Use of Anti-nectin-4 antibody drug conjugate in treatment of tumors

Abstract

A use of an anti-Nectin-4 antibody drug conjugate in the preparation of drugs for treating gynecological tumors.

Description

Uses of anti-Nectin-4 antibody-drug conjugates in the treatment of tumors Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to methods for treating tumors and pharmaceutical uses of anti-Nectin-4 antibody-drug conjugates. Background Technology

[0002] Nectin-4 (gene name PVRL4, poliovirus receptor 4) is a protein belonging to the Nectin family of the immunoglobulin superfamily. The Nectin family works in conjunction with cadherins to significantly influence the generation and maintenance of adhesive junctions (AJs) and tight junctions (TJs), regulating various cellular behaviors, including cell adhesion, growth, differentiation, migration, and apoptosis. Unlike Nectin 1-3, which are widely expressed in normal adult tissues, Nectin-4 is specifically expressed in the embryo and placenta, expressed in a few normal adult tissues (including skin), and overexpressed in tumor tissues (distributed not only in AJs but also at cell apex and released into plasma). Nectin-4 exhibits specific high expression in tumor tissues and is closely related to tumor prognosis. The potential mechanisms by which Nectin-4 promotes tumor development and metastasis include: 1) promoting tumor angiogenesis: by activating the PI3K / AKT signaling pathway; 2) promoting tumor cell growth, proliferation, and migration: by activating the Ras-associated C3 botulinum toxin substrate 1 (Rac1) signaling pathway; and 3) promoting epithelial-mesenchymal transition (EMT): Nectin-4 can regulate cell adhesion, remodel the actin cytoskeleton, and enhance the driving force for pseudopodia to extend in tumor cells, ultimately leading to tumor development and spread.

[0003] Antibody-drug conjugates (ADCs) are small molecule drugs with cytotoxic properties covalently linked to an antibody via a chemical link. Using the antibody as a carrier, the drug is delivered directly to target cells. ADCs combine the high targeting specificity of antibodies with the potent cytotoxic effects of cytotoxic drugs, and are considered a next-generation antibody-targeted therapy. In Nectin-4 ADCs, the antibody specifically recognizes and binds to the Nectin-4 receptor on the surface of target cells. It then enters the target cell via endocytosis, where it is broken down and released into the cell to release the cytotoxic drug. Finally, the cytotoxic drug exerts its anti-tumor effect by damaging DNA or acting on microtubules, preventing cell division, and inducing apoptosis.

[0004] Currently, there is a need in the field to develop safe and effective drug treatments targeting Nectin-4. Summary of the Invention

[0005] This disclosure provides a method for treating tumors with anti-Nectin-4 antibody-drug conjugates and their pharmaceutical uses.

[0006] In some implementations, this disclosure provides for any of the following uses:

[0007] (1) Use of anti-Nectin-4 antibody-drug conjugates in the preparation of drugs for treating tumors;

[0008] (2) Anti-Nectin-4 antibody-drug conjugate, which is used to treat tumors;

[0009] (3) An anti-Nectin-4 antibody-drug conjugate for the treatment of tumors, wherein the anti-Nectin-4 antibody-drug conjugate is administered to a subject;

[0010] (4) A pharmaceutical composition, kit or article for treating tumors, wherein the pharmaceutical composition, kit or article comprises an anti-Nectin-4 antibody-drug conjugate;

[0011] (5) Use of a pharmaceutical composition, kit or article in the preparation of a medicament for treating tumors, wherein the pharmaceutical composition, kit or article comprises an anti-Nectin-4 antibody-drug conjugate.

[0012] In some implementations, this disclosure provides a method as shown in any of the following:

[0013] (1) Methods of treating tumors, including administering a therapeutically effective amount of anti-Nectin-4 antibody-drug conjugate to subjects in need;

[0014] (2) A method of treating tumors, including administering a pharmaceutical composition, kit or article to a subject in need; wherein the pharmaceutical composition, kit or article comprises an anti-Nectin-4 antibody-drug conjugate.

[0015] In some implementations, this disclosure provides a product as shown in any of the following:

[0016] (1) A pharmaceutical composition comprising an anti-Nectin-4 antibody-drug conjugate;

[0017] (2) A kit containing an anti-Nectin-4 antibody-drug conjugate;

[0018] (3) Products, including anti-Nectin-4 antibody-drug conjugates.

[0019] In some implementations, the kit or article also includes one or more containers, each containing an anti-Nectin-4 antibody-drug conjugate.

[0020] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is present in the pharmaceutical composition in an individually packaged form.

[0021] In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is an advanced solid tumor.

[0022] In some implementations, the tumor is a gynecological tumor.

[0023] In some implementations, the gynecological tumors described in any of the foregoing are cervical cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

[0024] In some implementations, the tumor is an advanced gynecological tumor.

[0025] In some embodiments, the gynecological tumor described in any of the foregoing embodiments is advanced cervical cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent and / or metastatic cervical cancer. In some embodiments, the tumor is recurrent and / or metastatic cervical cancer and is no longer suitable for radical surgery and / or radical radiotherapy or chemoradiotherapy.

[0026] In some embodiments, the gynecological tumor described in any of the foregoing embodiments is advanced endometrial cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent and / or metastatic endometrial cancer. In some embodiments, the tumor is recurrent or metastatic endometrial cancer that is no longer suitable for radical surgery and / or radical radiotherapy or chemoradiotherapy.

[0027] In some embodiments, the gynecological tumor described in any of the foregoing embodiments is advanced ovarian cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is advanced fallopian tube cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is advanced primary peritoneal cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent and / or metastatic ovarian cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent epithelial ovarian cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent and / or metastatic fallopian tube cancer. In some embodiments, the gynecological tumor described in any of the foregoing embodiments is recurrent and / or metastatic primary peritoneal cancer.

[0028] In some embodiments, the cervical cancer described in any of the preceding embodiments is Nectin-4 positive cervical cancer. In some embodiments, the cervical cancer described in any of the preceding embodiments is cervical cancer with high Nectin-4 expression. In some embodiments, the cervical cancer described in any of the preceding embodiments is cervical cancer with low Nectin-4 expression. In some embodiments, the cervical cancer described in any of the preceding embodiments is Nectin-4 negative cervical cancer. In some embodiments, immunohistochemistry is used to detect the Nectin-4 expression level in tumor tissue samples, and the H-Score is calculated based on cell staining intensity and percentage, specifically as follows: H-Score = (3 x percentage of cells with strong staining intensity) + (2 x percentage of cells with moderate staining intensity) + (1 x percentage of cells with weak staining intensity). In some embodiments, this disclosure stratifies Nectin-4 H-Score scores calculated based on immunohistochemical staining, with low Nectin-4 expression defined as 0 < Hscore < 100 (Hscore of 0 represents negative Nectin-4 expression), medium Nectin-4 expression defined as 100 ≤ Hscore ≤ 200, and high Nectin-4 expression defined as > 200-300.

[0029] In some embodiments, the subject suffering from any of the foregoing gynecological tumors has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy is selected from chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises anti-PARP inhibitor therapy. In some embodiments, the subject suffering from any of the foregoing gynecological tumors has previously received platinum-based chemotherapy.

[0030] In some embodiments, the subject with any of the foregoing cervical cancers has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted therapy comprises anti-VEGF antibody therapy. In some embodiments, the subject has received ≤2 lines of systemic antitumor therapy. In some embodiments, the subject has received 1 line of systemic antitumor therapy. In some embodiments, the subject has received 2 lines of systemic antitumor therapy.

[0031] In some embodiments, the subject with any of the foregoing descriptions of cervical cancer has previously received platinum-based chemotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgery, and radiotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and immunotherapy.

[0032] In some embodiments, the subject with any of the foregoing descriptions of endometrial cancer has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy and / or immunotherapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the subject has received ≤2 lines of systemic antitumor therapy. In some embodiments, the subject has received 1 line of systemic antitumor therapy. In some embodiments, the subject has received 2 lines of systemic antitumor therapy.

[0033] In some embodiments, the subject with any of the foregoing descriptions of endometrial cancer has previously received platinum-based chemotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgical treatment, and radiotherapy.

[0034] In some embodiments, the subject with any of the foregoing descriptions of ovarian cancer has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0035] In some embodiments, the subject with any of the foregoing descriptions of ovarian cancer has previously received platinum-based chemotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgery, and radiotherapy. In some embodiments, the subject has previously received 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously received ≤2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received 1 line of systemic antitumor therapy. In some embodiments, the subject has previously received 2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received ≥3 lines of systemic antitumor therapy.

[0036] In some embodiments, the subject suffering from any of the aforementioned fallopian tube cancers has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0037] In some embodiments, the subject with any of the aforementioned fallopian tube cancers has previously received platinum-based chemotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgery, and radiotherapy. In some embodiments, the subject has previously received 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously received ≤2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received 1 line of systemic antitumor therapy. In some embodiments, the subject has previously received 2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received ≥3 lines of systemic antitumor therapy.

[0038] In some embodiments, the subject with any of the foregoing primary peritoneal cancers has previously received systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0039] In some embodiments, the subject with any of the aforementioned primary peritoneal cancer has previously received platinum-based chemotherapy. In some embodiments, the subject has previously received platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgery, and radiotherapy. In some embodiments, the subject has previously received 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously received ≤2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received 1 line of systemic antitumor therapy. In some embodiments, the subject has previously received 2 lines of systemic antitumor therapy. In some embodiments, the subject has previously received ≥3 lines of systemic antitumor therapy.

[0040] In some embodiments, a subject with any of the foregoing gynecological tumors has previously failed or is intolerant of systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy is selected from chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises anti-PARP inhibitor therapy. In some embodiments, a subject with any of the foregoing gynecological tumors has previously failed or is intolerant of platinum-based chemotherapy.

[0041] In some embodiments, a subject with any of the foregoing cervical cancers has previously failed or is intolerant of systemic antitumor therapy, radiotherapy, and / or surgery, said systemic antitumor therapy including chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy.

[0042] In some embodiments, the subject with any of the foregoing descriptions of cervical cancer has previously failed or is intolerant of platinum-based chemotherapy. In some embodiments, the subject has previously failed or is intolerant of platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgery, and radiotherapy. In some embodiments, the subject has previously failed or is intolerant of both platinum-based chemotherapy and immunotherapy.

[0043] In some embodiments, a subject with any of the foregoing descriptions of endometrial cancer has failed or is intolerant of prior systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes platinum-based chemotherapy and / or immunotherapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy.

[0044] In some embodiments, the subject with any of the foregoing descriptions of endometrial cancer has previously failed or is intolerant of platinum-based chemotherapy. In some embodiments, the subject has previously failed or is intolerant of platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgical treatment, and radiotherapy.

[0045] In some embodiments, a subject with any of the foregoing descriptions of ovarian cancer has previously failed or is intolerant of systemic antitumor therapy, radiotherapy, and / or surgery, said systemic antitumor therapy including chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0046] In some embodiments, the subject with any of the foregoing descriptions of ovarian cancer has previously failed or is intolerant of platinum-based chemotherapy. In some embodiments, the subject with any of the foregoing descriptions of ovarian cancer has previously failed or is intolerant of 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously failed or is intolerant of platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgical treatment, and radiotherapy.

[0047] In some implementations, the subject with any of the foregoing descriptions of ovarian cancer has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-resistant relapse) within 6 months during or after the last platinum-based chemotherapy treatment. In some implementations, the subject has received at most one line of systemic antitumor therapy after platinum-resistant relapse.

[0048] In some implementations, the subject with any of the foregoing descriptions of ovarian cancer has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-sensitive recurrence) ≥6 months after the completion of the last platinum-based chemotherapy. In some implementations, the subject has previously received PARP inhibitor therapy.

[0049] In some embodiments, a subject with any of the aforementioned fallopian tube cancer has failed or is intolerant of prior systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0050] In some embodiments, the subject with any of the aforementioned fallopian tube cancers has previously failed or is intolerant of platinum-based chemotherapy. In some embodiments, the subject with any of the aforementioned fallopian tube cancers has previously failed or is intolerant of 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously failed or is intolerant of platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgical treatment, and radiotherapy.

[0051] In some implementations, the subject with any of the aforementioned fallopian tube cancer has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-resistant recurrence) within 6 months during or after the last platinum-based chemotherapy treatment. In some implementations, the subject has received at most one line of systemic antitumor therapy after platinum-resistant recurrence.

[0052] In some implementations, the subject with any of the foregoing descriptions of fallopian tube cancer has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-sensitive recurrence) ≥6 months after the completion of the last platinum-based chemotherapy. In some implementations, the subject has previously received PARP inhibitor therapy.

[0053] In some embodiments, a subject with any of the foregoing primary peritoneal cancers has failed or is intolerant of prior systemic antitumor therapy, radiotherapy, and / or surgery, wherein the systemic antitumor therapy includes chemotherapy, immunotherapy, and / or targeted drug therapy. In some embodiments, the chemotherapy comprises platinum-based chemotherapy. In some embodiments, the immunotherapy comprises anti-PD-1 / PD-L1 antibody therapy. In some embodiments, the targeted drug therapy comprises anti-VEGF antibody therapy. In some embodiments, the targeted drug therapy comprises PARP inhibitor therapy.

[0054] In some embodiments, the subject with any of the aforementioned primary peritoneal cancers has previously failed or is intolerant of platinum-based chemotherapy. In some embodiments, the subject with any of the aforementioned primary peritoneal cancers has previously failed or is intolerant of 1 to 3 lines of platinum-based chemotherapy. In some embodiments, the subject has previously failed or is intolerant of platinum-based chemotherapy and other treatments selected from one or more of targeted therapy, immunotherapy, surgical treatment, and radiotherapy.

[0055] In some implementations, the subject with any of the aforementioned primary peritoneal cancer has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-resistant relapse) within 6 months during or after the last platinum-based chemotherapy treatment. In some implementations, the subject has received at most one line of systemic antitumor therapy after platinum-resistant relapse.

[0056] In some implementations, the subject with any of the foregoing primary peritoneal cancers has previously received platinum-based chemotherapy and experienced disease progression or recurrence (platinum-sensitive recurrence) ≥6 months after the completion of the last platinum-based chemotherapy. In some implementations, the subject has previously received PARP inhibitor therapy.

[0057] In this disclosure, systemic antitumor therapy regimens (including first-line, second-line, and third-line treatments) are treatment regimens for gynecological tumors well known to those skilled in the art, such as treatment regimens disclosed in treatment guidelines approved by regulatory authorities; and systemic therapy with investigational drugs for solid tumors. Examples include, but are not limited to, detailed and up-to-date information on standard treatment regimens for various cancers and systemic antitumor therapy regimens (including first-line, second-line, and third-line treatments) provided in the NCCN and CSCO guidelines.

[0058] In some implementations, the anti-Nectin-4 antibody-drug conjugates provided in this disclosure are used to treat subjects with cervical cancer who have failed platinum-based chemotherapy (≤2 lines of prior systemic antitumor therapy). These conjugates significantly improve the objective response rate (uORR) and progression-free survival (PFS), with an uORR of 52%, a disease control rate (DCR) of 88%, a median PFS of 6.8 months at a dose of 6 mg / kg, and 5.5 months at a dose of 8 mg / kg. Compared with other ADCs targeting the same target, these conjugates offer significant therapeutic advantages and provide a positive and effective clinical treatment option for patients with cervical cancer who have failed platinum-based chemotherapy.

[0059] In some implementations, the anti-Nectin-4 antibody-drug conjugates disclosed herein are used to treat subjects with cervical cancer who have failed platinum-based chemotherapy and immunotherapy. They significantly improve the objective response rate (CORR) and progression-free survival (PFS) in these subjects, with a cORR of 41.9%, a disease control rate (DCR) of 87.1%, and a median PFS of 5.4 months at a dose of 6 mg / kg. Compared with other ADCs targeting the same target, this demonstrates significant therapeutic advantages and provides a positive and effective clinical treatment option for patients with cervical cancer who have failed platinum-based chemotherapy and immunotherapy.

[0060] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure achieved an uncontrolled objective response rate (uORR) of 44.4% in subjects with low or negative Nectin-4 expression in cervical cancer, 43.8% in subjects with moderate Nectin-4 expression in cervical cancer, and 66.7% in subjects with high Nectin-4 expression in cervical cancer. Compared with other ADCs targeting the same target, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure has significant therapeutic advantages for the entire cervical cancer population (whether Nectin-4 positive or negative, regardless of whether they are at high or low Nectin-4 expression), significantly improving the objective response rate and progression-free survival, providing a positive and effective clinical treatment option for all cervical cancer patients.

[0061] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure was administered as a monotherapy to subjects with cervical cancer. In the 6 mg / kg dose group, 38.9% of subjects experienced ≥ grade 3 TRAE, demonstrating a tolerable and manageable clinical safety.

[0062] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure is used to treat subjects with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have failed platinum-based chemotherapy (platinum-resistant relapse), and can significantly improve the objective response rate and progression-free survival of the subjects, with an uORR of 47.6% and a DCR of 100%.

[0063] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure was administered as a monotherapy to subjects with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer. ≥ Grade 3 TRAEs occurred in 42.9% of all subjects, demonstrating a tolerable and manageable clinical safety profile.

[0064] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure is used to treat subjects with endometrial cancer who have failed platinum-based chemotherapy (≤2 lines of prior systemic antitumor therapy), and can significantly improve the objective response rate and progression-free survival of the subjects, with an uORR of 33.3% and a DCR of 100%.

[0065] In some implementations, the anti-Nectin-4 antibody-drug conjugate provided in this disclosure was administered as a monotherapy to subjects with endometrial cancer, and ≥ grade 3 TRAEs occurred in 33.3% of all subjects, demonstrating a tolerable and manageable clinical safety profile.

[0066] Anti-Nectin-4 antibody-drug conjugates

[0067] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is derived from antibody-drug conjugates of any structure in WO2022228406A1 and WO2023221971A1. The structure, preparation method and other related contents of the immunoconjugates in the above patents are incorporated into this disclosure by reference.

[0068] In some embodiments, the anti-Nectin-4 antibody-drug conjugate has the structure shown in the following formula:

[0069] Where n is from 1 to 10, n is a decimal or an integer, and Ab is an anti-Nectin-4 antibody. In some embodiments, n is from 1 to 8. For example, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or any decimal or integer between any two of the aforementioned values. In some embodiments, n is an integer or decimal of 3 to 5, for example, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0. In some embodiments, n is 3.5 to 4.7.

[0070] In some embodiments, the anti-Nectin-4 antibody is derived from any type of anti-Nectin-4 antibody or its antigen-binding fragment in WO2022228406A1. This disclosure incorporates the antibody sequences, preparation methods, and other related contents of the aforementioned patent by reference.

[0071] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1-3, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4-6.

[0072] The CDR sequences mentioned above are shown in Table 1 below:

[0073] Table 1. CDR sequences of anti-Nectin-4 antibodies (Kabat protocol)

[0074] In some implementations, the anti-Nectin-4 antibody comprises any one of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, or any combination of two, three, four, five, or six of them.

[0075] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the VH comprises HCDR1, HCDR2, and HCDR3 of the amino acid sequence shown in SEQ ID NO: 7, and the VL comprises LCDR1, LCDR2, and LCDR3 of the amino acid sequence shown in SEQ ID NO: 8. The aforementioned CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact definition schemes. In some specific embodiments, the CDRs are defined according to the Kabat definition scheme.

[0076] In some implementations, the anti-Nectin-4 antibody is a chimeric, humanized, fully human antibody or its antigen-binding fragment.

[0077] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO: 7, and the VL comprises an amino acid sequence as shown in or having at least 80% or 90% identity with SEQ ID NO: 8.

[0078] Heavy chain variable region:

[0079] Light chain variable region:

[0080] In some implementations, the anti-Nectin-4 antibody comprises any one or both of the aforementioned VH and VL.

[0081] In some embodiments, the anti-Nectin-4 antibody further comprises a heavy chain constant region and / or a light chain constant region. The heavy chain constant region of the antibody may be selected from the constant regions of human IgG1, IgG2, IgG3, IgG4, and their variants. In some embodiments, the light chain constant region may be selected from the light chain constant region of human κ, λ chains, or their variants.

[0082] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9 or having at least 80% or at least 90% sequence identity with it; and / or, the light chain comprises an amino acid sequence as shown in SEQ ID NO:10 or having at least 80% or at least 90% sequence identity with it.

[0083] In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain with an amino acid sequence as shown in SEQ ID NO:9 and a light chain with an amino acid sequence as shown in SEQ ID NO:10.

[0084] Heavy chain sequence of anti-Nectin-4 antibody:

[0085] Light chain sequence of anti-Nectin-4 antibody:

[0086] Note: The underlined portion is the variable region sequence of the antibody heavy or light chain, and the ununderlined portion is the constant region sequence of the antibody.

[0087] In the context of this disclosure, "antibody" is used in the broadest sense, encompassing a wide variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, or antigen-binding fragments thereof (also referred to as "antigen-binding portions"), provided they exhibit the desired antigen-binding activity. In some embodiments, the antibody is a full-length antibody or an antigen-binding fragment thereof.

[0088] In some implementations, the anti-Nectin-4 antibody-drug conjugate was prepared as in Example 1.

[0089] Dosing regimen

[0090] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is 0.1-20 mg / kg, for example, about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 12 mg / kg, about 1.0 mg / kg to about 10.5 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 9 mg / kg, about 1.5 mg / kg to about 10.5 mg / kg, about 1.5 mg / kg to about 9.0 mg / kg; about 3.0 mg / kg to about 9.0 mg / kg; about 4.5 mg / kg. From about 9.0 mg / kg; from about 6.0 mg / kg to about 9.0 mg / kg; from about 6.0 mg / kg to about 8.0 mg / kg; from about 4.0 mg / kg to about 8.0 mg / kg; from about 7.5 mg / kg to about 9.0 mg / kg; from about 1.5 mg / kg to about 7.5 mg / kg; from about 1.5 mg / kg to about 6.5 mg / kg; from about 1.0 mg / kg to about 5.4 mg / kg; from about 1.0 mg / kg to about 4.8 mg / kg; from about 3.0 mg / kg to about 7.5 mg / kg; or any range between these values.

[0091] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is selected from about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, and about 2.5 mg / kg. g / kg, approximately 2.6 mg / kg, approximately 2.7 mg / kg, approximately 2.8 mg / kg, approximately 2.9 mg / kg, approximately 3.0 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approximately 3.4 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.8 mg / kg, approximately 4.0 mg / kg, approximately 4.2 mg / kg, approximately 4.3 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.8 mg / kg, approximately 5.0 mg / kg, approximately 5.1 mg / kg. mg / kg, approximately 5.3 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately 5.8 mg / kg, approximately 6.0 mg / kg, approximately 6.1 mg / kg, approximately 6.3 mg / kg, approximately 6.4 mg / kg, approximately 6.5 mg / kg, approximately 6.6 mg / kg, approximately 6.8 mg / kg, approximately 6.9 mg / kg, approximately 7.0 mg / kg, approximately 7.2 mg / kg, approximately 7.4 mg / kg, approximately 7.5 mg / kg, approximately 7.6 mg / kg, approximately 7.8 mg / kg, approximately 8. 0 mg / kg, approximately 8.1 mg / kg, approximately 8.3 mg / kg, approximately 8.5 mg / kg, approximately 8.8 mg / kg, approximately 9.0 mg / kg, approximately 9.5 mg / kg, approximately 10.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, approximately 12.5 mg / kg, approximately 13 mg / kg, approximately 13.5 mg / kg, approximately 14 mg / kg, approximately 16 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, approximately 20 mg / kg; or any range between these values.

[0092] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is administered at least once every 1 week, at least once every 2 weeks, at least once every 3 weeks, at least once every 4 weeks, at least once every 6 weeks, or at least once every 8 weeks.

[0093] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is administered once every 1 week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks.

[0094] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is about about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg, administered twice every 3 weeks.

[0095] In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 6 mg / kg or about 8 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 4 mg / kg or about 5 mg / kg, administered twice every 3 weeks, on days D1 and D8 of each cycle.

[0096] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is administered orally, parenterally, or transdermally; the parenterial administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-Nectin-4 antibody-drug conjugate is administered via intravenous injection. In some specific embodiments, the anti-Nectin-4 antibody-drug conjugate is administered via intravenous infusion.

[0097] In some embodiments, the anti-Nectin-4 antibody-drug conjugate is formulated in an injectable form. Exemplarily, the injectable form of the anti-Nectin-4 antibody-drug conjugate is an injection solution or lyophilized powder for injection, comprising the anti-Nectin-4 antibody-drug conjugate and one or more pharmaceutically acceptable excipients. In some embodiments, the anti-Nectin-4 antibody-drug conjugate is formulated as any composition selected from WO2023221971A1.

[0098] The disclosed anti-Nectin-4 antibody-drug conjugate has shown certain clinical benefits in targeted therapy for cervical cancer, ovarian cancer, fallopian tube cancer, peritoneal cancer, or endometrial cancer, bringing patients clinical benefits superior to existing treatments, and controlling or alleviating their condition.

[0099] the term

[0100] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. Unless otherwise expressly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0101] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0102] "Optional" or "optionally" means that the event or circumstances described below may, but do not have to, occur, including the circumstances in which the event or circumstances may or may not occur.

[0103] The terms “about” and “approximately” mean that a numerical value is within the acceptable error range of a specific value as determined by a person skilled in the art, the numerical value depending in part on how it is measured or determined (i.e., the limits of the measurement system). For example, “about” may mean within or above 1 standard deviation. Alternatively, “about” or “substantially includes” may mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, or between 0.5% and 1%. In this disclosure, each instance of a number or range of values ​​preceded by the term “about” also includes embodiments of a given number. Unless otherwise stated, when a specific value appears in this application and claims, the meaning of “about” or “substantially includes” should be assumed to be within the acceptable error range of that specific value.

[0104] The term “and / or”, such as “X and / or Y”, should be understood to mean “X and Y” or “X or Y” and should be used to provide clear support for both meanings or either meaning.

[0105] In some implementations, this disclosure defines the following:

[0106] Antibody-drug conjugates (ADCs) are drugs that link antibodies or antibody fragments to biologically active cytotoxic drugs or small molecule drugs with cytotoxic activity via stable chemical linker compounds. They fully utilize the specificity of antibodies in binding to tumor cell-specific or highly expressed antigens and the high efficiency of cytotoxic agents, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, antibody-drug conjugates can precisely bind to tumor cells and reduce the impact on normal cells.

[0107] If an antibody-drug conjugate does not exhibit significant chemical changes, then the antibody "retains its chemical stability" in the drug formulation. Chemical stability can be assessed by detecting and quantifying the chemically altered form of the protein. Degradation processes that frequently alter the chemical structure of proteins include hydrolysis or truncation (evaluated by methods such as size exclusion chromatography and CE-SDS), oxidation (evaluated by methods such as peptide mapping combined with mass spectrometry or MALDI / TOF / MS), deamidation (evaluated by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, and isofpartate measurement), and isomerization (evaluated by measuring isofpartate content, peptide mapping, etc.).

[0108] If the biological activity of an antibody-drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the drug formulation is prepared, then the antibody-drug conjugate "retains its biological activity" in the drug formulation.

[0109] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0110] As used herein, the term "antibody" is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. Antibodies can refer to immunoglobulins, which are tetrapeptide chains composed of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The amino acid composition and sequence of the constant region of the immunoglobulin heavy chain differ, thus their antigenicity also differs. Based on this, immunoglobulins can be divided into five classes, or isotypes of immunoglobulins: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε chains, respectively. Within the same class of Ig, based on differences in the amino acid composition of their hinge region and the number and position of disulfide bonds in their heavy chains, different subclasses can be distinguished; for example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as κ chains or λ chains based on differences in their constant regions. Each of the five classes of Ig can have either a κ chain or a λ chain. The sequence of approximately 110 amino acids near the N-terminus of the antibody heavy and light chains varies considerably, forming the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable, forming the constant region (C region). The variable region includes three hypervariable regions (CDRs) and four relatively conserved backbone regions (FRs). The three hypervariable regions determine the antibody's specificity and are also known as complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain refer to LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0111] The determination or definition of a contact ligand (CDR) can be accomplished by resolving the structure of the antibody and / or the structure of the antibody-ligand complex, thereby enabling the definitive depiction of the CDR and the identification of residues containing the antibody binding site. This can be achieved using any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of analytical methods can be used to identify CDRs, including but not limited to the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0112] The amino acid sequence boundaries of CDRs can be determined using various well-known schemes, such as the "Kabat" numbering rule, the "Chothia" numbering rule, the "ABM" numbering rule, the "contact" numbering rule, and the ImMunoGenTics (IMGT) numbering rule.

[0113] The terms “antigen-binding fragment” or “functional fragment” or “antigen-binding portion” refer to one or more fragments of a complete antibody that retain the ability to specifically bind to an antigen. It has been shown that fragments of full-length antibodies can be used for antigen-binding function. Exemplary examples of binding fragments encompassed in the term “antigen-binding fragment” include: (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment, a bivalent fragment comprising two Fab fragments connected by disulfide bridges on their hinge regions; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of the antibody; (v) dsFv, a stable antigen-binding fragment formed by interchain disulfide bonds between VH and VL; (vi) scFv; and (vii) bispecific, bispecific, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.

[0114] The terms "specific binding," "selective binding," "selective binding," and "specific binding" refer to the binding of an antibody to a pre-defined epitope on an antigen. Typically, antibodies bind at a concentration of approximately less than 10... -8 M, for example, approximately less than 10 -9 M, 10 -10 M, 10 -11 M or lower affinity (KD) binding.

[0115] The term "KD" refers to the dissociation equilibrium constant of a specific antibody-antigen interaction. Typically, the antibodies disclosed herein have a KD value less than approximately 10⁻⁷ M, for example, less than approximately 10⁻⁷ M. -8 M, 10 -9 M or 10 -10 M or a smaller dissociation equilibrium constant (KD) is combined with IL-5, for example, as determined in a BIACORE instrument using surface plasmon resonance (SPR) technology.

[0116] "Homology" refers to the sequence similarity between two polynucleotide sequences or two polypeptides. Two compared sequences are homologous at positions occupied by the same bases or amino acid monomer subunits; for example, if every position in two DNA molecules is occupied by adenine. The percentage of homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared multiplied by 100. For example, in optimal sequence alignment, if 6 out of 10 positions in two sequences match or are homologous, then the two sequences are 60% homologous; if 95 out of 100 positions in two sequences match or are homologous, then the two sequences are 95% homologous. Typically, comparisons are made when aligning two sequences to give the maximum percentage of homology. For example, comparisons can be performed using the BLAST algorithm, where the algorithm's parameters are chosen to give the maximum match between the sequences over the entire length of each reference sequence. The following references relate to the BLAST algorithm frequently used in sequence analysis: BLAST Algorithms: Altschul, SF et al., (1990) J. Mol. Biol. 215: 403-410; Gish, W. et al., (1993) Nature Genet. 3: 266-272; Madden, TL et al., (1996) Meth. Enzymol. 266: 131-141; Altschul, SF et al., (1997) Nucleic Acids Res. 25: 3389-3402; Zhang, J. et al., (1997) Genome Res. 7: 649-656. Other common BLAST algorithms, such as those provided by NCBI BLAST, are also well-known to those skilled in the art.

[0117] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, "giving" and "treatment" refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. "Giving" and "treatment" can refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and cells, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cells. "Giving" and "treatment" also mean the treatment of, for example, cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, "treatment" refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0118] "Treatment" means administering an oral or topical therapeutic agent, such as a composition comprising any of the compounds disclosed herein, to a patient who has symptoms of one or more diseases, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, a therapeutic agent is administered in a treated patient or population in an amount that effectively relieves symptoms of one or more diseases to induce the regression of such symptoms or inhibit their progression to any clinically measurable extent. The amount of a therapeutic agent that effectively relieves any specific disease symptom (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the patient's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the patient. Whether the disease symptoms have been relieved can be evaluated using any clinical testing methods commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating symptoms of each target disease, they should reduce symptoms of the target disease in a statistically significant number of patients, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test.

[0119] An "effective amount" includes the amount sufficient to improve or prevent the symptoms or condition of a medically diagnosed disease. An effective amount also means the amount sufficient to allow or facilitate diagnosis. The effective amount for a particular patient or veterinary subject can vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or administration regimen that avoids significant side effects or toxicity.

[0120] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0121] This disclosure of "platinum-based treatment" includes treatment with platinum-based drugs such as cisplatin and carboplatin.

[0122] In this disclosure of antibody-drug conjugates, "n" refers to the average amount of cytotoxic drug loaded onto each antibody or its antigen-binding fragment in the antibody-drug conjugate molecule. It can also be expressed as the ratio of drug amount to antibody amount, for example, as the average amount of drug per ADC molecule after the conjugation reaction is identified by hydrophobic chromatography (HIC) mass spectrometry.

[0123] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Detailed Implementation

[0124] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the disclosure. Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions, such as those described in Cold Spring Harbor Laboratory's *Antibody Technology Laboratory Manual* and *Molecular Cloning Handbook*; or under conditions recommended by the raw material or commercial manufacturer. Reagents whose specific source is not specified are commercially available, conventional reagents.

[0125] Example 1. Preparation of anti-Nectin-4 antibody-drug conjugate

[0126] The anti-Nectin-4 antibody-drug conjugate can be prepared according to Examples 3-4 in WO2023221971A1 (incorporated hereby by reference in its entirety), with the following structure:

[0127] Average values ​​calculated by reversed-phase chromatography: n = 3.5–4.7.

[0128] The anti-Nectin-4 antibody is antibody NEC49, and its CDR sequence is shown in Table 1. The full-length heavy chain of antibody NEC49 is shown in SEQ ID NO: 9, and the full-length light chain is shown in SEQ ID NO: 10.

[0129] Example 2. Phase I clinical study of anti-Nectin-4 antibody-drug conjugate for the treatment of patients with advanced solid tumors.

[0130] 1. Investigational drug

[0131] The ADC prepared in Example 1 is NEC49-9-A (hereinafter referred to as "ADC"). The dosage form is an injection (sterile powder for injection), with a specification of 80 mg / vial.

[0132] 2. Test Results

[0133] 1) Validity:

[0134] As of November 14, 2023, a total of 20 patients with advanced urothelial carcinoma were enrolled in the Phase I clinical trial of ADC. The 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, and 8 mg / kg dose groups enrolled 1, 3, 3, 7, and 6 patients, respectively. In the 6 mg / kg and 8 mg / kg dose groups, 5 and 3 patients, respectively, had target lesions at baseline and completed at least one efficacy assessment. The unconfirmed ORRs were 40% (3 / 5) and 66.7% (2 / 3), respectively.

[0135] 2) Safety: As of November 14, 2023, a total of 20 patients with advanced urothelial carcinoma were enrolled in the Phase I clinical trial of ADC-4. The 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, and 8 mg / kg dose groups enrolled 1, 3, 3, 7, and 6 patients, respectively. The incidence of ≥Grade 3 TRAEs was 29% (2 / 7) in the 6 mg / kg and 33% (2 / 6) in the 8 mg / kg dose groups; no DLT occurred in the 1 mg / kg, 2 mg / kg, 4 mg / kg, and 6 mg / kg dose groups.

[0136] As of November 14, 2023, a total of 19 subjects with advanced solid tumors were enrolled in the Phase I clinical trial of ADC, including: 12 with lung cancer, 2 with breast cancer, 1 with esophageal cancer, 2 with colorectal cancer, 1 with urothelial carcinoma, and 1 with head and neck squamous cell carcinoma. The 2 mg / kg, 4 mg / kg, 6 mg / kg, and 8 mg / kg dose groups enrolled 3, 4, 10, and 2 subjects, respectively. The incidence of ≥ grade 3 TRAE in the 6 mg / kg dose group was 20% (2 / 10).

[0137] The results of the Phase I clinical trial of ADC showed that both the 6 mg / kg, Q3W and 8 mg / kg, Q3W dose groups were tolerable and preliminary therapeutic signals were observed in both dose groups.

[0138] Example 3. An open-label, multicenter phase II clinical trial of anti-Nectin-4 antibody-drug conjugates for the treatment of advanced gynecological malignancies.

[0139] 1. Investigational drug

[0140] The ADC prepared in Example 1 is NEC49-9-A (hereinafter referred to as "ADC"). The dosage form is an injection (sterile powder for injection), with a specification of 80 mg / vial.

[0141] 2. Enrolled subjects

[0142] 1) Age 18-75 (inclusive), gender not limited;

[0143] 2) The Eastern Cooperative Oncology Group (ECOG) performance status score is 0-1.

[0144] 3) Expected survival ≥ 12 weeks;

[0145] 4) For patients with advanced cervical cancer, advanced ovarian cancer, and advanced endometrial cancer, the requirements for each cohort are as follows:

[0146] Cohort 1 Cervical Cancer: Histologically or cytologically confirmed recurrent or metastatic cervical cancer that is no longer suitable for radical surgery and / or radical radiotherapy or chemoradiotherapy; having received platinum-based systemic therapy (excluding radiosensitizing chemotherapy) at the recurrent / metastatic stage, and experiencing disease recurrence or progression during or after treatment (requiring at least 4 cycles of treatment); having received ≤2 lines of prior systemic therapy.

[0147] Note: Patients receiving neoadjuvant or adjuvant therapy or radical concurrent chemoradiotherapy who receive platinum-based systemic therapy (excluding radiosensitizing chemotherapy) and whose disease relapses or progresses during treatment or within 6 months after treatment (at least 4 cycles of treatment are required) are considered to have received first-line systemic therapy.

[0148] Cohort 2 Platinum-resistant recurrent ovarian, fallopian tube, or primary peritoneal cancer: Histopathologically confirmed recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; prior platinum-based therapy, with progression or recurrence within 6 months of the last platinum-based therapy or the end of treatment (at least 4 cycles required); and a maximum of one line of systemic antitumor therapy received after platinum resistance.

[0149] Note: For patients who have only received first-line platinum-based therapy, platinum-based therapy must have been administered for ≥4 cycles; relapse or progression during or after the last platinum-based therapy regimen must be documented on imaging, and CA-125 progression can be used as a basis for determining the time of progression; there must be imaging evidence of disease progression during or after the last-line therapy.

[0150] Cohort 3 Endometrial Cancer: Histopathologically confirmed recurrent or metastatic endometrial cancer that is no longer suitable for radical surgery and / or radical radiotherapy or chemoradiotherapy; having received platinum-based systemic therapy (excluding radiosensitizing chemotherapy) at the recurrent / metastatic stage, and experiencing disease recurrence or progression during or after treatment (requiring at least 4 cycles of treatment); having received ≤2 lines of prior systemic therapy.

[0151] Note: Patients receiving neoadjuvant or adjuvant therapy or radical concurrent chemoradiotherapy who receive platinum-based systemic therapy (excluding radiosensitizing chemotherapy) and whose disease relapses or progresses during treatment or within 6 months after treatment (at least 4 cycles of treatment are required) are considered to have received first-line systemic therapy.

[0152] 5) Subjects must be able to provide specimens from the primary or metastatic tumor sites (paraffin blocks, paraffin-embedded sections, or fresh tissue sections are all acceptable) for a third-party laboratory designated by the sponsor to test the expression level of Nectin-4. The test results will not affect enrollment. For subjects who cannot provide tumor tissue samples that meet the above requirements, enrollment must be confirmed after discussion with the sponsor.

[0153] 6) At least one measurable lesion according to RECIST v1.1 criteria.

[0154] 3. Clinical protocol

[0155] 3.1 Research Design

[0156] This study is divided into a safety implementation phase and an efficacy expansion phase.

[0157] Phase 1: Secure Implementation Phase

[0158] 1) Cohort 1: Cervical Cancer

[0159] Dosage level 1: ADC 6 mg / kg, once every 3 weeks (Q3W);

[0160] Dosage level 2: ADC 8 mg / kg, once every 3 weeks (Q3W).

[0161] The second stage is the therapeutic effect expansion stage:

[0162] 1) Cohort 1: Received cervical cancer treatment at dose levels determined during the safe delivery phase of the ADC;

[0163] 2) Cohort 2: Patients receiving treatment at dose levels determined during the safe delivery phase of the ADC for platinum-resistant recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer;

[0164] 3) Cohort 3: Endometrial cancer patients treated with dose levels determined during the safe delivery phase of the ADC.

[0165] During or after the enrollment phase of the efficacy expansion phase, the drug safety monitoring committee (SMC) may, upon discussion and decision, further expand the enrollment of patients with enriched Nectin-4 expression levels.

[0166] 3.2 Administration method

[0167] ADC: Intravenous infusion, 6 mg / kg, 8 mg / kg, or other exploratory / determined doses.

[0168] 4. Results Evaluation

[0169] 4.1 Effectiveness Indicators

[0170] Tumor assessment was performed using the RECIST v1.1 criteria, and all subjects underwent baseline tumor imaging assessment during the screening period. Efficacy was evaluated using the RECIST v1.1 criteria, and the efficacy endpoints included investigator-assessed ORR, DCR, DoR, PFS, and OS.

[0171] Clinical trials are still ongoing. In cohort 1, 36 cervical cancer patients have been enrolled in the 6 mg / kg dose group and 14 cervical cancer patients have been enrolled in the 8 mg / kg dose group. In cohort 2, 21 patients have been enrolled and in cohort 3, 3 patients have been enrolled.

[0172] Of the 50 cervical cancer patients enrolled, all had progressed after platinum-based therapy, 88% had previously received radiotherapy, 40% had previously received surgery, 78% had previously received immunotherapy, and 66% had previously received targeted therapy.

[0173] Of the 21 patients enrolled with platinum-resistant recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, all had previously progressed after platinum-based therapy, all had previously undergone surgical treatment, 85.7% had previously received targeted therapy, and 4.8% had previously received immunotherapy. The three patients enrolled with endometrial cancer had all previously progressed after platinum-based therapy.

[0174] 4.1.1 Evaluation of efficacy against cervical cancer

[0175] The efficacy evaluation results of the enrolled subjects with cervical cancer are shown in Table 2. The uORR of all subjects with cervical cancer was 52%, the DCR was 88% (among which 2 subjects achieved complete remission (CR) at a dose of 6 mg / kg), the mPFS at a dose of 6 mg / kg was 6.8 months, and the mPFS at a dose of 8 mg / kg was 5.5 months.

[0176] Table 2. Evaluation of efficacy in cervical cancer patients enrolled in the study.

[0177] *Including unconfirmed ORRs

[0178] Table 3 shows the statistical results of efficacy analysis for all subjects enrolled at a dose of 6 mg / kg, categorized by cervical cancer subgroup. The results indicate that objective responses were observed in all subgroups. Specifically, 44.4% (4 / 9) of subjects in the Nectin-4 low-expression and Nectin-4 negative groups achieved response, 43.8% of subjects in the Nectin-4 medium-expression group achieved response, and 66.7% of subjects in the Nectin-4 high-expression group achieved response. This demonstrates that the entire population expressing Nectin-4 (regardless of whether they are Nectin-4 positive or negative) can benefit from this treatment.

[0179] Table 3. Evaluation of efficacy in cervical cancer subgroup classification

[0180] *Nectin-4 expression was detected in tissue samples from 34 subjects. One subject had an Hscore of 0 and achieved complete remission (CR) in the BOR test.

[0181] Among all subjects enrolled at a dose of 6 mg / kg, 31 subjects had previously failed platinum-based chemotherapy and immunotherapy. The statistical results of their efficacy analysis are shown in Table 4. The cORR was 41.9% (one subject achieved complete remission (CR)), the DCR was 87.1%, the mDoR was 5.4 months, the mPFS was 5.2 months, and the mOS had not yet been reached.

[0182] Table 4. Efficacy evaluation of subjects treated with platinum-based chemotherapy and immunotherapy

[0183] 4.1.2 Evaluation of efficacy against ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and endometrial cancer

[0184] The clinical trial is still ongoing. Among the 21 enrolled subjects with platinum-resistant recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who had completed at least one tumor assessment, the uORR was 47.6% and the DCR was 100%. Among the 3 subjects with endometrial cancer who had completed at least one tumor assessment, the uORR was 33.3% and the DCR was 100%.

[0185] 4.2 Safety Evaluation

[0186] Safety assessments will be conducted for all subjects after enrollment in the study at each treatment cycle. These assessments will include the incidence and severity of adverse events (AEs), serious adverse events (SAEs) (judged according to the NCI-CTCAEv5.0 criteria), changes in vital signs, abnormal laboratory test results, and the incidence of dose suspension, dose reduction, and dose termination due to study drug-related toxicity during the trial.

[0187] 4.2.1 Safety evaluation for cervical cancer

[0188] Among all cervical cancer participants, 38.9% of those in the 6 mg / kg group experienced a TRAE of grade ≥3. The most common TRAEs were hematologic toxicity (decreased white blood cell count, decreased neutrophil count, anemia, decreased platelet count) and gastrointestinal reactions (nausea, vomiting), hair loss, and decreased appetite.

[0189] 4.2.2 Safety evaluation for ovarian cancer, fallopian tube cancer, primary peritoneal cancer, and endometrial cancer

[0190] Among all subjects enrolled with platinum-resistant recurrent ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, 42.9% experienced a TRAE of grade ≥3. The most common TRAEs were hematological toxicities (decreased white blood cell count, decreased neutrophil count, decreased platelet count) and gastrointestinal reactions (nausea, vomiting), hair loss, and decreased appetite. Among all subjects enrolled with endometrial cancer, 33.3% experienced a TRAE of grade ≥3. The most common TRAEs were hematological toxicities (anemia, leukopenia, thrombocytopenia, decreased white blood cell count, decreased neutrophil count) and gastrointestinal reactions (nausea, vomiting), hair loss, and decreased appetite.

Claims

1. Use of an anti-Nectin-4 antibody drug conjugate in the manufacture of a medicament for treating a tumor, the structure of the anti-Nectin-4 antibody drug conjugate is shown as Formula I or Formula II: in: n is a decimal or integer from 1 to 10, preferably from 1 to 8, more preferably from 3 to 5; Ab is an anti-Nectin-4 antibody; the tumor is a gynecological tumor.

2. Use according to claim 1, wherein, The gynecological tumors mentioned are cervical cancer, endometrial cancer, ovarian cancer, fallopian tube cancer, or primary peritoneal cancer.

3. The use according to claim 1 or 2, wherein, The gynecological tumor is a late-stage gynecological tumor; preferably, it is late-stage cervical cancer, late-stage endometrial cancer, late-stage ovarian cancer, late-stage fallopian tube cancer, or late-stage primary peritoneal cancer.

4. The use according to claim 3, wherein, The advanced cervical cancer is recurrent and / or metastatic cervical cancer; the advanced endometrial cancer is recurrent and / or metastatic endometrial cancer; the advanced ovarian cancer is recurrent and / or metastatic ovarian cancer; the fallopian tube cancer is recurrent and / or metastatic fallopian tube cancer; the primary peritoneal cancer is recurrent and / or metastatic primary peritoneal cancer.

5. The use according to any one of claims 1-4, wherein, Subjects with the aforementioned gynecological tumors have previously received systemic anti-tumor therapy, radiotherapy, and / or surgical treatment; Preferably, the systemic antitumor treatment is selected from chemotherapy, immunotherapy, and / or targeted drug therapy, wherein the chemotherapy includes platinum-based chemotherapy; More preferably, the subject with the gynecological tumor has previously received platinum-based chemotherapy.

6. The use according to claim 5, wherein: Subjects with cervical cancer who have previously received platinum-based chemotherapy, preferably those who have previously received platinum-based chemotherapy and immunotherapy; Subjects with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously received platinum-based chemotherapy; Subjects with endometrial cancer had previously received platinum-based chemotherapy.

7. The use according to any one of claims 1-6, wherein, Subjects with the aforementioned gynecological tumors had previously failed or were intolerant of systemic anti-tumor therapy, radiotherapy, and / or surgical treatment; Preferably, the systemic antitumor treatment is selected from chemotherapy, immunotherapy, and / or targeted drug therapy, wherein the chemotherapy includes platinum-based chemotherapy; More preferably, the subject with the gynecological tumor had previously failed or was intolerant to platinum-based chemotherapy.

8. The use according to claim 7, wherein: Subjects with cervical cancer who had previously failed or were intolerant to platinum-based chemotherapy, preferably those who had previously failed or were intolerant to both platinum-based chemotherapy and immunotherapy; Subjects with ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously failed or are intolerant to platinum-based chemotherapy; preferably those who have previously received platinum-based chemotherapy and have experienced platinum-resistant or platinum-sensitive relapse. Subjects with endometrial cancer who had previously failed or were intolerant to platinum-based chemotherapy.

9. The use according to any one of claims 1-8, wherein, The anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively; and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 respectively; Preferably, the anti-Nectin-4 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises an amino acid sequence as shown in SEQ ID NO:7 or having at least 80% or 90% identity with it, and the VL comprises an amino acid sequence as shown in SEQ ID NO:8 or having at least 80% or 90% identity with it. Preferably, the anti-Nectin-4 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO:9 or having at least 80% or 90% identity with it, and the light chain comprises an amino acid sequence as shown in SEQ ID NO:10 or having at least 80% or 90% identity with it.

10. The use according to any one of claims 1-9, wherein, The dosage of the anti-Nectin-4 antibody-drug conjugate is 0.1-20 mg / kg, preferably 1-10 mg / kg, and more preferably about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg or about 10 mg / kg; The anti-Nectin-4 antibody-drug conjugate is administered at least once a week, at least once every two weeks, at least once every three weeks, at least once every four weeks, at least once every six weeks, or at least once every eight weeks; preferably once every three weeks or twice every three weeks. Preferably, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or about 10 mg / kg, and the dosing frequency is once every 3 weeks; or, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg, and the dosing frequency is twice every 3 weeks. More preferably, the dosage of the anti-Nectin-4 antibody-drug conjugate is about 6 mg / kg or about 8 mg / kg, and the dosing frequency is once every 3 weeks.

11. A pharmaceutical composition, kit, or article comprising an anti-Nectin-4 antibody-drug conjugate as defined in any one of claims 1, 9-10.

12. Use of the pharmaceutical composition, kit, or article of claim 11 in the preparation of a medicament for treating tumors; preferably, the tumor is defined as in any one of claims 2-8.

13. Methods for the prevention or treatment of tumors, including administering anti-Nectin-4 antibody-drug conjugates to subjects in need; The structure of the anti-Nectin-4 antibody-drug conjugate is shown in Formula I or Formula II: in: n is a decimal or integer from 1 to 10, preferably from 1 to 8, more preferably from 3 to 5; Ab is an anti-Nectin-4 antibody; Preferably, the anti-Nectin-4 antibody-drug conjugate is as defined in any one of claims 1, 9-10; The tumor is defined as in any one of claims 2-8.

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