TW202438107A - Use of drugs targeting trop2 in combination with anti trop2 antibodies for the treatment of cancer - Google Patents

Abstract

The disclosure relates to the use of drugs targeting TROP2 in combination with anti TROP2 antibodies for the treatment of cancer. Specifically, the disclosure relates to the use of anti TROP2 antibodies in the preparation of drugs for preventing, reducing, or eliminating adverse reactions caused by drugs targeting TROP2 in the body of subjects, the use of anti TROP2 antibodies combined with drugs targeting TROP2 in the preparation of drugs for treating tumors, methods for preventing, reducing, or eliminating adverse reactions caused by drugs targeting TROP2 in the body of subjects, methods for treating tumors, drug packaging boxes, and drug compositions.

Description

Use of anti-TROP2 antibodies combined with drugs targeting TROP2 in the treatment of cancer

This disclosure claims priority to Chinese patent application No. 202310312156.2 filed on March 28, 2023, the entire contents of which are incorporated into this disclosure by reference.

This disclosure relates to the field of biomedicine, and specifically to the use of anti-TROP2 antibodies in the preparation of drugs for preventing, alleviating or eliminating adverse reactions caused by drugs targeting TROP2 in the body of a subject, the use of anti-TROP2 antibodies combined with drugs targeting TROP2 in the preparation of drugs for treating tumors, methods for preventing, alleviating or eliminating adverse reactions caused by drugs targeting TROP2 in the body of a subject, methods for treating tumors, drug packaging boxes, and pharmaceutical compositions.

TROP2 is human trophoblast cell surface glycoprotein antigen 2, also known as tumor-associated calcium signal transducer 2 (TACSTD2), epidermal glycoprotein 1 (EGP-1), gastrointestinal tumor-associated antigen (GA733-1), surface marker 1 (M1S1). It is a cell surface glycoprotein encoded and expressed by the Tacstd2 gene in the chromosome 1p32 region. TROP2 belongs to the GA733 protein family and has a high structural sequence similarity with epithelial cell adhesion molecule (EpCAM, also known as Trop1, TACSTD1), with a homology of 49%.

The primary structure of TROP2 protein is a 36kD polypeptide composed of about 323 amino acids. The primary structure is modified by N-terminal glycosylation and then forms a type I cell membrane glycoprotein, namely TROP2 protein, which is different from EpCAM. TROP2 protein crosses the cell membrane, and the N-terminus is an extracellular domain (Trop2EC), which is connected to the intracellular short tail (Trop2IC) of a hydrophobic polypeptide composed of 26 amino acid residues through a unidirectional transmembrane helix (TM), thereby fixing it to the cell membrane.

It has been found that TROP2 is of great significance in the process of embryonic development and tumor cell proliferation and metastasis. TROP2 was first discovered in trophoblast cells and serves as their surface marker. Trophoblast cells originate from the extraembryonic trophoblast. TROP2 helps embryo implantation and placental tissue formation, and plays an important role in maintaining the proliferation characteristics of embryonic stem cells and in the process of organ formation and development. In addition, TROP2 is also an important factor related to tumor development. It is highly expressed in many tumors, such as pancreatic cancer, breast cancer, colon cancer, gastric cancer, oral squamous cell carcinoma, ovarian cancer, etc. It can promote tumor cell proliferation, invasion, metastasis and diffusion. Its high expression is closely related to the shortened survival and poor prognosis of tumor subjects. Therefore, the research on anti-tumor drugs targeting TROP2 is of great significance.

25%)包括：噁心、中心粒細胞計數減少、腹瀉、疲勞、貧血、嘔吐、脫髮、便秘、皮疹、食欲下降和腹痛。值得注意的是，戈沙妥珠單抗說明書中標注了嚴重或危及生命的中性粒細胞減少症和嚴重腹瀉的黑框警告。德達博妥單抗(Datopotamab deruxtecan)是一種靶向TROP2抗體偶聯DXd的ADC，臨床I期試驗報導中Datopotamab deruxtecan具有抗腫瘤活性和可控的安全性，最常見 (

30%)的治療期出現的不良事件(Treatment Emergent Adverse Events,TEAEs)包括噁心、口腔炎(Stomatitis)、脫髮、疲勞等，並出現由於口腔炎所致的劑量減少。 Sacituzumab govitecan (Trodelvy) is an antibody-drug conjugate (ADC) formed by covalently coupling an anti-TROP2 antibody with a topoisomerase I inhibitor (SN-38). It has been approved in many countries for the treatment of metastatic or advanced triple-negative breast cancer (TNBC).

25%) include: nausea, decreased neutrophil count, diarrhea, fatigue, anemia, vomiting, hair loss, constipation, rash, decreased appetite and abdominal pain. It is worth noting that the instructions for use of gosartan contain black box warnings for severe or life-threatening neutropenia and severe diarrhea. Datopotamab deruxtecan is an ADC that targets the TROP2 antibody and is conjugated to DXd. Phase I clinical trials reported that datopotamab deruxtecan has anti-tumor activity and manageable safety. The most common (

30%) of the treatment-emergent adverse events (TEAEs) included nausea, stomatitis, hair loss, fatigue, etc., and dose reduction due to stomatitis occurred.

Therefore, how to effectively reduce the toxic and side effects of anti-TROP2 antibody-drug conjugates is an important issue that needs to be solved urgently in this field.

This disclosure provides medical uses of anti-TROP2 antibodies and drugs targeting TROP2, methods for treating tumors, drug packaging boxes, and pharmaceutical compositions.

On the one hand, the present disclosure provides the use of anti-TROP2 antibodies as shown in any of the following items:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects;

(ii) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by drugs targeting TROP2 in subjects;

(iii) For the prevention or treatment of tumors;

(iv) Preparation of medicaments for use in the prevention or treatment of tumours.

On the other hand, the present disclosure provides the use of an anti-TROP2 antibody in combination with a drug targeting TROP2, or a combination of an anti-TROP2 antibody and a drug targeting TROP2 as shown in any of the following:

(v) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects;

(vi) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by drugs targeting TROP2 in subjects;

(vii) For the prevention or treatment of tumors;

(viii) Preparation of medicaments for the prevention or treatment of tumors.

In some embodiments, the subject has a tumor. In some embodiments, the subject has an advanced solid tumor.

In some embodiments, the tumor is non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, pancreatic cancer, gallbladder cancer, breast cancer, cervical cancer, colorectal cancer, gastrointestinal cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal cancer, urothelial carcinoma, salivary gland cancer.

In the present disclosure, a drug targeting TROP2 refers to a drug that can bind to a TROP2 antigen or its epitope and has one or more of the following effects: tumor cell killing, tumor cell growth inhibition, tumor growth inhibition, and tumor metastasis. Exemplarily, drugs targeting TROP2 include but are not limited to ligand-drug conjugates, proteins, peptides, chemotherapy drugs, etc. that can target and bind to TROP2. When the context does not specifically specify, in the case of antigen-antibody interaction, TROP2 covers the scope of complete proteins, extracellular domains, epitopes, etc.

In some embodiments, the aforementioned drug targeting TROP2 is an antibody targeting TROP2 or a polypeptide targeting TROP2.

In some embodiments, the aforementioned drug targeting TROP2 is a ligand-drug conjugate targeting TROP2. In some embodiments, the ligand targeting TROP2 includes anti-TROP2 antibodies, peptides and proteins targeting TROP2, etc.

In some specific embodiments, the ligand-drug conjugate targeting TROP2 is an anti-TROP2 antibody-drug conjugate.

In some embodiments, the present disclosure provides the use of anti-TROP2 antibodies as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects,

(ii) used to prevent or treat tumors,

(iii) Prepare drugs for preventing, reducing or eliminating adverse reactions caused by drugs targeting TROP2 in subjects,

(iv) preparing medicaments for the prevention or treatment of tumors,

(v) Used to prevent, alleviate or eliminate adverse reactions of drugs targeting TROP2 in the treatment of tumors, including combination with drugs targeting TROP2,

(vi) Prepare drugs that prevent, reduce or eliminate adverse reactions to tumor treatment with drugs targeting TROP2, including drugs used in combination with drugs targeting TROP2.

In some embodiments, the present disclosure provides the use of a drug targeting TROP2 as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects;

(ii) For the prevention or treatment of tumors;

(iii) Prepare drugs for preventing, reducing or eliminating adverse reactions caused by drugs targeting TROP2 in subjects;

(iv) Preparation of drugs for the prevention or treatment of tumors;

(v) Used to prevent, alleviate or eliminate adverse reactions of tumor treatment, including in combination with anti-TROP2 antibodies;

(vi) Preparation of drugs to prevent, reduce or eliminate adverse reactions to tumor treatment, including combination with anti-TROP2 antibodies;

(vii) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects, including combination with anti-TROP2 antibody drugs;

(viii) For the prevention or treatment of tumors, including in combination with anti-TROP2 antibodies;

(ix) Preparation of drugs for preventing, reducing or eliminating adverse reactions caused by drugs targeting TROP2 in subjects, including combination with drugs targeting TROP2 antibodies;

(x) Preparation of drugs for the prevention or treatment of tumors, including combination with anti-TROP2 antibodies.

In the present disclosure, a drug targeting TROP2 refers to a drug that can bind to a TROP2 antigen or its epitope and has one or more of the following effects: tumor cell killing, tumor cell growth inhibition, tumor growth inhibition, and tumor metastasis. Exemplarily, drugs targeting TROP2 include but are not limited to ligand-drug conjugates, proteins, peptides, chemotherapy drugs, etc. that can target and bind to TROP2. When the context does not specifically specify, in the case of antigen-antibody interaction, TROP2 covers the scope of complete proteins, extracellular domains, epitopes, etc.

In some embodiments, the aforementioned drug targeting TROP2 is an anti-TROP2 antibody or an antigen-binding fragment thereof, or a polypeptide targeting TROP2.

In some embodiments, the aforementioned drug targeting TROP2 is a ligand-drug conjugate targeting TROP2. The "ligand" in this disclosure is a macromolecule or small molecule compound that can recognize and bind to the target antigen or its epitope. The function of the ligand is to present the drug to the target cell population bound to the ligand. These ligands include but are not limited to protein hormones, lectins, growth factors, antibodies or other molecules that can bind to cells.

In some specific embodiments, the ligand-drug conjugate targeting TROP2 is an anti-TROP2 antibody-drug conjugate, for example, Sacituzumab govitecan (Trodelvy), Datopotamab Deruxtecan (DS-1062; Dato-DXd), and sacituzumab tirumotecan (SKB264, MK-2870).

In the context of this disclosure, "antibody" is used in a broad sense, covering various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies or antigen-binding fragments thereof (also referred to as "antigen-binding portions"), as long as they exhibit the desired antigen-binding activity. In some specific embodiments, the antibody is a full-length monoclonal antibody or an antigen-binding fragment thereof.

In some specific embodiments, the ligand-drug conjugate targeting TROP2 is a peptide-drug conjugate targeting TROP2.

In some embodiments, the present disclosure provides the use of anti-TROP2 antibodies as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects,

(ii) used to prevent or treat tumors,

(iii) preparing drugs for preventing, reducing or eliminating adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects,

(iv) preparing medicaments for the prevention or treatment of tumors,

(v) Used to prevent, alleviate or eliminate adverse reactions of ligand-drug conjugates targeting TROP2 in the treatment of tumors, including combined use with ligand-drug conjugates targeting TROP2,

(vi) Prepare drugs that prevent, reduce or eliminate adverse reactions of ligand-drug conjugates targeting TROP2 in the treatment of tumors, including drugs used in combination with ligand-drug conjugates targeting TROP2.

In some embodiments, the present disclosure provides the use of anti-TROP2 antibodies as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects,

(ii) used to prevent or treat tumors,

(iii) preparing drugs for preventing, reducing or eliminating adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects,

(iv) preparing medicaments for the prevention or treatment of tumors,

(v) Used to prevent, alleviate or eliminate adverse reactions of anti-TROP2 antibody-drug conjugates in the treatment of tumors, including combination with antibody-drug conjugates targeting TROP2,

(vi) Prepare drugs that prevent, reduce or eliminate adverse reactions of anti-TROP2 antibody-drug conjugates in the treatment of tumors, including drugs used in combination with antibody-drug conjugates targeting TROP2.

In some embodiments, the present disclosure provides the use of an anti-TROP2 antibody in combination with a ligand-drug conjugate targeting TROP2, or a combination of an anti-TROP2 antibody and a ligand-drug conjugate targeting TROP2 as shown in any of the following:

(1) For the prevention or treatment of subjects with tumors,

(2) preparing a drug for the prevention or treatment of a subject suffering from a tumor,

(3) Used to prevent, reduce or eliminate adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects,

(4) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects.

In some embodiments, the present disclosure provides the use of an anti-TROP2 antibody in combination with an anti-TROP2 antibody-drug conjugate, or a combination of an anti-TROP2 antibody and an anti-TROP2 antibody-drug conjugate as shown in any of the following:

(1) For the prevention or treatment of subjects with tumors,

(2) preparing a drug for the prevention or treatment of a subject suffering from a tumor,

(3) Used to prevent, reduce or eliminate adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects,

(4) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects.

In some embodiments, the present disclosure provides the use of a ligand-drug conjugate targeting TROP2 as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects;

(ii) For the prevention or treatment of tumors;

(iii) Preparation of drugs for preventing, reducing or eliminating adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects;

(iv) Preparation of drugs for the prevention or treatment of tumors;

(v) Used to prevent, alleviate or eliminate adverse reactions of tumor treatment, including in combination with anti-TROP2 antibodies;

(vi) Preparation of drugs to prevent, reduce or eliminate adverse reactions to tumor treatment, including combination with anti-TROP2 antibodies;

(vii) Used to prevent, alleviate or eliminate adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects, including combination with anti-TROP2 antibody drugs;

(viii) For the prevention or treatment of tumors, including in combination with anti-TROP2 antibodies;

(ix) Preparation of drugs for preventing, reducing or eliminating adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects, including drugs used in combination with anti-TROP2 antibodies;

(x) Preparation of drugs for the prevention or treatment of tumors, including combination with anti-TROP2 antibodies.

In some embodiments, the present disclosure provides the use of anti-TROP2 antibody-drug conjugates as shown in any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects;

(ii) For the prevention or treatment of tumors;

(iii) Preparation of drugs for preventing, reducing or eliminating adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects;

(iv) Preparation of drugs for the prevention or treatment of tumors;

(v) Used to prevent, alleviate or eliminate adverse reactions of anti-TROP2 antibody-drug conjugates in the treatment of tumors, including combination with anti-TROP2 antibody drugs;

(vi) Preparation of drugs for preventing, alleviating or eliminating adverse reactions of anti-TROP2 antibody-drug conjugates in the treatment of tumors, including drugs used in combination with anti-TROP2 antibodies;

(vii) Used to prevent, alleviate or eliminate adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects, including combination with anti-TROP2 antibody drugs;

(viii) For the prevention or treatment of tumors, including in combination with anti-TROP2 antibodies;

(ix) Preparation of drugs for preventing, reducing or eliminating adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects, including drugs used in combination with anti-TROP2 antibodies;

(x) Preparation of drugs for the prevention or treatment of tumors, including combination with anti-TROP2 antibodies.

In some embodiments, the ligand-drug conjugate targeting TROP2 comprises an anti-TROP2 antibody (for ease of expression, it is referred to as anti-TROP2 antibody II). When the anti-TROP2 antibody (for ease of expression, it is referred to as anti-TROP2 antibody I) is administered in combination with the ligand-drug conjugate targeting TROP2, anti-TROP2 antibody I and anti-TROP2 antibody II may be the same or different.

In this disclosure, the same antibody means that two antibodies contain at least the same CDR sequence.

In some embodiments, anti-TROP2 antibody I and anti-TROP2 antibody II have different CDR sequences. In some embodiments, anti-TROP2 antibody I and anti-TROP2 antibody II further comprise different heavy chain variable regions (VH), and/or different light chain variable regions (VL), and/or different heavy chain sequences, and/or different light chain sequences.

In some embodiments, anti-TROP2 antibody I and anti-TROP2 antibody II have the same CDR sequence. In some embodiments, anti-TROP2 antibody I and anti-TROP2 antibody II further comprise the same heavy chain variable region (VH), and/or the same light chain variable region (VL), and/or the same heavy chain sequence, and/or different light chain sequences.

In some embodiments, anti-TROP2 antibody I and anti-TROP2 antibody II have the same heavy chain sequence and the same light chain sequence.

In some embodiments, the ligand-drug conjugate targeting TROP2 may include any antibody sequence and/or structure. In some specific embodiments, the ligand-drug conjugate is WO2021147993A, WO2023001248A, WO2015047510A, WO2019114666A, WO2019154120A, WO2018192407A, WO2023143154A, WO2015098099A, WO2017002776 、WO2019044947A、WO2019039483A、WO20202404671、WO2018036438A、WO2009100194A、WO2004054622A、WO2007112193A、WO2014092804A、WO2015012904A Any type of ligand-drug conjugate disclosed in. In some specific embodiments, the aforementioned anti-TROP2 antibody can be any anti-TROP2 antibody disclosed in the above patents. This disclosure introduces the anti-TROP2 antibody, ligand-drug conjugate structure, preparation method, etc. in the above patents.

In some embodiments, anti-TROP2 antibodies can effectively prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP, such as ligand-drug conjugates targeting TROP2.

In some embodiments, the aforementioned adverse reactions are adverse reactions related to tumor treatment, for example, adverse reactions related to the blood and lymphatic system, adverse reactions related to the digestive system, adverse reactions related to the skin and subcutaneous tissue, adverse reactions related to the respiratory system, adverse reactions related to muscles and bones, and adverse reactions related to metabolism and nutrition.

In some embodiments, the adverse reaction is oral mucositis. In some specific embodiments, "oral mucositis" or "stomatitis" is a condition characterized by inflammation and ulcers in the oral cavity. Oral mucositis is a common complication in patients receiving cancer treatment (e.g., immunotherapy, chemotherapy, or radiation therapy). Oral mucositis can cause a variety of problems, including pain, nutritional problems due to inability to eat, and increased risk of infection due to open ulcers of the mucosa. Oral mucositis can also have a significant impact on the quality of life of cancer patients and can limit the effectiveness of certain treatment options (i.e., the need to reduce the dose of subsequent chemotherapy).

In this disclosure, "combination" or "combined use" is a mode of administration, which includes various situations where two drugs are administered successively or simultaneously. Here, "simultaneously" means that the anti-TROP2 antibody or its antigen-binding fragment and the ligand-drug conjugate are administered in the same administration cycle, for example, the two drugs are administered within 2 days or 1 day. The so-called "sequential" administration includes the situation where the anti-TROP2 antibody or its antigen-binding fragment and the ligand-drug conjugate are administered separately in different administration cycles. These modes of administration are all combined administration described in this disclosure.

In some embodiments, the anti-TROP2 antibody or its antigen-binding fragment is administered to the subject before the administration cycle of the drug targeting TROP (e.g., anti-TROP2 antibody-drug conjugate) begins. And, during the administration cycle of the drug targeting TROP2, the anti-TROP2 antibody or its antigen-binding fragment is maintained.

Exemplarily, the anti-TROP2 antibody or its antigen-binding fragment is administered to the subject 1 day, 2 days, 3 days, 4 days or 5 days before the start of the administration cycle of the drug targeting TROP (e.g., anti-TROP2 antibody-drug conjugate); and, after the start of the administration of the drug targeting TROP2, the administration of the anti-TROP2 antibody or its antigen-binding fragment is maintained.

In some embodiments, the anti-TROP2 antibody or its antigen-binding fragment is administered to the subject during the administration cycle of the drug targeting TROP (e.g., anti-TROP2 antibody-drug conjugate).

It should be noted that the anti-TROP2 antibody disclosed herein can be adjusted in terms of the time of initiation of administration and the duration of continued administration according to clinical needs, as long as it can prevent, alleviate or eliminate the side effects of drugs targeting TROP2.

In some embodiments, the anti-TROP2 antibody is administered at least once a day, for example, once a day, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, nine times a day, ten times a day, twelve times a day, etc.

In some embodiments, the dosage of the anti-TROP2 antibody is 1-500 mg/time, for example, the dosage is 5-500 mg/time, 5-400 mg/time, 5-300 mg/time, 5-200 mg/time, 5-100 mg/time, 10-500 mg/time, 10-400 mg/time, 10-300 mg/time, 10-200 mg/time, 10-100 mg/time, 10-18 0mg/time, 10-150mg/time, 10-120mg/time, 10-100mg/time, 15-100mg/time, 20-100mg/time, 30-100mg/time, 5-80mg/time, 5-60mg/time, 15-80mg/time, 15-60mg/time, 20-60mg/time, 30-60mg/time, 30-40mg/time, 45-60mg/time.

In some embodiments, the dosage of the anti-TROP2 antibody is selected from: about 5 mg/time, 10 mg/time, about 15 mg/time, about 20 mg/time, about 25 mg/time, about 30 mg/time, about 35 mg/time, about 40 mg/time, about 45 mg/time, about 50 mg/time, about 55 mg/time, about 60 mg/time, about 65 mg/time, about 70 mg/time, about 75 mg /time, about 80mg/time, about 90mg/time, about 100mg/time, about 120mg/time, about 140mg/time, about 160mg/time, about 180mg/time, about 200mg/time, about 220mg/time, about 250mg/time, about 280mg/time, about 300mg/time, about 400mg/time, about 500mg/time or any range between these points.

In some embodiments, the anti-TROP2 antibody is administered orally, for example, orally. For example, oral administration, gargle administration, oral buccal administration, oral topical administration, etc. The anti-TROP2 antibody or its antigen-binding fragment can be formulated into any pharmaceutically acceptable dosage form, for example, it can be formulated into tablets, solutions, suspensions, granules, pills, capsules, syrups, inhalants, sprays, injections, etc.

In some specific embodiments, the anti-TROP2 antibody or antigen-binding fragment thereof is administered by oral gargle. "Gargle administration" means that the drug remains in the subject's oral cavity for an appropriate time (e.g., 1-2 minutes) and then spit out.

In some specific embodiments, before the start of the dosing cycle of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) (e.g., 1, 2, 3, 4, 5 days before the start of the dosing cycle, etc.), the subject is administered an anti-TROP2 antibody-containing mouthwash, and the mouthwash is administered during the dosing cycle of the drug targeting TROP2. The dosing frequency of the mouthwash is at least once a day, for example, 2 times/day, 3 times/day, 4 times/day, 6 times/day, 8 times/day, 10 times/day, etc.; the dosage of the anti-TROP2 antibody in the mouthwash is 1-500 mg/time, 5-100 mg/time, 5-60 mg/time, 10-60 mg/time, 15-60 mg/time, 20-60 mg/time, or 30-60 mg/time. For example, 5mg/time, 10mg/time, 15mg/time, 20mg/time, 25mg/time, 30mg/time, 35mg/time, 40mg/time, 50mg/time, 60mg/time, 70mg/time, 80mg/time, 100mg/time, 120mg/time, 150mg/time, 200mg/time or any range between these point values.

In some embodiments, during the dosing cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate), a rinse containing an anti-TROP2 antibody is administered to the subject; the frequency of administration of the rinse is at least once a day, for example 1-10 times/day, for example 2 times/day, 3 times/day, 4 times/day, 6 times/day, 8 times/day, 10 times/day; the dosage of the anti-TROP2 antibody in the rinse is 1-500 mg/time, 5-100 mg/time, 5-60 mg/time, 10-60 mg/time, 15-60 mg/time, 20-60 mg/time, or 30-60 mg/time. For example, 5mg/time, 10mg/time, 15mg/time, 20mg/time, 25mg/time, 30mg/time, 35mg/time, 40mg/time, 50mg/time, 60mg/time, 70mg/time, 80mg/time, 100mg/time, 120mg/time, 150mg/time, 200mg/time or any range between these point values.

In some embodiments, the anti-TROP2 antibody gargle solution is used before the first administration of the drug targeting TROP2 (e.g., 3 days before). It is used once in the morning and evening every day, 8 to 12 hours apart, gargle 10 to 20 mL each time, last for 1 to 2 minutes, repeat 2 to 3 times, spit out all after gargling, and the drug is used until the last administration of the drug targeting TROP2 (e.g., 21 days after administration). In some embodiments, the concentration of the anti-TROP2 antibody in the gargle is 0.1-20 mg/ml, for example, about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 1.0 mg/ml, about 1.2 mg/ml, about 1.5 mg/ml, about 1.8 mg/ml, about 2.0 mg/ml, about 5 mg/ml, about 6 mg/ml, about 8 mg/ml, about 10 mg/ml, about 12 mg/ml, about 15 mg/ml, about 18 mg/ml, about 20 mg/ml or any range between these points.

In some embodiments, the anti-TROP2 antibody is administered by injection. In some specific embodiments, the anti-TROP2 antibody is administered by local injection into the mouth.

In some specific embodiments, the anti-TROP2 antibody is administered by local intraoral injection, and the administration frequency is selected from at least once every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks or every 10 weeks. In some specific embodiments, the administration frequency of the anti-TROP2 antibody is once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks or once every 10 weeks. In some specific embodiments, the administration frequency of the anti-TROP2 antibody is once every 3 weeks.

In some specific embodiments, the anti-TROP2 antibody is administered by local intraoral injection, and the dosage is selected from 0.1-500 mg/time, for example, 0.5-30 mg/time, 0.5-40 mg/time, 0.5-50 mg/time, 0.5-100 mg/time, 0.5-200 mg/time, 0.5-300 mg/time, 0.3-30 mg/time, 0.3-40 mg/time, 0.3-50 mg/time, 0.3-100 mg/time, 0.3-200 mg/time, 0.3-300 mg/time, 1-30 mg/time, 1-40 mg/time, 1-50 mg/time, 1-100 mg/time, 1-200 mg/time, 1-300 mg/time.

In some specific embodiments, the dosage of the anti-TROP2 antibody is about 0.1 mg/time, about 0.2 mg/time, about 0.3 mg/time, about 0.5 mg/time, about 0.6 mg/time, about 0.8 mg/time, about 0.9 mg/time, about 1.0 mg/time, about 1.1 mg/time, about 1.3 mg/time, about 1.4 mg/time, about 1.5 mg/time, about 1.6 mg/time, about 1.8 mg/time, about 2.0 mg/time, about 2.2 mg/time, about 2.4 mg/time. times, about 2.6mg/time, about 2.8mg/time, about 3.0mg/time, about 3.2mg/time, about 3.4mg/time, about 3.5mg/time, about 3.6mg/time, about 3.8mg/time, about 4.0mg/time, about 4.2mg/time, about 4.4mg/time, about 4.6mg/time, about 4.8mg/time, about 5.0mg/time, about 5.3mg/time, about 5.5mg/time, about 5.8mg/time, about 6.0mg/time, about 6.5mg/time, about 7.0m g/time, about 7.5mg/time, about 8.0mg/time, about 8.5mg/time, about 9.0mg/time, about 10mg/time, about 11mg/time, about 13mg/time, about 15mg/time, about 17mg/time, about 19mg/time, about 20mg/time, about 22mg/time, about 24mg/time, about 26mg/time, about 28mg/time, about 30mg/time, about 32mg/time, about 35mg/time, about 38mg/time, about 40mg/time, about 45mg/time, about 50mg/time, about 55mg/time, about 60mg/time, about 65mg/time, about 70mg/time, about 75mg/time, about 80mg/time, about 85mg/time, about 90mg/time, about 85mg/time, about 95mg/time, about 100mg/time, about 120mg/time, about 130mg/time, about 150mg/time, about 200mg/time, about 220mg/time, about 250mg/time, about 300mg/time or any range between any two of the above points.

In some specific implementation schemes, the dosage of the anti-TROP2 antibody is 0.1-50 mg/time, and the frequency of administration is once every 3 weeks.

In some specific implementation schemes, the dosage of the anti-TROP2 antibody is 0.3-30 mg/time, and the frequency of administration is once every 3 weeks.

In some embodiments, the dosage of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is 0.1-20 mg/kg. For example, the dosage of the drug targeting TROP is 1-18 mg/kg, 1-16 mg/kg, 1-12 mg/kg, 1.5-18 mg/kg, 1.5-16 mg/kg, 1.5-12 mg/kg, 1.5-10 mg/kg, 1.5-9 mg/kg, 1.5-8 mg/kg, 1.5-6 mg/kg, 1.5-4 mg/kg, 1.5-3 mg/kg, 1.5-2.5 mg/kg, 2-3 mg/kg, 2-4 mg/kg, 2-6 mg/kg, 2-8 mg/kg, 2-9 mg/kg, 2-12 mg/kg, 2-18 mg/kg.

In some specific embodiments, the dosage of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is selected from: 1-12 mg/kg, 1.5-9 mg/kg, 1.5-6 mg/kg, 1.5-4 mg/kg, 1.5-3.5 mg/kg, 1.5-3 mg/kg, 1-9 mg/kg, 1-6 mg/kg, 1-4 mg/kg, 1-3.5 mg/kg, 1-3 mg/kg.

In some embodiments, the dosage of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is selected from: about 0.1 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2.0 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg , about 2.3mg/kg, about 2.4mg/kg, about 2.5mg/kg, about 2.6mg/kg, about 2.7mg/kg, about 2.8mg/kg, about 2.9mg/kg, about 3.0mg/kg, about 3.1mg/kg, about 3.2mg/kg, about 3.3mg/kg, about 3.4mg/kg, about 3.5mg/kg, about 3.6mg/kg, about 3.7mg/kg, about 3.8mg/kg, about 3.9mg/kg, about 4.0mg/kg, about 4.1mg/kg, about 4.2mg/kg, about 4.3mg/kg, about 4.4mg/kg, about 4.5mg/kg, about 4.6 mg/kg, about 4.7mg/kg, about 4.8mg/kg, about 4.9mg/kg, about 5.0mg/kg, about 5.1mg/kg, about 5.2mg/kg, about 5.3mg/kg, about 5.4mg/kg, about 5.5mg/kg, about 5.6mg/kg, about 5.7mg/kg, about 5.8mg/kg, about 5.9mg/kg, about 6.0mg/kg, about 6.1mg/ kg, about 6.2mg/kg, about 6.3mg/kg, about 6.4mg/kg, about 6.6mg/kg, about 6.6mg/kg, about 6.7mg/kg, about 6.8mg/kg, about 6.9mg/kg, About 7.0mg/kg, about 7.2mg/kg, about 7.4mg/kg, about 7.5mg/kg, about 7.6mg/kg, about 7.8mg/kg, about 8.0mg/kg, 8.2mg/kg, about 8.4mg/kg, about 8.5mg/kg, about 8.6mg/kg, about 8.8mg/kg, about 9.0mg/kg, about 9.2mg/kg, about 9.4mg/kg, about 9 .5mg/kg, about 9.6mg/kg, about 9.8mg/kg, about 10.0mg/kg, about 12mg/kg, about 14mg/kg, about 16mg/kg, about 18mg/kg, about 20mg/kg.

In some specific embodiments, the dosage of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is selected from: about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 9 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg, or any range between these points.

In some embodiments, the administration frequency of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is selected from once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, and at least once every 10 weeks.

In the context of this disclosure, at least once includes but is not limited to 1 time, 2 times, 3 times, 4 times, 5 times, 6 times, 8 times, 10 times, etc.

In some embodiments, the administration frequency of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) is selected from once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 10 weeks.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is once a week.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is once every two weeks. Exemplarily, in a 2-week dosing cycle, the drug is administered on day 1.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is once every three weeks. Exemplarily, in a 3-week dosing cycle, the drug is administered on day 1.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is twice every three weeks. Exemplarily, in a 3-week dosing cycle, the drug is administered on the 1st and 8th days.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is once every four weeks.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is 1.5-12 mg/kg/time (e.g., about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg), and the dosing frequency is twice every four weeks.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is about 1.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4.0 mg/kg, or about 6.0 mg/kg, and the dosing frequency is once every three weeks. In each three-week dosing cycle, the drug is administered on day 1.

In some embodiments, the dosage of a drug targeting TROP (e.g., an anti-TROP2 antibody-drug conjugate) is about 2.0 mg/kg, and the dosing frequency is twice every three weeks. In each three-week dosing cycle, the drug is administered on the 1st and 8th day.

In some embodiments, the drug targeting TROP (e.g., anti-TROP2 antibody-drug conjugate) is administered at a dosage of about 2.4 mg/kg, and the administration frequency is once every two weeks. In each two-week administration cycle, the drug is administered on day 1.

In some embodiments, the administration route of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) can be oral administration, parenteral administration, or transdermal administration, and the parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the administration route of the ligand-drug conjugate is intravenous injection.

In some embodiments, the drug targeting TROP2 is configured in an injectable form. Exemplarily, the injectable form of the ligand-drug conjugate is an injection or a lyophilized powder injection, which contains the ligand-drug conjugate and one or more pharmaceutically acceptable excipients. In some embodiments, the drug targeting TROP2 comprises any composition selected from WO2023001248.

In some embodiments, the pharmaceutically acceptable excipients include one or more of a buffer, a surfactant, a sugar, an amino acid and a salt thereof. Wherein, the buffer can be histidine-histidine hydrochloride buffer; the surfactant can be selected from polysorbate, polysorbate 20, polysorbate 80, polyhydroxyethane, Triton, sodium dodecyl sulfonate, sodium lauryl sulfonate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, cetyl-betaine, lauryl Aminopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmitylamidopropyl-betaine, isostearamidopropyl-betaine, myristamidopropyl-dimethylamine, palmitylamidopropyl-dimethylamine, isostearamidopropyl-dimethylamine, methyl cocoyl sodium, methyl oleyl taurate sodium, polyethylene glycol, polypropylene glycol and copolymer of ethylene and propylene glycol, etc.; sugars include monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc. The sugar may be selected from glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, xylitol (sylitol), sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, isomaltulose, etc.; the amino acid and its salt may be glycine and/or arginine hydrochloride.

Exemplarily, the drug targeting TROP2 is formulated as the following formulation: (a) about 10 mM to about 50 mM histidine-histidine hydrochloride buffer, (b) about 1 mg/mL to about 100 mg/mL of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate); pH is about 5.0 to about 6.5; or,

(a) about 10 mg/mL to about 30 mg/mL of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate), (b) about 0.1 mg/mL to about 0.3 mg/mL of polysorbate, (c) about 30 mg/mL to about 50 mg/mL of sucrose, (d) about 7 mg/mL to about 11 mg/mL of glycine, and (e) about 20 mM to about 40 mM of histidine-histidine hydrochloride buffer, based on protein concentration; pH is about 5.5-6.5; or,

(a) about 18 mg/mL to about 22 mg/mL of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) based on protein concentration, (b) about 0.2 mg/mL of polysorbate 80, (c) about 40 mg/mL of sucrose, (d) about 9 mg/mL of glycine, and (e) about 30 mM histidine-histidine hydrochloride buffer, the pH of the composition being about 5.9-6.2.

In some embodiments, the administration regimen of the anti-TROP2 antibody combined with the drug targeting TROP2 is selected from:

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the ligand-drug conjugate is administered once every 3 weeks on the first day of each dosing cycle, and each dose is about 1.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 or about 6.0 mg/kg;

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) administering the ligand-drug conjugate to the subject, the ligand-drug conjugate is administered twice every 3 weeks, on the 1st and 8th day of each administration cycle, and the dosage of each administration is about 2.0 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each administration cycle, and each administration dose is about 2.0 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) Administering the ligand-drug conjugate to the subject once every 2 weeks on the first day of each dosing cycle, with each dose being approximately 2.4 mg/kg.

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered once every 2 weeks at a dose of approximately 2.4 mg/kg per administration.

In some specific embodiments, before the start of a dosing cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate), the subject is administered a gargle containing an anti-TROP2 antibody, and the gargle is administered during the dosing cycle of the drug targeting TROP2.

In some specific embodiments, a mouthwash containing an anti-TROP2 antibody is administered to a subject during a dosing cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate); for example, administration of the mouthwash is initiated on the same day as administration of the drug targeting TROP2 or after administration of the drug targeting TROP2, and the mouthwash is maintained during the dosing cycle of the drug targeting TROP2.

In some specific embodiments, after the administration cycle of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) ends, the subject continues to be administered a gargle containing an anti-TROP2 antibody; for example, after the administration cycle targeting TROP2 ends, the gargle continues to be administered for 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days, 21 days, 25 days, 30 days, 35 days, 40 days, 50 days, 60 days, etc. The duration of the gargle administration can be adjusted according to the actual clinical situation.

In some embodiments, the administration regimen of the anti-TROP2 antibody combined with the drug targeting TROP2 is selected from:

(i) administering an anti-TROP2 antibody to a subject by local oral injection; wherein the anti-TROP2 antibody is administered once or twice every 3 weeks, and the dosage is 0.1-50 mg/time, for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the ligand-drug conjugate is administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks, and each administration dose is approximately 3 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage of each administration is about 2.0 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) A drug targeting TROP2 is administered to the subject, with the drug targeting TROP2 being administered once every 2 weeks at a dosage of approximately 2.4 mg/kg each time.

In some specific embodiments, before the start of the dosing cycle of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate), the anti-TROP2 antibody is injected into the subject's oral cavity locally, and the anti-TROP2 antibody injection is maintained during the dosing cycle of the drug targeting TROP2.

In some specific embodiments, during the administration cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate), an anti-TROP2 antibody is administered to the subject by local oral injection; for example, the anti-TROP2 antibody injection is started on the same day as the administration of the drug targeting TROP2 or after the administration of the drug targeting TROP2, and the anti-TROP2 antibody injection is maintained during the administration cycle of the drug targeting TROP2.

In some specific embodiments, after the administration cycle of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) ends, the anti-TROP2 antibody is continued to be administered to the subject by local oral injection; for example, after the administration cycle targeting TROP2 ends, the anti-TROP2 antibody injection is continued for 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days, 21 days, 25 days, 30 days, 35 days, 40 days, 50 days, 60 days, etc. The duration of the anti-TROP2 antibody injection can be adjusted according to the actual clinical situation.

Anti-TROP2 antibody

In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

Among them, the CDR sequences mentioned above are shown in Table 1 below:

The above CDRs are defined according to the Kabat, IMGT, Chothia, AbM or Contact numbering systems. In some specific embodiments, the CDRs are defined according to the Kabat numbering system.

In some embodiments, an anti-TROP2 antibody is provided, comprising any 1, any 2, any 3, any 4, any 5 or 6 of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3.

In some embodiments, the anti-TROP2 antibody is a humanized antibody. In some specific embodiments, the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence having at least 80% sequence identity therewith; 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 80% sequence identity therewith.

Heavy chain variable area:

SEQ ID NO：7；

SEQ ID NO: 7;

Light chain variable area:

SEQ ID NO：8；

SEQ ID NO: 8;

Note: The underlined part is the CDR region defined according to the Kabat numbering system.

In some embodiments, the anti-TROP2 antibody or its antigen-binding fragment comprises any one or a combination of any two of the aforementioned VH and VL.

In some embodiments, the anti-TROP2 antibody or its antigen-binding fragment further comprises a heavy chain constant region and/or a light chain constant region. The heavy chain constant region of the antibody can be selected from the constant regions of human IgG1, IgG2, IgG4 and their variants, and the light chain constant region can be selected from the light chain constant regions of human κ, λ chains or their variants. Exemplarily, the heavy chain constant region of the antibody is selected from human IgG1 with a sequence as shown in SEQ ID NO: 11, and the light chain constant region is selected from the constant region of human κ chain with a sequence as shown in SEQ ID NO: 12.

Heavy chain constant region of human IgG1:

SEQ ID NO：11；

SEQ ID NO: 11;

Human κ light chain constant region:

SEQ ID NO：12；

SEQ ID NO: 12;

Exemplarily, the above-mentioned light chain/heavy chain constant region is combined with the variable region of the aforementioned anti-TROP2 antibody to form a complete antibody, and its light chain/heavy chain sequence is as follows:

Relink:

SEQ ID NO：9；

SEQ ID NO: 9;

Light chain:

SEQ ID NO：10；

SEQ ID NO: 10;

In some embodiments, the anti-TROP2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9, or an amino acid sequence having at least 80%, at least 90% sequence identity therewith; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10, or an amino acid sequence having at least 80%, at least 90% sequence identity therewith.

In some embodiments, the anti-TROP2 antibody provided by the present disclosure comprises any one or a combination of any two of the aforementioned heavy chains and light chains.

In the context of the present disclosure, "at least 80%" covers 80% and above, such as at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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%, at least 99%, and any range of values therebetween.

Ligand-drug conjugates

In some embodiments, the ligand-drug conjugate has the following structure:

Wherein, the PD3 is an anti-TROP2 antibody; n is an integer or decimal from 1 to 10 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or any integer or decimal between two).

In some embodiments, n is 4±0.6, for example, n is 3.4, 3.5, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6.

In some embodiments, the anti-TROP2 antibody contained in the ligand-drug conjugate is the same antibody as the anti-TROP2 antibody co-administered therewith. Exemplarily, PD3 is selected from any anti-TROP2 antibody or antigen-binding fragment thereof provided in the present disclosure.

Exemplarily, in some specific embodiments, PD3 comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

Exemplarily, in some specific embodiments, PD3 is a humanized antibody. In some specific embodiments, the heavy chain variable region of PD3 comprises an amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence having at least 80% sequence identity therewith; the light chain variable region of PD3 comprises an amino acid sequence as shown in SEQ ID NO: 8, or an amino acid sequence having at least 80% sequence identity therewith.

For example, in some specific embodiments, PD3 comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9, or an amino acid sequence having at least 80% or at least 90% sequence identity therewith; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10, or an amino acid sequence having at least 80% or at least 90% sequence identity therewith.

In some embodiments, the ligand-drug conjugate described above can be prepared by referring to the method in Example 3-1 of WO2021147993A1. The present disclosure incorporates the relevant contents of the ADC structure, antibody sequence and preparation method in WO2021147993A1 into the present disclosure by reference.

In some specific embodiments, the present disclosure provides ligand-drug conjugates having the following structures:

Wherein, n is an integer or decimal of 1-10, more specifically 4; PD3 is an anti-TROP2 antibody or an antigen-binding fragment thereof, the source of which refers to the antibody PD3 in Examples 1-2 in WO2021147993A1, comprising a heavy chain as shown in SEQ ID NO: 9 (sequence 13 in WO2021147993A1) and a light chain as shown in SEQ ID NO: 10 (sequence 14 in WO2021147993A1).

30%)是噁心(71.1%)、口腔炎(65.8%)、貧血(42.1%)、嘔吐、食欲下降、體重下降和皮疹(各36.8%)。未發生嚴重的中性粒細胞減少症(neutropenia)、腹瀉(diarrhea)、超敏反應(hypersensitivity)等不良反應，並且沒有患者因TRAEs而中斷研究治療。 In some embodiments, the aforementioned ligand-drug conjugate is used to treat tumors, showing good safety and positive anti-tumor activity, especially showing positive anti-tumor effects and good safety for patients with advanced tumors. In all dose groups of the Phase I clinical trial, the most common TRAEs (

30%) were nausea (71.1%), stomatitis (65.8%), anemia (42.1%), vomiting, decreased appetite, weight loss, and rash (36.8% each). No severe adverse reactions such as neutropenia, diarrhea, and hypersensitivity occurred, and no patient discontinued study treatment due to TRAEs.

In some embodiments, the ligand-drug conjugate may also contain other structures and/or sequences. Exemplarily, the ligand-drug conjugate is Sacituzumab govitecan, or any type of ligand-drug conjugate disclosed in WO2015098099A1, WO2020240467A1, WO2018036438A1, WO2009100194A3, WO2004054622A1, WO2007112193A2, WO2014092804A1, WO2015012904A3.

In some embodiments, the tumor is selected from a solid tumor.

In some embodiments, the tumor is selected from a mid- to late-stage tumor, for example, an advanced solid tumor.

In some embodiments, the tumor is a treatment failure. For example, the tumor is a standard treatment failure. In this disclosure, standard treatment failure means that the subject has failed a treatment regimen with Class IA evidence in the CSCO guidelines. In some specific embodiments, treatment failure is manifested as disease progression or toxic intolerance.

The anti-TROP2 antibody or its antigen-binding fragment combined with the ligand-drug conjugate disclosed herein can effectively prevent or reduce the occurrence of adverse reactions mediated by the ligand-drug conjugate in tumor treatment (for example, preventing the occurrence of stomatitis, reducing the incidence or severity of stomatitis), so as to improve the patient's quality of life and the therapeutic effectiveness of the ligand-drug conjugate.

In some embodiments, the incidence and severity of stomatitis are graded according to CTCAE v5.0.

On the other hand, the present disclosure provides a method for treating tumors, or a method for preventing, alleviating or eliminating adverse reactions caused by ligand-drug conjugates in a subject, the method comprising the following steps:

(i) administering to the subject an effective amount of an anti-TROP2 antibody for prevention, alleviation or elimination,

(ii) administering a therapeutically effective amount of a drug targeting TROP2 to the subject;

Among them, the subject suffered from tumor.

In some embodiments, the drug targeting TROP2 is a ligand-drug conjugate targeting TROP2. The method provided in the present disclosure comprises the following steps:

(1) administering to the subject an effective amount of an anti-TROP2 antibody to prevent, alleviate or eliminate the disease,

(2) Administering a therapeutically effective amount of a ligand-drug conjugate targeting TROP2 to the subject.

In some embodiments, the drug targeting TROP2 is an anti-TROP2 antibody-drug conjugate. The method provided in the present disclosure comprises the following steps:

(1) administering to the subject an effective amount of an anti-TROP2 antibody to prevent, alleviate or eliminate the disease,

(2) Administering a therapeutically effective amount of an anti-TROP2 antibody-drug conjugate to the subject.

In some embodiments, the present disclosure provides a method for treating tumors, or a method for preventing, alleviating or eliminating adverse reactions caused by ligand-drug conjugates in a subject, the method comprising the following steps: administering a therapeutically effective amount of a drug targeting TROP2 to the subject; wherein the subject suffers from a tumor.

In some embodiments, the drug targeting TROP2 is a ligand-drug conjugate targeting TROP2. The method provided by the present disclosure comprises the following steps: administering a therapeutically effective amount of a ligand-drug conjugate targeting TROP2 to a subject.

In some embodiments, the drug targeting TROP2 is an anti-TROP2 antibody-drug conjugate. The method provided by the present disclosure comprises the following steps: administering a therapeutically effective amount of an anti-TROP2 antibody-drug conjugate to a subject.

In some embodiments, the anti-TROP2 antibody is any of the aforementioned anti-TROP2 antibodies.

Exemplarily, the anti-TROP2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.

Exemplarily, the heavy chain variable region of the anti-TROP2 antibody comprises an amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence having at least 80% sequence identity therewith; 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 80% sequence identity therewith.

Exemplarily, the anti-TROP2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9, or an amino acid sequence having at least 80%, at least 90% sequence identity therewith; and/or, the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10, or an amino acid sequence having at least 80%, at least 90% sequence identity therewith.

In some embodiments, the anti-TROP2 antibody is administered according to any administration frequency, dosage, and administration method provided in the present disclosure.

Exemplarily, the anti-TROP2 antibody is administered orally, for example, by oral gargle.

Exemplarily, the anti-TROP2 antibody is administered before the start of the ligand-drug conjugate administration cycle and/or during the administration cycle. For example, the anti-TROP2 antibody is administered to the subject on the day of administration of the ligand-drug conjugate, after administration, or within 1 day, 2 days, 3 days, 4 days or 5 days before administration.

Exemplarily, the anti-TROP2 antibody is administered at least once a day, for example, once a day, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, or ten times a day.

Exemplarily, the dosage of the anti-TROP2 antibody is 1-500 mg/time, for example, about 5 mg/time, about 10 mg/time, about 15 mg/time, about 20 mg/time, about 25 mg/time, about 30 mg/time, about 35 mg/time, about 40 mg/time, about 45 mg/time, about 50 mg/time, about 55 mg/time, about 60 mg/time, about 65 mg/time, about 70 mg/time, about 75 mg/time, about 76 mg/time, about 77 mg/time, about 78 mg/time, about 79 mg/time, about 80 mg/time, about 81 mg/time, about 82 mg/time, about 83 mg/time, about 84 mg/time, about 86 mg/time, about 87 mg/time, about 88 mg/time, about 89 mg/time, about 90 mg/time, about 91 mg/time, about 92 mg/time, about 93 mg/time, about 94 mg/time, about 95 mg/time, about 96 mg/time, about 97 mg/time, about 98 mg/time, about 99 mg/time, about 100 mg/time, about 101 mg/time, about 102 mg/time, about 103 mg/time, about 104 mg/time, about 105 mg/time, about 106 mg/time, about 107 mg/time, about 108 mg/time, about 109 mg/time, about 110 mg/time, about 111 mg/time 5mg/time, about 80mg/time, about 90mg/time, about 100mg/time, about 120mg/time, about 140mg/time, about 160mg/time, about 180mg/time, about 200mg/time, about 220mg/time, about 250mg/time, about 280mg/time, about 300mg/time, about 400mg/time, about 500mg/time or any range between these points.

Exemplarily, the anti-TROP2 antibody is administered by injection, such as by local oral injection.

Exemplarily, the frequency of administration of the anti-TROP2 antibody is selected from at least once every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks or every 10 weeks. For example, the frequency of administration of the anti-TROP2 antibody is once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks or once every 10 weeks.

Exemplarily, the dosage of the anti-TROP2 antibody is selected from 0.1-500 mg/time, for example, the dosage of the anti-TROP2 antibody is about 0.1 mg/time, about 0.2 mg/time, about 0.3 mg/time, about 0.5 mg/time, about 0.6 mg/time, about 0.8 mg/time, about 0.9 mg/time, about 1.0 mg/time, about 1.1 mg/time, about 1.3 mg/time, about 1.4 mg/time, about 1.5 mg/time, about 1.6 mg/time, about 1.8 mg/time, about 2.0 mg/time , about 2.2mg/time, about 2.4mg/time, about 2.6mg/time, about 2.8mg/time, about 3.0mg/time, about 3.2mg/time, about 3.4mg/time, about 3.5mg/time, about 3.6mg/time, about 3.8mg/time, about 4.0mg/time, about 4.2mg/time, about 4.4mg/time, about 4.6mg/time, about 4.8mg/time, About 5.0mg/time, about 5.3mg/time, about 5.5mg/time, about 5.8mg/time, about 6.0mg/time, about 6. 5mg/time, about 7.0mg/time, about 7.5mg/time, about 8.0mg/time, about 8.5mg/time, about 9.0mg/time, about 10mg/time, about 11mg/time, about 13mg/time, about 15mg/time, about 17mg/time, about 19mg/time, about 20mg/time, about 22mg/time, about 24mg/time, about 26mg/time, about 28mg/time, about 30mg/time, about 32mg/time, about 35mg/time, about 38mg/time, about 40mg/time, about 45mg g/time, about 50mg/time, about 55mg/time, about 60mg/time, about 65mg/time, about 70mg/time, about 75mg/time, about 80mg/time, about 85mg/time, about 90mg/time, about 85mg/time, about 95mg/time, about 100mg/time, about 120mg/time, about 130mg/time, about 150mg/time, about 200mg/time, about 220mg/time, about 250mg/time, about 300mg/time, or any range between any two of the above points.

In some embodiments, the drug targeting TROP2 is any of the aforementioned ligand-drug conjugates targeting TROP2.

Exemplarily, the ligand-drug conjugate comprises the following structure:

Wherein, n is an integer or decimal of 1-10, more specifically 4; PD3 is an anti-TROP2 antibody or an antigen-binding fragment thereof, the source of which refers to the antibody PD3 in Examples 1-2 in WO2021147993A1, comprising a heavy chain as shown in SEQ ID NO: 9 (sequence 13 in WO2021147993A1) and a light chain as shown in SEQ ID NO: 10 (sequence 14 in WO2021147993A1).

In some embodiments, the ligand-drug conjugate is administered according to any administration frequency, dosage, and administration method provided in the present disclosure.

Exemplarily, the dosage of the ligand-drug conjugate is 0.1-20 mg/kg. For example, about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 9 mg/kg, about 8 mg/kg, about 10 mg/kg, about 12 mg/kg.

Exemplarily, the dosing frequency of the ligand-drug conjugate is selected from once a week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, at least once every 8 weeks, and at least once every 10 weeks. For example, the dosing frequency of the ligand-drug conjugate is once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, or once every 10 weeks.

Exemplarily, the ligand-drug conjugate is administered once every 2 weeks, once every 3 weeks, or twice every 3 weeks.

Exemplarily, the ligand-drug conjugate can be administered by intravenous injection.

In some embodiments, the administration regimen of the anti-TROP2 antibody combined with the drug targeting TROP2 is selected from:

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the ligand-drug conjugate is administered once every 3 weeks on the first day of each dosing cycle, and each dose is about 1.5 mg/kg, about 3.0 mg/kg, about 3.5 mg/kg, about 4.0 or about 6.0 mg/kg;

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) administering the ligand-drug conjugate to the subject, the ligand-drug conjugate is administered twice every 3 weeks, on the 1st and 8th day of each administration cycle, and the dosage of each administration is about 2.0 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each administration cycle, and each administration dose is about 2.0 mg/kg;

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 5-60 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, or any range between these values;

(ii) Administering the ligand-drug conjugate to the subject once every 2 weeks on the first day of each dosing cycle, with each dose being approximately 2.4 mg/kg.

or,

(i) administering a gargle containing an anti-TROP2 antibody to a subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, for example, 5 mg/time, 10 mg/time, 15 mg/time, 20 mg/time, 25 mg/time, 30 mg/time, 35 mg/time, 40 mg/time, 50 mg/time, 60 mg/time, 65 mg/time, 70 mg/time, 75 mg/time, 80 mg/time, 85 mg/time, 90 mg/time, 95 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the drug targeting TROP2 is administered once every 2 weeks at a dose of approximately 2.4 mg/kg per administration.

In some specific embodiments, before the start of a dosing cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate), the subject is administered a gargle containing an anti-TROP2 antibody, and the gargle is administered during the dosing cycle of the drug targeting TROP2.

In some specific embodiments, a mouthwash containing an anti-TROP2 antibody is administered to a subject during a dosing cycle of a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate); for example, administration of the mouthwash is initiated on the same day as administration of the drug targeting TROP2 or after administration of the drug targeting TROP2, and the mouthwash is maintained during the dosing cycle of the drug targeting TROP2.

In some specific embodiments, after the administration cycle of the drug targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugate) ends, the subject continues to be administered a mouthwash containing an anti-TROP2 antibody; for example, after the administration cycle targeting TROP2 ends, the mouthwash is continued to be administered for 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 20 days, 21 days, 25 days, 30 days, 35 days, 40 days, 50 days, 60 days, etc. The duration of the mouthwash administration can be adjusted according to the actual clinical situation.

In some embodiments, the administration regimen of the anti-TROP2 antibody combined with the drug targeting TROP2 is selected from:

(i) administering an anti-TROP2 antibody to a subject by local oral injection; wherein the anti-TROP2 antibody is administered once or twice every 3 weeks, and the dosage is 0.1-50 mg/time, for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) to the subject, wherein the ligand-drug conjugate is administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks, and each administration dose is approximately 3 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage of each administration is about 2.0 mg/kg;

or,

(i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; for example, about 0.3 mg/time, about 0.5 mg/time, about 1.0 mg/time, about 1.5 mg/time, about 2.0 mg/time, about 2.5 mg/time, about 3.0 mg/time, about 3.5 mg/time, about 5 mg/time, about 6 mg/time, about 8 mg/time, about 10 mg/time, about 12 mg/time, about 15 mg/time, about 30 mg/time, about 35 mg/time, about 38 mg/time, about 40 mg/time, about 45 mg/time;

(ii) administering a drug targeting TROP2 to the subject, with the drug targeting TROP2 being administered once every 2 weeks at a dosage of approximately 2.4 mg/kg each time;

On the other hand, the present disclosure provides a drug packaging box or product, which includes any of the aforementioned anti-TROP2 antibodies and any of the aforementioned drugs targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugates.

In some embodiments, the drug packaging box or product further comprises one or more containers, each of which independently contains an anti-TROP2 antibody and a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate).

In some embodiments, the present disclosure provides a pharmaceutical composition comprising any of the aforementioned anti-TROP2 antibodies and any of the aforementioned drugs targeting TROP2 (e.g., anti-TROP2 antibody-drug conjugates.

In some embodiments, the pharmaceutical composition comprises an anti-TROP2 antibody and a drug targeting TROP2 (e.g., an anti-TROP2 antibody-drug conjugate) that are each packaged independently.

In some embodiments, the present disclosure provides uses of pharmaceutical compositions, pharmaceutical packaging boxes or products selected from any of the following:

(i) Used to prevent, alleviate or eliminate adverse reactions caused by drugs targeting TROP2 in subjects,

(ii) used to prevent or treat tumors,

(iii) for preparing drugs for preventing, reducing or eliminating adverse reactions caused by drugs targeting TROP2 in subjects,

(iv) For the preparation of medicaments for the prevention or treatment of tumors.

In some embodiments, the present disclosure provides uses of pharmaceutical compositions, pharmaceutical packaging boxes or products selected from any of the following:

(1) For the prevention or treatment of subjects with tumors,

(2) preparing a drug for preventing or treating a subject suffering from a tumor,

(3) Used to prevent, reduce or eliminate adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects,

(4) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by ligand-drug conjugates targeting TROP2 in subjects.

In some embodiments, the present disclosure provides uses of pharmaceutical compositions, pharmaceutical packaging boxes or products selected from any of the following:

(1) For the prevention or treatment of subjects with tumors,

(2) preparing a drug for preventing or treating a subject suffering from a tumor,

(3) Used to prevent, reduce or eliminate adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects,

(4) Prepare drugs for preventing, alleviating or eliminating adverse reactions caused by anti-TROP2 antibody-drug conjugates in subjects.

On the one hand, the present disclosure combines an anti-TROP2 antibody with a ligand-drug conjugate targeting TROP2, thereby preventing or reducing the occurrence of adverse reactions mediated by the ligand-drug conjugate targeting TROP2 in tumor treatment (for example, preventing the occurrence of stomatitis, reducing the incidence or severity of stomatitis), so as to improve the patient's quality of life and the therapeutic effectiveness of the ligand-drug conjugate.

3級口腔炎的發生率，減輕或避免患者因為口腔黏膜炎導致的劑量暫停或劑量下調。 In some embodiments, the combination of anti-TROP2 antibodies and anti-TROP2 antibody-drug conjugates can significantly reduce CTCAE

The incidence of grade 3 stomatitis can be reduced or avoided, leading to dose suspension or dose reduction due to oral mucositis.

On the other hand, the anti-TROP2 antibody-drug conjugate disclosed in the present invention is used to treat tumors and shows good safety and positive anti-tumor activity. Compared with the administration of other drugs targeting TROP2, the subjects who were administered the anti-TROP2 antibody-drug conjugate disclosed in the present invention had significantly reduced incidence or severity of adverse reactions such as neutropenia, diarrhea, hypersensitivity, decreased white blood cell count, etc.,

On the other hand, the dosage of the anti-TROP2 antibody-drug conjugate is 3.0 mg/kg, and the frequency of administration is once every three weeks, which can effectively reduce the incidence of adverse reactions in patients. For example, it can effectively reduce the proportion of dose suspension and reduction due to oral mucositis.

Definition

In order to make it easier to understand the present disclosure, certain technologies and sciences are specifically defined below. Unless otherwise explicitly defined in the present disclosure, all other technologies and sciences used in the present disclosure have the meanings commonly understood by those of ordinary skill in the art to which the present disclosure belongs.

Unless the context clearly requires otherwise, throughout this specification and application, the words "comprising", "having", "including", etc. should be understood to have an inclusive sense rather than an exclusive or exhaustive sense; that is, the sense of "including but not limited to".

"As necessary" or "as necessary" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur.

"About" or "approximately" means that the value is within the acceptable error range of the specific value determined by a person of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean a standard deviation within or exceeding 1. Alternatively, "about" or "substantially includes" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each case in which the term "about" precedes a number or a numerical range also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in this application and claim, the meaning of "about" or "substantially includes" should be assumed to be within the acceptable error range of the specific value.

The three-letter and one-letter amino acid codes used in this disclosure are as described in J.biol.chem, 243, p3558 (1968).

The term "ligand-drug conjugate" refers to a ligand linked to a biologically active drug via a linker unit. In some specific embodiments, the "ligand-drug conjugate" is an "antibody-drug conjugate". In the present disclosure, "antibody-drug conjugate" (ADC) refers to a monoclonal antibody or antibody fragment linked to a biologically active toxic drug via a linker unit. The antibody can be coupled to the drug directly or via a linker. n is the average number of drug modules per antibody, which can be an integer or a decimal, and can range from, for example, about 0 to about 20 drug modules per antibody, in some embodiments, 1 to about 10 drug modules per antibody, and in some embodiments, 1 to about 8 drug modules per antibody, such as 2, 3, 4, 5, 6, 7, or 8 drug modules. The composition of the mixture of antibody-drug conjugates disclosed herein, wherein the average drug loading of each antibody is about 1 to about 10, including but not limited to about 3 to about 7, about 3 to about 6, about 3 to about 5, about 1 to about 9, about 7 or about 4.

The term "linker unit", "linker", "linker unit" or "linker fragment" refers to a chemical structure fragment or bond that is connected to a ligand at one end and to a drug at the other end. It can also be connected to other linkers and then connected to a ligand or drug.

The term "epitope" or "antigenic determinant" refers to the site on an antigen that is bound by an immunoglobulin or antibody. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive or non-consecutive amino acids in a unique spatial conformation. See, e.g., Epitope Mapping Protocols in Methods in Molecular B iology, Vol. 66, G.E.Morris, Ed. (1996).

As used herein, "polypeptide" refers to a polymer of amino acids, optionally including one or more amino acid analogs. "Polypeptide" covers natural or artificial polypeptides, polypeptide fragments and polypeptide analogs, which can be monomeric or polymeric. Proteins are molecules composed of one or more polypeptides. Peptides are relatively short polypeptides, usually between about 2 and 60 amino acids in length, for example between 8 and 40 amino acids in length. The terms "protein", "polypeptide" and "peptide" are used interchangeably.

"Antibody" is used in the broadest sense, covering various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. Antibodies can refer to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the immunoglobulin heavy chain are different, so their antigenicity is also different. Based on this, immunoglobulins can be divided into five categories, or called immunoglobulin isotypes, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are μ chain, δ chain, γ chain, α chain and ε chain. The same type of Ig can be divided into different subclasses according to the difference in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds, such as IgG can be divided into IgG1, IgG2, IgG3, IgG4. Light chains are divided into κ chain or λ chain by the difference in the constant region. Each of the five types of Ig can have κ chain or λ chain. The sequences of about 110 amino acids near the N-terminus of the antibody heavy chain and light chain vary greatly, which is the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable, which is the constant region (C region). The variable region includes 3 hypervariable regions (CDR) and 4 relatively conserved framework regions (FR). The 3 hypervariable regions determine the specificity of the antibody, also known as the complementarity determining regions (CDR). Each light chain variable region (VL) and heavy chain variable region (VH) consists of 3 CDR regions and 4 FR regions, and the order from the amino end to the carboxyl end is: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDR regions of the light chain are LCDR1, LCDR2, and LCDR3; the three CDR regions of the heavy chain are HCDR1, HCDR2, and HCDR3.

For the determination or definition of CDRs, definitive delineation of CDRs and identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and/or resolving the structure of the antibody-ligand complex. This can be accomplished by any of a variety of techniques known to those of ordinary skill in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definition, and conformational definition.

The Kabat numbering system is a standard for numbering residues in antibodies and is often used to identify CDR regions (see, e.g., Johnson & Wu, 2000, Nucleic Acids Res., 28:214-8). The Chothia numbering system is similar to the Kabat numbering system, but the Chothia numbering system takes into account the position of certain structural loop regions. (See, e.g., Chothia et al., 1986, J. Mol. Biol., 196:901-17; Chothia et al., 1989, Nature, 342:877-83). The AbM numbering system uses an integrated suite of computer programs produced by the Oxford Molecular Group that model antibody structure (see, e.g., Martin et al., 1989, Proc Natl Acad Sci (USA), 86:9268-9272; "AbM™, A Computer Program for Modeling Variable Regions of Antibodies," Oxford, UK; Oxford Molecular, Ltd). The AbM numbering system uses a combination of knowledge databases and ab initio methods to model the tertiary structure of antibodies from the primary sequence (see Samudrala et al., 1999, "Ab Initio Protein Structure Prediction Using a Combined Hierarchical Approach" in PROTEINS, Structure, Function and Genetics Suppl., 3:194-198 for those described). Contact definitions are based on analysis of available complex crystal structures (see, e.g., MacCallum et al., 1996, J. Mol. Biol., 5: 732-45). In conformational definitions, the positions of CDRs can be identified as residues that make enthalpic contributions to antigen binding (see, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283: 1156-1166). Other CDR boundary definitions may not strictly follow one of the above methods, but still overlap with at least a portion of the Kabat CDR, although they may be shortened or lengthened based on predictions or experimental results that a particular residue or residue group does not significantly affect antigen binding. As used in the present disclosure, CDRs may refer to CDRs defined by any method known in the art (including combinations of methods).

The term "humanized antibody", also known as CDR-grafted antibody, refers to an antibody produced by transplanting non-human CDR sequences into the human antibody variable region framework. This can overcome the strong immune response induced by chimeric antibodies due to the large amount of non-human protein components they carry. In order to avoid a decrease in activity while reducing immunogenicity, the variable region of the fully human antibody can be subjected to minimal reverse mutations to maintain activity. Examples of "humanization" include "humanizing" a VHH domain derived from Camelidae by replacing one or more amino acid residues in the amino acid sequence of the original VHH sequence with one or more amino acid residues present at corresponding positions in the VH domain of a human conventional tetrapeptide chain structure antibody (also referred to as "sequence optimization" in this disclosure. In addition to humanization, "sequence optimization" may also cover other modifications to the sequence by one or more mutations that provide improved properties of VHH, such as removing potential post-translation modification sites). The humanized VHH domain may contain one or more fully human framework region sequences. In addition, to avoid a decrease in activity caused by a decrease in immunogenicity, the human antibody variable region framework sequence may be subjected to minimal reverse mutation or reversion mutation to maintain activity.

"Antigen-binding fragment" includes single-chain antibodies (i.e., heavy chain or light chain); Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single domain antibodies (e.g., VH or VL or VHH), scFv, bivalent or trivalent or tetravalent antibodies, Bis-scFv, diabody, tribody, tetrabody and epitope-binding fragments of any of the above (see, e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9): 1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217). Methods for producing and preparing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181). The Fab-Fv format was first disclosed in WO2009/040562, and its disulfide-stabilized form Fab-dsFv was first disclosed in WO2010/035012. The antigen-binding fragments disclosed herein also include Fab and Fab' fragments described in WO2005/003169, WO2005/003170, and WO2005/003171. Multivalent antibodies may contain multiple specificities, such as bispecificity or monospecificity (see, e.g., WO92/22583 and WO05/113605).

The terms "homology", "identity" or "sequence identity" refer to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in the two compared sequences is occupied by the same nucleotide or amino acid monomer, for example, if every position in two DNA molecules is occupied by the same nucleotide, then the molecules are homologous at that position. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100%. For example, if 6 out of 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous. Generally, a comparison is made when the two sequences are aligned to obtain the maximum percentage of homology.

An "effective amount" includes an amount sufficient to improve or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount for a subject may vary depending on factors such as the condition to be treated, the subject's general health, the method and dosage of administration, and the severity of side effects. The effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects. The subject of the present disclosure may be an animal or human subject.

The term "pharmaceutical composition" refers to a mixture containing one or more active ingredients described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

"Cancer," "cancerous," "proliferative disorder," and "tumor" are not mutually exclusive when used in this disclosure.

The terms "administering," "applying," and "treating" when applied to an animal, a human, an experimental subject, a cell, a tissue, an organ, or a biological fluid, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid, such as for treatment, pharmacokinetic, diagnostics, research, and experimental procedures. Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with a cell. "Administering," "applying," and "treating" also mean the in vitro and ex vivo treatment of, for example, a cell by an agent, a diagnostic, a binding composition, or by another cell. When applied to human or veterinary medicine or research subjects, it refers to therapeutic treatment, prophylactic or preventive measures, research and diagnostic applications.

The term "treatment" means administering a therapeutic agent, such as any fusion protein or insulin analog disclosed herein, to a subject who has, is suspected of having, or is prone to having one or more diabetes or hyperglycemia-related diseases or symptoms thereof, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered to a subject or group of subjects in an amount effective to alleviate one or more disease symptoms, by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or illness to any clinically measurable extent. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") may vary according to a variety of factors, such as the disease state, age, and weight of the subject, and the ability of the drug to produce the desired therapeutic effect in the subject. Whether a disease symptom has been alleviated may be assessed by any clinical test normally used by a physician or other professional health care provider to assess the severity or progression of the symptom. Although the embodiments of the present disclosure (e.g., treatment methods or products) may not be effective in alleviating the symptoms of the target disease in a subject, they should reduce the symptoms of the target disease in a statistically significant number of subjects as determined by any statistical test method known in the art, such as Student's t test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test. The patient to be treated is a mammal, and preferably a human.

The term "prevent" means to reduce the risk or incidence of, or eliminate or slow the progression of, one or more conditions, symptoms, complications, or disorders.

The terms "subject" and "patient" refer to mammals, especially primates, and especially humans.

The "treatment failure" mentioned in this disclosure refers to the subject having measurable tumor lesions at baseline, and being in progressive disease (PD) or intolerable according to the RECIST v1.1 efficacy evaluation criteria.

"Intolerable" in this disclosure means that the patient cannot continue to receive treatment due to adverse reactions caused by the drug.

Overall survival (OS) refers to the period from the randomization period to death due to any cause. For subjects who are still alive at the last randomization visit, their OS is counted as data loss based on the time of the last randomization visit. For subjects who are lost to the visit, their OS is counted as data loss based on the last confirmed survival time before the loss. The OS of data loss is defined as the time from randomization grouping to loss.

Objective response rate (ORR) refers to the proportion of patients whose tumor shrinkage reaches a certain level and is maintained for a certain period of time, including cases of CR and PR. The tumor response evaluation criteria (RECIST 1.1 standard) are used to assess tumor objective response. The subjects must have measurable tumor lesions at baseline, and the efficacy evaluation criteria are divided into complete response (CR), partial response (PR), stable (SD), and progressive (PD) according to the RECIST 1.1 standard.

6週)病例數在可評價療效患者中的百分比。 Disease Control Rate (DCR) refers to the confirmed complete remission, partial remission and disease stabilization (

6 weeks) as a percentage of patients with evaluable efficacy.

Complete remission (CR): All target lesions disappear, and the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm.

Partial response (PR): The sum of target lesion diameters decreased by at least 30% compared with the baseline level.

Disease progression (PD): The minimum value of the sum of all target lesion diameters measured during the entire experimental 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 diameters must increase by at least 5mm (the appearance of one or more new lesions is also considered disease progression).

Stable disease (SD): The reduction of target lesions does not reach the level of PR, and the increase does not reach the level of PD, but is somewhere in between. The minimum value of the sum of diameters can be used as a reference for research.

The following embodiments are used to further describe the present disclosure, but these embodiments do not limit the scope of the present disclosure.

Experimental methods disclosed in the embodiments or test examples that do not specify specific conditions are generally carried out under conventional conditions or under conditions recommended by raw material or product manufacturers. See Sambrook et al., Molecular Cloning, a Laboratory Manual, Cold Spring Harbor Laboratory; Contemporary Methods in Molecular Biology, Ausubel et al., Greene Publishing Associates, Wiley Interscience, NY.

Reagents whose specific sources are not specified are common reagents purchased from the market.

Example 1. Ligand-drug conjugate (ADC-1)

(1) Ligand-drug conjugate (ADC-1)

ADC-1 has the following structure:

The preparation method of ADC-1 refers to WO2021147993A1, n=4.0, and the heavy chain and light chain sequences of the PD3 antibody are shown in SEQ ID NO: 9 and SEQ ID NO: 10 in this disclosure. Specification: 80 mg/bottle.

(2) Anti-TROP2 antibody: Its heavy chain sequence is SEQ ID NO: 9, and its light chain sequence is SEQ ID NO: 10. Specification: 13mL/bottle, 40mg/mL; Usage: Dilute to the target concentration with 0.9% sodium chloride injection, and administer by gargling or oral local injection.

Example 2. Results of Phase I Clinical Safety Study of Anti-TROP2 Antibody-Drug Conjugate (ADC-1)

In the dose escalation phase of the Phase I study, a total of 18 subjects were enrolled and 4 dose levels were explored, including 1 in the 1.5 mg/kg group, 4 in the 3.0 mg/kg group, 8 in the 4.0 mg/kg group (intermediate dose determined by SMC), and 5 in the 6.0 mg/kg group. A total of 16 subjects completed the dose-limiting toxicity (DLT) observation, of which 4 subjects had protocol-specified DLT events, all of which were CTCAE grade 3 oral mucositis (1 in the 4.0 mg/kg group and 3 in the 6.0 mg/kg group). After discussion by SMC, the maximum tolerated dose (MTD) of ADC-1 monotherapy was determined to be 4.0 mg/kg, Q3W, and four dose levels were determined to be expanded, namely 3.0 mg/kg, Q3W, 3.5 mg/kg, Q3W, 2.0 mg/kg, D1, D8 administration (2.0+2.0 mg/kg), Q3W, and 2.4 mg/kg, Q2W.

20.0%)為口腔黏膜炎(65.9%)、噁心(43.3%)、貧血(42.3%)、嘔吐(31.3%)、體重降低 (28.4%)、食欲減退(22.6%)、脫髮(22.1%)；發生於

2例受試者的CTCAE

3級TRAE為口腔黏膜炎(11.5%)、澱粉酶升高(3.4%)、嘔吐(2.9%)、咽部炎症(2.4%)、噁心、白細胞計數降低、中性粒細胞計數降低(各1.9%)、高甘油三酯血症、貧血、血小板計數降低、C反應蛋白升高、γ-穀胺醯轉移酶升高(各1.4%)、低鉀血症、丙胺酸胺基轉移酶升高、天門冬胺酸胺基轉移酶升高、血鹼性磷酸酶升高、血膽紅素升高、感染性肺炎(各1.0%)。未發生導致死亡的TRAE。 As of August 24, 2023, in the Phase I study of ADC-1, a total of 208 subjects with advanced solid tumors (not limited to non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, pancreatic cancer, gallbladder cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal cancer, urothelial carcinoma, salivary gland cancer) were enrolled in the dose range of 1.5mg/kg~6.0mg/kg. Among them, the treatment-related adverse events (TRAEs) are shown in Table 2. The most common TRAEs (incidence

20.0%) were oral mucositis (65.9%), nausea (43.3%), anemia (42.3%), vomiting (31.3%), weight loss (28.4%), loss of appetite (22.6%), and hair loss (22.1%);

CTCAE in 2 subjects

Grade 3 TRAEs included oral mucositis (11.5%), increased amylase (3.4%), vomiting (2.9%), pharyngitis (2.4%), nausea, decreased white blood cell count, decreased neutrophil count (1.9% each), hypertriglyceridemia, anemia, decreased platelet count, increased C-reactive protein, increased γ-glutamyl transferase (1.4% each), hypokalemia, increased alanine aminotransferase, increased aspartate aminotransferase, increased serum alkaline phosphatase, increased hemobilirubin, and infectious pneumonia (1.0% each). No TRAEs resulted in death.

10%或CTCAE

3級發生於

2例受試者的TRAE(基於SS)

Table 2. Incidence of all grades in the ADC-1 study

10% or CTCAE

Level 3 occurs in

TRAEs in 2 subjects (based on SS)

As shown in Table 2, the administration of ADC-1 can reduce the incidence and severity of adverse reactions such as neutropenia, diarrhea, decreased white blood cell count, and hypersensitivity in tumor patients during tumor treatment. The incidence of TRAEs for decreased white blood cell count and decreased neutrophil count was 1.9% each, and the incidence of TRAEs for increased C-reactive protein was 1.4%. Moreover, when ADC-1 was administered to subjects at 3.0 mg/kg, Q3W, the incidence of various adverse reactions such as oral mucositis could be further reduced.

Example 3. Results of Phase I Clinical Drug Metabolism Study of Anti-TROP2 Antibody-Drug Conjugate (ADC-1)

As of September 20, 2023, the Phase I study of ADC-1 has tested intensive PK samples (including dose escalation and PK expansion phases) of 1.5, 2.0+2.0, 3.0, 3.5, 4.0 and 6.0 mg/kg Q3W, and 2.4 mg/kg Q2W dose groups. Preliminary PK data showed that within the dose range of 1.5~6.0 mg/kg, the exposure of ADC and total antibody after a single intravenous infusion of ADC-1 was similar, and the C _max and AUC of ADC were approximately linear with the dose. After administration of 2.0+2.0 mg/kg Q3W, the C _max of each component was no higher than the C _max level of 3 mg/kg Q3W; its ADC AUC _0-21d was equivalent to the corresponding value of 3.5-4 mg/kg Q3W. The average terminal elimination half-life of ADC after a single dose of ADC-1 is about 2.5-3.8 days; the average clearance rate of ADC-1 is about 0.50-0.76L/day; the average distribution volume is about 2.7-3.2L. In the dosage range of 1.5~6.0mg/kg, the exposure of free toxin after a single dose of ADC-1 is low, and _Cmax and AUC increase approximately proportionally with the dose. The average half-life of free toxin after a single intravenous infusion is about 4.4-4.9 days. At the dosage of 3.0mg/kg Q3W and 2.0+2.0mg/kg Q3W, there is basically no accumulation of ADC, total antibody, and free toxin exposure after multiple doses.

Example 4. ADC-1 combined with anti-TROP2 antibody

1. Experimental drugs

ADC-1 prepared in Example 1, anti-TROP2 antibody gargle solution.

2. Participants

18週歲，男女不限； (1) Age

18 years old, male or female;

(2) Patients with clinically diagnosed or pathologically confirmed advanced solid tumors who have failed standard treatment (disease progression or toxic intolerance), or who have no effective standard treatment options or refuse standard treatment;

(3) At least one measurable lesion that meets the RECIST v1.1 criteria;

(4) Eastern Cooperative Oncology Group (ECOG) performance status is 0 or 1;

12週； (5) Expected survival

12 weeks;

(6) Vital organs function well;

(7) Female subjects of childbearing potential and male subjects whose partners are female subjects of childbearing potential need to use highly effective contraceptive measures from the time they sign the informed consent form to 210 days (female subjects) or 120 days (male subjects) after the last dose of the trial drug; female subjects of childbearing potential must have a negative serum HCG test within 7 days before the first dose, and must not be breastfeeding.

3. Method of medication administration

Medication plan I:

(1) Anti-TROP2 antibody: gargle once in the morning and once in the evening; the dosage each time is 5-60 mg. Prepare the anti-TROP2 antibody into a 1 mg/mL gargle solution, gargle 10-20 mL each time for 1-2 minutes, and repeat 2-3 times each time.

(2) ADC-1: once every three weeks (Q3W), administered on the first day of each cycle; administered by intravenous injection (iv), with a dose of 1.5, 3.0, 3.5, 4.0 or 6.0 mg/kg;

Anti-TROP2 antibodies are administered 1 day, 2 days, 3 days or on the same day before ADC-1 administration and are administered continuously during the ADC-1 administration cycle.

Medication regimen II:

(1) Anti-TROP2 antibody: gargle once in the morning and once in the evening; the dosage each time is 5-60 mg.

(2) ADC-1: Once every three weeks (Q3W), administered on the first and eighth day of each cycle; administered by intravenous injection (iv), the dosage is 2.0 mg/kg.

Anti-TROP2 antibodies are administered 1 day, 2 days, 3 days or on the same day before ADC-1 administration and are administered continuously during the ADC-1 administration cycle.

Dosage plan III:

(1) Anti-TROP2 antibody: gargle once in the morning and evening; the dosage each time is 5-60 mg.

(2) ADC-1: Once every two weeks (Q2W), administered on the first day of each cycle; administered by intravenous injection (iv), the dosage is 2.4 mg/kg.

Anti-TROP2 antibodies are administered 1 day, 2 days, 3 days or on the same day before ADC-1 administration and are administered continuously during the ADC-1 administration cycle.

4. Results

The incidence and severity of oral mucositis were evaluated according to the CTCAE v5.0 grading system. 34 subjects were administered anti-TROP2 antibodies and ADC-1 according to dosing regimen I, and 47 subjects were administered only ADC-1, and the administration regimen of ADC-1 was the same as that of dosing regimen I. The results are shown in Table 3 below:

Table 3. Incidence of oral mucositis in patients treated with ADC-1 with or without anti-TROP2 antibody

From the results in Table 3, it can be seen that after using anti-TROP2 antibody mouthwash, the occurrence of oral mucositis above grade 2 or 3 can be effectively prevented, thereby reducing the suspension or reduction of dosage due to oral mucositis.

Although the above describes the specific implementation schemes of the present disclosure, those with ordinary knowledge in the field should understand that these are only examples, and various changes or modifications can be made to these implementation schemes without departing from the principles and essence of the present disclosure. Therefore, the scope of protection of the present disclosure is limited by the scope of the attached patent application.

TW202438107A_113111857_SEQL.xml

Claims (22)

Use of an anti-TROP2 antibody in the preparation of a drug for preventing, alleviating or eliminating adverse reactions caused by a drug targeting TROP2 in a subject. The use as described in claim 1, wherein the adverse reaction is an adverse reaction related to the treatment of tumors with drugs targeting TROP2, preferably oral mucositis. Use of an anti-TROP2 antibody combined with a drug targeting TROP2 in the preparation of a drug for treating tumors or use of a combination of an anti-TROP2 antibody and a drug targeting TROP2 in the preparation of a drug for treating tumors. The use as described in claim 3, wherein the anti-TROP2 antibody reduces the adverse reaction caused by the drug targeting TROP2 in the subject, and the adverse reaction is preferably oral mucositis. The use as described in any one of claims 1 to 4, wherein the tumor is a solid tumor, or a mid- to late-stage solid tumor; preferably, the tumor is non-small cell lung cancer, small cell lung cancer, ovarian cancer, fallopian tube cancer, primary peritoneal cancer, pancreatic cancer, bile duct cancer, breast cancer, cervical cancer, colorectal cancer, gastric cancer, gastric or gastroesophageal junction adenocarcinoma, esophageal cancer, urothelial carcinoma, salivary gland cancer. The use as described in any one of claims 1 to 5, wherein the anti-TROP2 antibody is administered to the subject during the administration cycle of the drug targeting TROP2; Alternatively, the anti-TROP2 antibody is administered to the subject before the start of the dosing cycle of the drug targeting TROP2; Alternatively, the anti-TROP2 antibody is administered to the subject before and during the dosing cycle of the drug targeting TROP2. The use as described in any one of claims 1 to 6, wherein the anti-TROP2 antibody is administered orally; preferably, it is administered by oral gargle or local injection in the oral cavity. The use as described in any one of claims 1 to 7, wherein the anti-TROP2 antibody is administered via oral gargle, and the frequency of administration of the anti-TROP2 antibody is at least once a day; and/or, The dosage of the anti-TROP2 antibody is 1-500 mg/time, 5-100 mg/time, 5-60 mg/time, 10-60 mg/time, 15-60 mg/time, 20-60 mg/time, or 30-60 mg/time; preferably about 5 mg/time, about 10 mg/time, about 15 mg/time, about 30 mg/time, about 40 mg/time, about 60 mg/time, about 80 mg/time, about 100 mg/time, or about 200 mg/time. The use as described in any one of claims 1 to 8, wherein the anti-TROP2 antibody is administered by local intraoral injection, and the administration frequency of the anti-TROP2 antibody is selected from at least once every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks or every 10 weeks, preferably once every 2 weeks, once every 3 weeks, twice every 3 weeks, once every 4 weeks, or once every 6 weeks; and/or, The dosage of the anti-TROP2 antibody is 0.1-500 mg/time, 0.5-100 mg/time, 0.3-50 mg/time, or 0.3-30 mg/time; preferably about 0.5 mg/time, about 1 mg/time, about 3 mg/time, about 5 mg/time, about 10 mg/time, about 20 mg/time, about 50 mg/time, about 70 mg/time, or about 80 mg/time. The use as described in any one of claims 1 to 9, wherein the anti-TROP2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 90% sequence identity thereto; and, the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 90% sequence identity thereto; Preferably, the anti-TROP2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9 or having at least 90% sequence identity thereto; and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10 or having at least 90% sequence identity thereto. The use as described in any one of claims 1 to 10, wherein the drug targeting TROP2 is a ligand-drug conjugate targeting TROP2; the ligand-drug conjugate has the following structure:

Wherein, the PD3 is an anti-TROP2 antibody; n is an integer or decimal from 1 to 10, preferably 4±0.6; preferably, the anti-TROP2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; Preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 90% sequence identity thereto; and, the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 90% sequence identity thereto; Preferably, the anti-TROP2 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9 or having at least 90% sequence identity thereto; and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10 or having at least 90% sequence identity thereto. The use as described in any one of claims 1 to 11, wherein the dosage of the drug targeting TROP2 is 1-12 mg/kg, or 1.5-12 mg/kg; preferably about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, or about 12 mg/kg; and/or, The drug targeting TROP2 is administered at least once every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks or every 10 weeks, preferably once every 3 weeks, twice every 3 weeks or once every 2 weeks; Preferably, the administration regimen of the drug targeting TROP2 is selected from any of the following (a)-(c): (a) The frequency of administration is once every 3 weeks, and the administration is on the first day of each administration cycle. The dosage of each administration is about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, or about 12 mg/kg; (b) The frequency of administration is twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage for each administration is approximately 2.0 mg/kg; (c) The dosing frequency is once every 2 weeks, on the first day of each dosing cycle, and the dose per dose is approximately 2.4 mg/kg. The use as described in any one of claims 1 to 12, wherein the drug targeting TROP2 is administered by intravenous injection. The use as described in any one of claims 1 to 13, wherein the dosing regimen of the anti-TROP2 antibody and the drug targeting TROP2 is: (i) administering a gargle containing an anti-TROP2 antibody to the subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, (ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 being administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg; or, (i) administering a gargle containing an anti-TROP2 antibody to the subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, (ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 being administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg; or, (i) administering a gargle containing an anti-TROP2 antibody to the subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, (ii) administering a drug targeting TROP2 to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks, and each administration dose is approximately 3 mg/kg; or, (i) administering a gargle containing an anti-TROP2 antibody to the subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, (ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage of each administration is about 2.0 mg/kg; or, (i) administering a gargle containing an anti-TROP2 antibody to the subject; wherein the gargle is administered at least once a day, and the dosage of the anti-TROP2 antibody in the gargle is 1-200 mg/time, (ii) administering a drug targeting TROP2 to the subject, with the drug targeting TROP2 being administered once every 2 weeks at a dosage of approximately 2.4 mg/kg each time; or, (i) administering the anti-TROP2 antibody to the subject by local oral injection; wherein the dosage of the anti-TROP2 antibody is 0.1-50 mg/time, and the frequency of administration is once or twice every 3 weeks; (ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 being administered once every 3 weeks at a dosage of about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, about 12 mg/kg; (i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; (ii) administering a drug targeting TROP2 to the subject, wherein the drug targeting TROP2 is administered once every 3 weeks, and each administration dose is approximately 3 mg/kg; or, (i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once or twice every 3 weeks, and the dosage is 0.1-50 mg/time; (ii) administering a drug targeting TROP2 to the subject, the drug targeting TROP2 is administered twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage of each administration is about 2.0 mg/kg; or, (i) administering the anti-TROP2 antibody to the subject by local injection into the oral cavity; wherein the anti-TROP2 antibody is administered once every 3 weeks, and the dosage is 0.1-50 mg/time; (ii) administering a drug targeting TROP2 to the subject, with the drug targeting TROP2 being administered once every 2 weeks at a dosage of approximately 2.4 mg/kg each time; Preferably, the anti-TROP2 antibody is administered to the subject during the administration cycle of the drug targeting TROP2; or, the anti-TROP2 antibody is administered to the subject before the start of the administration cycle of the drug targeting TROP2, and the anti-TROP2 antibody is maintained during the administration cycle of the drug targeting TROP2. A method for preventing, alleviating or eliminating adverse reactions caused by a drug targeting TROP2 in a subject, comprising administering the following (i), or the following (i) and (ii) drugs to a subject in need: (i) a preventive or therapeutically effective amount of an anti-TROP2 antibody, (ii) a therapeutically effective amount of a drug targeting TROP2; Wherein, the subject suffers from a tumor, preferably a solid tumor or an advanced solid tumor; the anti-TROP2 antibody is as defined in any one of claims 1 to 14, and the drug targeting TROP2 is as defined in any one of claims 1 to 14; Preferably, the adverse reactions include oral mucositis, neutropenia, diarrhea, hypersensitivity, and decreased white blood cell count. A method for treating tumors, comprising administering a therapeutically effective amount of a drug targeting TROP2 to a subject in need thereof; wherein the drug targeting TROP2 has the following structure:

Wherein, the PD3 is an anti-TROP2 antibody; n is an integer or decimal from 1 to 10, preferably 4±0.4; The dosage of the drug targeting TROP2 is 1-12 mg/kg or 1.5-12 mg/kg; and/or, the frequency of administration of the drug targeting TROP2 is at least once every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks or every 10 weeks; Preferably, the administration regimen of the drug targeting TROP2 is selected from any of the following (a)-(c): (a) The frequency of administration is once every 3 weeks, and the dosage of each administration is about 1.5 mg/kg, about 2 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 6 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg, or about 12 mg/kg; (b) The frequency of administration is twice every 3 weeks, on the 1st and 8th day of each dosing cycle, and the dosage for each administration is approximately 2.0 mg/kg; (c) The frequency of administration is once every 2 weeks, and the dosage per administration is approximately 2.4 mg/kg. The method of claim 16, wherein the drug targeting TROP2 reduces the adverse reactions associated with tumor treatment in the subject, the adverse reactions including: oral mucositis, neutropenia, diarrhea, hypersensitivity, and/or decreased white blood cell count. A method as described in claim 16 or 17, which comprises administering a preventive or therapeutically effective amount of an anti-TROP2 antibody and a therapeutically effective amount of a drug targeting TROP2 to a subject in need; The anti-TROP2 antibody is defined in any one of claims 1 to 14, and the drug targeting TROP2 is defined in any one of claims 1 to 14. A pharmaceutical packaging box or product comprising an anti-TROP2 antibody as defined in any one of claims 1 to 14, and a drug targeting TROP2 as defined in any one of claims 1 to 14. A pharmaceutical composition comprising an anti-TROP2 antibody as defined in any one of claims 1 to 14, and a drug targeting TROP2 as defined in any one of claims 1 to 14. A use of a pharmaceutical composition, a drug packaging box or a product in the preparation of a drug for treating tumors; wherein the pharmaceutical composition, drug packaging box or product comprises an anti-TROP2 antibody as defined in any one of claims 1 to 14, and a drug targeting TROP2 as defined in any one of claims 1 to 14. A pharmaceutical composition, a drug packaging box or a product for use in preparing a drug for preventing, alleviating or eliminating adverse reactions caused by a drug targeting TROP2 in a subject; wherein the pharmaceutical composition, drug packaging box or product comprises an anti-TROP2 antibody as defined in any one of claims 1 to 14, and a drug targeting TROP2 as defined in any one of claims 1 to 14.