Method for treating cancer by using antibody-drug conjugate targeting trop2

Abstract

A method for treating cancer by means of administering to an individual in need thereof an antibody-drug conjugate targeting TROP2, a single-dose unit and a kit of parts containing same, and the use thereof.

Description

Methods for treating cancer with antibody-drug conjugates targeting TROP2 Technical Field

[0001] The present invention relates to the field of disease treatment. Specifically, the present invention relates to a method for treating cancer (especially solid tumors) using an antibody-drug conjugate targeting TROP2. Background Art

[0002] TROP2, a trophoblast cell surface antigen, also known as tumor-associated calcium signaling protein (TACSTD2), is overexpressed in a variety of human epithelial cancers, including breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, prostate cancer, cervical cancer, head and neck cancer, and ovarian cancer (Yezhe Cheng et al., Frontiers in Oncology, 2022 Dec 23;12:951589).

[0003] In the past decade, several TROP2-targeted therapies have entered clinical trials for the treatment of various cancers, and some indications have been approved. ) was developed by Immunomedics Inc. and is an ADC based on a humanized anti-TROP2 monoclonal antibody. It is currently the only approved anti-TROP2 therapy in the world. The IMMU-132-01 Phase I / II basket trial (NCT01631552) evaluated the safety and efficacy of SG in adult patients with various advanced epithelial malignancies who had progressed after at least one standard treatment regimen. The results showed that SG demonstrated anti-tumor efficacy in non-small cell lung cancer (n=47), small cell lung cancer (SCLC; n=50), metastatic urothelial carcinoma (n=45), metastatic hormone receptor (HR)-positive / human epidermal growth factor receptor 2 (HER2)-negative breast cancer (n=54), and metastatic triple-negative breast cancer (MTNBC; n=108). In the mTNBC cohort, the objective response rate (ORR) was 33.3%, with a median duration of response (DoR) of 7.7 months. These results support the accelerated approval of SG for the treatment of adult patients with mTNBC who have received at least two prior therapies for metastatic disease. The TROPHY trial was a single-arm, multicenter study that enrolled 112 patients with locally advanced or metastatic UC who had previously received platinum-based chemotherapy and a programmed death receptor 1 (PD-1) or its ligand PD-L1 inhibitor. Tumor assessments were performed by an independent review committee according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, resulting in an ORR of 27.7% and a median DoR of 7.2 months. These results support the accelerated approval of SG for the treatment of adult patients with locally advanced or metastatic UC who have previously received platinum-based chemotherapy and a PD-(L)1 inhibitor. The TROPiCS-02 study was a multicenter, open-label, randomized study (NCT03901339) that enrolled 543 patients (SG group: n = 272; single-agent chemotherapy group: n = 271) with locally advanced or metastatic HR-positive / HER-negative breast cancer. The median PFS for SG versus single-agent chemotherapy was 5.5 versus 4.0 months, and the median OS was 14.4 versus 11.2 months. SG demonstrated statistically significant improvements in PFS and OS compared with single-agent chemotherapy.These results support the further approval of SG for the treatment of patients with HR-negative / HER2-positive breast cancer who have previously received endocrine therapy and at least two other systemic therapies for metastatic disease.

[0004] For patients with advanced malignancies, current options are very limited, and there is an unmet clinical need. Although anti-TROP2 ADCs have been approved for marketing in some indications, they are currently limited to late-line treatment for patients with triple-negative breast cancer, urothelial carcinoma, and HR-positive / HER-negative breast cancer. For other malignancies with widespread and overexpressed TROP2, anti-TROP2 ADCs are worth further exploration, and there is still considerable room for further development of more effective and safe anti-TROP2 ADCs.

[0005] SUMMARY OF THE INVENTION

[0006] The present invention meets the above unmet needs by providing methods for treating solid tumors using antibody-drug conjugates targeting TROP2.

[0007] To achieve the above objectives, the present invention first provides a method for preventing or treating solid tumors, which comprises administering an effective amount of an antibody-drug conjugate targeting TROP2 to an individual in need thereof.

[0008] The present invention also provides use of an antibody-drug conjugate targeting TROP2 in preparing a drug for preventing or treating solid tumors.

[0009] The present invention also provides an antibody-drug conjugate targeting TROP2, which is used for preventing or treating solid tumors.

[0010] In order to achieve the above object, the present invention also provides a single-dose unit, comprising: an effective amount of the above-mentioned antibody-drug conjugate targeting TROP2 of the present invention;

[0011] Wherein, the antibody-drug conjugate targeting TROP2 is:

[0012] wherein Ab is an antibody or an antigen-binding fragment thereof targeting TROP2;

[0013] Wherein, p is the average drug to antibody ratio (ie, average DAR), for example, 1-15, 1-10, 2-8, 2-4, or 4-5.

[0014] Wherein, the antibody or antigen-binding fragment thereof targeting TROP2 comprises HCDR1, HCDR2, HCDR3 as shown in the following amino acid sequences: SEQ ID NO: 1, 2 and 3, and LCDR1, LCDR2 and LCDR3 as shown in the following amino acid sequences: SEQ ID NO: 6, 7 and 8, respectively.

[0015] The antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region

[0016] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or

[0017] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; and / or

[0018] Light chain variable region

[0019] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or

[0020] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, consisting of said amino acid sequence. Preferably, said amino acid changes do not occur in the CDR regions.

[0021] The antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain and a light chain, wherein the heavy chain

[0022] comprising or consisting of the amino acid sequence of SEQ ID NO: 5; or

[0023] An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 5; and

[0024] light chain

[0025] comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or

[0026] An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 10.

[0027] The method comprises administering to the individual approximately 0.1 mg / kg to 100 mg / kg of an antibody-drug conjugate targeting TROP2.

[0028] The method comprises administering to the individual approximately 0.2 mg / kg to 50 mg / kg of an antibody-drug conjugate targeting TROP2.

[0029] The method comprises administering to the individual approximately 0.3 mg / kg to 30 mg / kg of an antibody-drug conjugate targeting TROP2.

[0030] wherein the method comprises administering to the individual approximately 0.3 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.3 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.2 mg / kg, 3.5 mg / kg, 3.8 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.4 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2.

[0031] The method comprises administering to the individual approximately 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2.

[0032] The dosing cycle of this method is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W).

[0033] The dosing cycle of this method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W) or 4 weeks / 28 days (Q4W), and the drug is administered once on the first day of each cycle.

[0034] Wherein, the administration method includes intravenous administration.

[0035] Wherein, the antibody-drug conjugate targeting TROP2 is a lyophilized powder preparation.

[0036] The present invention also provides a use of an antibody-drug conjugate targeting TROP2 for preparing a drug for treating solid tumors, wherein the antibody-drug conjugate targeting TROP2 is as described above.

[0037] In order to achieve the above object, the present invention also provides a single-dose unit, comprising: an effective amount of the antibody-drug conjugate targeting TROP2 of the present invention.

[0038] The present invention further provides a complete drug kit, which comprises the above-mentioned effective amount of the antibody-drug conjugate targeting TROP2 of the present invention.

[0039] Use of the single-dose unit or complete kit of parts of the present invention in preparing drugs for preventing or treating solid tumors.

[0040] It is predicted that the antibody-drug conjugate targeting TROP2 of the present invention has certain safety and efficacy in treating solid tumors.

[0041] Other embodiments of the present invention will become apparent by reference to the detailed description which follows.

[0042] Detailed Description of the Invention

[0043] Before describing the present invention in detail, it should be understood that the present invention is not limited to the specific methods and experimental conditions in this specification, because the methods and conditions can be varied. In addition, the terminology used herein is only for describing specific embodiments and is not intended to be limiting.

[0044] definition

[0045] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present invention, the following terms are defined below.

[0046] The term "about" when used in conjunction with a numerical value is meant to encompass a range of numerical values ​​having a lower limit that is 5% (e.g., 4%, 3%, 2% or 1%) less than the specified numerical value and an upper limit that is 5% (e.g., 4%, 3%, 2% or 1%) greater than the specified numerical value.

[0047] The term "and / or" when used to link two or more alternatives should be understood to mean any one of the alternatives or any two or more of the alternatives.

[0048] As used herein, the terms "anti-TROP2 antibody," "anti-TROP2," "TROP2 antibody," or "anti-TROP2 antibody" refer to antibodies that bind to TROP2 protein with sufficient affinity. The antibodies can be used as diagnostic and / or therapeutic agents targeting TROP2, or used to construct immunoconjugates, such as antibody-drug conjugates.

[0049] The terms "complete antibody", "whole antibody" or "full-length antibody" are used interchangeably herein and refer to antibody molecules having the structure of a natural immunoglobulin molecule. In the case of a conventional four-chain IgG antibody, a full-length antibody comprises two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. In the case of a heavy chain antibody having only heavy chains and lacking light chains, a full-length antibody comprises two heavy chains (H) interconnected by disulfide bonds.

[0050] For conventional four-chain IgG antibodies, the full-length antibody heavy chain is generally composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region, wherein the heavy chain constant region comprises at least three domains: CH1, CH2, and CH3. The full-length antibody light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region, wherein the light chain constant region consists of one domain: CL. Each heavy chain variable region VH and each light chain variable region consists of three CDRs and four FRs, arranged from amino terminus to carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0051] The term "antibody fragment" includes a portion of an intact antibody. In a preferred embodiment, the antibody fragment is an antigen-binding fragment.

[0052] An "antigen-binding fragment" refers to a molecule, other than an intact antibody, that comprises a portion of an intact antibody and binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')2; dAb (domain antibody); linear antibodies; single-chain antibodies (e.g., scFv); single-domain antibodies such as VHH; diabodies or fragments thereof; or camelid antibodies.

[0053] The term "antigen" refers to a molecule that triggers an immune response. This immune response may involve the production of antibodies or the activation of specific immune cells, or both. It will be appreciated by those skilled in the art that any macromolecule, including substantially all proteins or peptides, can be used as an antigen. In addition, antigens can be derived from recombinant or genomic DNA. As used herein, the term "epitope" refers to a portion of an antigen (e.g., TROP2) that specifically interacts with an antibody molecule.

[0054] "Complementarity determining region" or "CDR region" or "CDR" is a region in an antibody variable domain that is highly variable in sequence and forms structurally determined loops ("hypervariable loops") and / or contains antigen contact residues ("antigen contact points"). CDRs are primarily responsible for binding to antigenic epitopes. The CDRs of the heavy and light chains are typically referred to as CDR1, CDR2, and CDR3, and are numbered sequentially starting from the N-terminus. The CDRs located within the antibody heavy chain variable domain are referred to as HCDR1, HCDR2, and HCDR3, while the CDRs located within the antibody light chain variable domain are referred to as LCDR1, LCDR2, and LCDR3. In a given light chain variable region or heavy chain variable region amino acid sequence, the precise amino acid sequence boundaries of each CDR can be determined using any one or a combination of a number of well-known antibody CDR assignment systems, including, for example, Chothia based on the three-dimensional structure of antibodies and the topology of the CDR loops (Chothia et al. (1989) Nature 342:877-883, Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), Kabat based on antibody sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), International ImMunoGeneTics database (IMGT) (on the World Wide Web at imgt.cines.fr / ), and North's CDR definitions based on affinity propagation clustering using a large number of crystal structures (North et al., "A New Clustering of Antibody CDR Loop Concepts", Journal of Molecular Biology, 406, 228-256 (2011)).

[0055] The following are the regional ranges of CDRs defined using the Kabat, AbM, Chothia, Contact, and IMGT schemes.

[0056] A CDR can also be identified based on having the same Kabat numbering position as a reference CDR sequence (eg, any of the exemplary CDRs of the invention).

[0057] Unless otherwise indicated, in the present invention, the term "CDR" or "CDR sequence" encompasses CDR sequences determined in any of the above-mentioned ways.

[0058] Unless otherwise indicated, in the present invention, when referring to residue positions in the variable region of an antibody (including heavy chain variable region residues and light chain variable region residues), the numbering refers to the position according to the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)).

[0059] In one embodiment, the heavy chain variable region CDRs of the antibodies of the present invention are determined according to the following rules:

[0060] VH CDR1 was determined according to the AbM rule; and VH CDR2 and 3 were both determined according to the Kabat rule.

[0061] In one embodiment, the light chain variable region CDRs of an antibody of the invention are determined according to the Kabat rules.

[0062] In one embodiment, the heavy chain variable region CDRs of the antibody of the invention are determined according to the following rules: VH CDR1 is determined according to the AbM rule; and VH CDR2 and 3 are both determined according to the Kabat rule; and the light chain variable region CDRs are each determined according to the Kabat rule.

[0063] It should be noted that the boundaries of the CDRs of the variable regions of the same antibody obtained based on different assignment systems may be different. That is, the CDR sequences of the variable regions of the same antibody defined under different assignment systems may be different. Therefore, when referring to antibodies defined by specific CDR sequences defined in the present invention, the scope of the antibodies also covers antibodies whose variable region sequences contain the specific CDR sequences, but whose claimed CDR boundaries are different from the specific CDR boundaries defined in the present invention due to the application of different schemes (e.g., different assignment system rules or combinations).

[0064] The term "Fc region" is used herein to define the C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. A native immunoglobulin "Fc domain" comprises two or three constant domains, namely a CH2 domain, a CH3 domain, and an optional CH4 domain. For example, in a native antibody, the immunoglobulin Fc domain comprises the second and third constant domains (CH2 domain and CH3 domain) of two heavy chains derived from IgG, IgA, and IgD class antibodies; or the second, third, and fourth constant domains (CH2 domain, CH3 domain, and CH4 domain) of two heavy chains derived from IgM and IgE class antibodies. Unless otherwise indicated herein, the numbering of amino acid residues in the Fc region or heavy chain constant region is according to the EU numbering system (also called the EU index) as described in Kabat et al., Sequences of Proteins of Immunological Interes, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Herein, the term "Fc region" does not include the heavy chain variable region VH and light chain variable region VL and the heavy chain constant region CH1 and light chain constant region CL of an immunoglobulin, but may include the hinge region at the N-terminus of the heavy chain constant region in some cases.

[0065] An "IgG-type antibody" refers to an antibody whose heavy chain constant region belongs to the IgG type. All antibodies of the same type have the same heavy chain constant region, while antibodies of different types differ in their heavy chain constant regions. For example, an antibody of the IgG4 type refers to an antibody whose heavy chain constant region is derived from IgG4, and an antibody of the IgG1 type refers to an antibody whose heavy chain constant region is derived from IgG1.

[0066] As used herein, the term "binding" or "specific binding" means that the binding effect is selective for the antigen and can be distinguished from unwanted or non-specific interactions. The ability of an antigen binding site to bind to a specific antigen can be determined by enzyme-linked immunosorbent assay (ELISA) or conventional binding assays known in the art, such as by radioimmunoassay (RIA) or thin-layer interferometry or MSD assays or surface plasmon resonance (SPR).

[0067] As used herein, "antibody-drug conjugate (ADC)" refers to a structure obtained by linking an antibody to a drug.

[0068] The term "drug:antibody ratio" or "DAR" refers to the ratio of the small molecule drug moiety (D) coupled to the Ab moiety described herein to the Ab moiety. In some embodiments described herein, the DAR can be determined by p or q, for example, the DAR can be 1 to 20, such as 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. The DAR can also be calculated as the average DAR of the population of molecules in the product, i.e., the overall ratio of the small molecule drug moiety coupled to the Ab moiety described herein to the Ab moiety in the product as measured by a detection method (e.g., by conventional methods such as mass spectrometry, ELISA assay, electrophoresis, and / or HPLC), and this DAR is referred to herein as the average DAR. In some embodiments, the average DAR value of the conjugate of the invention is 1 to 20, e.g., 2-18, 4-16, 5-12, 6-10, 2-8, 3-8, 2-6, 4-6, 6-10, e.g., 1.0-8.0, 2.0-6.0, e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1, 4.2, 4.3, 4.4 , 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9 or 10.0, and ranges having two of these values ​​as endpoints.

[0069] The term "pharmaceutical composition" or "formulation" refers to a composition suitable for administration to an animal, preferably a mammal (including a human) comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention is preferably in the form of parenteral administration, such as a solution, suspension, lyophilized powder, concentrated solution, etc.

[0070] The term "effective amount" refers to that amount or dosage of an antibody or fragment or composition or combination of the present invention which, after single or multiple doses, produces the desired effect in a patient in need of treatment or prevention.

[0071] A "therapeutically effective amount" is an amount effective to achieve the desired therapeutic outcome at the desired dosage and for the desired period of time. A therapeutically effective amount is also an amount in which any toxic or deleterious effects of the antibody or antibody fragment or composition or combination are outweighed by the therapeutically beneficial effects. A "therapeutically effective amount" preferably inhibits a measurable parameter (e.g., tumor volume) by at least about 30%, even more preferably by at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or even 100% relative to an untreated subject.

[0072] A "prophylactically effective amount" refers to an amount effective to achieve the desired preventive result, at the required dosage and for the required period of time. Typically, a prophylactic amount will be less than a therapeutically effective amount because a prophylactic dose is used in a subject prior to or at an earlier stage of disease.

[0073] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and progeny derived therefrom, without regard to the number of passages. Progeny may not be completely identical in nucleic acid content to the parent cell, but may contain mutations. Mutant progeny screened or selected for the same function or biological activity as the initially transformed cell are included herein.

[0074] The term "label" as used herein refers to a compound or composition that is directly or indirectly conjugated or fused to a reagent (such as a polynucleotide probe or antibody) and promotes the detection of the reagent to which it is conjugated or fused. The label itself can be detectable (e.g., a radioisotope label or a fluorescent label) or can catalyze a chemical change in a detectable substrate compound or composition in the case of an enzymatic label. The term is intended to encompass direct labeling of a probe or antibody by coupling (i.e., physically connecting) a detectable substance to the probe or antibody and indirect labeling of the probe or antibody by reacting with another reagent of the direct label.

[0075] "Individual" or "subject" includes mammals. Mammals include, but are not limited to, domestic animals (e.g., cattle, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual or subject is a human.

[0076] An "isolated" antibody or other molecule (e.g., ADC molecule) is one that has been separated from a component of its natural environment or the environment in which it is expressed. In some embodiments, the antibody or ADC molecule is purified to greater than 95% or 99% purity as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse phase HPLC).

[0077] The term "anti-tumor effect" refers to a biological effect that can be demonstrated by various means, including but not limited to, for example, a reduction in tumor volume, a reduction in tumor cell number, a reduction in tumor cell proliferation, or a reduction in tumor cell survival.

[0078] The terms "tumor" and "cancer" are used interchangeably herein to encompass both solid tumors and hematological tumors.

[0079] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. In certain embodiments, cancers suitable for treatment by the antibodies of the invention include gastric cancer, pancreatic cancer, or gastroesophageal junction cancer, including metastatic forms of those cancers.

[0080] The term "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer," "cancerous," and "tumor" are not mutually exclusive when referred to herein.

[0081] As used herein, "treat," ...

[0082] "Subject / patient / individual sample" refers to a collection of cells or fluids obtained from a patient or subject. The source of a tissue or cell sample can be solid tissue, such as an organ or tissue sample or a biopsy sample or a puncture sample from fresh, frozen and / or preserved; blood or any blood component; body fluids, such as cerebrospinal fluid, amniotic fluid (amniotic fluid), peritoneal fluid (ascites), or interstitial fluid; cells from any time during the subject's pregnancy or development. Tissue samples may contain compounds that are not naturally contaminated with tissue in nature, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, etc.

[0083] The term "lyophilized preparation" refers to a composition obtained or obtainable by freeze-drying a liquid preparation. Preferably, it is a solid composition having a water content of less than 5%, preferably less than 3%. The term "kit of parts" refers to a composition comprising one or more separate pharmaceutical compositions, at least one of which comprises an effective amount of an antibody-drug conjugate targeting TROP2, and preferably a package insert printed with instructions for using the antibody-drug conjugate targeting TROP2 for the prevention or treatment of solid tumors, in particular for administration according to the dosage regimen of the present invention. The kit of parts may also contain other therapeutic agents with the same or different activities. It will be understood that when the kit of parts contains multiple separate pharmaceutical compositions, each of the pharmaceutical compositions may contain different doses and / or be administered by different routes.

[0084] As used herein, the term "single-dose unit" refers to a discrete pharmaceutical unit containing an antibody or antigen-binding fragment thereof of the present invention to be administered to a patient, such as a vial, ampoule, prefilled needle or prefilled syringe for injection, which contains a solution or lyophilized powder of the drug, preferably a lyophilized powder.

[0085] As used herein, the term "parenteral administration" means modes of administration other than enteral and topical administration, usually by injection or infusion, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, and intrasternal injection and infusion.

[0086] The term "pharmaceutically acceptable" means that the substances, compositions, dosage forms, etc. described thereafter do not have excessive toxicity, irritation, allergic reactions or other undesirable properties to mammals, especially humans, and have a reasonable benefit / risk ratio when used in animals or humans.

[0087] The term "pharmaceutically acceptable excipient" refers to an ingredient in a pharmaceutical formulation other than the active ingredient, which is non-toxic to the subject.

[0088] The terms "standard anticancer treatment" or "standard treatment" are used interchangeably in this article and refer to the best treatment plan for a certain type of cancer that is widely recognized and widely used by the medical community at a specific time. It usually includes the single or combined use of multiple treatment methods such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. For example, the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Clinical Practice Guidelines in Oncology) describe the recognized standards for the treatment of various cancers.

[0089] The term "systemic anti-cancer therapy" refers to treatments that target tumors through a systemic approach. Unlike localized treatments, systemic therapy aims to deliver drugs or treatments throughout the body via the bloodstream to control tumor growth, metastasis, and recurrence.

[0090] The term "first-line treatment" refers to the first systemic treatment regimen received by patients with locally advanced, unresectable, recurrent or metastatic cancer. It is usually the best palliative treatment option for a specific type of cancer, and its purpose is to prolong patient survival. Generally speaking, standard treatment is selected for the first line of treatment. The term "second-line treatment" refers to the situation where, after the first line of treatment, the patient's tumor progresses again and is resistant to the first-line treatment regimen, and a regimen with a different anti-cancer mechanism needs to be replaced. Radical surgical resection or radiotherapy, preoperative neoadjuvant therapy, and postoperative adjuvant therapy are usually not counted as treatment lines.

[0091] Treatment

[0092] The present invention provides a method for preventing or treating solid tumors, which comprises administering an effective amount of an antibody-drug conjugate targeting TROP2 to an individual in need thereof.

[0093] The present invention also provides use of the TROP2-targeting antibody-drug conjugate of the present invention in preparing a drug for preventing or treating solid tumors.

[0094] The present invention also provides use of the TROP2-targeting antibody-drug conjugate of the present invention for preventing or treating solid tumors.

[0095] In one embodiment of the present invention, the antibody-drug conjugate targeting TROP2 is selected from:

[0096] wherein Ab is an antibody or an antigen-binding fragment thereof targeting TROP2;

[0097] p is the average drug to antibody ratio DAR (i.e., mean DAR), which is 1 to 15, such as 1-10, 2-8, 2-4 or 4-5, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, for example, p is 2-6; for example, p is a value between 2-6, 3-5, 4-5; preferably, the mean DAR is 4.

[0098] In one embodiment of the present invention, the antibody-drug conjugate targeting TROP2 is selected from:

[0099] wherein Ab is an antibody or an antigen-binding fragment thereof targeting TROP2;

[0100] q is the drug to antibody ratio DAR, which is 1 to 15, such as 1-10, 2-8, 2-4 or 4-5, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, for example, p is an integer between 2-6; for example, q is an integer between 2-6, 3-5, 4-5; preferably 4.

[0101] In a further specific embodiment of the present invention, the antibody targeting TROP2 or its antigen-binding fragment comprises HCDR1, HCDR2, and HCDR3 respectively containing the following amino acid sequences: SEQ ID NO: 1 (GYTFTNYGM), SEQ ID NO: 2 (WINTYTGEPTYTDDFKG) and SEQ ID NO: 3 (GGFGSSYWYFDV), and LCDR1, LCDR2, and LCDR3 respectively containing the following amino acid sequences: SEQ ID NO: 6 (KASQDVSIAVA), SEQ ID NO: 7 (SASYRYT) and SEQ ID NO: 8 (QQHYITPLT).

[0102] In a further specific embodiment of the present invention, the antibody targeting TROP2 or its antigen-binding fragment comprises HCDR1, HCDR2, HCDR3 as shown in the following amino acid sequences, respectively: SEQ ID NO: 1 (GYTFTNYGM), SEQ ID NO: 2 (WINTYTGEPTYTDDFKG) and SEQ ID NO: 3 (GGFGSSYWYFDV), and LCDR1, LCDR2 and LCDR3 as shown in the following amino acid sequences, respectively: SEQ ID NO: 6 (KASQDVSIAVA), SEQ ID NO: 7 (SASYRYT) and SEQ ID NO: 8 (QQHYITPLT).

[0103] Furthermore, the antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region

[0104] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or

[0105] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or

[0106] (iii) comprising an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 4;

[0107] and / or

[0108] Light chain variable region

[0109] (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or

[0110] (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or

[0111] (iii) comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:9.

[0112] In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain variable region and a light chain variable region, wherein

[0113] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:4, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:9.

[0114] In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain variable region and a light chain variable region, wherein

[0115] The heavy chain variable region consists of the amino acid sequence shown in SEQ ID NO: 4, and the light chain variable region consists of the amino acid sequence shown in SEQ ID NO: 9.

[0116] In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 of the present invention further comprises a heavy chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 of the present invention further comprises a light chain constant region. In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 of the present invention further comprises a heavy chain constant region and a light chain constant region.

[0117] In some embodiments, the heavy chain constant region HC of the present invention is the heavy chain constant region of IgG1, IgG2, IgG3, or IgG4, preferably the heavy chain constant region of IgG1, such as the wild-type IgG1 heavy chain constant region. In some embodiments, the heavy chain constant region HC of the present invention is the heavy chain constant region of human IgG1, IgG2, IgG3, or IgG4, preferably the heavy chain constant region of human IgG1, such as the wild-type human IgG1 heavy chain constant region. In some embodiments, the light chain constant region of the present invention is a lambda or kappa light chain constant region. In some embodiments, the light chain constant region of the present invention is a human lambda or human kappa light chain constant region.

[0118] In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain. In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 comprises a light chain. In some specific embodiments of the present invention, the heavy chain described herein comprises the heavy chain variable region and the heavy chain constant region, or consists of the heavy chain variable region and the heavy chain constant region. In some specific embodiments of the present invention, the light chain described herein comprises the light chain variable region and the light chain constant region, or consists of the light chain variable region and the light chain constant region.

[0119] More specifically, the antibody or antigen-binding fragment thereof targeting TROP2 described herein comprises a heavy chain and a light chain, wherein the heavy chain comprises or consists of the amino acid sequence of SEQ ID NO: 5 as shown below:

[0120] or

[0121] An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 5; or

[0122] comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 5; and

[0123] The light chain comprises or consists of the amino acid sequence shown below in SEQ ID NO: 10:

[0124] or

[0125] An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 10; or

[0126] comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:5.

[0127] In some embodiments, the antibodies or antigen-binding fragments thereof targeting TROP2 described herein comprise a heavy chain and a light chain, wherein

[0128] The heavy chain comprises the amino acid sequence shown in SEQ ID NO: 5, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 10.

[0129] In some embodiments, the antibody or antigen-binding fragment thereof targeting TROP2 of the present invention comprises a heavy chain and a light chain, wherein

[0130] The heavy chain consists of the amino acid sequence shown in SEQ ID NO: 5, and the light chain consists of the amino acid sequence shown in SEQ ID NO: 10.

[0131] In some embodiments, the antigen-binding fragment of the antibody targeting TROP2 is selected from Fab, Fab', F(ab')2, Fab'-SH, scFv or scFv-Fc.

[0132] In some embodiments, the antibody targeting TROP2 comprises two heavy chains and two light chains, for example, comprises two identical heavy chains and two identical light chains.

[0133] In some embodiments, the antibody targeting TROP2 is a full-length antibody.

[0134] In some embodiments, the antibody targeting TROP2 is a humanized antibody.

[0135] In some embodiments, the antibody targeting TROP2 is a monoclonal antibody.

[0136] In some embodiments, the antibody targeting TROP2 also encompasses multispecific antibodies that specifically bind to TROP2, such as bispecific antibodies.

[0137] In some embodiments, the antibody-drug conjugate targeting TROP2 suitable for use in the present invention is an antibody-drug conjugate disclosed in PCT Application No. PCT / CN2024 / 121813, which is incorporated herein in its entirety as if fully set forth herein. Preferably, the antibody-drug conjugate is the compound prepared in Example 4.1 of PCT Application No. PCT / CN2024 / 121813.

[0138] The antibody-drug conjugate targeting TROP2 of the present invention can be formulated into a preparation for administration. In some embodiments, the antibody-drug conjugate targeting TROP2 of the present invention is formulated into a liquid preparation or a lyophilized preparation, such as a lyophilized powder, such as a lyophilized powder injection for intravenous injection.

[0139] In a further embodiment of the present invention, the preparation of the antibody-drug conjugate targeting TROP2 is a lyophilized powder preparation, such as a lyophilized powder injection.

[0140] For example, the formulation of the TROP2-targeting antibody-drug conjugate of the present invention further comprises excipients such as histidine, histidine hydrochloride, sucrose, mannitol, and polysorbate 80.

[0141] In some specific embodiments, the administration of the TROP2 antibody-drug conjugate is by injection, such as subcutaneous injection or intravenous injection (e.g., infusion), preferably intravenous infusion or intravenous drip. In some specific embodiments, the TROP2 antibody-drug conjugate is administered by intravenous injection. More preferably, the TROP2 antibody-drug conjugate is administered by intravenous infusion. In some embodiments, the administration is administered through a peripheral vein. In some embodiments, the administration is performed by intravenous infusion using a microinjection pump through an indwelling intravenous cannula, preferably, the intravenous cannula is placed in a peripheral vein. In some embodiments, the administration is administered by a central venous catheter, an infusion port, or an infusion pump.

[0142] In a specific embodiment of the present invention, in the method of preventing or treating individual solid tumors of the present invention, it comprises administering to the individual 0.1 mg / kg-100 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 0.2 mg / kg-50 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 0.5 mg / kg-30 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 0.3 mg / kg-20 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 1 mg / kg-20 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 1 mg / kg-16 mg / kg of an antibody-drug conjugate targeting TROP2; further, the method comprises administering to the individual 1 mg / kg-12 mg / kg of an antibody-drug conjugate targeting TROP2. For example, the method comprises administering to the individual approximately 0.3 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.3 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.2 mg / kg, 3.5 mg / kg, 3.8 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.4 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2. Furthermore, the method comprises administering to the individual 0.3 mg / kg-20 mg / kg or 1-16 mg / kg of an antibody-drug conjugate targeting TROP2. For example, the method comprises administering to the individual approximately 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.5 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg.

[0143] In some embodiments, the antibody-drug conjugate targeting TROP2 can be administered continuously or discontinuously once or multiple times, for example, at least once, twice, three times or four times, for example, continuously administered at least four times. In some embodiments, the number of administrations is determined based on the patient's assessment of the effect. Therefore, in some embodiments, more than 4 times of the antibody-drug conjugate targeting TROP2 can be administered. It will be understood that the doses administered each time may be equal or unequal, preferably equal. Preferably, the dose is administered any integer number of times from 1 to 32 times, for example, 1 time, 5 times, 10 times, 15 times, 20 times, 25 times, 26 times, 27 times, 28 times, 29 times, 30 times, 31 times or 32 times. When multiple doses are administered, the dose is administered at intervals of 2 to 12 weeks, for example, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks or 12 weeks, preferably at intervals of 3 weeks. In some exemplary embodiments of the invention, when multiple doses are administered, the doses are administered at intervals of 3 weeks. Preferably, the same dose of antibody-drug conjugate targeting TROP2 is administered each time. In some embodiments, each dose is administered on the 1st day of each interval, or on the 2nd day or on the 3rd day, preferably on the 1st day. In some embodiments, the treatment phase lasts for 3 weeks to 24 months, for example, 3 months, 6 months, 12 months, 18 months or 24 months, from the first dose administration, preferably for 24 months. In one embodiment of the invention, the method comprises continuous administration for up to 24 months. In one embodiment of the invention, the method comprises continuous administration for 24 months. In some specific embodiments, the method administers an antibody-drug conjugate targeting TROP2 to a patient in need thereof by intravenous infusion for 24 months at intervals of 3 weeks.

[0144] In a specific embodiment of the present invention, the dosing cycle of the method is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W); further, the dosing cycle of the method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W), 4 weeks / 28 days (Q4W) or 5 weeks / 35 days (Q5W), and the drug is administered once on the 1st day of each cycle, or once on the 2nd day of each cycle, or once on the 3rd day of each cycle, preferably once on the 1st day of each cycle. Preferably, the dosing cycle of the method is 3 weeks / 21 days (Q3W), and the drug is administered once on the 1st day of each cycle.

[0145] In a specific embodiment of the present invention, the method comprises administering 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg or 16 mg of an antibody-drug conjugate targeting TROP2 to the individual, with a dosing cycle of 3 weeks / 21 days (Q3W), administered once on the first day of each cycle.

[0146] In one embodiment of the present invention, the administration method of the present invention comprises intravenous administration.

[0147] In a specific embodiment of the present invention, the method comprises administering to the individual intravenously (e.g., by infusion) 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2, with a dosing cycle of 3 weeks / 21 days (Q3W), administered once on day 1 of each cycle.

[0148] In a specific embodiment of the present invention, the method comprises administering to the individual intravenously (e.g., by infusion) 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2, with a dosing cycle of 3 weeks / 21 days (Q3W), once on day 1 of each cycle, for 24 months.

[0149] In some embodiments, the solid tumor is a malignant solid tumor. In some embodiments, the solid tumor is an advanced solid tumor. In some embodiments, the solid tumor is an advanced malignant solid tumor. In some embodiments, the solid tumor is a solid tumor that has failed standard treatment or is intolerant to standard treatment or the patient refuses standard treatment or there is no standard treatment regimen. In some embodiments, the solid tumor is an unresectable locally advanced or metastatic solid tumor, for example, the solid tumor is an unresectable locally advanced solid tumor or metastatic advanced solid tumor with at least one measurable lesion assessed according to RECIST v1.1. In some embodiments, the solid tumor is an unresectable locally advanced or metastatic advanced solid tumor that has failed standard treatment or is intolerant or the patient refuses standard treatment and has at least one measurable lesion assessed according to RECIST v1.1. In some embodiments, the solid tumor is a solid tumor that has previously received at least 1 line of anticancer treatment (e.g., systemic anticancer treatment). In some embodiments, the solid tumor is a solid tumor that has previously received 1 or 2 lines of anticancer treatment (e.g., systemic anticancer treatment). In some embodiments, the solid tumor is a solid tumor that has previously received two or more lines of anticancer therapy (e.g., systemic anti-tumor therapy).In some embodiments, the solid tumor is a solid tumor that has failed to be treated with a taxane or is intolerant to a taxane.

[0150] In some embodiments, the solid tumor is selected from breast cancer, such as triple-negative breast cancer, lung cancer, such as non-small cell lung cancer, or cervical cancer.

[0151] In some embodiments, the solid tumor is unresectable locally advanced or metastatic triple-differentiated breast cancer, non-small cell lung cancer, or cervical cancer.

[0152] In some embodiments, the solid tumor is unresectable locally advanced or metastatic advanced triple-differentiated breast cancer or non-small cell lung cancer or cervical cancer that has failed or is intolerant to standard treatment or the patient refuses standard treatment or has no standard treatment options, and has at least one measurable lesion assessed according to RECIST v1.1.

[0153] In some embodiments, the patient is a patient with locally advanced unresectable or metastatic triple-negative breast cancer who has failed or is intolerant to prior taxane therapy.

[0154] In some embodiments of the invention, the patient has previously received one or more treatments, such as other treatments for malignant tumors, such as treatments for other persistent disease conditions and palliative and supportive treatments for malignant tumors that are consistent with clinical intervention indications and institutional clinical standard procedures.

[0155] In some embodiments of the present invention, the patient may also receive other treatments, including but not limited to

[0156] (i) a preventive medication for reducing the toxicity of the antibody-drug conjugate targeting TROP2 of the present invention;

[0157] (ii) drugs used to treat any TRAEs or concurrent diseases that occurred during the medication and follow-up period, according to clinical indications;

[0158] (iii) blood products and / or growth factors, which are not given during the first week of treatment;

[0159] (iv) radiotherapy, such as radiotherapy that does not affect bone marrow function and is directed at non-target lesions to control pain;

[0160] (v) supportive medications to relieve tumor-related symptoms, such as bisphosphonates and denosumab for bone metastases;

[0161] (vi) immunosuppression or systemic hormone therapy (preferably not exceeding 10 mg / day prednisone equivalents), and optionally one or more treatments selected from the following:

[0162] Hormonal therapy to improve appetite (such as megestrol acetate);

[0163] · Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations;

[0164] Standard-dose hormone replacement therapy for end-organ failure;

[0165] Same as stable hormone therapy for prostate cancer*;

[0166] Stable hormone therapy for ovarian suppression, hormonal contraceptive therapy, or postmenopausal hormone replacement therapy

[0167] Steroid therapy to prevent contrast reactions;

[0168] Intra-articular steroid injections;

[0169] Low-dose maintenance steroid therapy for other conditions (e.g., asthma exacerbation, stable steroid therapy (excluding tapering of steroids) for cerebral edema);

[0170] In subjects with stable disease or ongoing remission, higher doses of steroids may be used to treat acute intercurrent illnesses (such as immune-related AEs or other adverse events). In such cases, study drug treatment should be interrupted during immunosuppressive therapy.

[0171] In some embodiments of the present invention, the therapeutic methods of the present invention using antibody-drug conjugates targeting TROP2 have tolerability, safety, and efficacy. In some embodiments of the present invention, the therapeutic methods of the present invention using antibody-drug conjugates targeting TROP2 have good hematological safety. In some embodiments of the present invention, the therapeutic methods of the present invention using antibody-drug conjugates targeting TROP2 have one or more of the following advantages:

[0172] (i) No adverse events greater than grade 3 occurred during treatment;

[0173] (ii) objective response rate greater than or equal to approximately 30%, 40%, or 50%;

[0174] (iii) a disease control rate greater than or equal to approximately 70%, 80%, 90%, or 100%; and / or

[0175] (iv) No dose-limiting toxicity and excellent hematological safety.

[0176] Single dose unit

[0177] In some aspects, the present invention relates to a single dose unit comprising: an effective amount of an antibody-drug conjugate targeting TROP2 of the present invention. Preferably, a fixed dose of 1-500 mg of an antibody-drug conjugate targeting TROP2 is included. For example, a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 mg of an antibody-drug conjugate targeting TROP2 is included. In some embodiments, the single dose unit is used for administration according to the dosing regimen of the present invention to prevent or treat solid tumors.

[0178] The single dose unit described herein is preferably used for parenteral administration, for example, for injection, such as intravenous injection (including intravenous infusion) or subcutaneous injection. In some embodiments, the single dose unit of the present invention is a solution or a lyophilized powder, preferably a lyophilized powder. The single dose unit can be a vial for injection, such as a vial, an ampoule, or a prefilled syringe, containing a solution or a lyophilized powder of an antibody-drug conjugate targeting TROP2, preferably a lyophilized powder. More preferably, the single dose unit described herein is a vial, such as a vial, of a lyophilized powder of an antibody-drug conjugate targeting TROP2 for parenteral administration. In some embodiments, the lyophilized powder formulation of the antibody-drug conjugate targeting TROP2 of the present invention is 50-150 mg / bottle (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg / bottle). In some embodiments, the single-dose unit described herein is 50-150 mg / vial (e.g., 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150 mg / vial) of a lyophilized powder of an antibody-drug conjugate targeting TROP2.

[0179] In some embodiments, a formulation comprising an antibody-drug conjugate targeting TROP2, such as a lyophilized powder, is reconstituted prior to administration. In some embodiments, the volume of drug to be infused is calculated based on the planned drug dosage and the solution, and the calculated volume of reconstituted drug is diluted in an intravenous infusion bag, such as one containing 0.9% sodium chloride injection. In some embodiments, the final concentration is in the range of approximately 1-9 mg / mL.

[0180] Complete set of medicine boxes

[0181] The present invention also provides a complete drug kit, comprising an effective amount of the antibody-drug conjugate targeting TROP2 of the present invention;

[0182] Preferably, a fixed dose of 1-500 mg of an antibody-drug conjugate targeting TROP2, or one or more single-dose units of an antibody-drug conjugate targeting TROP2, is included. For example, a fixed dose of 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200 or 500 mg of an antibody-drug conjugate targeting TROP2 is included.

[0183] Preferably, the kit further comprises a package insert containing instructions for using the antibody-drug conjugate targeting TROP2 in an individual to prevent or treat a solid tumor in the individual.

[0184] In some embodiments, the kit further comprises other therapeutic agents that can be combined or co-administered with the TROP2-targeting antibody-drug conjugate of the present invention, such as other therapeutic agents that can be used in concomitant therapy with the antibody-drug conjugate, such as other therapeutic agents in concomitant therapy as described herein.

[0185] application

[0186] The present invention also provides use of the single-dose unit or complete kit of the present invention in preparing a drug for preventing or treating solid tumors.

[0187] The present invention also provides a method for preventing or treating solid tumors, which comprises administering the single-dose unit or kit of parts of the present invention to an individual in need thereof.

[0188] The present invention also provides use of the single-dose unit or kit of parts of the present invention for preventing or treating solid tumors.

[0189] The antibody-drug conjugate targeting TROP2 in various embodiments of the present invention may also be replaced by a stereoisomer or a pharmaceutically acceptable salt or solvate of the antibody-drug conjugate.

[0190] The dosage regimens described herein (including antibody-drug conjugates with active agents targeting TROP2, dosage, mode of administration, dosing interval, number of doses, or duration of administration, etc.) and any one of their features or indications may be applied to any aspect or embodiment of the present invention. Moreover, the technical features, definitions, and any combination thereof in any embodiment described herein may also be applied to other embodiments.

[0191] Any embodiments, technical features and definitions described herein may be arbitrarily combined to form embodiments that are not directly recorded in the specification but are consistent with the spirit of the present invention, and these embodiments are also included in the scope of the present invention. Example

[0192] Example 1 Preparation of antibody-drug conjugates targeting TROP2

[0193] Compound NT3 was prepared according to the method disclosed in Example 4 of WO2021173773A1. Its physicochemical data, including 1HNMR and mass spectrometry data, were consistent with those disclosed in WO2021173773A1.

[0194] The antibody HRS7 (sequence shown in the sequence listing, full length heavy chain: SEQ ID NO: 5; full length light chain: SEQ ID NO: 10) was prepared as follows.

[0195] Expi293F cells (purchased from Gibco) were cultured with Expi293F medium (Gibco, REF#A14351-01). The cell density was checked one day before transfection (viability should be greater than 95%) and adjusted to 3 × 10 6 The cell density was adjusted to 3×10 cells / mL on the day of transfection. 6 cells / mL;

[0196] Take 1 / 10 of the final transfection volume of Opti-MEM medium (Gibco, REF#31985-070) as the transfection buffer, add the DNA to be transfected at a ratio of 1 mg / L, where the light and heavy chain plasmids are in a 1:1 ratio, mix well, add PEIMax (Polysciences Inc. Cat#24765-1) at a DNA:PEI mass ratio of 1:3, mix well, incubate at room temperature for 20 minutes, and then gently pour the mixture into the Expi293F cell suspension while shaking. The cells are cultured on a shaker at 8% CO2, 36.5°C, and 120 rpm.

[0197] After 16-18 hours of culture, the cell suspension was supplemented with 2% (volume ratio) of 200 g / L feed (100 g / L Phytone Peptone + 100 g / L Difco Select Phytone), a glucose solution with a final concentration of 5 g / L, and valproic acid sodium salt (Merk, Cat# P4543-100G) with a final concentration of 2.2 mM. The suspension was gently mixed and cultured for 7 days at 8% CO₂, 36.5°C, and 120 rpm before sampling. The cell suspension was then mixed with diatomaceous earth (Sartorius, Cat# 1000037025) (40 g of diatomaceous earth per 1 L of cell suspension) and filtered using a 0.22 μm disposable vacuum filter.

[0198] Purify target protein by affinity chromatography:

[0199] A HiTrap MabSelect PrismA (GE Healthcare, Cat#17549853) affinity chromatography column was used for affinity capture. Before purification, 10-20 column volumes of 0.1 M NaOH were passed through the tubing and affinity chromatography column, and then the tubing and column were washed with 10-20 column volumes of distilled water. The packed column was equilibrated with 5 column volumes of 1×PBS (Gibco). The filtered cell feed was passed through the column, and the packed column was washed with 10 column volumes of 1×PBS to remove non-specific binding proteins. The packed column was rinsed with 5 column volumes of elution buffer (100 mM sodium citrate, pH 3.5), and the eluate was collected. The pH was adjusted to 6.0 with 2 M Tris, filtered and sterilized, and after passing the purity test, the antibody coupling for ADC was carried out.

[0200] The prepared antibody hRS7 was dissolved in PBS buffer (thermofisher, 10010023). A reducing agent solution (TCEP, Aldrich, Catalog Number 646547, dissolved in water) was added and the reaction mixture was allowed to react at room temperature for 2-4 hours.

[0201] (i) The optimal concentration of hRS7 is 2-10 mg / mL,

[0202] (ii) The optimal molar ratio of TCEP / mAb is 10.0-20.0,

[0203] (iii) The optimal reaction temperature is 20-37°C,

[0204] (iv) The optimal pH value of the reaction is between 6.0 and 8.0.

[0205] (b) adding an excess of linker-toxin (MB-3, dissolved in DMSO) to react with the antibody reduced in step (a), and the reaction mixture is placed at room temperature for 1-2 hours, wherein

[0206] (i) The optimal molar ratio of NT-3 / mAb is 10.0-16.0,

[0207] (ii) The optimal reaction temperature is 20-37°C,

[0208] The crude ADC product was obtained.

[0209] (c) The obtained crude ADC product is purified by spin desalting, ultrafiltration or dialysis to obtain the final ADC product hRS7-NT3.

[0210] (d) Using RP-HPLC, the DAR value was calculated based on the peak area of ​​each peak at UV280 nm. The average DAR value of hRS7-NT3 was 4.3, and the SEC purity was 98.42.

[0211] The preparation and activity verification of HRS7-NT3 also refer to the preparation and property verification of the ADC molecule prepared in Example 4.1 of PCT / CN2024 / 121813, which is incorporated herein in its entirety.

[0212] Example 2

[0213] 1. Test antibodies and other drugs

[0214] Study drug: TROP2-targeting antibody-drug conjugate formulation of Example 1 (lyophilized powder injection) Prescription strength: 150 mg / vial (cillin bottle)

[0215] The freeze-dried preparation formula is as follows:

[0216] HRS7-NT3 stock solution, histidine, histidine hydrochloride, sucrose, mannitol, and polysorbate 80. HRS7-NT3 preparation is packaged in vials, rubber stoppers, and aluminum-plastic caps.

[0217] The placebo has no active ingredients and only contains excipients, the composition and pH of which are consistent with those of the antibody preparation for injection.

[0218] The antibody preparation and excipients are both white to light yellow lumpy loose bodies. The appearance of the reconstituted sample is clear to slightly opalescent, colorless to slightly yellow liquid, and free of foreign matter.

[0219] The antibody preparation / placebo must be reconstituted and further diluted before injection, and appropriate aseptic technique must be used during the operation. The dosage and administration of the product must be based on the corresponding research plan. The lyophilized powder is reconstituted with water for injection and diluted with 0.9% sodium chloride solution. The final concentration of HRS7-NT3 should be maintained between 1 and 9 mg / mL. HRS7-NT3 should be administered through an intravenous infusion tube equipped with a 0.2-5 μm in-line filter. During the preparation and handling of the preparation, avoid vigorous shaking and mixing. The prepared solution must be ensured to be sterile.

[0220] 2. Study objectives and endpoints

[0221] 3. Study Design

[0222] This study is a Phase I / II, multicenter, open-label, first-in-human (FIH) study of the TROP2-targeting antibody-drug conjugate HRS7-NT3. It consists of Phase I and Phase II. Phase I includes three phases: dose escalation, dose expansion, and dose optimization, with the goal of determining the MTD / RP2D of the TROP2-targeting antibody-drug conjugate HRS7-NT3. The Phase II phase aims to explore the efficacy, safety, and tolerability of the TROP2-targeting antibody-drug conjugate HRS7-NT3 in specific solid tumor types at the RP2D.

[0223] Phase I dose escalation phase

[0224] The Phase I dose-escalation phase will enroll patients with locally advanced, unresectable, or metastatic solid tumors. This phase will utilize a modified continuous reassessment method (MCRM), employing a Bayesian logistic regression model (BLRM) under the principle of escalation with the overdose control (EWOC). The BLRM model is designed to assess dose-toxicity relationships. The EWOC principle requires that the maximum recommended dose not be overtoxic (the probability of a DLT rate >33% is less than 25%).

[0225] To ensure the safety and accuracy of the experiment, the experiment will be carried out in accordance with the following rules:

[0226] -Based on preclinical pharmacology and toxicology data, the starting human dose of HRS7-NT3, an antibody-drug conjugate targeting TROP2, is 1.0 mg / kg.

[0227] - The study will primarily be evaluated at nine provisional pre-specified dose levels (1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, and 16 mg / kg), but additional and / or intermediate dose levels may be added during the study. In addition, the exploration of 14 mg / kg and 16 mg / kg dosing may be terminated based on emerging clinical data from lower dose level cohorts.

[0228] - The first two dose levels will use an accelerated titration method, with one subject enrolled in each group, starting at 1 mg / kg and 2 mg / kg, respectively. If any subject at a certain dose experiences a DLT during the DLT observation period, two additional subjects will be enrolled at that dose level, and BLRM dose escalation will be implemented starting from that dose group. If no DLT occurs, the next group will contain three subjects and enter the 4 mg / kg dose group. If more than one DLT occurs in the 4 mg / kg dose group, the dose will be forced downgraded to the 2 mg / kg dose group.

[0229] - The maximum recommended dose to which subjects can enter will be calculated based on the BLRM-EWOC model and incremental limits, where the incremental limits are: dose levels above 4 mg / kg should not be increased by more than 100%, dose levels above 6 mg / kg should not be increased by more than 50%, dose levels above 8 mg / kg should not be increased by more than 33%, and dose levels above 12 mg / kg should not be increased by more than 20%.

[0230] -The actual dose to which the subjects are admitted will be determined by the sponsor based on the maximum recommended dose (BLRM-EWOC model and incremental limits), clinical safety data, and PK data, but may not exceed the maximum recommended dose.

[0231] - The number of subjects enrolled simultaneously in each dose escalation cohort is 1 to 6.

[0232] - New subjects may only enter a higher, unexplored dose after all subjects at the current highest dose have completed DLT assessments and the DLT rate does not exceed 1 / 3.

[0233] The dose escalation phase is terminated after the MTD or multiple recommended doses for expansion (RDE) are determined. Both the MTD and RDE must meet the following conditions:

[0234] Condition 1: The dose group contains at least 6 subjects;

[0235] Condition 2: Meet any of the following criteria

[0236] The posterior probability of the target toxicity in this dose group is at least 50%, and it is the highest probability among the currently tested doses;

[0237] A total of at least 20 evaluable subjects have been enrolled.

[0238] Condition 3: The recommended MTD or RDE is determined by the investigator and the sponsor based on the current clinical data.

[0239] The antibody-drug conjugate HRS7-NT3 targeting TROP2 of the present invention is administered by intravenous infusion once every three weeks (Day1, Q3W). In the Phase I dose escalation stage, the subjects enter a 21-day DLT observation period after the first infusion of the antibody-drug conjugate HRS7-NT3 targeting TROP2 of the present invention. At the end of the observation period, all relevant safety data will be reviewed. After completing the first cycle, the subjects can continue to receive the antibody-drug conjugate HRS7-NT3 targeting TROP2 of the present invention once every 3 weeks (Day1, Q3W) until intolerable toxicity occurs, disease progression, the subject withdraws informed consent, the study treatment is terminated for other reasons, or the treatment duration reaches 24 months (whichever occurs first). The treatment cycle will be continuous and uninterrupted unless there is an adverse event that requires intervention. After the end of the DLT observation period, the safety and tolerability of the subjects will continue to be observed. After the end of the study treatment, safety and long-term follow-up will continue.

[0240] Blood samples will be collected for PK characterization and immunogenicity evaluation.

[0241] For certain subjects included in the ≤4 mg / kg dose level cohort, intra-patient dose escalation is allowed. Subjects must complete DLT observation for the initially assigned dose group before entering the next higher dose. If the subject does not experience any DLT event during the DLT observation period that would prevent self-dose escalation, the subject may be considered for entry into the next higher dose level, provided that the investigator and sponsor have fully reviewed the data and believe that the subject's safety can be guaranteed. After the subject enters the next dose group, the subject cannot be evaluated for DLT again, but safety monitoring, PK sampling and tumor assessment can continue according to the previous visit plan. Each subject is only allowed to receive one self-dose escalation to the next dose level.

[0242] Phase I dose expansion phase

[0243] To further explore the safety, tolerability, PK, and preliminary efficacy of the TROP2-targeting antibody-drug conjugate HRS7-NT3 of the present invention, additional subjects may be recruited at an evaluated dose level or an intermediate dose level below the estimated MTD before or during dose escalation by the investigator and sponsor. One or more dose levels may be expanded based on existing data.

[0244] The Phase I dose-expansion phase will enroll patients with unresectable, locally advanced or metastatic triple-negative breast cancer (TNBC; Cohort A), non-small cell lung cancer (NSCLC; Cohort B), cervical cancer (CC; Cohort C), or other solid tumors who have failed, are intolerant of, or refuse standard therapy and have at least one measurable lesion as assessed by RECIST v1.1. The planned enrollment of 150 patients in the dose-expansion phase is 150.

[0245] Phase I: Dose optimization phase

[0246] Up to three doses will be selected for dose optimization for each indication (possible dose levels: 4 mg / kg or 6 mg / kg, 8 mg / kg, possibly including 12 mg / kg Q3W). Enrollment will begin after the recommended dose for dose optimization is determined based on the data from the Phase I dose escalation and dose expansion phases. For example, if two doses are selected for dose optimization in cohort A, subjects may be randomly assigned to dose optimization cohorts, referred to as Group A1 and Group A2. In Cohorts A, B, and C, the number of subjects treated at each dose level will be approximately 30. Approximately 60 to 150 subjects will be included in the dose optimization phase.

[0247] The subjects are planned to receive the antibody-drug conjugate targeting TROP2 of the present invention on the first day of each cycle in a 21-day cycle (Q3W, or the interval determined by the investigator and the sponsor based on safety, toxicity and PK data) until unacceptable toxicity, disease progression, withdrawal of informed consent, termination of study treatment for other reasons, or a maximum of 24 months of treatment, whichever occurs first. After termination of study treatment, safety and survival follow-up will continue. RP2D will be determined based on the MTD estimated by mCRM and a comprehensive assessment of the safety, preliminary efficacy, and PK information of all subjects in Phase I.

[0248] Phase II

[0249] The sponsor will decide whether to conduct the Phase II study based on an overall evaluation of the safety data, preliminary efficacy data, and PK information of the enrolled subjects.

[0250] Phase II will enroll three cohorts, with the following subjects in each cohort:

[0251] (4) Cohort A: subjects with unresectable locally advanced or metastatic TNBC who have received at least one line of systemic anti-tumor therapy;

[0252] (5) Cohort B: subjects with unresectable locally advanced or metastatic CC who have received at least one line of systemic anti-tumor therapy;

[0253] (6) Cohort C: subjects with unresectable locally advanced or metastatic NSCLC who have previously received 1 or 2 lines of systemic anti-tumor therapy.

[0254] In each cohort, approximately 50 subjects will be enrolled and treated with the TROP2-directed antibody-drug conjugate HRS7-NT3 at the RP2D until unacceptable toxicity, disease progression, withdrawal of consent, discontinuation of study treatment for other reasons, or 24 months of treatment, whichever occurs first. Treatment cycles will continue without interruption unless an adverse event necessitates intervention. Subjects will continue to be followed for safety and survival after discontinuation of study treatment.

[0255] Investigators will perform tumor assessments using enhanced computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST v1.1. Throughout the study, imaging methods should be consistent for the same subject.

[0256] 4. Inclusion criteria:

[0257] 1. Understand and sign the written informed consent for this trial, and be willing and able to follow the visits and related procedures specified in the protocol;

[0258] 2. Age ≥ 18 years old, regardless of gender;

[0259] 3. Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1;

[0260] 4. Expected survival time ≥ 12 weeks;

[0261] 5. Have adequate bone marrow and organ function:

[0262] ANC ≥ 1.5 × 109 / L; platelet count (PLT) ≥ 100 × 109 / L; hemoglobin (Hb) ≥ 9.0 g / dL, and no erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), or blood transfusion (including red blood cell and platelet transfusion) within at least 14 days before the first dose;

[0263] Liver function: Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN); Albumin ≥ 2.8 g / dL; Patients without liver metastasis require AST and ALT ≤ 2.5 × ULN, and patients with liver metastasis require AST and ALT ≤ 5 × ULN ≥. Subjects receiving supportive care and with liver function within the above range are allowed to be enrolled;

[0264] Renal function: serum creatinine ≤1.5×ULN, or creatinine clearance ≥60ml / min (using the Cockcroft-Gault formula); urine protein <2+ or 24-hour urine protein quantitative <1g.

[0265] Coagulation function: International Normalized Ratio (INR) ≤ 1.5; Activated Partial Thromboplastin Time (APTT) ≤ 1.5 × ULN (subjects receiving anticoagulant therapy and with coagulation function within the above range are allowed to be included);

[0266] 6. Male and female subjects who are infertile or agree to use at least one effective contraceptive method during the study (from the start of screening or within 2 weeks before the first dose, whichever occurs first, and continuing until 6 months after the last dose of study drug).

[0267] Additional inclusion criteria for the Phase I dose-escalation phase:

[0268] 1. Patients with locally advanced unresectable or metastatic solid tumors confirmed by histopathology or cytopathology, who have failed standard treatment or are intolerant to standard treatment or for whom there is no standard treatment option;

[0269] 2. At least one evaluable lesion according to RECIST v1.1.

[0270] Additional inclusion criteria for the Phase I dose expansion phase:

[0271] 1. Subjects with locally advanced, unresectable or metastatic solid tumors such as TNBC, NSCLC, CC, confirmed by histopathology or cytopathology, who have failed standard treatment or are intolerant to standard treatment or for whom no standard treatment options are available;

[0272] 2. At least one measurable target lesion according to RECIST v1.1.

[0273] Additional inclusion criteria for Phase II Cohort A:

[0274] 1. Locally advanced unresectable or metastatic TNBC confirmed by histopathology or cytopathology;

[0275] 2. Subjects who have previously received at least one line of standard systemic anti-tumor treatment, have undergone standard treatment or are intolerant to standard treatment, and currently have no standard systemic anti-tumor treatment options;

[0276] 3. At least one measurable target lesion according to RECIST v1.1.

[0277] Additional inclusion criteria for Phase II Cohort B:

[0278] 1. Locally advanced unresectable or metastatic CC confirmed by histopathology or cytopathology;

[0279] 2. Patients who have received at least one line of standard systemic anti-tumor therapy and have failed or developed drug resistance, and there is currently no standard systemic anti-tumor treatment option;

[0280] 3. At least one measurable target lesion according to RECIST v1.1;

[0281] Additional inclusion criteria for Phase II Cohort C:

[0282] 1. Locally advanced unresectable or metastatic solid tumors confirmed by histopathology or cytopathology, including NSCLC;

[0283] 2. Patients who have previously received 1 or 2 lines of standard systemic anti-tumor therapy and have failed or developed drug resistance, and there is currently no standard systemic anti-tumor treatment option;

[0284] 3. At least one measurable target lesion according to RECIST v1.1.

[0285] Exclusion criteria:

[0286] Subjects should be excluded from the study if they meet any of the following criteria:

[0287] 1. Participating in other interventional clinical studies, excluding observational (non-interventional) studies or those in the survival follow-up phase of interventional studies.

[0288] 2. Patients have received TROP2 targeted therapy before.

[0289] 3. Patients have received previous anti-cancer treatment within 4 weeks before the first dose of study drug, including systemic chemotherapy, targeted therapy, immunotherapy, intraperitoneal chemotherapy, chemoembolization, or interventional chemotherapy. The washout period for oral fluoropyrimidines, small molecule targeted therapy, endocrine / hormonal therapy, and Chinese herbal medicines with anti-cancer indications is at least 2 weeks or 5 half-lives (whichever is longer).

[0290] 4. Receiving treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor within 2 weeks or 5 half-lives (whichever is longer) before the first dose of study drug (only applicable to subjects in the dose escalation phase).

[0291] 5. Plan to receive other anti-tumor treatments during the study, except for palliative radiotherapy for the purpose of relieving symptoms (such as pain), but such treatment must not affect tumor assessment during the entire study period;

[0292] 6. Received live attenuated vaccine within 4 weeks before the first dose of study drug or planned to receive vaccine during the study;

[0293] 7. Before the first administration of the study drug, adverse reactions caused by previous anti-tumor treatment have not been alleviated to NCI-CTCAE v5.0 grade 0-1 (except for hair loss, fatigue, pigmentation, etc. that the researchers believe do not pose a safety risk);

[0294] 8. Patients who have undergone major surgery (craniotomy, thoracotomy, or laparotomy, or other major surgery defined by the investigator, excluding puncture biopsy) within 4 weeks before the first dose of study drug, or plan to undergo major surgery during the study, or have severe unhealed wounds, trauma, ulcers, etc.;

[0295] Note: Palliative local surgical treatment of isolated lesions is allowed, provided that the treatment does not affect the tumor assessment during the entire study period.

[0296] 9. Pyloric obstruction and / or persistent recurrent vomiting (vomiting ≥ 3 times within 24 hours);

[0297] 10. Patients with gastrointestinal perforation and / or fistula within 6 months before the first administration of study drug and who have not recovered after surgical treatment;

[0298] 11. Known symptomatic central nervous system (CNS) metastases. Subjects with asymptomatic CNS metastases (i.e., no neurological symptoms, no need for corticosteroid treatment, and brain metastases ≤1.5 cm) or whose condition is stable after treatment as determined by the investigator may be considered for participation in this study if: no midbrain, pons, cerebellum, meninges, medulla oblongata, or spinal cord metastases; clinical stability for at least 4 weeks, with clinical evidence confirming the absence of new or enlarged brain metastases; and discontinuation of corticosteroids or anticonvulsants for at least 2 weeks prior to the first dose of study drug.

[0299] 12. Have a history of pneumonia requiring corticosteroid treatment, or a history of clinically significant lung disease (including interstitial lung disease, non-infectious pneumonia, or poorly controlled lung disease such as pulmonary fibrosis, severe radiation pneumonitis, and acute lung injury, etc.), or be suspected of having such diseases through imaging examinations during the screening period.

[0300] 13. Poorly controlled diseases such as:

[0301] Active or clinically poorly controlled infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks before the first dose of study drug;

[0302] Known human immunodeficiency virus (HIV) infection, or HIV positive (HIV-1 / 2 antibody positive);

[0303] Acute or chronic active hepatitis B (positive hepatitis B surface antigen [HBsAg] and / or positive hepatitis B core antibody [HBcAb], hepatitis B virus [HBV] DNA titer ≥ 1 × 10 4 ≥10 copies / ml or ≥2000 IU / ml or higher than the detection limit), or acute or chronic active hepatitis C (positive hepatitis C virus (HCV) antibody, HCV RNA>103 copies / ml);

[0304] Active COVID-19 infection; active tuberculosis infection, or still receiving anti-tuberculosis treatment, or received anti-tuberculosis treatment within 1 year before the first dose of study drug; active or latent syphilis requiring treatment; symptomatic congestive heart failure class II-IV (based on New York Heart Association [NYHA] classification); symptomatic or poorly controlled arrhythmias, QTcF>480ms or personal or family history of congenital long / short QT syndrome; poorly controlled hypertension (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg);

[0305] 14. History of arterial thromboembolic events within 6 months before the first dose of study drug, including myocardial infarction, unstable angina, cerebrovascular stroke or transient ischemic attack;

[0306] 15. The tumor invades surrounding important organs (such as mediastinal vessels, superior vena cava, trachea, esophagus, etc.), or there is a risk of gastrointestinal / respiratory fistula;

[0307] 16. Ascites, pleural effusion, or pericardial effusion with clinical symptoms requiring drainage intervention;

[0308] 17. Esophageal or gastric varices requiring immediate intervention (e.g., ligation or sclerotherapy) or considered to have a high risk of bleeding based on the opinion of the investigator or consultation with a gastroenterologist or hepatologist; subjects with evidence of portal hypertension (including splenomegaly found on imaging examinations) or a history of variceal bleeding must undergo endoscopic evaluation within 3 months prior to the first dose;

[0309] 18. Subjects with biliary obstruction, excluding those whose obstruction has been treated locally with endoscopic stent placement or percutaneous transhepatic drainage and whose total bilirubin has dropped below 1.5×ULN;

[0310] 19. Any life-threatening bleeding event or grade 3 or 4 gastrointestinal / variceal bleeding event requiring blood transfusion, endoscopic or surgical treatment within 3 months before the first dose of study drug;

[0311] 20. History of deep vein thrombosis, pulmonary embolism, or any other severe venous thromboembolism within 3 months before the first dose of study drug (implanted venous port or catheter-derived thrombosis, or superficial vein thrombosis is not considered "severe" thromboembolism);

[0312] 21. Hepatic encephalopathy, hepatorenal syndrome, or Child-Pugh grade B or above cirrhosis;

[0313] 22. Risk of gastrointestinal obstruction or perforation (including but not limited to acute diverticulitis, intra-abdominal abscess) or history of inflammatory bowel disease or extensive intestinal resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea;

[0314] 23. Obvious malnutrition, such as requiring intravenous infusion; patients may be included if malnutrition has been corrected 4 weeks before the first dose of study drug;

[0315] 24. Other acute or chronic diseases or abnormal laboratory test values ​​that may result in: increasing the risks associated with study participation or study drug administration, or interfering with the interpretation of study results, and according to the investigator's judgment, classifying the subject as ineligible for participation in this study;

[0316] 25. Known history of other malignant tumors within 5 years, excluding fully resected non-melanoma skin cancer, carcinoma in situ, and cured non-invasive tumors;

[0317] 26. History of known immunodeficiency disease, including congenital or acquired immunodeficiency disease;

[0318] 27. Known history of organ transplantation, allogeneic bone marrow transplantation, or hematopoietic stem cell transplantation;

[0319] 28. Known hypersensitivity to other monoclonal antibodies or Exatecan-based treatments or any formulation components of the TROP2-targeting antibody-drug conjugates of the present invention;

[0320] 29. Previous use of irinotecan or other camptothecins (such as topotecan) is allowed, unless there is a known history of allergic reaction to such drugs or a history of grade 3 or higher gastrointestinal toxicity;

[0321] 30. Female subjects who are pregnant or breastfeeding.

[0322] 31. Neurological or psychiatric illnesses / social conditions that affect compliance with study requirements, significantly increase the risk of adverse events, or affect the subject's ability to provide written informed consent.

[0323] 32. The researcher considers that the candidate is not eligible to participate in this study.

[0324] 5. Dose-limiting toxicity

[0325] Definition of Dose-Limiting Toxicity (DLT)

[0326] Toxicity evaluation will be performed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

[0327] DLT was defined as any of the following HRS7-NT3-related AEs occurring during the DLT observation period:

[0328] For hematologic toxicity, DLT was defined as:

[0329] Grade 4 neutropenia lasting for more than 7 days;

[0330] Grade 3 or higher febrile neutropenia (defined as an absolute neutrophil count (ANC) <1.0 × 10⁹ / L and a single temperature >38.3°C or a temperature ≥38°C for >1 hour) persisting for >7 days despite adequate supportive care;

[0331] Grade 4 anemia that cannot be explained by underlying disease;

[0332] Grade 4 thrombocytopenia;

[0333] Grade 3 or higher thrombocytopenia lasting for more than 7 days;

[0334] Grade 3 or higher thrombocytopenia with clinically significant bleeding.

[0335] For non-hematologic toxicities, DLT was defined as:

[0336] 1. Any organ toxicity ≥ Grade 3 without laboratory abnormalities, except for the following:

[0337] Grade 3 arthralgia;

[0338] Grade 3 myalgia;

[0339] Grade 3 hair loss;

[0340] Grade 3 fatigue / asthenia;

[0341] Grade 3 hypertension or hypotension;

[0342] Grade 3 skin reactions, including rash, pruritus, dry skin, skin fissures, and paronychia;

[0343] Grade 3 mucosal inflammation or oral mucositis that resolves to ≤ Grade 2 within 7 days after adequate treatment;

[0344] Grade 3 nausea, vomiting, diarrhea, or decreased appetite that resolves to ≤ Grade 2 within 3 days after adequate treatment;

[0345] 2. Any laboratory abnormality other than hematology that is grade 3 or higher and requires treatment or leads to hospitalization, except for the following:

[0346] Grade 3 electrolyte abnormalities;

[0347] Grade 3-4 elevated gamma-glutamyltransferase (GGT);

[0348] Grade 3-4 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation that resolves to ≤ Grade 2 within 7 days after adequate treatment;

[0349] Grade 3-4 total bilirubin elevation that resolves to ≤ Grade 2 within 3 days after adequate treatment;

[0350] Isolated laboratory test results not associated with signs or symptoms, including grade 3-4 elevated alkaline phosphatase (ALP), hyperuricemia, elevated serum amylase, and elevated lipase.

[0351] Any grade 5 drug-related AE was defined as a DLT.

[0352] Other AEs determined to be DLTs after discussion between the investigator and the Safety Evaluation Team (SET).

[0353] 6. Evaluation Metrics

[0354] 6.1 Safety Assessment

[0355] AEs will be reported using NCI CTCAE v5.0, including all treatment-emergent adverse events (TEAEs), adverse events of special interest (AESIs), serious adverse events (SAEs), and those related to study drug.

[0356] Vital signs (including temperature, pulse, respiratory rate, oxygen saturation, and blood pressure), physical examination (weight and pulmonary / cardiac assessment at each visit), 12-lead ECG, ECOG performance status, and laboratory tests before, during, and after treatment.

[0357] Definition of adverse events

[0358] Adverse events are defined as any adverse medical events that occur to clinical trial subjects after they sign the informed consent form, regardless of whether they are causally related to the study drug. AEs include but are not limited to the following:

[0359] Exacerbation of existing medical conditions / diseases (including aggravation of symptoms, signs, and laboratory abnormalities) prior to entering the clinical trial.

[0360] Any new adverse medical condition (including symptoms, signs, and newly diagnosed diseases);

[0361] Abnormal clinically significant laboratory test values ​​or results.

[0362] Definition of serious adverse events

[0363] A serious adverse event is an adverse event that meets at least one of the following criteria:

[0364] Resulting in death, excluding death due to disease progression in the investigational indication.

[0365] Life-threatening ("life-threatening" is defined as an AE that carries a risk of death for the subject when it occurs, and does not include AEs that could result in death only if the event worsens).

[0366] ·Requires hospitalization or prolonged hospitalization, excluding the following:

[0367] a) Rehabilitation institutions;

[0368] b) Nursing homes;

[0369] c) routine emergency room admission;

[0370] d) Same-day surgery (e.g. outpatient / same-day / ambulatory surgery);

[0371] e) Hospitalization or prolonged hospitalization not related to worsening of an AE is not an SAE in itself. Examples include: hospitalization for a pre-existing condition without new AEs and worsening of the underlying condition (e.g., laboratory abnormalities that persisted even before the study); hospitalization for administrative reasons (e.g., annual physical examinations); hospitalization during a clinical trial that is protocol-mandated (e.g., to perform procedures as required by the protocol); elective hospitalization not related to worsening of an adverse event (e.g., elective surgery); scheduled treatments or surgical procedures that should be documented throughout the trial protocol and / or in the subject's individual baseline data; and hospitalization solely for the use of blood products.

[0372] · Resulting in permanent or severe disability / incapacity.

[0373] Cause congenital anomalies / birth defects.

[0374] Other important medical events: defined as events that could endanger the subject and may require medical or surgical intervention to prevent the above outcomes.

[0375] Special attention to adverse events

[0376] Adverse Event of Special Interest (AESI) refers to an adverse event that requires close monitoring to improve understanding of the safety of the study drug. AESI can be non-serious events and mainly include:

[0377] Grade 3 or higher hematologic toxicity (including grade 3 or higher leukopenia, grade 3 or higher neutropenia, grade 3 or higher anemia, and grade 3 or higher thrombocytopenia);

[0378] Grade 3 or higher hepatic dysfunction (including grade 3 or higher ALT / AST elevation, grade 3 or higher TBIL or DBIL elevation);

[0379] Grade 3 or higher IRR, including allergic reactions;

[0380] Grade 3 or higher oral mucositis / stomatitis, including inflammation of the mucosa;

[0381] ≥Grade 2 ocular surface toxicity.

[0382] AESIs were collected from the first dose of HRS7-NT3 to 30 days after the last dose. If a new anti-tumor treatment was initiated within 30 days of the last dose, only AESIs related to the study drug were collected.

[0383] AESI should be reported to the sponsor within 24 hours of becoming aware of the event, regardless of severity (i.e., including serious and non-serious AEs), following the SAE procedures described above, and requiring enhanced data collection.

[0384] 6.2 Effectiveness Evaluation

[0385] Diagnostic imaging is used for disease assessment, with tumor imaging typically performed using contrast-enhanced CT or enhanced MRI, and the examination sites must include the chest, abdomen, and pelvis. Screening imaging examinations need to be performed within 28 days before the first dose of study drug (except bone scans). Tumor imaging assessments are performed every 6 weeks (±7 days) for 48 weeks after the first dose; after week 48, tumor imaging assessments are performed every 12 weeks (±7 days) until the start of new anti-tumor treatment, disease progression, withdrawal of informed consent by the subject, study termination, loss to follow-up, or death, whichever occurs first. For all imaging examination time points, the following will be recorded according to RECIST v1.1: target lesions, including size, location, and type (nodular / non-nodular); sum of target lesion diameters, including location and type; non-target lesions; any new lesions discovered during the trial, including size, location, and type (nodular / non-nodular).

[0386] Tumor assessments were performed every 6 to 12 weeks according to RECIST v1.1.

[0387] Objective response rate (ORR)

[0388] o Duration of remission (DoR)

[0389] οDisease control rate (DCR)

[0390] Time to remission (TTR)

[0391] οProgression-free survival (PFS)

[0392] Overall survival (OS)

[0393] 6.3 PK Assessment

[0394] PK parameters, including but not limited to: AUC, Cmax, Tmax, CL, V and t1 / 2.

[0395] 6.4 Immunogenicity

[0396] The incidence and characteristics of ADA and / or neutralizing antibodies (NAb).

[0397] Each subject will undergo anti-drug antibody (ADA) testing for HRS7-NT3. ADA-positive serum samples can be tested for neutralizing antibodies (NAb). 3.5 ml of whole blood will be collected using a vacutainer containing a clot activator. Serum will then be separated and stored frozen for ADA testing.

[0398] The incidence of HRS7-NT3 ADA will be summarized in subjects who received at least one dose of study drug.

[0399] 6.5 Biomarker Assessment:

[0400] Tumor TROP2 expression was confirmed using formalin-fixed and paraffin-embedded (FFPE) tissue sections.

[0401] 7. Statistical Methods

[0402] Sample size determination:

[0403] The Phase I study consists of a dose-escalation phase, a dose-expansion phase, and a dose-optimization phase. The sample size of the Phase I study depends on the number of dose levels evaluated, the occurrence of DLTs, and the number of dose expansion and optimization phases. The Phase I dose-escalation phase is planned to enroll approximately 20 to 32 subjects, the Phase I dose-expansion phase is planned to enroll approximately 50 to 110 subjects, and the Phase I dose-optimization phase is planned to enroll approximately 60 to 150 subjects.

[0404] The sample sizes for the Phase II study are as follows:

[0405] Cohort A: For the preferred dose, assuming an ORR of 27% with HRS7-NT3 and a 10% dropout rate in subjects with unresectable locally advanced or metastatic TNBC, a sample size of 50 subjects would provide 80% confidence that the lower limit of the 95% confidence interval would be greater than 12%.

[0406] Cohorts B and C: No formal statistical assumptions are made about sample size. Approximately 50 subjects will be treated in each cohort.

[0407] Statistical analysis methods:

[0408] Unless otherwise specified, descriptive statistics for selected demographic, safety, efficacy, and PK data are presented by dose level / cohort, as appropriate. Continuous variables are described using number of cases, mean, standard deviation, median, minimum, and maximum values; categorical variables are described using number of cases and percentages. Data are presented graphically, where applicable.

[0409] 7.1 Safety and Tolerability Analysis

[0410] Adverse events will be graded using the NCI CTCAE v5.0 criteria. Coded TEAEs, TRAEs, AESIs, SAEs, and AEs leading to study drug discontinuation will be summarized by system organ class and preferred terminology.

[0411] DLTs will be summarized descriptively by dose level.

[0412] Pre- and post-treatment vital signs, physical examinations, 12-lead ECGs, ECOG performance status, and laboratory tests will be summarized descriptively by dose level / cohort.

[0413] AE

[0414] The incidence and severity of TEAEs, TRAEs, AESIs, SAEs, and AEs leading to discontinuation of treatment will be summarized by system organ class, preferred term, and dose level / cohort according to the Medical Dictionary for Regulatory Activities (MedDRA) (according to NCI CTCAE version 5.0).

[0415] If necessary, the PK data of HRS7-NT3 will be pooled for Pop PK analysis and, if performed, will be reported separately.

[0416] A list will be provided for subjects who discontinued medication due to adverse events, subjects who developed SAEs, and subjects who died (including the start date, end date, severity, relationship with the drug, measures taken, outcome, etc. of the AE).

[0417] Laboratory tests

[0418] Descriptive statistics will be used to analyze the quantitative laboratory test values ​​and changes from baseline. Based on CTCAE v5.0, cross-tabulations will be used to describe the change in the most severe outcome from baseline.

[0419] Electrocardiogram

[0420] Descriptive statistics will be presented for ECG quantitative index measurements and changes from baseline. Cross-tabulations will be used to summarize the changes from baseline in the most severe outcome.

[0421] Vital signs, physical examination, and other safety-related examinations

[0422] Descriptive statistics will be presented for the measurements of vital signs and the changes from baseline.

[0423] Subjects with abnormal changes from baseline in physical examination and other safety studies will be listed.

[0424] 7.2 Immunogenicity

[0425] ADA and / or NAb will be summarized descriptively by dose level / cohort.

[0426] 7.3 Effectiveness Analysis:

[0427] ORR and DCR and their 95% confidence intervals (CI) will be calculated. PFS, DoR, TTR, and OS will be analyzed using the Kaplan-Meier method.

[0428] The ORR was defined as the proportion of subjects who achieved a CR or PR. The number and percentage of subjects with a CR or PR will be summarized. The 95% confidence interval (CI) for the ORR will be estimated using the Clopper-Pearson method.

[0429] DCR is defined as the proportion of subjects who achieved CR, PR, or SD. The analysis method for DCR is the same as that for ORR.

[0430] DoR was defined as the time from the first achievement of a CR or PR to the first documented disease progression (based on RECIST v1.1) or death. Only subjects with a CR or PR were included in the DoR analysis. Subjects who were alive and without disease progression at the analysis cutoff date were censored. DoR was analyzed using the Kaplan-Meier method.

[0431] PFS was defined as the time from the first dose of study drug to death or disease progression (based on RECIST v1.1), whichever occurred first. Subjects who were alive and without disease progression at the analysis cutoff date were censored at the end of the study.

[0432] PFS will be analyzed using the Kaplan-Meier method.

[0433] TTR was defined as the time from the first dose of study drug to the first CR or PR (based on RECIST v1.1). Only subjects with a CR or PR were included in the TTR analysis. TTR was summarized using the Kaplan-Meier method.

[0434] OS was defined as the time from the first dose of study drug to death from any cause. Subjects who were alive at the analysis cutoff date were censored. OS was analyzed using the Kaplan-Meier method.

[0435] 7.4 Pharmacokinetic Analysis

[0436] Descriptive statistics will be performed on the PK parameters of the antibody-drug conjugate targeting TROP2 of the present invention.

[0437] PK analysis will be performed on the PK analysis set. The densely sampled PK data will be analyzed primarily using non-compartmental methods. Key PK parameters will be determined for each subject, including but not limited to AUC, Cmax, Tmax, CL, V, and t1 / 2.

[0438] Exploratory analysis:

[0439] If applicable, the relationship between tumor TROP2 expression and preliminary efficacy will be further explored.

[0440] 8. Dosage method and process

[0441] Dosage:

[0442] 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, or 16 mg / kg. The actual dose (mg) will be calculated based on the subject's body weight (kg). The first dose will be calculated based on the subject's baseline body weight. If the subject's body weight changes by less than ±10% from baseline (at the time of the first dose of study treatment), the baseline body weight will be used to calculate the dose. Otherwise, the actual dose will be calculated based on the body weight on the scheduled dosing day or the day before dosing.

[0443] Route of administration:

[0444] If indicated, the study drug will be infused intravenously (IV) using a microsyringe pump through an indwelling venous cannula. The catheter can be placed in a peripheral vein (if accessible); administration through a central venous catheter or infusion port (if already in place) is permitted.

[0445] Dosing frequency:

[0446] The dosing cycle is 3 weeks / 21 days (Q3W), with one dose given on Day 1 of each cycle. Dosing continues until intolerable toxicity occurs, disease progression, the subject withdraws informed consent, study treatment is terminated for other reasons, or the treatment duration reaches 24 months (whichever occurs first).

[0447] 9. Experimental Results

[0448] The TROP2-targeting antibody-drug conjugate of the present invention, as an ADC with a bystander effect, exhibited significant tumor inhibition in a mouse tumor-bearing model. It is expected that the TROP2-targeting antibody-drug conjugate of the present invention will have good tolerability, safety, and efficacy.

[0449] As of December 15, 2024, a total of 71 patients from China and Australia were enrolled (median age: 60 years [range: 30-81 years], female: 85.9%, white (Caucasian): 16.9%, ECOGP S1: 48.6%; previously received ≥2 lines of anticancer treatment: 63.8%). The median follow-up time of the study was 4.6 months (range: 0.8-9.7 months). During the dose escalation period (1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg), no dose-limiting toxicity (DLT, n=18) was observed at all dose levels. The median treatment duration was 18 weeks (range: 3-45 weeks), of which 40 (56.3%) patients are still receiving treatment. Treatment-emergent adverse events (TEAEs) occurred in 68 patients (95.8%, of which 90.1% were treatment-related adverse events [TRAEs]), including 17 grade 3 (G3) events (23.9%, of which 15.5% were TRAEs). No grade 4 or 5 events occurred. Common TEAEs (≥30%) included stomatitis (52.1%, of which 9.9% were G3), nausea (31.0%, of which 2.8% were G3), and rash (31.0%, of which 1.4% were G3). Interstitial lung disease occurred in one patient (1.4%, G1). Only one patient (1.4%) experienced a grade 3 decreased lymphocyte count. No other grade ≥3 hematologic toxicities were observed. TRAEs led to dose reductions in five patients (7.0%) and treatment discontinuation in one patient (1.4%). The efficacy of HRS7-NT3 was evaluated in 30 patients with triple-negative breast cancer (TNBC) (all stage IV, 96.7% of whom had failed or were intolerant to taxanes) who received 4 / 6 / 8 / 10 mg / kg of HRS7-NT3. The overall objective response rate (ORR) was 50.0% (95% CI: 31.3-68.7) and the disease control rate (DCR) was 83.3% (95% CI: 65.3-94.4).For different dose levels, the ORR and DCR of 4 mg / kg (n=5) were 40.0% (95% CI: 5.3-85.3) and 60.0% (95% CI: 14.7-94.7), the ORR and DCR of 6 mg / kg (n=5) were 40.0% (95% CI: 5.3-85.3) and 80.0% (95% CI: 28.4-99.5), the ORR and DCR of 8 mg / kg (n=10) were 50.0% (95% CI: 18.7-81.3) and 100% (95% CI: 69.2-100.0), and the ORR and DCR of 10 mg / kg (n=10) were 60.0% (95% CI: 26.2-87.8) and 80.0% (95% CI: 44.4-97.5).

[0450] Therefore, HRS7-NT3 is well tolerated and has an excellent hematologic safety profile. The encouraging efficacy observed in patients with advanced TNBC supports its potential as a best-in-class TROP2 antibody-drug conjugate (ADC).

[0451] 10. Concomitant treatment

[0452] Prior to entry into or during the study, subjects may receive treatment for other ongoing medical conditions and palliative and supportive care for malignancies consistent with clinical indications and institutional standard clinical protocols, except as specified in the exclusion criteria.

[0453] Other treatments allowed during the study include:

[0454] 1. Prevention of IRRs and Study Drug-Related Toxicity: Subjects who experience an IRR during the study should receive standard treatment as defined in the protocol as preventive medication before each dose of study drug to reduce the risk of such events. Subjects who experience other study drug-related reactions may receive standard treatment in advance to reduce the likelihood of such reactions in the future.

[0455] 2. Management of AEs or concurrent diseases related to study drugs: Drugs used to treat any TRAEs or concurrent diseases occurring during the medication and follow-up period according to clinical indications.

[0456] 3. Blood Products and Growth Factors: Prophylactic hematopoietic growth factors should not be administered during Cycle 1; thereafter, prophylactic use of growth factors is permitted based on clinical indications. If deemed necessary by the investigator, interventional / therapeutic use of growth factors is permitted during the study (including Cycle 1). The use of growth factors must comply with the corresponding product instructions.

[0457] 4. Radiotherapy: For radiotherapy that does not affect bone marrow function and is performed on non-target lesions to control pain, the decision on whether to implement it should be discussed with the sponsor's medical monitor.

[0458] 5. Supportive medications to relieve tumor-related symptoms, such as bisphosphonates and denosumab for bone metastases.

[0459] 6. Immunosuppression or systemic steroid therapy not exceeding 10 mg / day of prednisone equivalents, and:

[0460] Hormone therapy to improve appetite (such as megestrol acetate);

[0461] · Nasal, ophthalmic, inhaled, and topical glucocorticoid preparations;

[0462] Standard-dose hormone replacement therapy for end-organ failure;

[0463] Same as stable hormone therapy for prostate cancer*;

[0464] Stable hormone therapy for ovarian suppression, hormonal contraceptive therapy, or postmenopausal hormone replacement therapy;

[0465] Steroid therapy to prevent contrast reactions;

[0466] Intra-articular steroid injections;

[0467] Low-dose maintenance steroid therapy for other conditions (e.g., asthma exacerbation, stable steroid therapy (excluding tapering of steroids) for cerebral edema);

[0468] In subjects with stable disease or ongoing remission, higher doses of steroids may be used to treat acute intercurrent illnesses (e.g., immune-related AEs or other adverse events). In such cases, study drug treatment should be interrupted during immunosuppressive therapy.

[0469] *Concomitant therapies are allowed; however, subjects must have been receiving a stable dose for at least 6 months prior to study entry and, if continuing study treatment, must remain on a stable dose while receiving study treatment (i.e., such treatment will not be considered systemic hormonal therapy for the purpose of considering subject enrollment).

[0470] Any concomitant treatments and other interventions or procedures occurring during the trial must be recorded on the appropriate pages of the subject's CRF.

[0471] Sequence information

[0472] While the exemplary embodiments of the present invention have been described above, it should be understood by those skilled in the art that these disclosures are merely exemplary and that various other substitutions, adaptations, and modifications may be made within the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments listed herein.

Claims

1. A method for preventing or treating solid tumors, comprising administering to an individual in need thereof an effective amount of an antibody-drug conjugate targeting TROP2; in, The antibody-drug conjugate targeting TROP2 is: wherein Ab is an antibody or an antigen-binding fragment thereof targeting TROP2; Here, p represents the average DAR, for example, 1-15, 1-10, 2-8, 2-4 or 4-5.

2. The method according to claim 1, wherein The antibody or antigen-binding fragment thereof targeting TROP2 comprises HCDR1, HCDR2, HCDR3 respectively containing or consisting of the following amino acid sequences: SEQ ID NO: 1, 2 and 3, and LCDR1, LCDR2 and LCDR3 respectively containing or consisting of the following amino acid sequences: SEQ ID NO: 6, 7 and 8.

3. The method according to claim 1 or 2, wherein: The antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain variable region and / or a light chain variable region, wherein the heavy chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 4; or (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 4, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or (iii) comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO: 4; and / or Light chain variable region (i) comprises or consists of the amino acid sequence of SEQ ID NO: 9; or (ii) an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 9, consisting of said amino acid sequence, preferably, said amino acid changes do not occur in the CDR regions; or (iii) comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO:

9.

4. The method according to any one of claims 1 to 3, wherein The antibody or antigen-binding fragment thereof targeting TROP2 comprises a heavy chain and a light chain, wherein the heavy chain comprising or consisting of the amino acid sequence of SEQ ID NO: 5; or An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 5; or comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence set forth in SEQ ID NO:5; and light chain comprising or consisting of the amino acid sequence of SEQ ID NO: 10; or An amino acid sequence comprising or consisting of one or more (preferably no more than 20 or 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative amino acid substitutions) compared to the amino acid sequence of SEQ ID NO: 10; or comprising an amino acid sequence that is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence shown in SEQ ID NO:

5.

5. The method according to any one of claims 1 to 4, wherein: The method comprises administering to the individual 0.2 mg / kg-50 mg / kg, for example 0.5 mg / kg-30 mg / kg of an antibody-drug conjugate targeting TROP2, for example The method comprises administering to the individual approximately 0.3 mg / kg, 0.8 mg / kg, 1 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.8 mg / kg, 2 mg / kg, 2.3 mg / kg, 2.5 mg / kg, 3 mg / kg, 3.2 mg / kg, 3.5 mg / kg, 3.8 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.4 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 9.5 mg / kg, 9.6 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 13.5 mg / kg, 14 mg / kg, 14.5 mg / kg, 15 mg / kg, 15.5 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2; Optionally, the method comprises administering to the individual about 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg or 16 mg / kg of an antibody-drug conjugate targeting TROP2.

6. The method according to any one of claims 1 to 5, wherein: The dosing cycle of this method is 2 weeks / 14 days (Q2W) to 5 weeks / 35 days (Q5W); optionally, the dosing cycle of this method is 2 weeks / 14 days (Q2W), 3 weeks / 21 days (Q3W) or 4 weeks / 28 days (Q4W), with one administration on the first day of each cycle.

7. The method according to any one of claims 1 to 6, wherein: The administration mode includes intravenous administration, such as intravenous infusion or injection, preferably intravenous infusion.

8. The method according to any one of claims 1 to 7, wherein: The antibody-drug conjugate targeting TROP2 is a lyophilized powder preparation.

9. Use of an antibody-drug conjugate targeting TROP2 for preparing a drug for treating solid tumors, wherein: The antibody-drug conjugate targeting TROP2 is as described in any one of claims 1-8, and the administration of the drug is as described in any one of claims 1-8.

10. A single dose unit comprising: An effective amount of the TROP2-targeting antibody-drug conjugate according to any one of claims 1 to 8.

11. A complete drug kit comprising an effective amount of the antibody-drug conjugate targeting TROP2 according to any one of claims 1 to 8; Preferably, the invention further comprises a package insert containing instructions for using the antibody-drug conjugate targeting TROP2 in an individual to prevent or treat a solid tumor in the individual.

12. Use of the single-dose unit according to claim 10 or the kit of parts according to claim 11 in the preparation of a medicament for preventing or treating solid tumors.

13. The method of any one of claims 1 to 8, or the use of claim 9 or 12, wherein the solid tumor is an advanced solid tumor, such as an unresectable locally advanced or metastatic solid tumor, such as a solid tumor having one or more of the following characteristics: (i) Standard treatment has failed or the patient is intolerant to standard treatment, or the patient refuses standard treatment or there is no standard treatment option; (ii) locally advanced or metastatic, e.g., locally advanced or metastatic late; (iii) unresectable with at least one measurable lesion assessed according to RECIST v1.1; (iv) have previously received at least one line, such as first-line or second-line anticancer therapy (such as systemic anti-tumor therapy); (v) previously received two or more lines of anticancer therapy (e.g., systemic anti-tumor therapy); (vi) failure of treatment with taxanes or intolerance to taxanes; Preferably, the solid tumor is triple-negative breast cancer, lung cancer such as non-small cell lung cancer or cervical cancer, such as triple-negative breast cancer, lung cancer such as non-small cell lung cancer or cervical cancer having one or more of the above characteristics; Preferably, the solid tumor is locally advanced or metastatic triple-negative breast cancer, lung cancer such as non-small cell lung cancer, or cervical cancer; More preferably, the solid tumor is locally advanced unresectable or metastatic triple-negative breast cancer that has previously failed or is intolerant to taxane therapy.

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