Method for treating cancer using Anti-b7h3 antibody-drug conjugate

Abstract

Provided in the present invention is a method for treating cancer, comprising administering a therapeutically effective amount of an anti-B7H3 antibody-drug conjugate to a subject in need thereof once or twice during each administration cycle. The therapeutic effect of the anti-B7H3 antibody-drug conjugate is fully exerted on the basis of an appropriate administration cycle, administration dose, and administration interval, thereby improving medication safety and patient medication compliance.

Description

Methods of using anti-B7H3 antibody-drug conjugates to treat cancer

[0001] This application claims priority to Chinese Patent Application No. 202411169660.2, filed August 24, 2024, entitled "Method for Using Anti-B7H3 Antibody Drug Conjugate to Treat Cancer", and Chinese Patent Application No. 202511164296.5, filed August 20, 2025, also entitled "Method for Using Anti-B7H3 Antibody Drug Conjugate to Treat Cancer". The contents of that application are incorporated herein by reference. Technical Field

[0002] This application belongs to the field of pharmaceutical technology, specifically relating to a dosing regimen for an anti-B7H3 antibody-drug conjugate used to treat cancer. Background Technology

[0003] B7H3 is a transmembrane receptor that is highly prevalent in malignant cells and is an important member of the immune checkpoint group. B7H3 is widely expressed in normal tissues, constitutively expressed only in non-immune resting fibroblasts, endothelial cells, osteoblasts, and amniotic fluid stem cells, and inducibly expressed on activated T, NK, DC, and macrophages. No positive expression has been detected in lymphoid organs (Chapoval, AI, et al., B7H3: A costimulatory molecule for T cell activation and IFN production. Nature Immunology, 2001, 2(3): p. 269-274). According to incomplete statistics, there are currently over one hundred drugs under development targeting B7H3, covering monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), antibody-drug conjugates, cell therapy, fusion proteins, etc., but no related therapies have yet been approved.

[0004] An antibody-drug conjugate (ADC) consists of three parts: an antibody, a bioactive molecule (drug molecule), and a linker. Its purpose is to deliver the bioactive molecule into cells in a target-dependent manner, thereby exerting effective anti-tumor activity against cancer cells expressing the target. Currently, several B7H3 ADC drugs have entered clinical trials globally, such as Ifinatamab deruxtecan, vobramitamab duocarmazine, and HS-20093. However, while preclinical studies of B7H3 ADCs have shown promising anti-tumor effects, their efficacy against certain tumor types in clinical trials has not been entirely ideal.

[0005] Because most clinical trials of cancer drugs target second-line and later-line patients with weakened immune systems, they are prone to adverse reactions of varying degrees, such as neutropenia, leukopenia, thrombocytopenia, lymphopenia, and anemia. In some cases, severe adverse reactions have even occurred, including interstitial pneumonia, pleural effusion, and death. Therefore, the efficacy and safety of these treatments require further evaluation. Maximizing benefit for cancer patients, exploring treatment regimens that combine efficacy and safety, improving patient tolerance, and reducing toxic reactions are of great significance to the clinical treatment of cancer.

[0006] Therefore, there is still a need in this field to develop cancer therapies with better therapeutic effects and / or safety. Summary of the Invention

[0007] To address the shortcomings of existing technologies and meet practical needs, the present invention aims to provide anti-B7H3 antibody drug conjugates, including pharmaceutically acceptable salts, stereoisomers, metabolites, or solvates, for use in cancer treatment. By optimizing the dosing cycle, dosage, frequency and interval of administration, and duration of each administration (e.g., intravenous infusion time), the therapeutic effect of the anti-B7H3 antibody drug conjugates can be fully realized, thereby improving drug safety and patient compliance.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] The first aspect of this invention provides a method for treating cancer, comprising administering an effective amount of an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to a subject in need during each cycle.

[0010] The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula I:

[0011] Wherein, Tb is the anti-B7H3 antibody or its antigen-binding fragment; S is the sulfur atom on Tb; q is any value between 1 and 16, including both extreme values; wherein, the effective amount is 0.8-3.0 mg / kg; and the cycle is preferably three weeks.

[0012] In some implementation methods, this includes administering an effective amount of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, to a subject in need in the following manner:

[0013] (a) Single administration: Administer once per cycle at a dose of 0.8–3.0 mg / kg; or

[0014] (b) Two-time administration: Administer twice in each cycle at a dose of 0.5-1.5 mg / kg.

[0015] In some embodiments, the single application is administered once per cycle at a dose of 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, or 3.0 mg / kg.

[0016] In some embodiments, the single application is administered once per cycle at a dose of 1.6-2.4 mg / kg, 1.6-2.0 mg / kg, or 2.0-2.4 mg / kg; preferably, it is administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg.

[0017] In some embodiments, the double administration is performed twice in each cycle at a dose of 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, or 1.5 mg / kg.

[0018] In some embodiments, the double administration is: administered twice in each cycle at a dose of 0.8-1.4 mg / kg, 1.0-1.2 mg / kg, or 1.2-1.4 mg / kg; preferably, administered twice in each cycle at a dose of 1.0 mg / kg, 1.2 mg / kg, or 1.4 mg / kg.

[0019] In some implementations, the first and second doses are the same.

[0020] In some implementations, the dosages for the first and second administrations are different.

[0021] In some implementations, the single administration is administered via intravenous infusion on day 1 of each cycle.

[0022] In some implementations, the interval between the two applications is 7 ± 3 days.

[0023] In some embodiments, the administration interval between the two administrations is 7-10 days, preferably administered intravenously on day 1 and day 8 of each cycle.

[0024] In some implementations, the dosing interval for the two administrations is allowed to be flexible, for example, administration on day 1 and day 10 respectively.

[0025] In some implementations, the intravenous infusion time for the subject is 60 ± 10 minutes.

[0026] In some implementations, the cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), lymphoepithelial neoplastic carcinoma (LELC), esophageal cancer (such as esophageal squamous cell carcinoma (ESCC)), head and neck squamous cell carcinoma, prostate cancer, breast cancer, and / or colon cancer.

[0027] In some embodiments, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer; preferably, the driver gene-negative non-small cell lung cancer includes adenocarcinoma or squamous cell carcinoma, more preferably adenocarcinoma.

[0028] In some implementations, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0029] In some embodiments, the method includes administering the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to a subject in need in the following manner:

[0030] (a) Single administration: Administer once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg, via intravenous infusion on day 1 of each cycle; or

[0031] (b) Double administration: Administer twice in each cycle at a dose of 1.0 mg / kg or 1.2 mg / kg; preferably, the first and second administrations are 7 days apart; preferably, the administration is administered intravenously on day 1 and day 8 of each cycle; preferably, the first and second administrations are at the same dose.

[0032] In some embodiments, q in Formula I is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably q is 2, 4, 6 or 8.

[0033] In some implementations, the form of Tb includes, but is not limited to: Fab, Fab', F(ab')2, Fd, Fv (e.g., scFv), dAb, complementarity-determining region fragment, non-human antibody, humanized antibody, chimeric antibody, fully human antibody, and probody.

[0034] In some embodiments, the Tb is an antibody or antigen-binding fragment thereof that binds to the B7H3-2Ig subtype and / or the B7H3-4Ig subtype.

[0035] In some embodiments, the binding activity of the Tb with the B7H3-4Ig isoform is higher than that with the B7H3-2Ig isoform.

[0036] In some implementations, the Tb is a monoclonal antibody or its antigen-binding fragment.

[0037] In some embodiments, the antibody or antigen-binding fragment further comprises a framework region derived from human or mouse immunoglobulins. In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises: (i) CDR-H1, which comprises or is composed of the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2, which comprises or is composed of the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3, which comprises or is composed of the amino acid sequence of SEQ ID NO: 3; and the light chain variable region comprises: (i) CDR-L1, which comprises or is composed of the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2, which comprises or is composed of the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3, which comprises or is composed of the amino acid sequence of SEQ ID NO: 6; preferably, the CDRs are defined according to the Kabat numbering system.

[0038] In some embodiments, the anti-B7H3 antibody is the 1D1, 1D1-01, 2E3, or 2E3-02 antibody disclosed in international patent WO2022170971A1; preferably, the anti-B7H3 antibody is either the 1D1-01 antibody or the 2E3-02 antibody.

[0039] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 8; preferably, the heavy chain variable region of the anti-B7H3 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0040] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 9, and the light chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; preferably, the heavy chain of the anti-B7H3 antibody comprises the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprises the amino acid sequence shown in SEQ ID NO: 10.

[0041] In some embodiments, the structural formula of the anti-B7H3 antibody-drug conjugate is shown below:

[0042] In some embodiments, the structure of the anti-B7H3 antibody-drug conjugate is shown in Formula II:

[0043] Wherein, 2E3-02 includes CDR-H1, CDR-H2, CDR-H3 as shown in SEQ ID NO: 1-3 and / or CDR-L1, CDR-L2, CDR-L3 as shown in SEQ ID NO: 4-6;

[0044] In some embodiments, the 2E3-02 comprises a heavy chain variable region of SEQ ID NO: 7 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 7, and / or comprises a light chain variable region of SEQ ID NO: 8 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 8;

[0045] In some embodiments, the 2E3-02 comprises a heavy chain of SEQ ID NO: 9 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 9, and / or comprises a light chain of SEQ ID NO: 10 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 10.

[0046] In the cancer treatment method described in the first aspect of the present invention, the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, is administered as a drug for monotherapy or combination therapy.

[0047] In some implementations, the combination therapy refers to the use of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, in combination with other anticancer therapeutic agents.

[0048] In some implementations, the subject preferably has completed prior treatment with other anticancer agents before administration of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate.

[0049] In some embodiments, the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, is administered as a monotherapy.

[0050] A second aspect of the invention provides an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, for use in the treatment of cancer, comprising administering an effective amount of the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to a subject of need in each cycle.

[0051] The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula I:

[0052] in,

[0053] Tb is an anti-B7H3 antibody or its antigen-binding fragment;

[0054] S represents the sulfur atom on Tb;

[0055] q is any value between 1 and 16, including both extreme values;

[0056] The effective dose is 0.8-3.0 mg / kg; and the treatment period is preferably three weeks.

[0057] Wherein, Tb is the anti-B7H3 antibody or its antigen-binding fragment; S is the sulfur atom on Tb; q is any value between 1 and 16, including both extreme values; wherein, the effective amount is 0.8-3.0 mg / kg; and the cycle is preferably three weeks.

[0058] In some implementation methods, this includes administering an effective amount of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, to a subject in need in the following manner:

[0059] (a) Single administration: Administer once per cycle at a dose of 0.8–3.0 mg / kg; or

[0060] (b) Two-time administration: Administer twice in each cycle at a dose of 0.5-1.5 mg / kg.

[0061] In some embodiments, the single application is administered once per cycle at a dose of 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, 1.5 mg / kg, 1.6 mg / kg, 1.7 mg / kg, 1.8 mg / kg, 1.9 mg / kg, 2.0 mg / kg, 2.1 mg / kg, 2.2 mg / kg, 2.3 mg / kg, 2.4 mg / kg, 2.5 mg / kg, 2.6 mg / kg, 2.7 mg / kg, 2.8 mg / kg, 2.9 mg / kg, or 3.0 mg / kg.

[0062] In some embodiments, the single application is administered once per cycle at a dose of 1.6-2.4 mg / kg, 1.6-2.0 mg / kg, or 2.0-2.4 mg / kg; preferably, it is administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg.

[0063] In some embodiments, the double administration is performed twice in each cycle at a dose of 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1.0 mg / kg, 1.1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.4 mg / kg, or 1.5 mg / kg.

[0064] In some embodiments, the double administration is: administered twice in each cycle at a dose of 0.8-1.4 mg / kg, 1.0-1.2 mg / kg, or 1.2-1.4 mg / kg; preferably, administered twice in each cycle at a dose of 1.0 mg / kg, 1.2 mg / kg, or 1.4 mg / kg.

[0065] In some implementations, the first and second doses are the same.

[0066] In some implementations, the dosages for the first and second administrations are different.

[0067] In some implementations, the single administration is administered via intravenous infusion on day 1 of each cycle.

[0068] In some embodiments, the administration interval between the two administrations is 7-10 days, preferably administered intravenously on day 1 and day 8 of each cycle.

[0069] In some implementations, the intravenous infusion time for the subject is 60 ± 10 minutes.

[0070] In some implementations, the cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), lymphoepithelial neoplastic carcinoma (LELC), esophageal cancer (such as esophageal squamous cell carcinoma (ESCC)), head and neck squamous cell carcinoma, prostate cancer, breast cancer, and / or colon cancer.

[0071] In some embodiments, the non-small cell lung cancer is driver gene-negative non-small cell lung cancer; preferably, the driver gene-negative non-small cell lung cancer includes adenocarcinoma or squamous cell carcinoma, more preferably adenocarcinoma.

[0072] In some implementations, the prostate cancer is metastatic castration-resistant prostate cancer (mCRPC).

[0073] In some embodiments, the method includes administering the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to a subject in need in the following manner:

[0074] (a) Single administration: Administer once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg, via intravenous infusion on day 1 of each cycle; or

[0075] (b) Double administration: Administer twice in each cycle at a dose of 1.0 mg / kg or 1.2 mg / kg; preferably, the first and second administrations are 7 days apart; preferably, the administration is administered intravenously on day 1 and day 8 of each cycle; preferably, the first and second administrations are at the same dose.

[0076] In some embodiments, q in Formula I is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably q is 2, 4, 6 or 8.

[0077] In some implementations, the form of Tb includes, but is not limited to: Fab, Fab', F(ab')2, Fd, Fv (e.g., scFv), dAb, complementarity-determining region fragment, non-human antibody, humanized antibody, chimeric antibody, fully human antibody, and probody.

[0078] In some embodiments, the Tb is an antibody or antigen-binding fragment thereof that binds to the B7H3-2Ig subtype and / or the B7H3-4Ig subtype.

[0079] In some embodiments, the binding activity of the Tb with the B7H3-4Ig isoform is higher than that with the B7H3-2Ig isoform.

[0080] In some implementations, the Tb is a monoclonal antibody or its antigen-binding fragment.

[0081] In some embodiments, the antibody or antigen-binding fragment further includes a framework region derived from human or mouse immunoglobulins.

[0082] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises: (i) CDR-H1, which comprises or is composed of the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2, which comprises or is composed of the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3, which comprises or is composed of the amino acid sequence of SEQ ID NO: 3; and the light chain variable region comprises: (i) CDR-L1, which comprises or is composed of the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2, which comprises or is composed of the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3, which comprises or is composed of the amino acid sequence of SEQ ID NO: 6; preferably, the CDRs are defined according to the Kabat numbering system.

[0083] In some embodiments, the anti-B7H3 antibody is the 1D1, 1D1-01, 2E3, or 2E3-02 antibody disclosed in international patent WO2022170971A1; preferably, the anti-B7H3 antibody is either the 1D1-01 antibody or the 2E3-02 antibody.

[0084] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 8; preferably, the heavy chain variable region of the anti-B7H3 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO: 8.

[0085] In some embodiments, the anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 9, and the light chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; preferably, the heavy chain of the anti-B7H3 antibody comprises the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprises the amino acid sequence shown in SEQ ID NO: 10.

[0086] In some embodiments, the structural formula of the anti-B7H3 antibody-drug conjugate is shown below:

[0087] In some embodiments, the structure of the anti-B7H3 antibody-drug conjugate is shown in Formula II:

[0088] Wherein, 2E3-02 includes CDR-H1, CDR-H2, CDR-H3 as shown in SEQ ID NO: 1-3 and / or CDR-L1, CDR-L2, CDR-L3 as shown in SEQ ID NO: 4-6;

[0089] In some embodiments, the 2E3-02 comprises a heavy chain variable region of SEQ ID NO: 7 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 7, and / or comprises a light chain variable region of SEQ ID NO: 8 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 8;

[0090] In some embodiments, the 2E3-02 comprises a heavy chain of SEQ ID NO: 9 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 9, and / or comprises a light chain of SEQ ID NO: 10 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 10.

[0091] In the cancer treatment method described in the first aspect of the present invention, the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, is administered as a drug for monotherapy or combination therapy.

[0092] In some implementations, the combination therapy refers to the use of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, in combination with other anticancer therapeutic agents.

[0093] In some implementations, the subject preferably has completed prior treatment with other anticancer agents before administration of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate.

[0094] In some embodiments, the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, is administered as a monotherapy.

[0095] definition

[0096] Unless otherwise defined, all terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Relevant definitions and terms can be found, for example, in Current Protocols in Molecular Biology (Ausubel), NCCN (National Comprehensive Cancer Network), or CSCO (Chinese Society of Clinical Oncology) guidelines. Furthermore, to better understand this invention, definitions and explanations of relevant terms are provided below. All references mentioned herein are incorporated herein by reference in their entirety.

[0097] The naturally occurring B7H3 antibodies described in this article can be isolated from nature or prepared using recombinant DNA technology, chemical synthesis, or a combination thereof.

[0098] As used herein, the terms "antibody" and "immunoglobulin" are used interchangeably and generally refer to immunoglobulins that can specifically bind to corresponding antigens, possessing the ability to specifically bind to specific antigens. The antibodies can be secreted by immune cells and include, but are not limited to, full-length antibodies comprising two light chains and two heavy chains, and / or heavy chain antibodies. The antibodies can be monoclonal or polyclonal. The antibodies can be monospecific, bispecific, or multispecific antibodies. The antibodies can be murine antibodies, camelid antibodies, humanized antibodies, fully human antibodies (fully human antibodies), or chimeric antibodies. The antibodies may contain additional modifications, such as non-naturally occurring amino acids, mutations in the Fc region, and mutations at glycosylation sites.

[0099] In this paper, the term "monoclonal antibody" refers to an antibody derived from a largely homogeneous group of antibodies, meaning that the antibodies constituting this cluster are identical except for a small number of possible natural mutations. Monoclonal antibodies possess high specificity against a single determinant (epitope) of an antigen, while polyclonal antibodies, in contrast, contain different antibodies targeting different determinants (epitopes). Besides specificity, a key advantage of monoclonal antibodies is that their synthesis is unaffected by contamination from other antibodies. The modifier "monoclonal" here indicates that the antibody is characterized by originating from a largely homogeneous group of antibodies, and should not be interpreted as requiring special methods for preparation.

[0100] In this document, monoclonal antibodies also specifically include chimeric antibodies, i.e., a portion of the heavy chain and / or light chain is identical or homologous to one, a class, or a subclass of antibody, while the remainder is identical or homologous to another, a different class, or a different subclass of antibody, provided they possess the desired biological activity (see, for example, US 4,816,567; and Morrison et al., 1984, PNAS, 81:6851-6855). Chimeric antibodies that can be used in this invention include primatized antibodies, which comprise a variable region antigen-binding sequence from a non-human primate (e.g., ancient monkey, chimpanzee, etc.) and a human constant region sequence.

[0101] In this document, the term "antigen-binding fragment" refers to a portion of an antibody, preferably an antigen-binding region or a variable region. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab)2, Fv fragments, F(ab')2, crossFab, scFv, di-scFv, sdAb (single-domain antibody, including nanobodies), or diabody.

[0102] In this paper, the "sulfur atom on Tb" can be a thiol group contained in the antibody itself after the disulfide bond is opened (e.g., the disulfide bond can be opened by reducing it with the reducing agent TCEP to generate a thiol group -SH). For example, the thiol group can be selected from the thiol groups after the disulfide bonds between the hinge regions Cys232-Cys232, Cys229-Cys229, and Cys223-Cys215 in the Fab regions are opened. For example, the eight sulfur atoms in Formula II can be from the thiol groups after the four pairs of disulfide bonds between the hinge regions Cys232-Cys232, Cys229-Cys229, and the two Fab regions Cys223-Cys215 are opened.

[0103] "Sequence identity" between two polypeptide sequences indicates the percentage of identical amino acids between the sequences. "Sequence similarity" indicates the percentage of identical or conserved amino acid substitutions. Methods for evaluating the degree of sequence identity between amino acids or nucleotides are known to those skilled in the art. For example, amino acid sequence identity is typically measured using sequence analysis software. For instance, the BLAST program in the NCBI database can be used to determine identity. For determining sequence identity, see, for example: Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M., Stockton Press, New York, 1991.

[0104] The sequences described in this invention may have deletions, insertions, or substitutions of one or more amino acid residues, which produce silencing changes and result in functionally equivalent molecules. Intentional amino acid substitutions can be made based on the similarity of residue polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or amphiphilicity, as long as activity is preserved.

[0105] As used herein, the percentage homology between two amino acid sequences is equal to the percentage identity between the two sequences. The percentage identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = number of identical positions / total number of positions x 100), where the number of gaps and the length of each gap need to be taken into account for optimal comparison of the two sequences. Sequence comparison and determination of percentage identity between sequences can be performed using methods commonly known in the art, and such sequence comparison and determination of percentage identity can be implemented using mathematical algorithms. For example, the algorithm of Meyers and Miller, 1988 Comput. Appl. Biosci. 4: 11-17 (integrated into the ALIGN program (version 2.0)) can be used to determine the percentage identity between amino acid sequences and / or nucleotide sequences. Furthermore, the GAP program (using its default parameters) in the GCG software package available online from Accelrys can be used to determine the percentage identity between amino acid sequences or nucleotide sequences. In one embodiment, the two sequences are of equal length.

[0106] In this invention, the term "drug" refers to a substance that inhibits or prevents cell function and / or causes cell death or damage.

[0107] The antibody-drug conjugates of the present invention may be in the form of a pharmaceutically acceptable salt, or in the form of a stereoisomer, or in the form of a metabolite, or in the form of a solvate, and the salt, stereoisomer, or metabolite may also be in the form of a solvate.

[0108] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of a compound and is biologically or otherwise suitable for use as a drug. In many cases, the antibody-drug conjugates of the present invention can form acid addition salts and / or base addition salts by virtue of the amino and / or carboxyl or similar groups present therein.

[0109] Pharmaceutically acceptable acid addition salts can be salts formed with inorganic or organic acids. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. The organic acids include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0110] Pharmaceutically acceptable base addition salts can be salts formed with inorganic or organic bases. Salts formed with inorganic bases include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts, with ammonium, potassium, sodium, calcium, and magnesium salts being particularly preferred. Organic bases include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins. Specific examples of organic bases are isopropylamine, trimethylamine, diethylamine, N-ethylethylamine, tripropylamine, and ethanolamine.

[0111] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting an adequate amount of a basic compound with a suitable acid that provides a pharmaceutically acceptable anion.

[0112] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In compounds having one or more asymmetric centers, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers can be produced. Specific individual molecules may also exist as geometric isomers (cis / trans). Unless otherwise stated, when the stereochemistry of a disclosed compound is not explicitly described in its name or structure and it has one or more asymmetric centers, it should be understood that all possible stereoisomers of the compound are represented.

[0113] The term "solvent" refers to a solvate formed by the association of one or more solvent molecules with any antibody-drug conjugate of Formula I or its pharmaceutically acceptable salt or isomer. The term solvate includes hydrates (e.g., hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and similar hydrates).

[0114] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body upon administration of the compounds of this invention. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0115] In this document, the term "treatment" refers to a method performed to achieve a beneficial or desired clinical outcome. For the purposes of this invention, a beneficial or desired clinical outcome includes, but is not limited to, alleviating symptoms, reducing the extent of disease, stabilizing (i.e., no longer worsening) the state of disease, delaying or slowing the progression of disease, improving or alleviating the state of disease, and relieving symptoms (whether partial or complete), whether detectable or undetectable. Furthermore, "treatment" can also refer to prolonging survival compared to the expected survival (if no treatment was received).

[0116] In this document, the term "therapeutic effective dose" or "effective dose" refers to the amount of an anti-B7H3 antibody-drug conjugate that effectively prevents or alleviates the disease or condition to be treated when administered to cells, tissues, or a treated subject. A therapeutic effective dose further refers to the amount of antibody-drug conjugate (ADC) and / or antibody or fragment thereof sufficient to result in symptom relief, such relief being, for example, treatment, cure, or alleviation of an associated medical condition, or an increase in the rate of treatment, cure, or alleviation of said symptom. The effective dose for a specific treated subject can vary depending on a variety of factors, such as the disease to be treated, the patient's overall health condition, the route and dosage of administration, and the severity of side effects. An effective dose may be the maximum dose or administration regimen that avoids significant side effects or toxicity. A therapeutic effective dose will typically reduce symptoms by at least 10%; typically at least 20%; at least about 30%; at least 40%; or at least 50%.

[0117] As used herein, the terms “subject” or “patient” refer to (but not limited to) mammals, including (but not limited to) humans, as the subject of treatment, observation, or experimentation.

[0118] As used herein, the term "about" indicates an accuracy interval that a person skilled in the art would understand to still ensure the technical effect of the feature under discussion. This term typically indicates a deviation from a specified numerical value of ±10%, such as ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, for example, ±0.01%. A person skilled in the art will understand that the specific deviation of such a value for a given technical effect will depend on the nature of that technical effect. For example, natural or biotechnological effects generally have a larger such deviation than man-made or engineered effects. The term "about" allows for the interpretation of technical measurement uncertainty and variation, such as when referring to a specific quantity or concentration.

[0119] The terms “selective binding” and “specific binding” are used interchangeably here.

[0120] The term "drug-to-antibody ratio" or "DAR" refers to the amount of drug, such as a small molecule toxin attached to an antibody-drug conjugate (ADC). The DAR of an ADC can range from 1 to 16, but higher loadings (e.g., 20) are possible depending on the number of binding sites on the antibody. In this invention, the terms "DAR" and "number of binding sites" are synonymous, as are "average DAR" and "average number of binding sites." The term DAR may be used when referring to the amount of drug loaded onto a single antibody, or alternatively, when referring to the average or mean DAR of a group of ADCs. It can be characterized by conventional methods such as UV / Vis spectroscopy, mass spectrometry, enzyme-linked immunosorbent assay (ELISA), and high-performance liquid chromatography (HPLC).

[0121] The term "single administration" refers to administering the drug once per treatment cycle, while the term "double administration" refers to administering the drug twice per treatment cycle.

[0122] The term "cycle" refers to a clinical treatment cycle; for example, every three weeks (Q3W) constitutes a treatment cycle.

[0123] In this document, the complementarity-determining regions (CDRs) contained in the antibodies or antigen-binding fragments of the present invention are determined using the Kabat numbering system.

[0124] In this article, the term "monotherapy" refers to an antibody-drug conjugate being the only anticancer agent administered to the subject during the treatment cycle. However, other therapeutic agents may be administered to the subject. For example, anti-inflammatory agents or other agents may be administered to the cancer subject during this period to treat cancer-related symptoms but not the underlying cancer itself, including, for example, inflammation, pain, weight loss, and general malaise.

[0125] In this article, the term "combination therapy" refers to the administration of antibody-drug conjugates in combination with other anticancer agents to subjects during a treatment cycle. These other anticancer agents include, but are not limited to, immune checkpoint inhibitors.

[0126] In this article, the term "relapse" refers to the return of the disease to its pre-treatment state after the disease has been controlled.

[0127] In this article, the term "ECOGPS score" refers to the ECOGPS assessment performed during visits specified in the study procedure schedule and when clinically indicated, based on the Eastern Cooperative Oncology Group Performance Status (ECOGPS) scale.

[0128] In this article, the term "complex SCLC" refers to pathological types that include not only small cell lung cancer but also other pathological types, such as large cell carcinoma, squamous cell carcinoma, and adenocarcinoma.

[0129] As used in this article, the terms “complete remission (CR)”, “partial remission (PR)”, “stable disease (SD)”, “progressive disease (PD)”, “objective response rate (ORR)”, and “disease control rate (DCR)” are defined as follows:

[0130] When the disease is a solid tumor, the efficacy of treatment for solid tumors is evaluated according to the following criteria (see New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), EAEisenhauer et al., *EUROPEAN JOURNAL OF CANCER*, 45 (2009), pp. 228-247): "Complete Response (CR)," "Partial Response (PR)," "Stable Disease (SD)," "Progressive Disease (PD)," "Objective Response Rate (ORR)," and "Disease Control Rate (DCR)." The specific evaluation of target lesions is as follows:

[0131] Complete remission (CR): All target lesions disappear, the short diameter of all pathological lymph nodes (including target nodules and non-target nodules) must be reduced to <10mm, and there are no new lesions.

[0132] Partial remission (PR): The sum of the diameters of target lesions (using the shortest diameter of lymph nodes) is reduced by at least 30% from baseline. There is no significant progression of non-target lesions and no new lesions.

[0133] Disease stability (SD): The degree of reduction in target lesions does not reach the PR level, nor does the degree of increase reach the PD level; it falls between the two. The minimum value of the sum of diameters can be used as a reference in studies.

[0134] Disease progression (PD): The minimum sum of the diameters of all measured target lesions throughout the entire trial study is used as a reference, with a relative increase of at least 20% in the sum of diameters (or the baseline value if the baseline measurement is the minimum); in addition, the absolute value of the sum of the measured target lesion diameters must increase by at least 5 mm (the appearance of one or more new lesions is also considered disease progression).

[0135] Objective response rate (ORR): This refers to the proportion of patients whose tumors shrink to a certain extent and remain so for a certain period of time, including cases of complete remission (CR) and partial response (PR). Subjects must have measurable tumor lesions at baseline, and the efficacy assessment criteria are based on RECIST 1.1.

[0136] Disease control rate (DCR): The percentage of patients who achieved complete remission (CR), partial remission (PR), or stable disease (SD) out of the total number of patients analyzed. Beneficial effects

[0137] This invention provides a novel cancer treatment method that achieves significant cancer treatment effects by administering anti-B7H3 antibody-drug conjugates through a specific dosing regimen (dosing cycle, dosage, number of doses, and dosing interval).

[0138] The dosing regimen of this invention significantly improves overall patient tolerance and safety during the dosing process, thereby enhancing the safety of clinical medication.

[0139] The drug delivery regimen of this invention achieves better cancer treatment results and has significant clinical application prospects. Attached Figure Description

[0140] Figure 1 shows the peak concentration C of the free-loaded toxin. max Correlation with ≥ grade 3 neutrophil count.

[0141] Figure 2 shows the trough concentration C of the ADC drug. min Correlation with objective response rate (ORR).

[0142] Figure 3 shows the pharmacokinetic curves of ADC drugs under different dosing regimens simulated by the model.

[0143] Figures 4A and 4B show the simulated changes in neutrophil count under different dosing regimens (total dose of 2.0 mg / kg).

[0144] Figures 5A and 5B show the simulated changes in neutrophil count under different dosing regimens (total dose of 2.4 mg / kg). Detailed Implementation

[0145] The present invention will be further described below through specific embodiments, but this is not intended to limit the invention. Those skilled in the art can make various modifications or improvements based on the teachings of the present invention without departing from the basic ideas and scope of the invention.

[0146] Sequence information

[0147] The sequence information involved in this invention is described in Table 1 below.

[0148] Table 1 Sequence information of anti-B7H3 antibody

[0149] Example 1: Preparation of anti-B7H3 antibody

[0150] The 2E3-02 antibody was prepared and its activity was verified in accordance with the method in international patent WO2022170971A1.

[0151] Following the method described in Example 3.4 of WO2022170971A1, the heavy and light chain sequences of the 2E3-02 antibody were constructed into a PTT5 vector through codon optimization and gene synthesis (General Biosystems (Anhui) Co., Ltd.). The expression plasmids of the heavy and light chains were co-transfected into HEK293F cells using PEI max reagent and expressed for 7 days at 37°C with 5% CO2. The supernatant was collected and purified using ProA magnetic beads to obtain the anti-B7H3 antibody, named 2E3-02. The affinity and specificity of 2E3-02 for B7H3 protein were confirmed by ELISA, following the methods described in Examples 3.5 and 3.8 of WO20222170971A1.

[0152] Example 2: Synthesis of drug linker conjugates (DL-01)

[0153] The drug linker conjugate DL-01 with the structure described above (DL-01 corresponds to the compound of formula Ia in WO2023143208A1) was prepared by the production method described in Example 17 of International Patent WO2023143208A1, and the small molecule toxin structure therein is as follows, with CAS number 2821768-98-1.

[0154] Example 3: Synthesis of B7H3-ADC

[0155] Example 3.1: Synthesis of B7H3-ADC-01(DAR8)

[0156] Referring to the synthesis method described in Example 4.1.7.1 Preparation Method B of International Patent WO2022170971A1, an anti-B7H3 antibody-drug conjugate (hereinafter referred to as "B7H3-ADC-01(DAR8)"), namely Tambotatug pelitecan (Proposed International Nonproprietary Names: List 133), was synthesized using a humanized B7H3 antibody (2E3-02).

[0157] Example 3.2: Synthesis of B7H3-ADC-01(DAR2)

[0158] Referring to the synthesis method described in Example 4.1.7.2 of International Patent WO2022170971A1, an anti-B7H3 antibody-drug conjugate (hereinafter referred to as "B7H3-ADC-01(DAR2)") was synthesized using a humanized B7H3 antibody (2E3-02).

[0159] Example 3.3: Synthesis of B7H3-ADC-01(DAR4)

[0160] Referring to the synthesis method described in Example 4.1.7.3(1) of International Patent WO2022170971A1, an anti-B7H3 antibody-drug conjugate (hereinafter referred to as "B7H3-ADC-01(DAR4)") was synthesized using a humanized B7H3 antibody (2E3-02).

[0161] Example 3.4: Synthesis of B7H3-ADC-01(DAR6)

[0162] Referring to the synthesis method described in Example 4.1.7.4 of International Patent WO2022170971A1, an anti-B7H3 antibody-drug conjugate (hereinafter referred to as "B7H3-ADC-01(DAR6)") was synthesized using a humanized B7H3 antibody (2E3-02).

[0163] Experiment Example 4: Clinical trial of anti-B7H3 antibody-drug conjugate for the treatment of advanced solid tumors

[0164] This study is a multicenter, open-label, phase I trial of B7H3-ADC-01 (DAR8) to evaluate the safety, efficacy, and pharmacokinetic characteristics of B7H3-ADC-01 (DAR8) in the following selected patients with advanced solid tumors:

[0165] I. Selection Criteria

[0166] Participants must meet all of the following criteria to be included in the study:

[0167] 1) The participants were informed of the trial details before the trial began and voluntarily signed their name and the date on the informed consent form;

[0168] 2) Age ≥ 18 years;

[0169] 3) Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1;

[0170] 4) Organ and bone marrow functions meet the requirements, as defined below:

[0171] • Hemoglobin ≥90g / L (no blood transfusion or erythropoietin therapy within 14 days prior to the first dose),

[0172] • Absolute neutrophil count ≥1.5×10 9 / L (no granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days prior to the first dose)

[0173] • Platelet count ≥100×10⁶ in the absence of obvious liver lesions (primary or metastatic) 9 / L, or ≥75×10 when liver lesions are present. 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment received within 14 days prior to the first dose)

[0174] • Total bilirubin ≤1.5×ULN in the absence of obvious liver lesions (primary or metastatic), or ≤3×ULN in the presence of liver lesions.

[0175] • ALT and AST levels ≤3×ULN in the absence of significant liver lesions (primary or metastatic), or ≤5×ULN in the presence of liver lesions.

[0176] Creatinine clearance ≥ 60 mL / min (calculated according to the Cockcroft-Gault formula),

[0177] • Patients who have not received anticoagulation therapy have an activated partial thromboplastin time and an international normalized ratio ≤1.5×ULN, or patients who have received anticoagulation therapy have a stable anticoagulation therapy regimen.

[0178] 5) Female patients of childbearing potential must agree to use highly effective contraception from the time of screening until the entire study period and for at least 6 months after the last dose of the study drug, and must not donate or retrieve eggs for their own use. Male patients must agree to use highly effective contraception from the time of screening until the entire study period and for at least 6 months after the last dose of the study drug, and must not freeze or donate sperm.

[0179] 6) Life expectancy ≥ 3 months;

[0180] 7) Able and willing to comply with the visits and procedures stipulated in the research protocol;

[0181] 8) Pathologically confirmed as advanced solid tumor, previous standard treatment has been proven ineffective or intolerable, or no standard treatment is available;

[0182] 9) According to the Evaluation Criteria for Treatment of Solid Tumors (RECIST) version 1.1, there must be at least one evaluable tumor lesion; for prostate cancer patients with only bone lesions, enrollment may be made based on the specific circumstances after discussion with the sponsor.

[0183] II. Exclusion Criteria

[0184] Subjects meeting any of the following criteria should not be enrolled in the study:

[0185] 1) Previous treatment with B7H3-targeted drugs (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs);

[0186] 2) Intolerance to previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors, including but not limited to topotecan, irinotecan, and Dxd (e.g., severe diarrhea);

[0187] 3) Enrollment in another clinical study simultaneously, unless it is an observational (non-interventional) clinical study or is in the follow-up period of an interventional study;

[0188] 4) Received systemic anticancer therapy within 3 weeks prior to the first administration of the study drug, including chemotherapy, molecular targeted therapy, hormone therapy, immunotherapy, or biotherapy (oral fluorouracil [e.g., tegafur and capecitabine] or small molecule targeted therapy within 2 weeks or 5 half-lives [whichever is shorter] prior to the first administration; mitomycin or nitrosoureas within 6 weeks prior to the first administration; traditional Chinese medicine or non-specific immunomodulators with antitumor indications [e.g., thymosin, interferon, and interleukin] within 2 weeks prior to the first administration);

[0189] Note: For patients with prostate cancer (PC), androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs (GnRH agonists or GnRH antagonists) is permitted;

[0190] 5) Received radiation therapy within 4 weeks prior to the first administration of the study drug, including palliative stereotactic radiotherapy to the abdomen (for non-abdominal palliative stereotactic radiotherapy, within 2 weeks prior to the first administration);

[0191] 6) Underwent major surgery (excluding diagnostic surgery) within 4 weeks prior to the first administration of the study drug, or is expected to undergo major surgery during the study period;

[0192] 7) Had undergone allogeneic hematopoietic stem cell transplantation (HSCT) before the first administration of the investigational drug, or had undergone autologous HSCT within 3 months before the first administration of the investigational drug;

[0193] 8) Received systemic steroids (>10 mg / day prednisone or equivalent) or other immunosuppressive therapy within 2 weeks prior to the first dose of the study drug. This criterion does not apply in the following situations:

[0194] • Intranasal, inhaled, or topical steroids, or local steroid injections (such as intra-articular injections),

[0195] • Physiological doses of systemic steroids as replacement therapy (such as physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).

[0196] Steroids are used as a preventative measure for hypersensitivity reactions (e.g., for CT scan prophylaxis).

[0197] 9) Has received any live vaccine within 4 weeks prior to the first administration of the study drug, or plans to receive a live vaccine during the study period;

[0198] 10) History of leptomeningeal carcinoma;

[0199] 11) Brain metastases or spinal cord compression, unless asymptomatic, or symptoms are stable after treatment and steroid and anticonvulsant treatment is not required for at least 2 weeks prior to the first administration of the investigational drug;

[0200] 12) Having uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0201] • A history of symptomatic congestive heart failure (NYHA Class II to IV) or any arterial thromboembolic event (such as myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months prior to the first dose.

[0202] Uncontrolled hypertension is defined as systolic blood pressure (SBP) > 160 mmHg and / or diastolic blood pressure (DBP) > 100 mmHg after antihypertensive treatment.

[0203] • Severe arrhythmias requiring treatment

[0204] • The QT interval (QTcF) corrected according to the Fridricilia formula is prolonged to >470 ms;

[0205] 13) History of (non-infectious) interstitial lung disease (ILD) / pulmonary inflammation requiring steroid treatment, or current ILD / pulmonary inflammation, or suspected ILD / pulmonary inflammation that cannot be ruled out by imaging at the time of screening.

[0206] 14) Clinically significant comorbid lung diseases, including but not limited to:

[0207] • Pulmonary embolism occurred within 3 months prior to the start of the study treatment.

[0208] • Any autoimmune, connective tissue, or inflammatory disease documented at the time of screening (e.g., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis), or suspected lung involvement.

[0209] • Previous total pneumonectomy;

[0210] 15) Diagnosed with Gilbert's syndrome;

[0211] 16) Patients with uncontrolled third-space effusion (e.g., pleural effusion, ascites, pericardial effusion) requiring repeated drainage;

[0212] 17) Having active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigators believe may cause bleeding or perforation;

[0213] 18) Patients who have an uncontrolled infection requiring systemic treatment within one week prior to the first dose;

[0214] 19) Human immunodeficiency virus (HIV) infection is known to exist;

[0215] 20) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg) and HBV DNA level higher than the ULN of the research center; active HCV is defined as positive for hepatitis C antibody and HCV RNA level higher than the ULN of the research center.

[0216] 21) Unrecovered toxicity from previous anticancer treatment, defined as toxicity not yet recovered to NCI CTCAE grade ≤1, baseline level, or the level specified in the inclusion / exclusion criteria, excluding alopecia (any grade), hyperpigmentation (any grade), and peripheral neuropathy (≤2 grade). Patients with irreversible toxicity (such as hearing loss) that are not reasonably expected to be aggravated by the investigational drug may be enrolled after discussion with the sponsor;

[0217] 22) History of severe hypersensitivity reactions to inactive components in active pharmaceutical ingredients, formulations, or other monoclonal antibodies;

[0218] 23) Breastfeeding women, or women who have been confirmed pregnant by a pregnancy test within 3 days prior to the first administration;

[0219] 24) Any disease, medical condition, organ system dysfunction, or social condition that the researcher believes may interfere with a patient’s ability to sign an informed consent form, adversely affect a patient’s ability to cooperate and participate in the study, or affect the interpretation of the study results, including but not limited to mental illness or substance / alcohol abuse.

[0220] III. Dosing Regimen

[0221] Subjects meeting all inclusion criteria and not any exclusion criteria received monotherapy with anti-B7H3 antibody-drug conjugate (B7H3-ADC-01(DAR8)) (dose 0.8, 1.6, 2.0, 2.4, 2.8, or 3.0 mg / kg, administered intravenously every three weeks, with administration on day 1 of each cycle). Efficacy was evaluated every two cycles for the first eight cycles, and every three cycles thereafter. The number of cycles was not fixed in this study, continuing until disease progression, intolerable toxicity, or voluntary withdrawal. Study endpoints included safety, objective response rate (ORR), disease control rate (DCR), pharmacokinetics, and immunogenicity.

[0222] IV. Treatment Effects

[0223] As of June 24, 2024, the clinical study enrolled 49 participants, including those with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), esophageal cancer, head and neck squamous cell carcinoma, breast cancer, and colorectal cancer. Efficacy data showed that among the 40 evaluable participants, 38 exhibited varying degrees of tumor stabilization or shrinkage, with 18 achieving an objective response (ORR) of 45.0% and a disease control rate (DCR) of 95.0%. The 2.0 mg / kg and 2.4 mg / kg dose groups demonstrated better treatment efficacy. In the 2.0 mg / kg dose group, patients with NSCLC, SCLC, and NPC had an ORR of 57.1% (4 / 7) and a DCR of 85.7% (6 / 7); in the 2.4 mg / kg dose group, patients with NSCLC, SCLC, NPC, and esophageal cancer had an ORR of 47.1% (8 / 17) and a DCR of 100% (17 / 17).

[0224] As of July 4, 2025, the dose-escalation phase clinical trial enrolled 49 subjects, including those with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), esophageal cancer, head and neck squamous cell carcinoma, prostate cancer, breast cancer, and colon cancer. Efficacy data showed that among the 45 evaluable subjects, 39 subjects observed varying degrees of tumor stabilization or shrinkage, with 18 achieving an objective response (ORR) of 40.0% (18 / 45) and a disease control rate (DCR) of 86.7% (39 / 45). Specifically, the SCLC, NPC, and NSCLC patients showed better treatment outcomes, with ORRs of 50.0% (6 / 12), 71.4% (5 / 7), and 38.9% (7 / 18), respectively; and DCRs of 100.0% (12 / 12), 100.0% (7 / 7), and 83.3% (15 / 18), respectively. During the dose escalation phase, the 2.0 mg / kg and 2.4 mg / kg dose groups demonstrated good therapeutic efficacy and acceptable safety. In patients with NSCLC, SCLC, NPC, and prostate cancer, the 2.0 mg / kg dose group showed an ORR of 40.0% (4 / 10) and a DCR of 60.0% (6 / 10). In patients with NSCLC, SCLC, NPC, and esophageal cancer, the 2.4 mg / kg dose group showed an ORR of 47.1% (8 / 17) and a DCR of 100% (17 / 17). Regarding safety, the incidence of TRAEs leading to treatment discontinuation was 0% in both the 2.0 mg / kg and 2.4 mg / kg dose groups.

[0225] The positive rate of ADA (Anti-drug antibody) after treatment was 0.00%, indicating that its immunogenicity in the human body is extremely low.

[0226] Experimental Example 2: Clinical trial of anti-B7H3 antibody-drug conjugate for the treatment of selected advanced solid tumors.

[0227] This study is a multicenter, open-label, phase I / II trial of B7H3-ADC-01 (DAR8) to evaluate the safety, efficacy, and pharmacokinetic characteristics of B7H3-ADC-01 (DAR8) in selected patients with advanced solid tumors:

[0228] I. Selection Criteria

[0229] Participants must meet all of the following criteria to be included in the study:

[0230] 1) The participants were informed of the trial details before the trial began and voluntarily signed their name and date on the Informed Consent Form (ICF);

[0231] 2) Must be ≥18 years old and ≤75 years old when signing the ICF;

[0232] 3) Subjects enrolled in the driver gene-negative NSCLC cohort must meet the following criteria:

[0233] • Diagnosed with NSCLC by histology or cytology

[0234] • Patients with locally advanced (stage IIIB / IIIC) or metastatic (stage IV) disease at enrollment (using the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) staging system, 8th edition), who were not suitable for radical surgery or radiotherapy.

[0235] For NSCLC with adenocarcinoma or adenocarcinoma components, there must be clear documentation showing no epidermal growth factor receptor (EGFR) sensitive mutations, and no anaplastic lymphoma kinase (ALK) or c-ross proto-oncogene (ROS1) fusions. For other pathological types of NSCLC, such as squamous cell carcinoma, if the previous EGFR, ALK, and ROS1 gene status is unknown, corresponding testing is not required before enrollment.

[0236] • For locally advanced or metastatic disease, patients must have previously received at least platinum-based chemotherapy and anti-PD-(L)1 therapy, and have a history of disease progression or intolerance during or after treatment;

[0237] Subjects enrolled in the SCLC cohort must meet the following criteria:

[0238] • Individuals diagnosed with SCLC by histology or cytology were not eligible for inclusion in this study; combined SCLC was not permitted.

[0239] Subjects enrolled in the NPC cohort must meet the following criteria:

[0240] • Diagnosed as NPC by histology or cytology

[0241] • Patients with metastatic (stage IVB, using the UICC and AJCC staging systems, 8th edition) or recurrent disease at enrollment who were unsuitable for local or radical treatment.

[0242] Note: For all the above cohorts, if a subject experiences disease progression during or within 6 months of receiving neoadjuvant, adjuvant, or radical chemoradiotherapy, the treatment regimen will be considered as first-line treatment for advanced / metastatic disease.

[0243] 4) According to RECIST v1.1, there must be at least one measurable extracranial lesion. Lesions previously treated with radiotherapy or other local therapies cannot be used as target lesions unless there is clear progression. For mCRPC patients with only bone lesions, enrollment may be considered based on specific circumstances after discussion with the sponsor;

[0244] 5) Archived or fresh tumor tissue samples can be provided. For subjects unable to provide tumor samples or with insufficient samples, enrollment may be considered based on the specific circumstances after discussion with the sponsor;

[0245] 6) An Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1;

[0246] 7) The body's organs and bone marrow function must meet the requirements within 7 days prior to the first dose, as defined below:

[0247] • Hemoglobin (Hb) ≥ 9.0 g / dL (no blood transfusion or erythropoietin therapy within 14 days prior to the first dose),

[0248] • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹ / L (no prior granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor therapy within 14 days prior to first dose),

[0249] • Platelet count (PLT) ≥100×10⁹ / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment received within 14 days prior to the first dose),

[0250] • Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) in the absence of significant liver metastasis, or ≤3 × ULN in the presence of liver metastasis.

[0251] • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are ≤3×ULN in the absence of significant liver metastasis, or ≤5×ULN in the presence of liver metastasis.

[0252] • Serum albumin ≥2.5g / dL,

[0253] Creatinine clearance ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula),

[0254] • Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for subjects receiving anticoagulation therapy. These subjects must have a stable anticoagulation therapy regimen, and APTT and INR must be within the range that the investigator deems appropriate.

[0255] 8) Female participants of childbearing potential must agree to use highly effective contraception from the time of screening until the entire study period and for at least 6 months after the last dose of the investigational drug. Male participants must agree to use highly effective contraception from the time of screening until the entire study period and for at least 6 months after the last dose of the investigational drug.

[0256] 9) Expected survival ≥ 3 months;

[0257] 10) Has the ability and willingness to comply with the visits and procedures stipulated in the research protocol.

[0258] II. Exclusion Criteria

[0259] Subjects meeting any of the following criteria should not be enrolled in the study:

[0260] 1) Previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T], and other drugs);

[0261] 2) Previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors;

[0262] 3) Enrollment in another clinical study simultaneously, unless it is an observational (non-interventional) clinical study or is in the follow-up period of an interventional study;

[0263] 4) Insufficient washout period of prior anticancer therapy before the first administration of the investigational drug, as defined below:

[0264] Chemotherapy or small molecule targeted therapy lasting less than 2 weeks or 5 half-lives, whichever is shorter.

[0265] Antibody treatment <3 weeks,

[0266] Hormone therapy for less than 3 weeks,

[0267] • Traditional Chinese medicine treatment with anti-tumor indications for less than 2 weeks

[0268] Brain radiotherapy <2 weeks,

[0269] Palliative radiotherapy <2 weeks, radical radiotherapy <4 weeks;

[0270] 5) Had major surgery (excluding diagnostic surgery) within 4 weeks prior to the first administration of the investigational drug, or is expected to have major surgery during the study period;

[0271] 6) Has previously received an allogeneic bone marrow transplant or a solid organ transplant;

[0272] 7) Patients who have received systemic steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive therapy within 2 weeks prior to the first administration of the investigational drug, excluding the following:

[0273] • Intranasal, inhaled, or topical steroids, or local steroid injections (such as intra-articular injections),

[0274] • Physiological doses of systemic steroids as replacement therapy (such as physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency).

[0275] • Steroids are used as a preventative treatment for hypersensitivity reactions (such as CT contrast agent allergy) or chemotherapy-induced nausea and vomiting (CINV);

[0276] 8) Has received any live vaccine within 4 weeks prior to the first administration of the investigational drug, or plans to receive a live vaccine during the study period;

[0277] 9) Leptomeningeal metastasis or carcinomatous meningitis;

[0278] 10) Brain metastasis or spinal cord compression, excluding the following:

[0279] • Asymptomatic brain metastases that do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are permitted to enroll.

[0280] • If a subject’s brain metastases have been treated and the metastases are stable (brain imaging at least 4 weeks before the first dose shows that the lesions are stable, there are no new neurological symptoms, and no immediate local or systemic treatment is required within 2 weeks before the first dose), and there is no evidence of new or enlarged brain metastases, then the subject is allowed to enroll.

[0281] 11) Having uncontrolled or clinically significant cardiovascular disease, including but not limited to:

[0282] • A history of symptomatic congestive heart failure (NYHA Class II to IV) or any arterial thromboembolic event (such as myocardial infarction, unstable angina, cerebrovascular accident, and transient ischemic attack) within 6 months prior to the first dose.

[0283] Uncontrolled hypertension is defined as systolic blood pressure (SBP) > 160 mmHg and / or diastolic blood pressure (DBP) > 100 mmHg after antihypertensive treatment.

[0284] • Severe arrhythmias requiring treatment

[0285] • The QT interval (QTcF) corrected by the Fridricilia formula is prolonged to >450ms (male) or 470ms (female);

[0286] 12) Clinically significant comorbid lung diseases, including but not limited to:

[0287] • A history of (non-infectious) interstitial lung disease (ILD) / interstitial pneumonia requiring steroid treatment, or currently having ILD / interstitial pneumonia.

[0288] • Pulmonary embolism occurred within 3 months prior to the first dose.

[0289] • Any autoimmune, connective tissue, or inflammatory disease (such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) or suspected lung involvement documented at the time of screening.

[0290] • Previous total pneumonectomy,

[0291] • Other moderate to severe lung diseases that may interfere with the detection or treatment of drug-related pulmonary toxicity and seriously affect respiratory function;

[0292] 13) Diagnosed with Gilbert's syndrome;

[0293] 14) Patients with uncontrolled third-space effusion (such as pleural effusion, ascites, pericardial effusion) requiring repeated drainage;

[0294] 15) History of gastrointestinal perforation and / or fistula within 6 months prior to the first dose, or active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation;

[0295] 16) Subjects who have experienced a serious infection (NCI CTCAE grade ≥3) within 4 weeks prior to the first dose, such as severe pneumonia requiring hospitalization, bacteremia, or infectious complications, or who have experienced an active infection requiring systemic treatment within 2 weeks prior to the first dose. Subjects receiving prophylactic anti-infective therapy (e.g., prevention of urinary tract infections or exacerbations of chronic obstructive pulmonary disease) may be eligible for enrollment after discussion with the sponsor.

[0296] 17) Human immunodeficiency virus (HIV) infection is known to exist;

[0297] 18) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg), and HBV deoxyribonucleic acid (DNA) level >200 IU / ml or 1000 copies / ml. HBV-infected individuals should receive antiviral therapy according to local treatment guidelines and be willing to receive antiviral therapy for the entire duration of the study. Active HCV is defined as positive for hepatitis C antibody and HCV ribonucleic acid (RNA) level higher than the study center's ULN.

[0298] 19) Patients with any other primary malignancy within 3 years prior to the first administration of the investigational drug, except for non-melanoma skin cancer that has been adequately excised, cured in situ disease, or other cured solid tumors;

[0299] 20) The toxicity of previous anticancer treatment has not been relieved, defined as toxicity not relieved to NCI CTCAE ≤ 1 (excluding hair loss and pigmentation) or the level specified in the inclusion / exclusion criteria; For subjects with chronic grade 2 toxicity, if they are asymptomatic or can be adequately controlled with stable drugs, they may be eligible for enrollment after discussion with the sponsor.

[0300] 21) History of severe hypersensitivity reactions to inactive components in active pharmaceutical ingredients, formulations, or other monoclonal antibodies;

[0301] 22) Breastfeeding women, or women who have been confirmed pregnant by a pregnancy test within 3 days prior to the first dose;

[0302] 23) Any disease, medical condition, organ system dysfunction, or social condition that the researcher believes may interfere with a subject’s ability to sign informed consent, adversely affect a subject’s ability to cooperate and participate in the study, or affect the interpretation of the study results, including but not limited to mental illness or substance / alcohol abuse.

[0303] III. Dosing Regimen

[0304] Subjects meeting all inclusion criteria and not any exclusion criteria received monotherapy with anti-B7H3 antibody-drug conjugate (B7H3-ADC-01(DAR8)) (dose 2.0 or 2.4 mg / kg, intravenous infusion, every three weeks as one cycle, administered on day 1 of each cycle). Efficacy was evaluated every 6 weeks for the first 24 weeks, and every 9 weeks thereafter. The number of dosing cycles was not fixed in this study, continuing until disease progression, intolerable toxicity, or voluntary withdrawal. Study endpoints included safety, objective response rate (ORR), disease control rate (DCR), pharmacokinetics, and immunogenicity.

[0305] IV. Treatment Effects

[0306] As of July 26, 2024, the clinical study enrolled 167 evaluable participants, including 60 participants with SCLC, 63 with NPC, 19 with LELC, and 25 with driver gene-negative NSCLC. Tumor stabilization or shrinkage was observed in 156 participants, with 100 achieving objective response. The ORR was 59.88% (100 / 167), and the DCR was 93.41% (156 / 167).

[0307] As of July 4, 2025, the clinical study enrolled 452 participants, of whom 184 were evaluable for treatment. These included 60 participants with SCLC, 64 with NPC, 39 with driver gene-negative NSCLC, and 21 with LELC. Good treatment outcomes were observed in SCLC, NPC, driver gene-negative NSCLC, and LELC, with ORRs of 90.0% (54 / 60), 53.1% (34 / 64), 35.9% (14 / 39), and 57.1% (12 / 21), respectively, and DCRs of 98.3% (59 / 60), 92.2% (59 / 64), 87.2% (34 / 39), and 90.5% (19 / 21), respectively.

[0308] Both the 2.0 mg / kg and 2.4 mg / kg dose levels demonstrated good therapeutic efficacy and acceptable safety. The ORR in the 2.0 mg / kg dose group was 66.2% (49 / 74) and the DCR was 95.9% (71 / 74). The ORR in the 2.4 mg / kg dose group was 59.1% (65 / 110) and the DCR was 90.9% (100 / 110).

[0309] The ADA positivity rate after treatment was 0.00%, indicating that its immunogenicity in the human body is extremely low.

[0310] Experimental Example 3: Clinical trial of anti-B7H3 antibody-drug conjugate for the treatment of metastatic castration-resistant prostate cancer.

[0311] This study is a multicenter, open-label, phase II trial of B7H3-ADC-01 (DAR8) to evaluate the safety, efficacy, and pharmacokinetic characteristics of B7H3-ADC-01 (DAR8) in patients with metastatic castration-resistant prostate cancer (mCRPC):

[0312] I. Selection Criteria

[0313] Participants must meet all of the following criteria to be included in the study:

[0314] 1) The participants were informed of the trial details before the trial began and voluntarily signed their names and dates on the ICF;

[0315] 2) Age ≥ 18 years;

[0316] 3) Enrolled subjects must meet the following criteria:

[0317] • Diagnosed with prostate cancer by histology or cytology. Note: Adenocarcinoma must be the primary histological type in the biopsy.

[0318] • Meets the clinical diagnostic criteria for mCRPC:

[0319] Castration testosterone levels (serum testosterone levels <50 ng / dL or 1.7 nmol / L),

[0320] Progression of serum prostate-specific antigen (PSA) (PSA > 2 ng / ml with three consecutive increases at least 1 week apart, two of which are >50% higher than baseline), or radiographic progression (according to PCWG3 criteria, bone scan shows ≥ 2 new bone lesions; and / or according to RECIST v1.1, computed tomography (CT) or magnetic resonance imaging (MRI) shows progression of soft tissue lesions); meeting one or more of these criteria.

[0321] Continuous luteinizing hormone-releasing hormone (LHRH) analog castration therapy (medical castration) or a history of bilateral orchiectomy (surgical castration); surgical castration therapy must have been performed at least 3 months prior to enrollment. Subjects who have not undergone bilateral orchiectomy must plan to begin medical castration therapy at least 3 months before the first dose and continue treatment throughout the study.

[0322] • In the mCRPC stage, patients who have previously received at least one novel endocrine therapy (NHT) (such as enzalutamide, abiraterone, darotamid, apatamide, revelulide, etc.) and whose disease has progressed or who are intolerant to it,

[0323] Previous treatment is permitted if no more than two lines of chemotherapy have been received.

[0324] Previous treatment may have allowed the use of first-generation androgen receptor inhibitors (e.g., bicalutamide).

[0325] However, this treatment is not considered a previous NHT treatment.

[0326] • Prostate adenocarcinoma patients with a known history of breast cancer susceptibility gene (BRCA1 / 2) mutations must have received treatment with a poly(ADP-ribose) polymerase (PARP) inhibitor, unless there are contraindications to the use of PARP inhibitors or other reasons deemed appropriate by the investigator.

[0327] 4) There must be metastatic lesions confirmed by CT, MRI or bone scan imaging within 28 days prior to the first dose;

[0328] 5) Archived or fresh tumor tissue samples can be provided. For subjects unable to provide tumor samples or with insufficient samples, enrollment may be considered based on the specific circumstances after discussion with the sponsor;

[0329] • Fresh tumor tissue samples are required for retrospective IHC testing of B7H3 expression at the central laboratory (sample type: formalin-fixed, paraffin-embedded [FFPE] tumor tissue blocks or FFPE sections); if fresh tumor tissue samples are unavailable, archived FFPE tumor tissue blocks within the past 2 years are acceptable, and newly prepared FFPE sections must be from within the past 2 weeks.

[0330] 6) An Eastern Cooperative Oncology Group Performance Status (ECOGPS) score of 0 or 1;

[0331] 7) The body's organs and bone marrow function must meet the requirements within 7 days prior to the first dose, as defined below:

[0332] • Hemoglobin (Hb) ≥ 9.0 g / dL (no blood transfusion or erythropoietin therapy within 14 days prior to the first dose),

[0333] • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L (no prior granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days prior to the first dose)

[0334] • Platelet count (PLT) ≥ 100 × 10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment received within 14 days prior to the first dose)

[0335] • Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) in the absence of significant liver metastasis, or ≤3 × ULN in the presence of liver metastasis.

[0336] • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are ≤3×ULN in the absence of significant liver metastasis, or ≤5×ULN in the presence of liver metastasis.

[0337] Serum albumin ≥3.0 g / dL,

[0338] • Creatinine clearance ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula) or creatinine ≤ 1.5 × ULN,

[0339] • Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for subjects receiving anticoagulation therapy. These subjects must have a stable anticoagulation therapy regimen, and APTT and INR must be within the range that the investigator deems appropriate.

[0340] 8) Participants must agree to use highly effective contraception from the time of screening until the end of the study and for at least 6 months after the last dose of the investigational drug;

[0341] 9) Expected survival ≥ 6 months;

[0342] 10) Has the ability and willingness to comply with the visits and procedures stipulated in the research protocol.

[0343] II. Exclusion Criteria

[0344] Subjects meeting any of the following criteria should not be enrolled in the study:

[0345] 1) Previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T] and other drugs, such as MGC018, DS-7300a, ABBV-155, BAT8009, Enoblituzumab and Omburtamab, etc.);

[0346] 2) Enrollment in another clinical study simultaneously, unless it is an observational (non-interventional) clinical study or is in the follow-up period of an interventional study;

[0347] 3) Previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors;

[0348] 4) Insufficient washout period of prior anticancer therapy before the first administration of the investigational drug, as defined below:

[0349] • Taxane treatment or small molecule targeted therapy lasts for <2 weeks or 5 half-lives, whichever is shorter.

[0350] Antibody treatment <3 weeks,

[0351] Hormone therapy for less than 3 weeks,

[0352] • Traditional Chinese medicine treatment with anti-tumor indications for less than 2 weeks

[0353] Brain radiotherapy <2 weeks,

[0354] Palliative radiotherapy <2 weeks, radical radiotherapy <4 weeks;

[0355] 5) Had major surgery (e.g., craniotomy, thoracotomy or laparotomy, excluding diagnostic surgery) within 4 weeks prior to the first administration of the investigational drug, or is expected to have major surgery during the study period;

[0356] 6) Has previously received an allogeneic bone marrow transplant or a solid organ transplant (excluding corneal transplant);

[0357] 7) Individuals who have received continuous glucocorticoid therapy for more than 28 days within 28 days prior to the first dose, or who require long-term (≥28 days) glucocorticoid therapy, or who have other acquired or congenital immunodeficiency diseases, excluding the following conditions:

[0358] • Intranasal, inhaled, or topical steroids, or local steroid injections (such as intra-articular injections),

[0359] • Physiological doses of systemic steroids as replacement therapy (e.g., physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, ≤10 mg / day of prednisone or equivalent).

[0360] Steroids are used as a preventative treatment for hypersensitivity reactions (such as CT contrast agent allergy) or chemotherapy-induced nausea and vomiting [CINV].

[0361] 8) Has received any live vaccine within 4 weeks prior to the first administration of the investigational drug, or plans to receive a live vaccine during the study period;

[0362] 9) There is a pathological long bone fracture, or there is a risk of an impending pathological long bone fracture (imaging suggests cortical erosion >50%).

[0363] 10) Metastatic carcinoma of the leptomeninges or carcinomatous meningitis;

[0364] 11) Accompanied by uncontrollable bladder outflow obstruction or urinary incontinence. Note: Subjects with bladder outflow obstruction or urinary incontinence who can control it with available best standard of care (including pads, drainage) are eligible to participate in the study;

[0365] 12) Brain metastasis or spinal cord compression, excluding the following:

[0366] • Asymptomatic brain metastases that do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are permitted to enroll.

[0367] • If a subject’s brain metastases have been treated and the metastases are stable (brain imaging at least 2 weeks before the first dose shows that the lesions are stable, there is no evidence of new or increased growth of the original brain metastases, no new neurological symptoms, and no need for immediate local or systemic treatment), then the subject is allowed to enroll.

[0368] 13) Suffering from uncontrolled or clinically significant cardiovascular or cerebrovascular diseases, including but not limited to:

[0369] • A history of symptomatic congestive heart failure (NYHA Class II to IV) or myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within 6 months prior to the first dose.

[0370] • Patients who have undergone percutaneous coronary angioplasty or coronary artery bypass grafting within 6 months prior to the first dose.

[0371] • Serious arterial or venous thrombotic events, such as deep vein thrombosis or pulmonary embolism, that occurred within 3 months prior to the first dose.

[0372] • Uncontrolled hypertension, defined as systolic blood pressure (SBP) > 160 mmHg and / or diastolic blood pressure (DBP) > 100 mmHg after antihypertensive treatment, within 2 weeks prior to the first dose of medication due to poor blood pressure control.

[0373] • Clinically significant rhythmic, conduction, or ECG morphological abnormalities as determined by the investigator (e.g., complete left bundle branch block, third-degree atrioventricular block, and PR interval >250 ms).

[0374] • The presence of any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, a family history of long QT syndrome, or unexplained sudden death of a first-degree relative under 40 years of age.

[0375] • A QT interval (QTcF) corrected for according to the Fridricia formula is prolonged to >450 ms (male).

[0376] • Left ventricular ejection fraction (LVEF) < 50%;

[0377] 14) Clinically significant comorbid lung diseases, including but not limited to:

[0378] • A history of (non-infectious) interstitial lung disease (ILD) / lung inflammation requiring steroid treatment, or current ILD / lung inflammation that may interfere with the assessment of drug-related pulmonary toxicity.

[0379] • Any autoimmune, connective tissue, or inflammatory disease (such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) or suspected lung involvement documented at the time of screening.

[0380] • Moderate to severe lung disease that significantly affects respiratory function;

[0381] 15) Diagnosed with Gilbert's syndrome;

[0382] 16) Patients with uncontrolled third-space effusion (such as pleural effusion, ascites, pericardial effusion) requiring repeated drainage (patients whose condition has stabilized for more than 1 week after drainage can be enrolled);

[0383] 17) History of gastrointestinal perforation and / or fistula within 6 months prior to the first dose, or active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation;

[0384] 18) Serious infection (NCI CTCAE grade ≥3) occurring within 4 weeks prior to the first dose, including but not limited to infectious complications of intravenous antibiotic therapy for ≥2 weeks, bacteremia, severe pneumonia, etc.; or uncontrollable active infection during the screening period; subjects receiving prophylactic anti-infective therapy (such as prevention of urinary tract infection or exacerbation of chronic obstructive pulmonary disease) may be eligible for enrollment after discussion with the sponsor;

[0385] 19) Human immunodeficiency virus (HIV) infection is known to exist;

[0386] 20) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV is defined as positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg), and HBV deoxyribonucleic acid (DNA) level >200 IU / ml or 1000 copies / ml. HBV-infected individuals should receive antiviral therapy according to local treatment guidelines and be willing to receive antiviral therapy for the entire duration of the study. Active HCV is defined as positive for hepatitis C antibody and HCV ribonucleic acid (RNA) level higher than the study center's ULN.

[0387] 21) Diagnosed with other malignancies that may alter life expectancy or interfere with disease evaluation. The patient must have had any other primary malignancy within 5 years prior to the first administration of the investigational drug, excluding malignancies that have received radical treatment, and must have no known active disease for ≥5 years prior to the first administration of the study intervention, with a low potential risk of recurrence. Exceptions include basal cell carcinoma and squamous cell carcinoma of the skin that have received potentially curative treatment;

[0388] 22) The toxicity of previous anticancer treatment has not been relieved, defined as the toxicity (excluding hair loss and pigmentation) has not been relieved to NCI CTCAE ≤ 1, the baseline level or the level specified in the inclusion / exclusion criteria; For subjects with chronic grade 2 toxicity, if they are asymptomatic or can be adequately controlled with stable drugs, they may be eligible for enrollment after discussion with the sponsor.

[0389] 23) History of severe hypersensitivity reactions to inactive components in active pharmaceutical ingredients, formulations, or other monoclonal antibodies (e.g., anaphylactic shock, or a history of severe infusion reactions);

[0390] 24) Any disease, medical condition, organ system dysfunction, or social condition that the researcher believes may interfere with a subject’s ability to sign an informed consent form, adversely affect a subject’s ability to cooperate and participate in the study, or affect the interpretation of the study results, including but not limited to mental illness or substance / alcohol abuse.

[0391] III. Dosing Regimen

[0392] Subjects meeting all inclusion criteria and not any exclusion criteria received monotherapy with anti-B7H3 antibody-drug conjugate (B7H3-ADC-01(DAR8)) (dose 2.0 or 2.4 mg / kg, intravenous infusion, every three weeks as one cycle, administered on day 1 of each cycle). Efficacy was evaluated every 9 weeks for the first 24 weeks, and every 12 weeks thereafter. The number of dosing cycles was not fixed in this study, continuing until disease progression, intolerable toxicity, or voluntary withdrawal. Study endpoints included safety, PSA response rate, ORR, pharmacokinetics, and immunogenicity.

[0393] IV. Treatment Effects

[0394] As of July 26, 2024, the clinical study had enrolled 20 patients with mCRPC. Efficacy data showed that among the 17 evaluable patients with PSA remission, 5 patients experienced a ≥50% decrease in PSA from baseline and a ≥50% decrease in prostate-specific antigen (PSA) after treatment. 50 The remission rate was 29.4%.

[0395] As of July 4, 2025, the clinical study had enrolled 82 mCRPC subjects. Efficacy data showed that among the 78 subjects with evaluable PSA remission, 35 subjects experienced a ≥50% decrease in PSA from baseline and a ≥50% decrease in prostate-specific antigen (PSA) after treatment. 50 The remission rate was 44.9% (35 / 78). PSA levels in the 2.0 mg / kg and 2.4 mg / kg dose groups were [not specified]. 50 The remission rates were 33.3% (11 / 33) and 53.3% (24 / 45), respectively.

[0396] Criteria for Selecting the Dosage for Two-Time Administration in Experiment Example 4

[0397] Clinical pharmacological analysis (Overgaard RV, et al. Establishing Good Practices for Exposure-Response Analysis of Clinical Endpoints in Drug Development. CPT Pharmacometrics Syst Pharmacol. 2015 Oct; 4(10):565-75) showed that: exposure-safety analysis showed that the peak concentration C of the free toxin (CAS: 2821768-98-1) was... max It was significantly associated with the probability of grade ≥3 neutrophil count decline and dose downregulation (see Figure 1); exposure-efficacy analysis showed that the trough concentration C of the ADC drug (B7H3-ADC-01(DAR8)) was significantly associated with the probability of grade ≥3 neutrophil count decline and dose downregulation (see Figure 1);min It was significantly associated with the objective response rate (ORR) (see Figure 2).

[0398] Population pharmacokinetic (PopPK) model simulation was used (Zou P, et al. Applications of human pharmacokinetic prediction in first-in-human dose estimation. AAPS J. 2012 Jun; 14(2):262-81): The dosing pattern of B7H3-ADC-01 (DAR8) was adjusted from a single administration: once every 3 weeks, on day 1 (i.e., D1, Q3W dosing: 2.0 mg / kg, 2.4 mg / kg) to a double administration: twice every 3 weeks, on day 1 and day 8, with the total dose remaining the same, but the single dose was reduced by half (i.e., D1, D8, Q3W dosing: 1.0 mg / kg, 1.2 mg / kg). The pharmacokinetic (PK) of the two models was compared. The C-value of the ADC drug (B7H3-ADC-01 (DAR8)) was also compared. max The two-dose administration regimen significantly reduced C compared to the single-dose administration regimen, while the C of the ADC drug (B7H3-ADC-01(DAR8)) was also reduced. min The double-dose regimen was slightly more effective than the single-dose regimen (see Figure 3). Simulations were made under single / double-dose regimens to observe changes in neutrophil count after ADC drug administration (Ait-Oudhia S, et al. A Mechanism-Based PK / PD Model for Hematological Toxicities Induced by Antibody-Drug Conjugates. AAPS J. 2017 Sep; 19(5):1436-1448). Figures 4A, 4B and 5A, 5B show that with the total doses of 2.0 mg / kg and 2.4 mg / kg remaining constant, the change in neutrophil count after double-dose administration was relatively gradual.

[0399] The above model simulation suggests that, with the total dose remaining constant, double administration can significantly reduce toxicity and increase efficacy to some extent compared to single administration, thereby reducing risk and increasing benefit, and improving the benefit / risk ratio.

[0400] Basis for selecting the dosing cycle in Experiment Example 5

[0401] Figures 4A, 4B, 5A, and 5B show that neutrophils began to recover 10–14 days after drug administration. Furthermore, from a model simulation perspective, the efficacy of ADC drugs is related to the Cd of the effective payload. minThe correlation was good, as shown in Figure 3. The C-value of the ADC drug (B7H3-ADC-01(DAR8)) appeared approximately three weeks after administration. min Therefore, to ensure the efficacy of treatment for patients, a three-week dosing cycle was chosen, and a longer interval was not used.

[0402] On the other hand, the dosing cycle of antitumor drugs usually needs to consider the drug's half-life, efficacy, and recovery from toxicity. The ADC drug (B7H3-ADC-01(DAR8)) uses camptothecin toxin molecules as its effective payload, with a half-life of approximately 100 hours. Considering that complete drug clearance requires more than five half-lives, a dosing cycle of three weeks (504 hours) is defined. From non-clinical toxicity results, cynomolgus monkeys administered high doses of the ADC drug experienced adverse reactions such as decreased neutrophils, diarrhea, and weight loss. The animals began to recover from the second week and returned to baseline levels by the third week.

[0403] Therefore, taking into account the patient's risk-benefit ratio, a dosing cycle of three weeks is selected as the recommended dosing interval.

[0404] Experimental Example 6: Clinical trial of anti-B7H3 antibody-drug conjugate for the treatment of metastatic castration-resistant prostate cancer

[0405] This study is a multicenter, open-label phase II trial evaluating the safety, efficacy, and pharmacokinetics of B7H3-ADC-01 (DAR8) in the treatment of metastatic castration-resistant prostate cancer.

[0406] I. Selection Criteria

[0407] Participants must meet all of the following criteria to be included in the study:

[0408] 1) The participants were informed of the trial details before the trial began and voluntarily signed their names and dates on the ICF;

[0409] 2) Age ≥ 18 years;

[0410] 3) Enrolled subjects must meet the following criteria:

[0411] • Diagnosed with prostate cancer by histology or cytology. Note: Adenocarcinoma must be the primary histological type in the biopsy.

[0412] • Meets the clinical diagnostic criteria for mCRPC:

[0413] Castration testosterone levels (serum testosterone levels <50 ng / dL or 1.7 nmol / L),

[0414] Serum PSA progression (PSA > 1 ng / ml with two consecutive PSA increases of >50% from baseline at least 1 week apart), or radiographic progression (according to PCWG3 criteria, bone scan showing ≥ 2 new bone lesions; and / or according to RECIST v1.1, computed tomography (CT) or magnetic resonance imaging (MRI) showing soft tissue lesion progression); meeting one or more of these criteria.

[0415] Continuous luteinizing hormone-releasing hormone (LHRH) analog castration therapy (medical castration) or a history of bilateral orchiectomy (surgical castration); surgical castration therapy must have been performed at least 3 months prior to enrollment. Subjects who have not undergone bilateral orchiectomy must plan to begin medical castration therapy at least 3 months before the first dose and continue treatment throughout the study.

[0416] • Previous treatment with at least one novel endocrine therapy (NHT) (such as enzalutamide, abiraterone, darotamivide, apatamivide, revelulide, etc.) followed by disease progression or intolerance.

[0417] • Previous treatment is permitted if no more than two lines of chemotherapy have been received.

[0418] • Prostate adenocarcinoma patients with a known history of breast cancer susceptibility gene (BRCA1 / 2) (germline or somatic) mutations must have received treatment with a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (if the drug is available and well tolerated);

[0419] 4) There must be metastatic lesions confirmed by CT, MRI or bone scan imaging within 28 days prior to the first dose;

[0420] 5) Archived or fresh tumor tissue samples can be provided. For subjects unable to provide tumor samples or with insufficient samples, enrollment may be considered based on the specific circumstances after discussion with the sponsor.

[0421] • Fresh tumor tissue samples are required for retrospective detection of B7H3 expression using the IHC method in the central laboratory (sample type: formalin-fixed, paraffin-embedded [FFPE] tumor tissue blocks or FFPE sections); if fresh tumor tissue samples are unavailable, previously archived FFPE tumor tissue blocks are acceptable, and newly prepared FFPE sections must be within 2 weeks.

[0422] 6) The Eastern Cooperative Oncology Group Performance Status (ECOGPS) score is 0 or 1.

[0423] 7) The body's organs and bone marrow function must meet the requirements within 7 days prior to the first dose, as defined below:

[0424] • Hemoglobin (Hb) ≥ 90 g / L (no blood transfusion or erythropoietin therapy within 14 days prior to the first dose),

[0425] • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L (no prior granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor treatment within 14 days prior to the first dose)

[0426] • Platelet count (PLT) ≥ 100 × 10 9 / L (no platelet transfusion, thrombopoietin, or interleukin-11 treatment received within 14 days prior to the first dose)

[0427] • Total bilirubin (TBIL) ≤1.5 × upper limit of normal (ULN) in the absence of significant liver metastasis, or ≤3 × ULN in the presence of liver metastasis.

[0428] • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are ≤3×ULN in the absence of significant liver metastasis, or ≤5×ULN in the presence of liver metastasis.

[0429] Serum albumin ≥30g / L,

[0430] • Creatinine clearance ≥ 50 mL / min (calculated according to the Cockcroft-Gault formula) or creatinine ≤ 1.5 × ULN,

[0431] • Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤ 1.5 × ULN, except for subjects receiving anticoagulation therapy. These subjects must have a stable anticoagulation therapy regimen, and APTT and INR must be within the range that the investigator deems appropriate.

[0432] 8) Participants must agree to use highly effective contraception from the time of screening until the end of the study and for at least 6 months after the last dose of the investigational drug;

[0433] 9) Expected survival ≥ 6 months;

[0434] 10) Has the ability and willingness to comply with the visits and procedures stipulated in the research protocol.

[0435] II. Exclusion Criteria

[0436] Subjects meeting any of the following criteria should not be enrolled in the study:

[0437] 1) Previous treatment with drugs targeting B7H3 (including antibodies, antibody-drug conjugates [ADCs], chimeric antigen receptor T cells [CAR-T] and other drugs, such as MGC018, DS-7300a, ABBV-155, BAT8009, Enoblituzumab and Omburtamab, etc.);

[0438] 2) Enrollment in another clinical study simultaneously, unless it is an observational (non-interventional) clinical study or is in the follow-up period of an interventional study;

[0439] 3) Previous treatment with topoisomerase I inhibitors or ADCs composed of topoisomerase I inhibitors;

[0440] 4) Insufficient washout period of prior anticancer therapy before the first administration of the investigational drug, as defined below:

[0441] Chemotherapy, novel endocrine therapy, or small molecule targeted therapy lasting less than 2 weeks or 5 half-lives, whichever is shorter.

[0442] Antibody treatment <3 weeks,

[0443] • Nuclide with a half-life of <5

[0444] • Traditional Chinese medicine treatment with anti-tumor indications for less than 2 weeks

[0445] • Palliative radiotherapy or brain radiotherapy for <2 weeks, radical radiotherapy for <4 weeks;

[0446] 5) Had major surgery (e.g., craniotomy, thoracotomy or laparotomy, excluding diagnostic surgery) within 4 weeks prior to the first administration of the investigational drug, or is expected to have major surgery during the study period;

[0447] 6) Has previously received an allogeneic bone marrow transplant or a solid organ transplant (excluding corneal transplant);

[0448] 7) Patients who have received continuous glucocorticoid therapy for more than 28 days within 28 days prior to the first dose, or who require continuous long-term (≥28 days) glucocorticoid therapy, or who have other acquired or congenital immunodeficiency diseases.

[0449] Except for the following cases:

[0450] • Intranasal, inhaled, or topical steroids, or local steroid injections (such as intra-articular injections),

[0451] • Physiological doses of systemic steroids as replacement therapy (e.g., physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, ≤10 mg / day of prednisone or equivalent).

[0452] Steroids are used as preventative medications for adverse reactions such as nausea and vomiting caused by hypersensitivity reactions (such as allergies to CT contrast agents) or chemotherapy.

[0453] 8) Has received any live vaccine within 4 weeks prior to the first administration of the investigational drug, or plans to receive a live vaccine during the study period;

[0454] 9) There is a pathological long bone fracture, or there is a risk of an impending pathological long bone fracture (imaging suggests cortical erosion >50%).

[0455] 10) Metastatic carcinoma of the leptomeninges or carcinomatous meningitis;

[0456] 11) Accompanied by uncontrollable bladder outflow obstruction or urinary incontinence. Note: Subjects with bladder outflow obstruction or urinary incontinence who can control it with available best standard of care (including pads, drainage) are eligible to participate in the study;

[0457] 12) Brain metastasis or spinal cord compression, excluding the following:

[0458] • Asymptomatic brain metastases that do not require immediate local or systemic treatment (such as mannitol or corticosteroids) are permitted to enroll.

[0459] • If a subject’s brain metastases have been treated and the metastases are stable (brain imaging at least 2 weeks before the first dose shows that the lesions are stable, there is no evidence of new or increased growth of the original brain metastases, no new neurological symptoms, and no need for immediate local or systemic treatment), then the subject is allowed to enroll.

[0460] 13) Suffering from uncontrolled or clinically significant cardiovascular or cerebrovascular diseases, including but not limited to:

[0461] • A history of symptomatic congestive heart failure (NYHA Class II to IV) or myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within 6 months prior to the first dose.

[0462] • Patients who have undergone percutaneous coronary angioplasty or coronary artery bypass grafting within 6 months prior to the first dose.

[0463] • Serious arterial or venous thrombotic events, such as deep vein thrombosis or pulmonary embolism, that occurred within 3 months prior to the first dose.

[0464] • Uncontrolled hypertension, defined as systolic blood pressure (SBP) > 160 mmHg and / or diastolic blood pressure (DBP) > 100 mmHg after antihypertensive treatment, within 2 weeks prior to the first dose of medication due to poor blood pressure control.

[0465] • Clinically significant rhythmic, conduction, or ECG morphological abnormalities as determined by the investigator (e.g., complete left bundle branch block, third-degree atrioventricular block, and PR interval >250 ms).

[0466] • The presence of any factors that increase the risk of QTc prolongation or arrhythmic events, such as heart failure, refractory hypokalemia, congenital long QT syndrome, a family history of long QT syndrome, or unexplained sudden death of a first-degree relative under 40 years of age.

[0467] • A QT interval (QTcF) corrected for according to the Fridricia formula is prolonged to >450 ms (male).

[0468] • Left ventricular ejection fraction (LVEF) < 50%;

[0469] 14) Clinically significant comorbid lung diseases, including but not limited to:

[0470] • A history of (non-infectious) interstitial lung disease (ILD) / lung inflammation requiring steroid treatment, or current ILD / lung inflammation that may interfere with the assessment of drug-related pulmonary toxicity.

[0471] • Moderate to severe lung disease that significantly affects respiratory function;

[0472] 15) Any autoimmune, connective tissue, or inflammatory disease (such as rheumatoid arthritis, Sjögren's syndrome, sarcoidosis) that is documented at the time of screening, or suspected lung involvement;

[0473] 16) Diagnosed with Gilbert's syndrome;

[0474] 17) Patients with uncontrolled third-space effusion (such as pleural effusion, ascites, pericardial effusion) who require repeated drainage (patients who have been stable for more than 1 week after drainage can be enrolled).

[0475] 18) History of gastrointestinal perforation and / or fistula within 6 months prior to the first dose, or active gastric and duodenal ulcers, ulcerative colitis, or other gastrointestinal diseases that the investigator believes may cause bleeding or perforation;

[0476] 19) Serious infection (NCI CTCAE grade ≥3) occurring within 4 weeks prior to the first dose, including but not limited to infectious complications of intravenous antibiotic therapy for ≥2 weeks, bacteremia, severe pneumonia, etc.; or uncontrollable active infection during the screening period. Subjects receiving prophylactic anti-infective therapy (e.g., prevention of urinary tract infection or exacerbation of chronic obstructive pulmonary disease) may be eligible for enrollment after discussion with the sponsor;

[0477] 20) Human immunodeficiency virus (HIV) infection is known to exist;

[0478] 21) Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Active HBV infection is defined as positive for hepatitis B core antibody (HBcAb) or hepatitis B surface antigen (HBsAg), and HBV deoxyribonucleic acid (DNA) level >200 IU / ml or 1000 copies / ml. HBV-infected individuals should receive antiviral therapy according to local treatment guidelines and be willing to receive antiviral therapy for the entire duration of the study. Active HCV infection is defined as positive for hepatitis C antibody and HCV ribonucleic acid (RNA) level higher than the study center's ULN.

[0479] 22) Diagnosis of other malignancies that may alter life expectancy or interfere with disease evaluation. Patients must have had any other primary malignancy within 5 years prior to the first administration of the investigational drug, excluding malignancies that have received radical treatment, and must have no known active disease for ≥5 years prior to the first administration of the study intervention, with a low potential risk of recurrence. Exceptions include basal cell carcinoma and squamous cell carcinoma of the skin that have received potentially curative treatment.

[0480] 23) Unresolved toxicity from prior anticancer therapy is defined as toxicity (excluding alopecia and hyperpigmentation) not being resolved to NCI CTCAE grade ≤1, at baseline level, or at the level specified in the inclusion / exclusion criteria. Subjects with chronic grade 2 toxicity may be eligible for enrollment if they are asymptomatic or adequately managed with stable medication, after discussion with the sponsor.

[0481] 24) History of severe hypersensitivity reactions to inactive components in active pharmaceutical ingredients, formulations, or other monoclonal antibodies (e.g., anaphylactic shock, or a history of severe infusion reactions);

[0482] 25) Any disease, medical condition, organ system dysfunction, or social condition that the researcher believes may interfere with a subject’s ability to sign informed consent, adversely affect a subject’s ability to cooperate and participate in the study, or affect the interpretation of the study results, including but not limited to mental illness or substance / alcohol abuse.

[0483] III. Dosing Regimen

[0484] Option 1: Single administration: Administer at doses of 1.6 mg / kg, 2.0 mg / kg, and 2.4 mg / kg, with each treatment cycle lasting 3 weeks, starting on day 1 of each cycle;

[0485] Option 2: Double administration: Treatment cycles consist of 1.0 mg / kg and 1.2 mg / kg, administered on day 1 and day 8 of each cycle.

[0486] The intravenous infusion time for each subject is 60 ± 10 minutes. The initial dose will be calculated based on the subject's weight on the day prior to the first dose. If the subject's weight changes by more than 10% of their weight prior to the first dose during treatment, the dose will be recalculated based on the updated subject weight.

[0487] IV. Treatment Effects

[0488] Whether using a single-dose or double-dose regimen, the anti-B7H3 antibody-drug conjugate of this invention has a good therapeutic effect on mCRPC. The double-dose regimen can reduce toxicity to a certain extent, thereby reducing risk and increasing benefit, and improving the benefit / risk ratio.

[0489] Although specific embodiments of the present invention have been described in detail, those skilled in the art will understand that various modifications and variations can be made to the details based on all the published teachings, and all such changes are within the scope of protection of the present invention. The scope of protection of the present invention is given by the appended claims and any equivalents thereof.

Claims

1. A method of treating cancer, comprising administering to a subject in need, in each cycle, an effective amount of an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, in, The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula I: in, Tb is an anti-B7H3 antibody or its antigen-binding fragment; S represents the sulfur atom on Tb; q is any value between 1 and 16, including both extreme values; The effective amount is 0.8-3.0 mg / kg; and the cycle is preferably three weeks.

2. The method of claim 1, further comprising administering to a subject in need an effective amount of an anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, in the manner described in claim 1. (a) Single administration: Administer once per cycle at a dose of 0.8–3.0 mg / kg; or (b) Double administration: Administer twice in each cycle at a dose of 0.5-1.5 mg / kg.

3. The method according to claim 2, wherein, The single application is administered once per cycle at a dose of 1.6-2.4 mg / kg, 1.6-2.0 mg / kg, or 2.0-2.4 mg / kg; preferably, it is administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg.

4. The method according to claim 2, wherein, The double administration: in each cycle, the drug is administered twice at a dose of 0.8-1.4 mg / kg, 1.0-1.2 mg / kg, or 1.2-1.4 mg / kg; preferably, in each cycle, the drug is administered twice at a dose of 1.0 mg / kg, 1.2 mg / kg, or 1.4 mg / kg; preferably, the first and second administrations are the same or different doses.

5. The method according to claim 2, wherein, The single administration is an intravenous infusion administered on day 1 of each cycle.

6. The method according to claim 2 or 4, wherein, The administration interval for the two doses is 7±3 days, preferably 7-10 days, and more preferably, administered intravenously on day 1 and day 8 of each cycle.

7. The method according to any one of claims 1-6, wherein, The intravenous infusion time for the subjects was 60 ± 10 minutes.

8. The method for treating cancer according to any one of claims 1-7, wherein, The cancers mentioned include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), lymphoepithelial neoplastic carcinoma (LELC), esophageal cancer (such as esophageal squamous cell carcinoma (ESCC)), head and neck squamous cell carcinoma, prostate cancer, breast cancer, and / or colon cancer.

9. The method according to claim 8, wherein, The non-small cell lung cancer mentioned is driver gene-negative non-small cell lung cancer; Preferably, the driver gene-negative non-small cell lung cancer includes adenocarcinoma or squamous cell carcinoma, more preferably adenocarcinoma.

10. The method according to claim 8, wherein, The prostate cancer mentioned is metastatic castration-resistant prostate cancer (mCRPC).

11. The method according to any one of claims 1-10, wherein, The method comprises administering the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to a subject in need in the following manner: (a) a single administration: administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg, via intravenous infusion on day 1 of each cycle; or (b) Double administration: Administer twice in each cycle at a dose of 1.0 mg / kg or 1.2 mg / kg; preferably, the first and second administrations are 7 days apart; preferably, the administration is administered intravenously on day 1 and day 8 of each cycle; preferably, the first and second administrations are at the same dose.

12. The method according to any one of claims 1-11, wherein q in formula I is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably q is 2, 4, 6 or 8.

13. The method according to any one of claims 1-12, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region includes: (i) CDR-H1, which contains or consists of the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2, which comprises or consists of the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3, which contains or is composed of the amino acid sequence of SEQ ID NO: 3; and The light chain variable region includes: (i) CDR-L1, which contains or consists of the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2, which comprises or consists of the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3, which contains or consists of the amino acid sequence of SEQ ID NO:

6.

14. The method according to any one of claims 1-13, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region. The heavy chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO:

8. Preferably, the heavy chain variable region of the anti-B7H3 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

8.

15. The method according to any one of claims 1-14, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 9, and the light chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; preferably, the heavy chain of the anti-B7H3 antibody comprises the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprises the amino acid sequence shown in SEQ ID NO:

10.

16. The method according to any one of claims 1-15, wherein, The structural formula of the anti-B7H3 antibody-drug conjugate is shown below:

17. The method according to any one of claims 1-16, wherein, The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula II: The 2E3-02 includes CDR-H1, CDR-H2, CDR-H3 as shown in SEQ ID NO: 1-3 and / or CDR-L1, CDR-L2, CDR-L3 as shown in SEQ ID NO: 4-6; Preferably, the 2E3-02 comprises a heavy chain variable region of SEQ ID NO: 7 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 7, and / or comprises a light chain variable region of SEQ ID NO: 8 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 8; Preferably, the 2E3-02 comprises a heavy chain of SEQ ID NO: 9 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 9, and / or comprises a light chain of SEQ ID NO: 10 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO:

10.

18. Anti-B7H3 antibody-drug conjugates, pharmaceutically acceptable salts, stereoisomers, metabolites, or solvates thereof, for use in the treatment of cancer, wherein, This includes administering an effective amount of the anti-B7H3 antibody-drug conjugate, its pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate, to subjects in need during each cycle. The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula I: in, Tb is an anti-B7H3 antibody or its antigen-binding fragment; S represents the sulfur atom on Tb; q is any value between 1 and 16, including both extreme values; The effective dose is 0.8-3.0 mg / kg; and the treatment period is preferably three weeks.

19. The use according to claim 18, comprising administering to a subject in need an effective amount of the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, in the manner described in claim 18. (a) Single administration: Administer once per cycle at a dose of 0.8–3.0 mg / kg; or (b) Double administration: Administer twice in each cycle at a dose of 0.5-1.5 mg / kg.

20. The use according to claim 19, wherein, The single application is administered once per cycle at a dose of 1.6-2.4 mg / kg, 1.6-2.0 mg / kg, or 2.0-2.4 mg / kg; preferably, it is administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg.

21. The use according to claim 19, wherein, The double administration: in each cycle, the drug is administered twice at a dose of 0.8-1.4 mg / kg, 1.0-1.2 mg / kg, or 1.2-1.4 mg / kg; preferably, in each cycle, the drug is administered twice at a dose of 1.0 mg / kg, 1.2 mg / kg, or 1.4 mg / kg; preferably, the first and second administrations are the same or different doses.

22. The use according to claim 19, wherein, The single administration is an intravenous infusion administered on day 1 of each cycle.

23. The use according to claim 19 or 21, wherein, The interval between the two administrations is 7±3 days, preferably 7-10 days, and more preferably, administered intravenously on day 1 and day 8 of each cycle.

24. The use according to any one of claims 18-23, wherein, The intravenous infusion time for the subjects was 60 ± 10 minutes.

25. The use in treating cancer according to any one of claims 18-24, wherein, The cancers mentioned include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), nasopharyngeal carcinoma (NPC), lymphoepithelial neoplastic carcinoma (LELC), esophageal cancer (such as esophageal squamous cell carcinoma (ESCC)), head and neck squamous cell carcinoma, prostate cancer, breast cancer, and / or colon cancer.

26. The use according to claim 25, wherein, The non-small cell lung cancer mentioned is driver gene-negative non-small cell lung cancer; Preferably, the driver gene-negative non-small cell lung cancer includes adenocarcinoma or squamous cell carcinoma, more preferably adenocarcinoma.

27. The use according to claim 25, wherein, The prostate cancer mentioned is metastatic castration-resistant prostate cancer (mCRPC).

28. The use according to any one of claims 18-27, wherein, The intended use includes administering the anti-B7H3 antibody-drug conjugate, a pharmaceutically acceptable salt, stereoisomer, metabolite, or solvate thereof, to subjects in need in the following manner: (a) a single administration: administered once per cycle at a dose of 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg, via intravenous infusion on day 1 of each cycle; or (b) Double administration: Administer twice in each cycle at a dose of 1.0 mg / kg or 1.2 mg / kg; preferably, the first and second administrations are 7 days apart; preferably, the administration is administered intravenously on day 1 and day 8 of each cycle; preferably, the first and second administrations are at the same dose.

29. The use according to any one of claims 18-28, wherein q in formula I is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably q is 2, 4, 6 or 8.

30. The use according to any one of claims 18-29, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region includes: (i) CDR-H1, which contains or consists of the amino acid sequence of SEQ ID NO: 1; (ii) CDR-H2, which comprises or consists of the amino acid sequence of SEQ ID NO: 2; and (iii) CDR-H3, which contains or is composed of the amino acid sequence of SEQ ID NO: 3; and The light chain variable region includes: (i) CDR-L1, which contains or consists of the amino acid sequence of SEQ ID NO: 4; (ii) CDR-L2, which comprises or consists of the amino acid sequence of SEQ ID NO: 5; and (iii) CDR-L3, which contains or consists of the amino acid sequence of SEQ ID NO:

6.

31. The use according to any one of claims 18-30, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain variable region and a light chain variable region. The heavy chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO:

8. Preferably, the heavy chain variable region of the anti-B7H3 antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO: 7, and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

8.

32. The use according to any one of claims 18-31, wherein, The anti-B7H3 antibody or its antigen-binding fragment comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 9, and the light chain comprises an amino acid sequence having at least 80%, 90%, 95%, 96%, 97%, 98%, and 99% sequence identity with the amino acid sequence of SEQ ID NO: 10; preferably, the heavy chain of the anti-B7H3 antibody comprises the amino acid sequence shown in SEQ ID NO: 9, and the light chain comprises the amino acid sequence shown in SEQ ID NO:

10.

33. The use according to any one of claims 18-32, wherein, The structural formula of the anti-B7H3 antibody-drug conjugate is shown below:

34. The use according to any one of claims 18-33, wherein, The structural formula of the anti-B7H3 antibody-drug conjugate is shown in Formula II: The 2E3-02 comprises CDR-H1, CDR-H2, CDR-H3 as shown in SEQ ID NO: 1-3 and / or CDR-L1, CDR-L2, CDR-L3 as shown in SEQ ID NO: 4-6; preferably, the 2E3-02 comprises a heavy chain variable region of SEQ ID NO: 7 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 7, and / or comprises a light chain variable region of SEQ ID NO: 8 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 8; Preferably, the 2E3-02 comprises a heavy chain of SEQ ID NO: 9 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 9, and / or comprises a light chain of SEQ ID NO: 10 or having at least 80%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with SEQ ID NO: 10.

Images