KR-20260068098-A - Use of anti-B7H3 antibody-drug conjugates in the manufacture of drugs for treating nasopharyngeal carcinoma and/or lymphoepithelial carcinoma

Abstract

The present invention falls within the field of pharmaceutical technology. Specifically, the present invention relates to an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate of any of the aforementioned items, and the use thereof in the manufacture of a drug for treating nasopharyngeal carcinoma and/or lymphoepithelial carcinoma.

Inventors

• 쉬에 통통
• 장 리
• 장 시안
• 친 스티브
• 차이 지아치앙

Assignees

• 메디링크 테라퓨틱스 (쑤저우) 컴퍼니, 리미티드

Dates

Publication Date

20260513

Application Date

20240919

Priority Date

20230919

Claims (20)

1. For use of an anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, or metabolite, or a solvate of any of the aforementioned items in the manufacture of a drug for treating nasopharyngeal carcinoma and/or lymphoepithelial carcinoma, said anti-B7H3 antibody-drug conjugate has the structure of the following formula I: Chemical Formula I Here: Tb is an anti-B7H3 antibody or its antigen-binding fragment; S is a sulfur atom in Tb; q is the drug-antibody conjugate ratio, and is selected from any numerical value between 0.1 and 16.0.
2. In claim 1, the anti-B7H3 antibody or the antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region; said heavy chain variable region comprises the amino acid sequences CDR-H1, CDR-H2, and CDR-H3 described respectively in SEQ ID NOs: 1-3; said light chain variable region comprises the amino acid sequences CDR-L1, CDR-L2, and CDR-L3 described respectively in SEQ ID NOs: 4-6, wherein CDR is defined according to the Kabat numbering system; Preferably, the heavy chain variable region comprises an amino acid sequence described 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 described 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, and Use in which the heavy chain has an amino acid sequence described in SEQ ID NO: 9 or having at least 85% sequence identity with SEQ ID NO: 9, and the light chain has an amino acid sequence described in SEQ ID NO: 10 or having at least 85% sequence identity with SEQ ID NO: 10.
3. The use according to claim 1, wherein q is selected from any numeric value between 1 and 10; preferably q is 1, 2, 3, 4, 5, 6, 7 or 8; more preferably q is 2, 4, 6 or 8.
4. In claim 1, 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 any of the aforementioned items: Chemical formula II.
5. In any one of paragraphs 1 to 4, the nasopharyngeal carcinoma is a keratinized squamous cell carcinoma.
6. In any one of paragraphs 1 to 4, the use is that the nasopharyngeal carcinoma is a non-keratinized nasopharyngeal carcinoma including differentiated and undifferentiated types.
7. In any one of paragraphs 1 to 4, the nasopharyngeal carcinoma is a basal cell-like squamous cell carcinoma.
8. A use according to any one of claims 1 to 4, wherein the nasopharyngeal carcinoma is an intraepithelial nasopharyngeal carcinoma or an infiltrative nasopharyngeal carcinoma, and the infiltrative nasopharyngeal carcinoma is preferably selected from squamous cell carcinoma, adenocarcinoma, microinvasive carcinoma, follicular cell carcinoma, and undifferentiated nasopharyngeal carcinoma.
9. In any one of paragraphs 1 to 4, the use is in which the nasopharyngeal carcinoma is a recurrent and/or progressive and/or metastatic nasopharyngeal carcinoma.
10. Use according to any one of claims 1 to 4, wherein the nasopharyngeal carcinoma and/or lymphoepithelial carcinoma is surgically unresectable; or the patient having the nasopharyngeal carcinoma and/or lymphoepithelial carcinoma has previously received chemotherapy and/or monoclonal antibody therapy and/or radiation therapy; or the patient having the nasopharyngeal carcinoma and/or lymphoepithelial carcinoma has disease progression after previously receiving chemotherapy and/or monoclonal antibody therapy and/or radiation therapy.
11. In paragraph 9, a patient with metastatic or recurrent nasopharyngeal carcinoma means a patient who has previously received platinum-containing chemotherapy and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, a patient with metastatic or recurrent nasopharyngeal carcinoma means a patient who has previously received at least second-line (at least platinum-containing) chemotherapy and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, the use refers to a patient with metastatic or recurrent nasopharyngeal carcinoma who has previously received at least two-line (at least one-line platinum-containing) chemotherapy and in whom disease progression or intolerance has been recorded during or after treatment.
12. In paragraph 9, a patient with metastatic or recurrent nasopharyngeal carcinoma means a patient who has previously received anti-PD-1 and/or anti-PD-L1 drug treatment and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, a patient with metastatic or recurrent nasopharyngeal carcinoma refers to a patient who has previously received anti-PD-1 drug therapy and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, the use refers to a patient with metastatic or recurrent nasopharyngeal carcinoma who has previously received anti-PD-L1 drug therapy and has recorded disease progression or intolerance during or after treatment.
13. In paragraph 9, a patient with metastatic or recurrent nasopharyngeal carcinoma means a patient who has previously received at least platinum-containing chemotherapy, anti-PD-1 drugs and/or anti-PD-L1 drugs and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, a patient with metastatic or recurrent nasopharyngeal carcinoma refers to a patient who has previously received platinum-containing chemotherapy and anti-PD-1 drug therapy and in whom disease progression or intolerance has been recorded during or after treatment; Preferably, the use refers to a patient with metastatic or recurrent nasopharyngeal carcinoma who has previously received platinum-containing chemotherapy and anti-PD-L1 drug therapy and has recorded disease progression or intolerance during or after treatment.
14. Use according to any one of claims 1 to 13, wherein the patient having nasopharyngeal carcinoma and/or lymphoepithelial carcinoma has previously received one or more of the chemotherapy agents including gemcitabine, capecitabine, cisplatin, lovaplatin, nedaplatin, fluorouracil, paclitaxel, albumin-bound paclitaxel, docetaxel, vinorelbine, cyclophosphamide, and pemetrexid.
15. In any one of claims 1 to 14, the use is for a patient with nasopharyngeal carcinoma who has previously received a monoclonal antibody therapeutic including camrelizumab, treprinumab, nivolumab, pembrolizumab, cerflurimab, tislellizumab, cetuximab, or bevacizumab.
16. In any one of claims 1 to 14, the treatment comprises 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 any of the aforementioned items, said effective amount administered at a dose of 0.1 to 15 mg per kg of body weight of the individual, said dose preferably 0.1 to 10 mg/kg, 0.2 to 8 mg/kg, 0.3 to 6 mg/kg, 0.4 to 4 mg/kg, 0.5 to 3.6 mg/kg, or 1 to 3 mg/kg, more preferably 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.8 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, For use at 2.1 mg/kg, 2.2 mg/kg, 2.3 mg/kg, 2.4 mg/kg, 2.5 mg/kg, 2.6 mg/kg, 2.7 mg/kg, 2.8 mg/kg, 2.9 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, or 5.0 mg/kg.
17. In any one of claims 1 to 14, the treatment comprises 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 any of the aforementioned items, wherein the route of administration includes oral administration, parenteral administration, and transdermal administration; and the parenteral administration is preferably intravenous injection, subcutaneous injection, or intramuscular injection.
18. In claim 17, the route of administration is intravenous injection, and the injection form is an injection solution or lyophilized powder, containing an anti-B7H3 antibody-drug conjugate (preferably Formula II), a pharmaceutically acceptable salt, stereoisomer, or metabolite thereof, or a solvate of any one of the aforementioned items, and optionally a buffer, a stabilizer, a pH adjuster, and/or a surfactant, wherein the buffer may be selected from one or more of acetates, citrates, succinates, and phosphates; the stabilizer may be selected from sugars or amino acids, preferably disaccharides such as sucrose, lactose, trehalose, or maltose; the pH adjuster may be selected from one or more of sodium hydroxide, lithium hydroxide, and potassium hydroxide; and 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 above polyoxyethylene sorbitan fatty acid ester is preferably one or more of polysorbate 20, 40, 60, or 80, and most preferably polysorbate 20.
19. In any one of claims 1 to 14, the treatment comprises 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 any one of the aforementioned items, wherein the treatment comprises one or both of the following features: 1) The frequency of administration is once a day, once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, or once a month, once every 5 weeks, once every 6 weeks, or twice every 2 weeks, twice every 3 weeks, twice every 4 weeks, or twice a month, twice every 5 weeks, or twice every 6 weeks; preferably once every 3 weeks or twice every 3 weeks; 2) The dosing cycle is 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months or longer; optionally, the duration of each dosing cycle is the same or different, and the interval between each dosing cycle is the same or different.
20. An use in which, in any one of claims 1 to 16, the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, or metabolite, or a solvate of any of the aforementioned items is used as the sole active ingredient.

Description

Use of anti-B7H3 antibody-drug conjugates in the manufacture of drugs for treating nasopharyngeal carcinoma and/or lymphoepithelial carcinoma 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 by reference the entire contents of the said Chinese patent applications. Technology field The present invention falls within the field of pharmaceutical technology. More specifically, the present invention relates to an anti-B7H3 antibody-drug conjugate therapeutic agent for the treatment of nasopharyngeal carcinoma and/or lymphoepithelial carcinoma, and/or a method and use of an anti-B7H3 antibody-drug conjugate in the manufacture of a drug for treating nasopharyngeal carcinoma and/or lymphoepithelial carcinoma. Background Technology Malignant tumors have emerged as a global public health issue, and nearly 10 million people died from the disease in 2020. The number of cancer patients and deaths caused by cancer worldwide continues to rise, and consequently, the overall market size for cancer treatment is steadily expanding, leading to a continuous increase in demand for new therapeutic drugs and treatment methods. Nasopharyngeal carcinoma (NPC) is a malignant tumor that arises from the normal and lateral walls of the pharyngeal nasal cavity and has the highest incidence among malignancies in the otolaryngology. The World Health Organization (WHO) classifies nasopharyngeal carcinoma into three major pathological subtypes: keratinizing squamous cell carcinoma, non-keratinizing carcinoma (including differentiated and undifferentiated types), and basal cell-like squamous cell carcinoma. Non-keratinizing carcinoma accounts for the majority of nasopharyngeal carcinomas and is closely associated with Epstein-Barr virus (EBV) infection. Since most nasopharyngeal carcinomas are sensitive to radiation therapy, it is the preferred treatment method for early-stage nasopharyngeal carcinomas. However, due to the complex anatomical structure of the nasopharynx and the presence of deep, hidden pathogenic sites, approximately 75% of patients are already in an advanced stage at the time of initial diagnosis. Furthermore, for patients with a late disease course, high differentiation, or recurrence after radiation therapy, the therapeutic effect of radiation therapy is limited and the prognosis is very poor; consequently, surgical resection and chemotherapy remain the most important treatment options. Currently, chemotherapy for nasopharyngeal carcinoma lacks individualized specific treatment methods and drugs. It primarily utilizes small molecule cytotoxic agents (e.g., platinum, paclitaxel, gemcitabine, 5-FU, etc.) and PD-(L)1 inhibitors, requiring the combination of multiple drugs to achieve efficacy. However, due to poor patient tolerance to the aforementioned treatments (caused by high drug toxicity), the therapeutic effect for nasopharyngeal carcinoma remains insufficient, and the 5-year survival rate is still low. Therefore, the development of new therapeutic drugs is urgently required. Lymphoepithelial carcinoma (LELC) belongs to the category of primary non-small cell lung cancer (NSCLC) and is classified as other unclassified carcinomas in the 2015 version of the WHO Histological Classification of Lung Cancer. Due to a lack of prospective studies, optimal treatment regimens and survival outcomes remain unclear, and the treatment of this disease relies primarily on experience. The most commonly used chemotherapy regimens include combination therapy with cisplatin or carboplatin, 5-fluorouracil, paclitaxel, docetaxel, or gemcitabine. However, all of the aforementioned drugs have disadvantages such as high toxicity, poor tolerability, and a tendency toward drug resistance, thus requiring the development of more effective therapeutic drugs and treatment methods. Monoclonal antibody drugs possess advantages such as potent targeting ability, high specificity, and a low incidence of side effects, and antibody-drug conjugates (ADCs) are representative products of these antibody drugs. ADCs combine the efficacy of small molecule drugs with the targeting ability of antibody drugs, enabling improved therapeutic effects while reducing the toxicity and side effects of cytotoxic agents. Currently, 15 ADC drugs have received marketing approval worldwide for breast, lung, and gastrointestinal cancers, demonstrating excellent clinical efficacy and high safety; however, there is a high clinical demand for such drugs for nasopharyngeal carcinoma and lymphoepithelial carcinoma due to the lack of such agents. B7H3 is a member of the B7 family and belongs to the type 1 transmembrane proteins. While B7H3 protein is not expressed or is expressed at very low levels in normal tissues and cells, it is expressed at high levels in various tumor tissues and is closely associated with tumor pro