Application of anti-B7H3 antibody drug conjugate in preparation of drug for treating nasopharyngeal carcinoma and / or pulmonary lymphatic epithelioid carcinoma

Abstract

The invention belongs to the technical field of medicine. Specifically, the invention relates to the anti-B7H3 antibody drug conjugate, pharmaceutically acceptable salts, stereoisomers or metabolites thereof or solvates of the salts, the stereoisomers or the metabolites thereof, and application of the anti-B7H3 antibody drug conjugate in preparation of drugs for treating nasopharyngeal carcinoma and / or pulmonary lymphatic epithelioid carcinoma.

Description

Use of anti-B7H3 antibody-drug conjugates in the preparation of drugs for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma

[0001] This application claims priority to Chinese patent application No. 202311206601.3, filed on September 19, 2023, and Chinese patent application No. 202411170320.1, filed on August 24, 2024. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present disclosure belongs to the field of pharmaceutical technology. Specifically, the present invention relates to anti-B7H3 antibody-drug conjugates as therapeutic agents for nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, and / or methods and uses of anti-B7H3 antibody-drug conjugates in preparing medicaments for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma. 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] Nasopharyngeal carcinoma (NPC) is a malignant tumor that develops on the roof and lateral walls of the nasopharynx. It ranks first in incidence among malignant tumors of the otolaryngology and nose. The World Health Organization (WHO) classifies NPC into three main pathological types: keratinizing squamous cell carcinoma, non-keratinizing carcinoma (including differentiated and undifferentiated types), and basaloid squamous cell carcinoma. Non-keratinizing carcinoma accounts for the majority of NPC cases and is closely associated with Epstein-Barr virus (EBV) infection.

[0005] Most nasopharyngeal carcinomas are sensitive to radiotherapy, so radiotherapy is the preferred treatment for early-stage nasopharyngeal carcinoma. However, due to the complex structure of the nasopharynx and the deep and hidden site of the disease, about 75% of patients have reached the advanced stage at the time of first diagnosis. For patients with a late course of disease, high degree of differentiation, and recurrence after radiotherapy, the therapeutic effect of radiotherapy is limited, and the prognosis is extremely poor. Surgical resection and chemotherapy are still the main means. At present, there is a lack of individualized specific treatment methods and drugs for chemotherapy of nasopharyngeal carcinoma. Small molecule cytotoxic drugs (such as platinum, paclitaxel, gemcitabine, 5-FU, etc.) and PD-(L)1 are the main ones, and multiple drugs need to be used in combination to be effective. However, due to the poor tolerance of patients to the above-mentioned treatment methods (caused by the high toxicity of the drugs), the treatment effect of nasopharyngeal carcinoma is poor, and the 5-year survival rate is always low. There is an urgent need to develop new therapeutic drugs.

[0006] Pulmonary lymphoepithelioma-like carcinoma (LELC) is a type of primary non-small cell lung cancer (NSCLC) and is classified as "other unclassified cancers" in the 2015 WHO classification of lung cancer. Due to a lack of prospective studies, optimal treatment options and survival outcomes remain unclear, and treatment for this disease is empirical. The most commonly used chemotherapy regimens include cisplatin or carboplatin combined with 5-fluorouracil, paclitaxel, docetaxel, or gemcitabine. These drugs all have drawbacks such as high toxicity, poor tolerability, and the development of drug resistance, necessitating the development of more therapeutic agents and approaches.

[0007] Monoclonal antibody drugs have the advantages of strong targeting, high specificity and low incidence of adverse reactions. Antibody-drug conjugates (ADCs) are representative products among them. Because ADCs combine the effectiveness of small molecule drugs with 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. They have demonstrated excellent clinical therapeutic effects and high safety for breast cancer, lung cancer and gastrointestinal cancer. However, there are no varieties for nasopharyngeal carcinoma and pulmonary lymphoepithelioma-like carcinoma, and there is a high unmet clinical need.

[0008] B7H3 is a member of the B7 family and a type I transmembrane protein. B7H3 protein is not expressed or is expressed at very low levels in normal tissues and cells, but is highly expressed in various tumor tissues and is closely associated with tumor progression, patient survival, and prognosis. It has been reported (Wang YQ, et al. Development and validation of an immune checkpoint-based signature to predict prognosis in nasopharyngeal carcinoma using computational pathology analysis. J Immunother Cancer. 2019 Nov 13; 7(1): 298.) that B7H3 is expressed in more than 79% of nasopharyngeal carcinomas. In terms of histopathological histomorphology, pulmonary lymphoepithelioma-like carcinoma is highly similar to undifferentiated nasopharyngeal carcinoma.

[0009] Summary of the Invention

[0010] In order to overcome the problems existing in the prior art, the present invention provides a use of an anti-B7H3 antibody-drug conjugate in the preparation of a medicament for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma.

[0011] Antibody Drug Conjugates

[0012] In some embodiments, the B7H3 antibody-drug conjugate is an antibody-drug conjugate of Formula III, a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof. The antibody-drug conjugate of Formula III is as follows:

[0013] Tb-[LD] q

[0014] Formula III

[0015] in:

[0016] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0017] L is a linker;

[0018] D is a bioactive molecular fragment;

[0019] q is the drug-antibody coupling ratio, selected from any value between 0.1-16.0; in a preferred embodiment, q is selected from any integer between 1-10.

[0020] In some embodiments, q is the drug-antibody coupling ratio, selected from any value between 0.1 and 16.0, inclusive.

[0021] In some embodiments, Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof, which is an antibody numbered 1D1, 1D1-01, 2E3, or 2E3-02 in WO2022170971, enoblituzumab, mirzotamab, or omburtamab, or an antigen-binding fragment thereof.

[0022] In some embodiments, the anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein:

[0023] The heavy chain variable region comprises:

[0024] (i) CDR-H1 comprising the amino acid sequence shown in SEQ ID NO: 1;

[0025] (ii) CDR-H2 comprising the amino acid sequence shown in SEQ ID NO: 2; and

[0026] (iii) CDR-H3 comprising the amino acid sequence shown in SEQ ID NO: 3; and

[0027] The light chain variable region comprises:

[0028] (i) CDR-L1 comprising the amino acid sequence shown in SEQ ID NO: 4;

[0029] (ii) CDR-L2 comprising the amino acid sequence shown in SEQ ID NO: 5; and

[0030] (iii) CDR-L3 comprising the amino acid sequence shown in SEQ ID NO: 6;

[0031] Among them, CDRs are defined according to the Kabat numbering system.

[0032] In some embodiments, the heavy chain variable region of the anti-B7H3 antibody or antigen-binding fragment thereof comprises an amino acid sequence as shown in SEQ ID NO:7, or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:8, or an amino acid sequence having at least 85% sequence identity to SEQ ID NO:8.

[0033] In some embodiments, the heavy chain variable region of the anti-B7H3 antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO:8.

[0034] 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.

[0035] In some embodiments, the heavy chain of the anti-B7H3 antibody comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:9, and the light chain comprises an amino acid sequence having at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to SEQ ID NO:10.

[0036] In some embodiments, the anti-B7H3 antibody comprises a heavy chain having an amino acid sequence as shown in SEQ ID NO:9, and a light chain having an amino acid sequence as shown in SEQ ID NO:10.

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

[0038] wherein Tb is the anti-B7H3 antibody or antigen-binding fragment thereof as described above;

[0039] S is the sulfur atom on Tb;

[0040] 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.

[0041] In some embodiments, the anti-B7H3 antibody drug conjugate is an antibody drug conjugate represented by Formula II, a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof, and the structure of Formula II is as follows:

[0042] Therapeutic uses and methods

[0043] In some embodiments, the present invention provides an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof for use in the preparation of a medicament for treating nasopharyngeal carcinoma, wherein the nasopharyngeal carcinoma includes but is not limited to keratinizing squamous cell carcinoma, non-keratinizing nasopharyngeal carcinoma, and basaloid squamous cell carcinoma.

[0044] In some embodiments, the present invention provides an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof for the preparation of a medicament for treating non-keratinizing nasopharyngeal carcinoma, wherein the non-keratinizing nasopharyngeal carcinoma includes differentiated or undifferentiated types.

[0045] In some embodiments, the present invention provides an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate thereof, for use in the preparation of a medicament for treating in situ nasopharyngeal carcinoma or invasive nasopharyngeal carcinoma. Furthermore, the invasive nasopharyngeal carcinoma includes but is not limited to squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, vesicular cell carcinoma, and undifferentiated nasopharyngeal carcinoma.

[0046] In some embodiments, the present invention provides an anti-B7H3 antibody-drug conjugate (preferably Formula II), its pharmaceutically acceptable salts, stereoisomers or metabolites, or solvates thereof for the preparation of a medicament for treating recurrent and / or advanced and / or metastatic nasopharyngeal carcinoma.

[0047] In some embodiments, a method for treating keratinizing squamous cell carcinoma of the nasopharynx is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0048] In some embodiments, a method for treating non-keratinizing nasopharyngeal carcinoma is provided, wherein the non-keratinizing nasopharyngeal carcinoma includes differentiated or undifferentiated types, the method comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0049] In some embodiments, a method for treating basaloid squamous cell carcinoma of the nasopharynx is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0050] In some embodiments, a method for treating in situ nasopharyngeal carcinoma is provided, comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0051] In some embodiments, a method for treating invasive nasopharyngeal carcinoma is provided, wherein the invasive nasopharyngeal carcinoma includes but is not limited to squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, vesicular cell carcinoma and undifferentiated nasopharyngeal carcinoma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0052] In some embodiments, a method for treating recurrent and / or advanced and / or metastatic nasopharyngeal carcinoma is provided, comprising administering to a patient a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

[0053] In some embodiments, the nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma is not surgically resectable.

[0054] In some embodiments, the patient with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has previously received chemotherapy and / or monoclonal antibody therapy and / or radiotherapy.

[0055] In some embodiments, the patient with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has previously received chemotherapy and / or monoclonal antibody therapy and / or radiotherapy, and the disease has progressed.

[0056] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received platinum-containing chemotherapy and has documented disease progression or intolerance during or after treatment.

[0057] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has been treated with at least two lines of chemotherapy (at least containing platinum) and has documented disease progression or intolerance during or after treatment.

[0058] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has received at least two lines of chemotherapy (at least one line containing platinum) and has documented disease progression or intolerance during or after treatment.

[0059] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received treatment with an anti-PD-1 drug and / or an anti-PD-L1 drug, and disease progression or intolerance is recorded during or after treatment.

[0060] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received anti-PD-1 drug treatment, and disease progression or intolerance is recorded during or after treatment.

[0061] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received anti-PD-L1 drug treatment, and disease progression or intolerance is recorded during or after treatment.

[0062] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has received at least two lines of chemotherapy (at least platinum-containing) treatment, anti-PD-1 drugs and / or anti-PD-L1 drugs, and disease progression or intolerance is recorded during or after treatment.

[0063] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received platinum-containing chemotherapy and anti-PD-1 drug treatment, and disease progression or intolerance is recorded during or after treatment.

[0064] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received platinum-containing chemotherapy and anti-PD-L1 drug treatment, and disease progression or intolerance is recorded during or after treatment.

[0065] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has received at least two lines of chemotherapy (at least platinum-containing) and anti-PD-(L)1 treatment, and disease progression or intolerance is recorded during or after treatment.

[0066] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received at least one platinum-containing chemotherapy, including but not limited to cisplatin, carboplatin, nedaplatin, carboquone and / or loxaliplatin, or a combination thereof.

[0067] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received anti-PD1 drug therapy, including: 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, STI-A1110 or one or more of the foregoing.

[0068] In some embodiments, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received anti-PDL1 drug therapy including: Durvalumab, Atezolizumab, Envafolimab, Sugemalimab, Adebrelimab, Tagitanlimab, Socazolimab, Benmelstobart, or a combination of the foregoing.

[0069] In some embodiments, the patient with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has previously received one or more of the following chemotherapy agents: gemcitabine, capecitabine, cisplatin, lobaplatin, nedaplatin, fluorouracil, paclitaxel, nab-paclitaxel, docetaxel, irinotecan, vinorelbine, cyclophosphamide, and pemetrexed.

[0070] In some embodiments, the patient with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has previously received one or more of the following chemotherapy agents: gemcitabine, capecitabine, cisplatin, lobaplatin, nedaplatin, fluorouracil, paclitaxel, nab-paclitaxel, docetaxel, vinorelbine, cyclophosphamide, and pemetrexed.

[0071] In some embodiments, the NPC patient has previously received monoclonal antibody therapy including camrelizumab, toripalimab, nivolumab, pembrolizumab, serotonin, tislelizumab, cetuximab, or bevacizumab.

[0072] In some embodiments, the treatment comprises administering to the patient a therapeutically effective amount of an anti-B7H3 antibody drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof, wherein the anti-B7H3 antibody drug conjugate (preferably Formula II) is administered at a dose of 0.1-15 mg / kg of individual body weight, preferably 0.1-10 mg / kg, 0.2-8 mg / kg, 0.3-6 mg / kg, 0.4-4 mg / kg, 0.5-3.6 mg / kg or 1-3 mg / kg, more preferably 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 10 mg / kg, 15 ... .6mg / kg, 0.8mg / kg, 1.0mg / kg, 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.2mg / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg or 5.0mg / kg.

[0073] In some embodiments, the treatment comprises administering to the patient a therapeutically effective amount of an anti-B7H3 antibody drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the anti-B7H3 antibody drug conjugate (preferably Formula II) is administered at a dose of 0.8-2.4 mg / kg of individual body weight, preferably 1.6-2.4 mg / kg or 2.0-2.4 mg / kg, more preferably 1.6 mg / kg, 2.0 mg / kg or 2.4 mg / kg.

[0074] In some embodiments, the route of administration 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. Furthermore, the route of administration is preferably intravenous injection.

[0075] Among them, the injection form includes an injection solution or a lyophilized powder, which contains an anti-B7H3 antibody drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, and an optional buffer, stabilizer, pH adjuster and / or surfactant; wherein the buffer 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 adjuster can be selected from one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide; the surfactant can be selected from one or more of polyoxyethylene hydrogenated castor oil, glycerol fatty acid ester and polyoxyethylene sorbitan fatty acid ester, preferably the polyoxyethylene sorbitan fatty acid ester is one or more of polysorbate 20, 40, 60 or 80, and most preferably polysorbate 20.

[0076] In some embodiments, the frequency of administration is once a day, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, once every five weeks, once every six weeks, or twice every two weeks, twice every three weeks, twice every four weeks, or twice a month, twice every five weeks, or twice every six weeks.

[0077] In some embodiments, the administration frequency is preferably once or twice three weeks.

[0078] In some embodiments, the administration cycle is one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months or longer, optionally, the duration of each administration cycle is the same or different, and the intervals between each administration cycle are the same or different.

[0079] In some embodiments, the present invention further measures the expression level of B7H3 in tumor tissue, or the level of soluble B7H3 in peripheral blood, or detects biomarkers associated with therapeutic efficacy, and guides drug administration by studying their correlation with the therapeutic efficacy of anti-B7H3 antibody-drug conjugates.

[0080] In another aspect, the present invention provides an anti-B7H3 antibody-drug conjugate, or a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, for use in a method for treating cancer, wherein the method for treating cancer comprises administering the anti-B7H3 antibody-drug conjugate to a subject with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma in need thereof, wherein the anti-B7H3 antibody-drug conjugate has structural formula I:

[0081] in:

[0082] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0083] S is the sulfur atom on Tb;

[0084] q is any value between 1 and 16, inclusive.

[0085] In some embodiments, the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, wherein, in the method for treating cancer, the anti-B7H3 antibody-drug conjugate is as described in any of the embodiments herein.

[0086] In another aspect, the present invention provides an anti-B7H3 antibody-drug conjugate for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, and a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, wherein the anti-B7H3 antibody-drug conjugate has structural formula I:

[0087] in:

[0088] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0089] S is the sulfur atom on Tb;

[0090] q is any value between 1 and 16, including both ends;

[0091] The nasopharyngeal carcinoma and the pulmonary lymphoepithelioma-like carcinoma are as described above.

[0092] In another aspect, the present invention provides a method for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, wherein the treatment comprises administering to a subject in need thereof an anti-B7H3 antibody drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, wherein the anti-B7H3 antibody drug conjugate has structural formula I:

[0093] in:

[0094] Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof;

[0095] S is the sulfur atom on Tb;

[0096] q is any value between 1 and 16, including both ends;

[0097] The nasopharyngeal carcinoma and the pulmonary lymphoepithelioma-like carcinoma are as described above.

[0098] In some embodiments, in the method for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, the anti-B7H3 antibody-drug conjugate is as described in any one of the embodiments herein.

[0099] In some embodiments, in the method for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, the definition, dosage, route of administration, administration cycle and frequency of nasopharyngeal carcinoma and pulmonary lymphoepithelioma-like carcinoma are as described in any of the schemes herein.

[0100] Single active ingredient

[0101] Use of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof as the sole active ingredient in the preparation of a medicament for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, or for sole administration to a medicament for nasopharyngeal carcinoma patients.

[0102] In the above uses and treatment methods, the anti-B7H3 antibody-drug conjugate (preferably Formula II), its pharmaceutically acceptable salts, stereoisomers or metabolites, or solvates thereof are used as the sole active ingredient or administered alone to nasopharyngeal carcinoma patients.

[0103] medicine box

[0104] The present invention provides a drug kit comprising (a) at least one unit dose of an anti-B7H3 antibody-drug conjugate (preferably Formula II) or a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof, and (b) instructions for use for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma. Beneficial effects

[0105] Clinical trials have found that the anti-B7H3 antibody-drug conjugate of the present invention significantly improved the objective response rate (ORR) and disease control rate (DCR) after administration to patients with nasopharyngeal carcinoma and pulmonary lymphoepithelioma-like carcinoma. It can effectively control the progression of the patient's tumor and has a significant inhibitory effect on tumor lesions. It has good clinical therapeutic significance and produced unexpected technical effects.

[0106] Detailed Description of the Invention

[0107] 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.

[0108] All documents mentioned herein are incorporated by reference in their entirety.

[0109] The native sequence B7H3 antibody herein can be isolated from nature, or prepared by recombinant DNA technology, chemical synthesis, or a combination thereof.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] The term "antibody fragment" refers to a portion of an antibody, preferably the antigen-binding region (e.g., antigen-binding fragment) or the variable region. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; and single-chain antibody molecules.

[0114] As used herein, the term "drug" refers to a substance that inhibits or interferes with the function of cells and / or causes cell death or damage.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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).

[0122] 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.

[0123] 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 scope of the disease, stabilizing (i.e., no longer worsening) the state of the disease, delaying or slowing the development of the disease, improving or alleviating the state of the disease, and alleviating symptoms (whether partially or completely), whether detectable or undetectable. In addition, "treatment" can also refer to extending survival compared to the expected survival (if not receiving treatment).

[0124] As used herein, the term "progression of disease" or "disease progression" means an increase of at least 20% in the sum of the diameters of target lesions, relative to the minimum value of the sum of the diameters of all target lesions in the entire study (including the baseline sum if it is the minimum value in the study), and an absolute increase of at least 5 mm in the sum of the diameters; or the appearance of one or more new lesions.

[0125] As used herein, the term "therapeutically effective amount" or "effective amount" refers to an amount of an anti-B7H3 antibody drug conjugate 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 antibody drug conjugate (ADC) and / or antibody or fragment thereof sufficient to cause symptom relief, such as treatment, cure, or alleviation of a related medical condition, or to increase the rate of treatment, cure, or alleviation of said condition. 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 dosage regimen that avoids significant side effects or toxic effects. A therapeutically effective amount will generally alleviate symptoms by at least 10%; typically at least 20%; at least about 30%; at least 40% or at least 50%.

[0126] As used herein, the term "subject" or "patient" refers to a mammal, including but not limited to a human, who is the target of treatment, observation, or experiment.

[0127] 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:

[0128] 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:

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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).

[0133] 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.

[0134] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] Figure 1: Shows the changes in tumor remission over treatment time in 7 patients with nasopharyngeal carcinoma.

[0136] Figure 2: Shows the optimal percentage change in the sum of target lesion diameters in 7 patients with nasopharyngeal carcinoma.

[0137] Figure 3: Shows the changes in tumor lesions in nasopharyngeal carcinoma patient 201008 before and after treatment with anti-B7H3 antibody-drug conjugate.

[0138] Figure 4 shows the changes in tumor lesions in patient 201007 with pulmonary lymphoepithelioma carcinoma before and after treatment with an anti-B7H3 antibody-drug conjugate. DETAILED DESCRIPTION

[0139] 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.

[0140] Sequence and its specific information:

[0141] Table 1

[0142] Example 1: Production of anti-B7H3 antibody drug conjugates

[0143] Referring to the production method described in patent application WO2022170971A1, a humanized B7H3 antibody was used to produce the anti-B7H3 antibody drug conjugate shown in Formula I.

[0144] Example 2: Production of anti-B7H3 antibody drug conjugate (1)

[0145] Referring to the production method described in patent application WO2023143208A1, the anti-B7H3 antibody drug conjugate shown above (hereinafter referred to as "anti-B7H3 antibody drug conjugate (1)") was produced using a humanized B7H3 antibody (2E3-02).

[0146] Example 3: Clinical trial of anti-B7H3 antibody-drug conjugates for the treatment of nasopharyngeal carcinoma

[0147] This trial is a Phase I, multicenter, non-randomized, open-label, first-in-human study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the anti-B7H3 antibody drug conjugate of the present invention in patients with nasopharyngeal carcinoma.

[0148] 1. The selection criteria for subjects are:

[0149] The inclusion criteria are:

[0150] 1) The participants were informed of the trial details before the start of the trial and voluntarily signed their names and dates on the informed consent form;

[0151] 2) Age ≥18 years;

[0152] 3) Eastern Cooperative Oncology Group performance status (ECOGPS) score of 0 or 1;

[0153] 4) Organ and bone marrow function meet the requirements, as defined below:

[0154] Hemoglobin ≥90 g / L (no blood transfusion or erythropoietin treatment within 14 days before the first dose);

[0155] Absolute neutrophil count ≥ 1.5 × 10 9 / L (not receiving granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose);

[0156] Platelet count ≥ 100 × 10 in the absence of obvious liver lesions (primary or metastatic)9 / L, or ≥75×10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose);

[0157] Total bilirubin ≤1.5×ULN in the absence of significant liver lesions (primary or metastatic), or ≤3×ULN in the presence of liver lesions;

[0158] ALT and AST ≤ 3 × ULN in the absence of significant liver lesions (primary or metastatic), or ≤ 5 × ULN in the presence of liver lesions;

[0159] Creatinine clearance ≥ 60 mL / min (calculated according to the Cockcroft-Gault formula);

[0160] Activated partial thromboplastin time and international normalized ratio ≤ 1.5 × ULN in patients not receiving anticoagulant therapy, or a stable anticoagulant regimen in patients receiving anticoagulant therapy;

[0161] 5) 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, and must not donate eggs or retrieve eggs for their own use. 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, and must not freeze or donate sperm;

[0162] 6) life expectancy ≥ 3 months;

[0163] 7) Able and willing to comply with the visits and procedures specified in the study protocol;

[0164] 8) Patients diagnosed with advanced solid tumors (including nasopharyngeal carcinoma) by pathology, for whom previous standard treatments have been proven to be ineffective or intolerable, or for whom no standard treatment is available;

[0165] 9) According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, there is at least one evaluable tumor lesion.

[0166] Exclusion criteria were:

[0167] 1) Previous treatment with B7H3 targeted drugs (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs);

[0168] 2) Previous intolerance to topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors, including but not limited to topotecan, irinotecan, and Dxd (e.g., severe diarrhea);

[0169] 3) concurrently enrolled in another clinical study, unless it is an observational (non-interventional) clinical study or in the follow-up period of an interventional study;

[0170] 4) Received systemic anticancer treatment within 3 weeks before the first dose of study drug, including chemotherapy, molecular targeted therapy, hormone therapy, immunotherapy or biological therapy (oral fluorouracil [such as tegafur and capecitabine] or small molecule targeted therapy: 2 weeks or 5 half-lives before the first dose [whichever is shorter]; mitomycin or nitrosourea: within 6 weeks before the first dose; Chinese herbal medicine with anti-tumor indications or nonspecific immunomodulators [such as thymosin, interferon and interleukin]: within 2 weeks before the first dose);

[0171] 5) Received radiotherapy within 4 weeks before the first dose of study drug, including palliative stereotactic radiotherapy of the abdomen (non-abdominal palliative stereotactic radiotherapy within 2 weeks before the first dose);

[0172] 6) Underwent major surgery (excluding diagnostic surgery) within 4 weeks before the first dose of study drug, or expected to undergo major surgery during the study;

[0173] 7) Received allogeneic hematopoietic stem cell transplantation (HSCT) before the first dose of study drug, or received autologous HSCT within 3 months before the first dose of study drug;

[0174] 8) Received systemic steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive treatment within 2 weeks before the first dose of study drug. This criterion does not apply in the following cases:

[0175] Intranasal, inhaled, topical, or local steroid injections (such as intra-articular injections);

[0176] Physiological doses of systemic steroids as replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency);

[0177] Steroids are used as prophylaxis for hypersensitivity reactions (e.g., CT scan prophylaxis);

[0178] 9) Received any live vaccine within 4 weeks before the first dose of study drug, or planned to receive live vaccine during the study;

[0179] 10) History of leptomeningeal cancer;

[0180] 11) Brain metastasis or spinal cord compression, unless asymptomatic, or symptoms are stable after treatment and no steroids or anticonvulsants are required for at least 2 weeks before the first dose of study drug;

[0181] 12) Suffering from uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0182] 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;

[0183] Uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and / or diastolic blood pressure (DBP) >100 mmHg despite antihypertensive treatment;

[0184] Serious arrhythmias requiring treatment;

[0185] A prolonged QT interval (QTcF) corrected by the Fridericia formula to >470 milliseconds;

[0186] 13) Have a history of (non-infectious) interstitial lung disease (ILD) / pulmonary inflammation requiring steroid treatment, or currently have ILD / pulmonary inflammation, or have suspected ILD / pulmonary inflammation that cannot be ruled out by imaging at screening;

[0187] 14) Clinically significant pulmonary diseases, including but not limited to:

[0188] Pulmonary embolism within 3 months before the start of study treatment;

[0189] Any autoimmune, connective tissue, or inflammatory disease (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) documented at screening, or suspected lung involvement;

[0190] Previous pneumonectomy;

[0191] 15) diagnosed with Gilbert syndrome;

[0192] 16) Patients with uncontrolled third space effusion (e.g., pleural effusion, ascites, pericardial effusion) requiring repeated drainage;

[0193] 17) Patients with active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation;

[0194] 18) Uncontrolled infection within 1 week before the first dose, requiring systemic treatment;

[0195] 19) Known human immunodeficiency virus (HIV) infection;

[0196] 20) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg), and HBV DNA level higher than the ULN of the research center; active HCV is defined as positive hepatitis C antibody and HCV RNA level higher than the ULN of the research center;

[0197] 21) The toxicity of previous anticancer treatment has not recovered, which is defined as the toxicity has not recovered to NCI CTCAE ≤ 1 level, baseline level or the level specified in the inclusion / exclusion criteria, excluding alopecia (any level), pigmentation (any level) and peripheral neuropathy (≤ 2 levels). Patients who have irreversible toxicity (such as hearing loss) that is not reasonably expected to be aggravated by the study drug can be enrolled after discussion with the sponsor;

[0198] 22) History of severe hypersensitivity reaction to the drug substance, inactive ingredients in the preparation, or other monoclonal antibodies;

[0199] 23) Lactating women, or women whose pregnancy has been confirmed by a pregnancy test within 3 days before the first dose;

[0200] 24) The researcher believes that there is any disease, medical condition, organ system dysfunction or social condition 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 mental illness or substance / alcohol abuse;

[0201] 2. Treatment plan: Subjects who meet all inclusion criteria and do not meet any exclusion criteria will receive monotherapy with anti-B7H3 antibody drug conjugate (1) (lyophilized injection prepared according to conventional methods in the art) (dosage: 0.8, 1.6, 2.0, 2.4, 2.8, or 3.0 mg / kg, intravenous drip, once every three weeks as a cycle). Efficacy will be evaluated every two dosing cycles until disease progression, intolerable toxicity, or voluntary withdrawal occurs. Endpoints of the study include safety, ORR, DCR, pharmacokinetics, and immunogenicity.

[0202] 3. Therapeutic Efficacy: The clinical study enrolled 7 patients with nasopharyngeal carcinoma who had failed standard treatment. Five patients achieved a complete response (PR) and two patients achieved sustained response (SD), with an overall ORR of 71.4% (5 / 7) and a DCR of 100% (7 / 7). See Figures 1 and 2 . Detailed efficacy is shown in Example 4. This indicates that the anti-B7H3 antibody-drug conjugate of the present invention effectively controls tumor lesions in nasopharyngeal carcinoma patients, leading to gradual improvement in their disease condition.

[0203] Example 4: Specific efficacy of anti-B7H3 antibody drug conjugates in patients with nasopharyngeal carcinoma

[0204] Patient 201008: Male, 39 years old, pathologically diagnosed with nasopharyngeal carcinoma with multiple lung metastases and cervical lymph node metastases. After 18 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the tumor lesion located in the right lower lobe of the lung shrank from 25 mm to 5 mm, a reduction of 80% (see Figure 3).

[0205] Patient 201012: Male, 28 years old, pathologically diagnosed with nasopharyngeal carcinoma with lung metastasis, cervical and parotid lymph node metastasis, and bone metastasis. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the tumor lesion in the neck shrank from 15 mm to 5 mm, a reduction of 66.7%.

[0206] Patient 201017: Male, 53 years old, pathologically diagnosed with nasopharyngeal carcinoma with multiple lung metastases, mediastinal and hilar lymph node metastases. After 6 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the tumor lesion in the right middle lobe of the lung shrank from 15 mm to 9 mm, a 40% reduction.

[0207] Patient 201018: Male, 41 years old, pathologically diagnosed with nasopharyngeal carcinoma. After left upper lobectomy, left lower lobectomy, and right parietal-occipital craniotomy, he developed lung, liver, brain, mediastinal and hilar lymph node, and bone metastases. After 12 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the tumor lesions in the liver segments S7 and S2 shrank from 44 mm to 28 mm, a decrease of 36.4%. The tumor lesions in the liver segment S2 shrank from 23 mm to 16 mm, a decrease of 30.4%.

[0208] Patient 201019: male, 56 years old, pathologically diagnosed with nasopharyngeal carcinoma, multiple lung metastases, liver metastases, kidney metastases, pleural metastases, hilar and mediastinal lymph node metastases, and bone metastases; after 12 weeks of anti-B7H3 antibody drug conjugate (1) treatment, the tumor lesions in the right middle lobe and left upper lobe shrank from 13 mm to 7 mm, a reduction of 46.2%; the tumor lesions in the left upper lobe shrank from 13 mm to 9 mm, a reduction of 30.8%.

[0209] Example 5: Clinical trial of anti-B7H3 antibody-drug conjugates for the treatment of pulmonary lymphoepithelioma-like carcinoma

[0210] This trial is a Phase I, multicenter, non-randomized, open-label, first-in-human study to evaluate the safety, tolerability, pharmacokinetics and efficacy of the anti-B7H3 antibody-drug conjugate of the present invention in patients with pulmonary lymphoepithelioma-like carcinoma.

[0211] 1. The selection criteria for subjects are:

[0212] The inclusion criteria are:

[0213] 1) The participants were informed of the trial details before the start of the trial and voluntarily signed their names and dates on the informed consent form;

[0214] 2) Age ≥18 years;

[0215] 3) Eastern Cooperative Oncology Group performance status (ECOGPS) score of 0 or 1;

[0216] 4) Organ and bone marrow function meet the requirements, as defined below:

[0217] Hemoglobin ≥90 g / L (no blood transfusion or erythropoietin treatment within 14 days before the first dose);

[0218] Absolute neutrophil count ≥ 1.5 × 10 9 / L (not receiving granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days before the first dose);

[0219] Platelet count ≥ 100 × 10 in the absence of obvious liver lesions (primary or metastatic) 9 / L, or ≥75×10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose);

[0220] Total bilirubin ≤1.5×ULN in the absence of significant liver lesions (primary or metastatic), or ≤3×ULN in the presence of liver lesions;

[0221] ALT and AST ≤ 3 × ULN in the absence of significant liver lesions (primary or metastatic), or ≤ 5 × ULN in the presence of liver lesions;

[0222] Creatinine clearance ≥ 60 mL / min (calculated according to the Cockcroft-Gault formula);

[0223] Activated partial thromboplastin time and international normalized ratio ≤ 1.5 × ULN in patients not receiving anticoagulant therapy, or a stable anticoagulant regimen in patients receiving anticoagulant therapy;

[0224] 5) 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, and must not donate eggs or retrieve eggs for their own use. 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, and must not freeze or donate sperm;

[0225] 6) life expectancy ≥ 3 months;

[0226] 7) Able and willing to comply with the visits and procedures specified in the study protocol;

[0227] 8) Patients diagnosed with advanced solid tumors by pathology, for whom previous standard treatments have been proven to be ineffective or intolerable, or for whom no standard treatment is available;

[0228] 9) According to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, there is at least one evaluable tumor lesion.

[0229] Exclusion criteria were:

[0230] 1) Previous treatment with B7H3 targeted drugs (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs);

[0231] 2) Previous intolerance to topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors, including but not limited to topotecan, irinotecan, and Dxd (e.g., severe diarrhea);

[0232] 3) concurrently enrolled in another clinical study, unless it is an observational (non-interventional) clinical study or in the follow-up period of an interventional study;

[0233] 4) Received systemic anticancer treatment within 3 weeks before the first dose of study drug, including chemotherapy, molecular targeted therapy, hormone therapy, immunotherapy or biological therapy (oral fluorouracil [such as tegafur and capecitabine] or small molecule targeted therapy: 2 weeks or 5 half-lives before the first dose [whichever is shorter]; mitomycin or nitrosourea: within 6 weeks before the first dose; Chinese herbal medicine with anti-tumor indications or nonspecific immunomodulators [such as thymosin, interferon and interleukin]: within 2 weeks before the first dose);

[0234] 5) Received radiotherapy within 4 weeks before the first dose of study drug, including palliative stereotactic radiotherapy of the abdomen (non-abdominal palliative stereotactic radiotherapy within 2 weeks before the first dose);

[0235] 6) Underwent major surgery (excluding diagnostic surgery) within 4 weeks before the first dose of study drug, or expected to undergo major surgery during the study;

[0236] 7) Received allogeneic hematopoietic stem cell transplantation (HSCT) before the first dose of study drug, or received autologous HSCT within 3 months before the first dose of study drug;

[0237] 8) Received systemic steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive treatment within 2 weeks before the first dose of study drug. This criterion does not apply in the following cases:

[0238] Intranasal, inhaled, topical, or local steroid injections (such as intra-articular injections);

[0239] Physiological doses of systemic steroids as replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency);

[0240] Steroids are used as prophylaxis for hypersensitivity reactions (e.g., CT scan prophylaxis);

[0241] 9) Received any live vaccine within 4 weeks before the first dose of study drug, or planned to receive live vaccine during the study;

[0242] 10) History of leptomeningeal cancer;

[0243] 11) Brain metastasis or spinal cord compression, unless asymptomatic, or symptoms are stable after treatment and no steroids or anticonvulsants are required for at least 2 weeks before the first dose of study drug;

[0244] 12) Suffering from uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0245] 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;

[0246] Uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and / or diastolic blood pressure (DBP) >100 mmHg despite antihypertensive treatment;

[0247] Serious arrhythmias requiring treatment;

[0248] A prolonged QT interval (QTcF) corrected by the Fridericia formula to >470 milliseconds;

[0249] 13) Have a history of (non-infectious) interstitial lung disease (ILD) / pulmonary inflammation requiring steroid treatment, or currently have ILD / pulmonary inflammation, or have suspected ILD / pulmonary inflammation that cannot be ruled out by imaging at screening;

[0250] 14) Clinically significant pulmonary diseases, including but not limited to:

[0251] Pulmonary embolism within 3 months before the start of study treatment;

[0252] Any autoimmune, connective tissue, or inflammatory disease (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) documented at screening, or suspected lung involvement;

[0253] Previous pneumonectomy;

[0254] 15) diagnosed with Gilbert syndrome;

[0255] 16) Patients with uncontrolled third space effusion (e.g., pleural effusion, ascites, pericardial effusion) requiring repeated drainage;

[0256] 17) Patients with active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation;

[0257] 18) Uncontrolled infection within 1 week before the first dose, requiring systemic treatment;

[0258] 19) Known human immunodeficiency virus (HIV) infection;

[0259] 20) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg), and HBV DNA level higher than the ULN of the research center; active HCV is defined as positive hepatitis C antibody and HCV RNA level higher than the ULN of the research center;

[0260] 21) The toxicity of previous anticancer treatment has not recovered, which is defined as the toxicity has not recovered to NCI CTCAE ≤ 1 level, baseline level or the level specified in the inclusion / exclusion criteria, excluding alopecia (any level), pigmentation (any level) and peripheral neuropathy (≤ 2 levels). Patients who have irreversible toxicity (such as hearing loss) that is not reasonably expected to be aggravated by the study drug can be enrolled after discussion with the sponsor;

[0261] 22) History of severe hypersensitivity reaction to the drug substance, inactive ingredients in the preparation, or other monoclonal antibodies;

[0262] 23) Lactating women, or women whose pregnancy has been confirmed by a pregnancy test within 3 days before the first dose;

[0263] 24) The researcher believes that there is any disease, medical condition, organ system dysfunction or social condition 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 mental illness or substance / alcohol abuse;

[0264] 2. Treatment plan: Subjects who meet all inclusion criteria and do not meet any exclusion criteria will receive monotherapy with anti-B7H3 antibody drug conjugate (1) (lyophilized injection prepared according to conventional methods in the art) (dosage: 0.8, 1.6, 2.0, 2.4, 2.8, or 3.0 mg / kg, intravenous drip, once every three weeks as a cycle). Efficacy will be evaluated every two dosing cycles until disease progression, intolerable toxicity, or voluntary withdrawal occurs. Endpoints of the study include safety, ORR, DCR, pharmacokinetics, and immunogenicity.

[0265] 3. Therapeutic Efficacy: The clinical study enrolled four patients with pulmonary lymphoepithelioma-like carcinoma who had failed standard treatment. Three patients achieved a complete response (PR) and one patient experienced sustained disease (SD), with an overall ORR of 75% (3 / 4) and a DCR of 100% (4 / 4). The specific efficacy data are shown in Example 6. It can be seen that the anti-B7H3 antibody-drug conjugate of the present invention can effectively control tumor lesions in patients with pulmonary lymphoepithelioma-like carcinoma, and the tumor condition gradually improved.

[0266] Example 6: Specific efficacy of anti-B7H3 antibody drug conjugates in patients with pulmonary lymphoepithelioma-like carcinoma

[0267] Patient 201007: Female, 64 years old, pathologically diagnosed with pulmonary lymphoepithelioma-like carcinoma with multiple lung metastases, liver metastases, and metastases to the cervical, thoracic, and abdominal lymph nodes. After 24 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the tumor lesions in the right middle lobe of the lung, neck, and liver segment S7 shrank from 23 mm to 19 mm, a decrease of 17.4%; the tumor lesion in the neck shrank from 19 mm to 12 mm, a decrease of 36.8%; and the tumor lesion in the liver segment S7 shrank from 16 mm to 8 mm, a decrease of 50% (see Figure 4).

[0268] Patient 201016: Female, 60 years old, pathologically diagnosed with pulmonary lymphoepithelioma-like carcinoma, with multiple lung metastases, liver metastases, subpleural metastases, hip metastases, cervical, thoracic, and abdominal lymph node metastases, and bone metastases. After 6 weeks of treatment with an anti-B7H3 antibody-drug conjugate (1), the cervical and subpleural tumor lesions shrank from 15 mm to 6 mm, a 60% reduction; the subpleural tumor lesions shrank from 16 mm to 15 mm, a 6.3% reduction.

[0269] Patient 201025: female, 46 years old, pathologically diagnosed with pulmonary lymphoepithelioma-like carcinoma, with multiple lung metastases, hilar metastases, pleural metastases, and mediastinal, hilar, and clavicular lymph node metastases. After 6 weeks of treatment with anti-B7H3 antibody-drug conjugate (1), the tumor lesions in the left lower lobe, left upper lobe, and clavicle shrank from 11 mm to 9 mm, a decrease of 18.2%; the tumor lesions in the left upper lobe shrank from 13 mm to 7 mm, a decrease of 46.2%; and the tumor lesions in the clavicle shrank from 15 mm to 11 mm, a decrease of 26.7%.

[0270] Example 7: Clinical trial of anti-B7H3 antibody drug conjugates for the treatment of selected advanced solid tumors

[0271] This study is a multicenter, open-label, Phase I / II study of an anti-B7H3 antibody-drug conjugate to evaluate the safety, efficacy, and PK characteristics of the anti-B7H3 antibody-drug conjugate in selected patients with advanced solid tumors:

[0272] 1. Selection Criteria

[0273] Subjects must meet all of the following criteria to be included in the study:

[0274] 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).

[0275] 2) The applicant must be ≥18 years old and ≤75 years old when signing the ICF.

[0276] 3) Subjects enrolled in the NPC cohort must meet the following conditions:

[0277] NPC confirmed by histology or cytology;

[0278] Patients with metastatic (stage IVB, using the 8th edition UICC and AJCC staging system) or recurrent disease who are not suitable for local or curative therapy at the time of enrollment;

[0279] For metastatic or recurrent disease, patients have received at least one prior platinum-containing chemotherapy and anti-PD-(L)1 therapy, and have documented disease progression or intolerance during or after treatment.

[0280] Subjects enrolled in other solid tumor cohorts must meet the following conditions:

[0281] · Patients with advanced solid tumors confirmed by histology or cytology;

[0282] · Documented disease progression or intolerance during or after previous standard treatment, or no standard treatment options are available.

[0283] Note: For all cohorts listed above, if the subject had disease progression during or within 6 months of completing neoadjuvant, adjuvant, or definitive chemoradiotherapy, that treatment regimen was considered first-line treatment for advanced / metastatic disease.

[0284] 4) At least one measurable extracranial lesion according to RECIST v1.1. Lesions previously treated with radiotherapy or other local therapies are not eligible as target lesions unless they have clearly progressed. Patients with mCRPC with only bone lesions may be enrolled on a case-by-case basis after discussion with the sponsor.

[0285] 5) Archival or fresh tumor tissue samples can be provided. Subjects who are unable to provide tumor samples or whose samples are insufficient may be enrolled based on their specific circumstances after discussion with the sponsor.

[0286] 6) Eastern Cooperative Oncology Group performance status (ECOGPS) score is 0 or 1.

[0287] 7) The body organ and bone marrow function meet the requirements within 7 days before the first dose, as defined below:

[0288] Hemoglobin (Hb) ≥9.0 g / dL (no blood transfusion or erythropoietin treatment within 14 days before the first dose);

[0289] 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);

[0290] Platelet count (PLT) ≥100 × 10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment within 14 days before the first dose);

[0291] Total bilirubin (TBIL) ≤ 1.5 × upper limit of normal (ULN) in the absence of overt liver metastases or ≤ 3 × ULN in the presence of liver metastases;

[0292] Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN in the absence of overt liver metastases, or ≤ 5 × ULN in the presence of liver metastases;

[0293] Serum albumin ≥2.5 g / dL (≥2.5 g / dL)

[0294] Creatinine clearance ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula);

[0295] Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for subjects receiving anticoagulant therapy. These subjects must have a stable anticoagulant regimen, and the APTT and INR must be within the appropriate therapeutic range as determined by the investigator.

[0296] 8) Female subjects 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 trial drug. Male subjects 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 trial drug.

[0297] 9) Expected survival period ≥ 3 months.

[0298] 10) Able and willing to comply with the visits and procedures specified in the study protocol.

[0299] II. Exclusion criteria

[0300] Subjects who meet any of the following criteria are not eligible for inclusion in the study:

[0301] 1) Previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs);

[0302] 2) Previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors;

[0303] 3) Enrolled in another clinical study at the same time, unless it is an observational (non-interventional) clinical study or in the follow-up period of an interventional study.

[0304] 4) Insufficient washout period for previous anticancer therapy before the first dose of the investigational drug, defined as follows:

[0305] Chemotherapy or small molecule targeted therapy < 2 weeks or 5 half-lives, whichever is shorter

[0306] Antibody treatment for < 3 weeks;

[0307] Hormone therapy for < 3 weeks;

[0308] Treatment with Chinese herbal medicine for anti-tumor indications for less than 2 weeks;

[0309] Brain radiation therapy for less than 2 weeks;

[0310] Palliative radiotherapy: < 2 weeks; radical radiotherapy: < 4 weeks.

[0311] 5) Underwent major surgery (excluding diagnostic surgery) within 4 weeks before the first dose of the trial drug, or is expected to undergo major surgery during the study.

[0312] 6) Previously received allogeneic bone marrow transplantation or solid organ transplantation.

[0313] 7) Received systemic steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive treatment within 2 weeks before the first dose of the trial drug, except for the following cases:

[0314] Intranasal, inhaled, topical, or local steroid injections (such as intra-articular injections);

[0315] Physiological doses of systemic steroids as replacement therapy (e.g., physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency);

[0316] Steroids as prophylaxis for hypersensitivity reactions (e.g., allergy to CT contrast agents) or chemotherapy-induced nausea and vomiting (CINV).

[0317] 8) Received any live vaccine within 4 weeks before the first dose of the trial drug, or planned to receive a live vaccine during the study.

[0318] 9) Leptomeningeal metastasis or carcinomatous meningitis.

[0319] 10) Brain metastasis or spinal cord compression, excluding the following:

[0320] Subjects with asymptomatic brain metastases who do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are allowed to enroll;

[0321] Enrollment is permitted if the patient's brain metastases have been treated and are stable (brain imaging for at least 4 weeks prior to the first dose shows stable lesions, no new neurological symptoms, and no need for immediate local or systemic treatment within 2 weeks prior to the first dose), with no evidence of new or enlarged brain metastases.

[0322] 11) Suffering from uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0323] A history of symptomatic congestive heart failure (New York Heart Association [NYHA] class II to IV) or any arterial thromboembolic event (e.g., myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months prior to the first dose.

[0324] Uncontrolled hypertension, defined as systolic blood pressure (SBP) >160 mmHg and / or diastolic blood pressure (DBP) >100 mmHg despite antihypertensive treatment;

[0325] Serious arrhythmias requiring treatment;

[0326] The QT interval corrected by the Fridericia formula (QTcF) is prolonged to >450 ms (males) or 470 ms (females).

[0327] 12) Clinically significant pulmonary diseases, including but not limited to:

[0328] A history of (non-infectious) interstitial lung disease (ILD) / interstitial pneumonitis requiring steroid treatment, or current ILD / interstitial pneumonitis;

[0329] Pulmonary embolism within 3 months before the first dose;

[0330] Any autoimmune, connective tissue, or inflammatory disease (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) documented at screening, or suspected lung involvement;

[0331] Previous pneumonectomy;

[0332] Other moderate to severe lung diseases that may interfere with the detection or treatment of drug-related pulmonary toxicity and seriously affect respiratory function.

[0333] 13) Diagnosed with Gilbert syndrome.

[0334] 14) Patients with uncontrolled third space effusion (such as pleural effusion, ascites, pericardial effusion) who require repeated drainage.

[0335] 15) 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.

[0336] 16) Severe infection (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] ≥ Grade 3) within 4 weeks prior to the first dose, such as severe pneumonia, bacteremia, infectious complications requiring hospitalization, or active infection requiring systemic treatment within 2 weeks prior to the first dose. Subjects receiving prophylactic anti-infective therapy (such as prevention of urinary tract infection or exacerbation of chronic obstructive pulmonary disease) may be eligible for enrollment after discussion with the sponsor.

[0337] 17) Known human immunodeficiency virus (HIV) infection.

[0338] 18) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive hepatitis B core antibody (HBcAb) 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.

[0339] 19) Suffering from any other primary malignant tumor within 3 years before the first dose of the investigational drug, except for adequately resected non-melanoma skin cancer, cured in situ disease, or other cured solid tumors.

[0340] 20) Toxicity from previous anticancer therapy has not been alleviated, defined as toxicity that has not been alleviated to NCI CTCAE ≤ Grade 1 (excluding alopecia and hyperpigmentation) or the level specified in the inclusion / exclusion criteria. Subjects with chronic Grade 2 toxicity who are asymptomatic or adequately controlled with stable medication may be eligible for enrollment after discussion with the sponsor.

[0341] 21) History of severe hypersensitivity reaction to the API, inactive ingredients in the preparation, or other monoclonal antibodies.

[0342] 22) Lactating women, or women whose pregnancy has been confirmed by a pregnancy test within 3 days before the first dose.

[0343] 23) The presence of any disease, medical condition, organ system dysfunction, or social condition, including but not limited to mental illness or substance / alcohol abuse, that the researcher believes may interfere with the subject's ability to sign informed consent, adversely affect the subject's ability to cooperate and participate in the study, or affect the interpretation of the study results.

[0344] 3. Dosage Regimen

[0345] Subjects who met all inclusion criteria and did not meet any of the exclusion criteria received monotherapy with anti-B7H3 antibody drug conjugate (1) (lyophilized injection prepared according to conventional methods in the art) (dose 2.0 or 2.4 mg / kg, intravenous drip, once every three weeks as a cycle). Efficacy evaluation was performed every 6 weeks for the first 24 weeks and every 9 weeks thereafter until disease progression, intolerable toxicity, or voluntary withdrawal occurred. Endpoints of the study included safety, ORR, DCR, pharmacokinetics, immunogenicity, etc.

[0346] 4. Treatment Effect

[0347] The clinical study enrolled 90 subjects, including 68 with nasopharyngeal carcinoma (NPC) and 22 with lymphoepithelioma-like carcinoma (LELC). Among the 63 evaluable NPC subjects, 60 observed varying degrees of tumor shrinkage, 32 of whom achieved an objective response, with an objective response rate (ORR) of 50.8% and a progression-free response rate (DCR) of 95.2%. Among the 19 evaluable LELC subjects, 17 observed varying degrees of tumor shrinkage, 9 of whom achieved an objective response, with an objective response rate (ORR) of 47.4% and a progression-free response rate (DCR) of 89.5%.

[0348] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. Use of an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate thereof in the preparation of a medicament for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma, wherein the anti-B7H3 antibody-drug conjugate has a structure of the following formula I: in: Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof; S is the sulfur atom on Tb; q is the drug-antibody coupling ratio, which can be selected from any value between 0.1 and 16.

0.

2. The use according to claim 1, characterized in that The anti-B7H3 antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises CDR-H1, CDR-H2 and CDR-H3 with amino acid sequences as shown in SEQ ID NOs: 1-3, respectively; and the light chain variable region comprises CDR-L1, CDR-L2 and CDR-L3 with amino acid sequences as shown in SEQ ID NOs: 4-6, respectively; wherein CDRs are defined according to the Kabat numbering system; Preferably, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:7, or having at least 85% sequence identity with SEQ ID NO:7, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO:8, or having at least 85% sequence identity with SEQ ID NO:8; More preferably, the anti-B7H3 antibody comprises a heavy chain and a light chain, wherein: The heavy chain has an amino acid sequence as shown in SEQ ID NO:9, or having at least 85% sequence identity to SEQ ID NO:9, and the light chain has an amino acid sequence as shown in SEQ ID NO:10, or having at least 85% sequence identity to SEQ ID NO:

10.

3. The use according to claim 1, characterized in that The q is selected from any value between 1-10; preferably, q is 1, 2, 3, 4, 5, 6, 7 or 8; more preferably, q is 2, 4, 6 or 8.

4. The use according to claim 1, characterized in that The anti-B7H3 antibody-drug conjugate is an antibody-drug conjugate of formula II, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing.

5. The use according to any one of claims 1 to 4, characterized in that The nasopharyngeal carcinoma is keratinizing squamous cell carcinoma.

6. The use according to any one of claims 1 to 4, characterized in that The nasopharyngeal carcinoma is non-keratinizing nasopharyngeal carcinoma, including differentiated type and undifferentiated type.

7. The use according to any one of claims 1 to 4, characterized in that The nasopharyngeal carcinoma is basaloid squamous cell carcinoma.

8. The use according to any one of claims 1 to 4, characterized in that The nasopharyngeal carcinoma is nasopharyngeal carcinoma in situ or invasive nasopharyngeal carcinoma, and the invasive nasopharyngeal carcinoma is preferably selected from squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, vesicular cell carcinoma and undifferentiated nasopharyngeal carcinoma.

9. The use according to any one of claims 1 to 4, characterized in that The nasopharyngeal carcinoma is recurrent and / or advanced and / or metastatic nasopharyngeal carcinoma.

10. The use according to any one of claims 1 to 4, characterized in that: The nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma cannot be surgically removed; or the patient with the nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has previously received chemotherapy and / or monoclonal antibody therapy and / or radiotherapy; or the patient with the nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma has had disease progression after previously receiving chemotherapy and / or monoclonal antibody therapy and / or radiotherapy.

11. The use according to claim 9, characterized in that The patients with metastatic or recurrent NPC are those who have received platinum-containing chemotherapy in the past and have documented disease progression or intolerance during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma has received at least two lines of chemotherapy (at least platinum-containing) in the past, and disease progression or intolerance has been recorded during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma has received at least two lines of chemotherapy (at least one line containing platinum) in the past, and disease progression or intolerance is recorded during or after treatment.

12. The use according to claim 9, characterized in that The patients with metastatic or recurrent nasopharyngeal carcinoma are those who have previously received anti-PD-1 drugs and / or anti-PD-L1 drugs and have documented disease progression or intolerance during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma is a patient who has previously received anti-PD-1 drug treatment and has disease progression or intolerance recorded during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received anti-PD-L1 drug treatment and has recorded disease progression or intolerance during or after treatment.

13. The use according to claim 9, characterized in that The patients with metastatic or recurrent nasopharyngeal carcinoma are those who have previously received at least platinum-containing chemotherapy, anti-PD-1 drugs and / or anti-PD-L1 drugs, and have recorded disease progression or intolerance during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma is a patient who has previously received platinum-containing chemotherapy and anti-PD-1 drug treatment, and has disease progression or intolerance recorded during or after treatment; Preferably, the patient with metastatic or recurrent nasopharyngeal carcinoma has previously received platinum-containing chemotherapy and anti-PD-L1 drug treatment, and disease progression or intolerance is recorded during or after treatment.

14. The use according to any one of claims 1 to 13, characterized in that The patients with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma have previously received one or more of the following chemotherapy agents, including gemcitabine, capecitabine, cisplatin, lobaplatin, nedaplatin, fluorouracil, paclitaxel, albumin-paclitaxel, docetaxel, vinorelbine, cyclophosphamide, and pemetrexed.

15. The use according to any one of claims 1 to 14, characterized in that: The patients with NPC have previously received monoclonal antibody treatments, including carrelizumab, toripalizumab, nivolumab, pembrolizumab, slulizumab, tislelizumab, cetuximab or bevacizumab.

16. The use according to any one of claims 1 to 14, characterized in that The treatment comprises administering to the patient a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the effective amount is administered at a dose of 0.1-15 mg / kg of individual body weight, preferably 0.1-10 mg / kg, 0.2-8 mg / kg, 0.3-6 mg / kg, 0.4-4 mg / kg, 0.5-3.6 mg / kg or 1-3 mg / kg, more preferably 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.8 mg / kg. g / kg, 1.0mg / kg, 1.2mg / kg, 1.4mg / kg, 1.6mg / kg, 1.8mg / kg, 2.0mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / kg, 3.0mg / kg, 3.2mg / kg, 3.4mg / kg, 3.6mg / kg, 3.8mg / kg, 4.0mg / kg or 5.0mg / kg.

17. The use according to any one of claims 1 to 14, characterized in that The treatment comprises administering to the patient a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the administration routes include oral administration, parenteral administration, and transdermal administration, wherein the parenteral administration is preferably intravenous injection, subcutaneous injection or intramuscular injection.

18. The use according to claim 17, characterized in that The administration route is intravenous injection; wherein the injection form is an injection solution or a lyophilized powder, which comprises an anti-B7H3 antibody drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof or a solvate of the foregoing, and optional buffers, stabilizers, pH regulators and / or surfactants; wherein the buffer may be selected from one or more of acetate, citrate, succinate, and phosphate; the stabilizer may be selected from sugars or amino acids, preferably disaccharides, such as sucrose, lactose, trehalose or maltose; the pH regulator may be selected from one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide; the surfactant may be selected from one or more of polyoxyethylene hydrogenated castor oil, glycerol fatty acid esters and polyoxyethylene sorbitan fatty acid esters; the polyoxyethylene sorbitan fatty acid esters are preferably one or more of polysorbate 20, 40, 60 or 80, and most preferably polysorbate 20.

19. The use according to any one of claims 1 to 14, characterized in that: The treatment comprises administering to the patient a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing, wherein the treatment comprises one or two of the following features: 1) The frequency of administration is once a day, once a week, once every two weeks, once every three weeks, once every four weeks, or once a month, once every five weeks, once every six weeks, or twice in two weeks, twice in three weeks, twice in four weeks, or twice in a month, twice in five weeks, or twice in six weeks; preferably, once in three weeks or once in three weeks. Twice a week; 2) The dosing cycle is one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months or longer, optionally, the duration of each dosing cycle is the same or different, and the intervals between each dosing cycle are the same or different.

20. The use according to any one of claims 1 to 16, characterized in that: The anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer or metabolite or the solvate of the foregoing is used as the sole active ingredient.

21. An anti-B7H3 antibody-drug conjugate for use in a method for treating cancer, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, wherein: The method for treating cancer is to administer an anti-B7H3 antibody-drug conjugate to a subject with nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma in need thereof, wherein the anti-B7H3 antibody-drug conjugate has a structural formula I: in: Tb is an anti-B7H3 antibody or an antigen-binding fragment thereof; S is the sulfur atom on Tb; q is any value between 1 and 16, including both ends; Preferably, the anti-B7H3 antibody-drug conjugate is as described in any one of claims 1-4.

22. A drug kit comprising (a) at least one unit dose of an anti-B7H3 antibody drug conjugate, a pharmaceutically acceptable salt, stereoisomer or metabolite thereof, or a solvate of the foregoing and (b) instructions for use for treating nasopharyngeal carcinoma and / or pulmonary lymphoepithelioma-like carcinoma; The anti-B7H3 antibody-drug conjugate is as described in any one of claims 1 to 4, preferably in Formula II.

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