or is an amino acid sequence having at least 85% sequence identity to the amino acid sequence shown in SEQ ID NO:7, and the light chain variable region comprises or is an amino acid sequence having at least 85% sequence identity to the amino acid sequence shown in SEQ ID NO:8; Preferably, the heavy chain variable region comprises or is the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable region comprises or is the amino acid sequence shown in SEQ ID NO: 8; More preferably, the anti-B7H3 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO:9 or having at least 85% sequence identity with SEQ ID NO:9, and a light chain having an amino acid sequence as shown in SEQ ID NO:10 or having at least 85% sequence identity with SEQ ID NO:10; Even more preferably, the heavy chain of the anti-B7H3 antibody comprises the amino acid sequence shown in SEQ ID NO:9, and the light chain comprises the amino acid sequence shown in SEQ ID NO:

10.

3. The method according to claim 1 or 2, wherein: The anti-B7H3 antibody or its antigen-binding fragment is the antibody numbered 2E3 or 2E3-02 in WO2022170971; more preferably, the anti-B7H3 antibody is the antibody numbered 2E3-02.

4. The method according to any one of claims 1 to 3, wherein: The method comprises administering to a subject in need thereof an effective amount of: (a) an anti-B7H3 antibody-drug conjugate, wherein the anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having a structure represented by the following formula, or a pharmaceutically acceptable salt, stereoisomer, metabolite or solvate thereof: Tb-(LD)q, in: Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof; preferably, Tb is defined as the anti-B7H3 antibody or an antigen-binding fragment thereof according to any one of claims 1 to 3; L is a linker and has the following structure: The 1st bit is connected to Tb, and the 2nd bit is connected to D; D is a biologically active molecular fragment, preferably a camptothecin drug; 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 and 10; more preferably, q is 2, 4, 6 or 8; and (b) other therapeutic agents selected from: one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug.

5. The method of claim 4, wherein: The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate having a structure shown in Formula I, or a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof: Here, S is the sulfur atom on Tb.

6. The method according to any one of claims 1 to 5, wherein: The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula II, or a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof: Wherein, S is the sulfur atom on Tb; 2E3-02 is an anti-B7H3 antibody.

7. The method according to any one of claims 1 to 6, wherein: The other therapeutic agents are: i. anti-PD-1 antibody or antigen-binding fragment thereof; ii. anti-PD-1 antibody or antigen-binding fragment thereof and chemotherapeutic drug.

8. The method according to any one of claims 1 to 7, wherein: The other therapeutic agent meets one or both of the following conditions: i. The anti-PD-1 antibody or antigen-binding fragment thereof is selected from: one or more of AK103 (HX008), Treprinumab, Sintilimab, Camrelizumab, Tislelizumab, Opdivo or Nivolumab, Keytruda or Pembrolizumab, nofazinlimab, serplulimab (HLX10 or Hans), Geptanolimab, Lipustobart, BAT-1306, Finotonlimab, Rulonilimab, SG001, Zimberelimab, Spartalizumab, Cemiplimab and STI-A1110; ii. The chemotherapy drug is selected from platinum drugs; preferably, the platinum drug is selected from: one or more of cisplatin, carboplatin, cyclothioplatin, nedaplatin, oxaliplatin, lobaplatin, satraplatin, miboplatin, enloplatin, Iproplatin and dicycloplatin.

9. The method according to any one of claims 1 to 8, wherein: The anti-B7H3 antibody-drug conjugate is administered to the subject at a dose ranging from about 0.1 mg / kg to about 15 mg / kg; Preferably, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose in the following range: 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 of the subject's body weight; More preferably, the anti-B7H3 antibody-drug conjugate is administered to a subject at a dose of 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.2 mg / kg, 2.4 mg / kg, 2.6 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 4.0 mg / kg or 5.0 mg / kg of subject body weight.

10. The method according to any one of claims 1 to 9, wherein: 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 a dose of 1-10 mg / kg; Preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose in the following range: 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 or 550-650 mg; More preferably, the anti-PD-1 antibody or antigen-binding fragment thereof is administered to the subject in a uniform dose of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg or 600 mg; Even more preferably, the anti-PD-1 antibody or its antigen-binding fragment is administered to the subject at the following doses: 1.0 mg / kg, 1.2 mg / kg, 1.4 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 2.8 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, 4.5 mg / kg, 5.0 mg / kg of subject body weight.

11. The method according to any one of claims 1 to 10, wherein: The chemotherapy drug is a platinum drug, and the platinum drug is: i. Range of about 50-150 mg / m 2 Preferably, the platinum drug is administered to the subject at a dose of: 50 mg / m 2 , 70mg / m 2 , 75mg / m 2 , 80mg / m 2 , 100mg / m 2 , 120mg / m 2 or 150 mg / m 2 ; or, ii. The dose administered to the subject is calculated by the area under the curve (AUC) for each administration, and the injection rate of the administered dose is 1-10 mg / mL / min; preferably, the platinum drug is administered to the subject at the following injection rate: 3 mg / mL / min, 4 mg / mL / min, 5 mg / mL / min, 6 mg / mL / min or 7 mg / mL / min.

12. The method according to any one of claims 1 to 11, wherein: The administration cycle of the anti-B7H3 antibody-drug conjugate, anti-PD-1 antibody or antigen-binding fragment thereof, or platinum drug is 7-42 days, for example 21-42 days; Preferably: The anti-B7H3 antibody-drug conjugate is administered 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; The anti-PD-1 antibody or antigen-binding fragment thereof is administered 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; The platinum drug is administered 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.

13. The method according to any one of claims 1 to 12, wherein: The anti-B7H3 antibody-drug conjugate and other therapeutic agents are administered simultaneously, separately or sequentially.

14. The method according to any one of claims 1 to 13, wherein: The cancer is selected from solid tumors; Optionally, 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; Preferably, the cancer is selected from the group consisting of: nasopharyngeal carcinoma, non-small cell lung cancer (NSCLC) and small cell lung cancer; More preferably, the non-small cell lung cancer (NSCLC) is selected from: NSCLC squamous cell carcinoma, NSCLC adenocarcinoma, pulmonary lymphoepithelioma-like carcinoma and large cell lung cancer; 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.

15. The method of claim 14, wherein: The subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has failed previous treatment with a platinum-containing regimen; or the subject is a patient with locally recurrent or metastatic nasopharyngeal carcinoma who has not received systemic treatment.

16. The method of claim 14, wherein: The subject is a patient with small cell lung cancer who has not received systemic treatment.

17. The method of claim 14, wherein: 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 mutation, negative for anaplastic lymphoma kinase (ALK) and / or negative for c-ros oncogene (ROS1) and who has failed previous platinum-containing treatment; or the subject is a patient with locally advanced or metastatic non-small cell lung cancer who is negative for EGFR sensitive mutation, negative for ALK and / or negative for c-ros oncogene (ROS1) and has not received systemic treatment.

18. The method according to any one of claims 1 to 17, wherein: The administration route of the anti-B7H3 antibody-drug conjugate or other therapeutic agent is oral administration, transdermal administration, intravenous injection, subcutaneous injection or intramuscular injection; preferably, the administration route of the anti-B7H3 antibody-drug conjugate or other therapeutic agent is intravenous injection.

19. The method according to any one of claims 1 to 18, wherein: The subject's one or more therapeutic effects 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); Preferably, the size of a tumor derived from said 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 said anti-B7H3 antibody-drug conjugate and said anti-PD-1 antibody or antigen-binding fragment thereof.

20. A pharmaceutical composition comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents, wherein: The other therapeutic agent is selected from one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, and the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or an antigen-binding fragment thereof and the chemotherapeutic drug are as defined in any one of claims 1 to 19; preferably, the pharmaceutical composition is a pharmaceutical composition for treating cancer, and the cancer is as defined in claim 14; Optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, diluents or carriers.

21. A kit comprising an anti-B7H3 antibody-drug conjugate and other therapeutic agents, wherein: The other therapeutic agent is selected from one or both of an anti-PD-1 antibody or an antigen-binding fragment thereof and a chemotherapeutic drug, and the anti-B7H3 antibody-drug conjugate, the anti-PD-1 antibody or an antigen-binding fragment thereof and the chemotherapeutic drug are as defined in any one of claims 1 to 19; Preferably, the kit comprises kit A and kit B, wherein kit A comprises the anti-B7H3 antibody-drug conjugate as an active ingredient, and kit B comprises the other therapeutic agent as an active ingredient; and / or, the kit is a kit for treating cancer, wherein the cancer is as defined in claim 14.