Use of Anti-DLL3 antibody-drug conjugate for treating cancer

Abstract

The present disclosure relates to use of an anti-DLL3 antibody drug-conjugate for treating a cancer. Specifically, the present disclosure relates to use of an anti-DLL3 antibody-drug conjugate for treating a disease or condition, such as a cancer, including but not limited to neuroendocrine neoplasm (NEN).

Description

Use of anti-DLL3 antibody-drug conjugates in cancer treatment

[0001] This application claims priority to Chinese patent application CN202411945032.9 filed on December 27, 2024, and Chinese patent application CN202510042471.7 filed on January 10, 2025, and Chinese patent application CN202511008755.0 filed on July 22, 2025, and Chinese patent application CN202511262525.7 filed on September 5, 2025, and Chinese patent application CN202511823438.4 filed on December 5, 2025. Technical Field

[0002] This disclosure pertains to the biopharmaceutical field and specifically relates to the use of an anti-DLL3 antibody-drug conjugate for the treatment of diseases or conditions, such as cancer, including but not limited to neuroendocrine neoplasms (NEN). Background Technology

[0003] The statements herein are provided only as background information in connection with this disclosure and do not necessarily constitute prior art.

[0004] DLL3 is a ligand that inhibits Notch. Under normal conditions, DLL3 resides on the Golgi apparatus. In cancer cells (such as small cell lung cancer cells), DLL3 translocates to the cell surface and binds to Notch in a cis-regulatory manner, hindering cell-cell binding and Notch endocytosis within target cells, thereby inhibiting the Notch signaling pathway and promoting tumor cell growth. DLL3 is primarily expressed in neuroendocrine tumors, including SCLC, large cell neuroendocrine carcinoma, gastrointestinal neuroendocrine tumors, small cell bladder cancer, glioma multiforme, metastatic castration prostate cancer, and melanoma. Especially in SCLC, DLL3 is expressed in over 80% of SCLC cases, while it is not expressed in normal lung cancer tissue or adjacent tissues. This differential expression makes DLL3 a potential therapeutic target for SCLC.

[0005] Ecinotecan toxoid is a camptothecin derivative that inhibits topoisomerase I, selectively inhibiting DNA replication in proliferating tumor cells. Furthermore, eccinotecan toxoid exhibits excellent membrane permeability, allowing it to penetrate killed cancer cells and continue killing adjacent cancer cells, demonstrating a clear bystander effect in clinical practice.

[0006] Antibody-drug conjugates (ADCs) are obtained by linking antibodies to biologically active drugs via linkers. ADCs fully utilize the specificity of antibodies in binding to antigens on the surface of normal and tumor cells, as well as the high efficiency of drugs (such as cytotoxic agents), while avoiding the drawbacks of low efficacy of antibodies and excessive toxic side effects of drugs. Compared with traditional chemotherapy drugs, antibody-drug conjugates can more precisely kill tumor cells and reduce the impact on normal cells.

[0007] Neuroendocrine neoplasms (NENs) are a type of rare tumor originating from peptidergic neurons and neuroendocrine cells, exhibiting neuroendocrine differentiation and expressing neuroendocrine markers. They can occur anywhere in the body, with the lung, gastrointestinal, and pancreatic NENs being the most common. Based on whether the tumor secretes hormones and produces hormone-related symptoms, NENs can be classified as functional or non-functional. Pathologically, based on the degree of differentiation, NENs are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). NENs from different locations have different pathological nomenclature, classification, and grading. Primary NECs in the lung mainly include large cell neuroendocrine carcinoma of the lung (LCNEC) and small-cell lung cancer (SCLC).

[0008] Small cell lung cancer (SCLC) is a relatively malignant type of lung cancer, accounting for 10% to 15% of all lung cancer cases. SCLC tumors grow rapidly, are prone to metastasis, and have a 5-year survival rate of less than 7%. Treatment for SCLC often involves platinum-based chemotherapy combined with etoposide. SCLC patients initially respond well to chemotherapy, but resistance and relapse are highly likely. Recent immunotherapies, such as PD-L1 and PD-1 antibodies, have shown some efficacy in SCLC patients, but the response rate is approximately 15%.

[0009] Therefore, there is an urgent clinical need for more effective treatment options to improve the current treatment status of NENs, especially SCLC. Summary of the Invention

[0010] This disclosure provides the use and methods of using anti-DLL3 antibody-drug conjugates for the treatment of advanced malignant solid tumors.

[0011] In some implementations, this disclosure provides for any of the following uses:

[0012] (1) Use of anti-DLL3 antibody-drug conjugates in the preparation of drugs for the treatment of advanced malignant solid tumors;

[0013] (2) An anti-DLL3 antibody-drug conjugate for the treatment of advanced malignant solid tumors, wherein the anti-DLL3 antibody-drug conjugate is administered to a subject;

[0014] (3) A pharmaceutical composition, kit or article for treating advanced malignant solid tumors, wherein the pharmaceutical composition, kit or article comprises an anti-DLL3 antibody-drug conjugate;

[0015] (4) Use of a pharmaceutical composition, kit or article in the preparation of a medicament for the treatment of advanced malignant solid tumors, wherein the pharmaceutical composition, kit or article comprises an anti-DLL3 antibody-drug conjugate.

[0016] In some implementations, this disclosure provides a method as shown in any of the following:

[0017] (1) Methods of treating advanced malignant solid tumors, including administering a therapeutically effective amount of anti-DLL3 antibody-drug conjugate to subjects in need;

[0018] (2) A method of treating advanced malignant solid tumors, comprising administering a pharmaceutical composition, kit, or article to a subject in need, wherein the pharmaceutical composition, kit, or article comprises an anti-DLL3 antibody-drug conjugate.

[0019] In some implementations, the advanced malignant solid tumor is a recurrent or metastatic solid tumor.

[0020] In some implementations, the advanced malignant solid tumor is a histologically or cytologically confirmed recurrent or metastatic solid tumor that is inoperable.

[0021] In some implementations, the advanced malignant solid tumor is a neuroendocrine tumor.

[0022] In some implementations, the subjects are selected based on one or more of the following criteria:

[0023] (i) Voluntarily participate in clinical research, understand the research procedures and be able to sign an informed consent form in writing;

[0024] (ii) Age 18 to 75 years old, gender not limited;

[0025] (iii) Histologically or cytologically confirmed inoperable recurrent or metastatic solid tumors that have progressed or recurred after prior standard treatment, as shown below:

[0026] (a) Small-cell lung cancer (SCLC): Prior to receiving at least one standard treatment

[0027] Progression or relapse, and previous systemic chemotherapy not exceeding two lines;

[0028] (b) Other DLL3-positive neuroendocrine carcinomas: failure of prior standard treatment, or treatment received at least one

[0029] Progression or relapse after platinum-based treatment regimens, and prior systemic chemotherapy not exceeding two lines;

[0030] (iv) An ECOG score of 0 or 1;

[0031] (v) Expected survival of more than 3 months; and

[0032] (vi) Has sufficient bone marrow and organ function.

[0033] This disclosure provides the use and methods of using anti-DLL3 antibody-drug conjugates for the treatment of neuroendocrine neoplasm (NEN).

[0034] In some implementations, this disclosure provides for any of the following uses:

[0035] (1) Use of anti-DLL3 antibody-drug conjugates in the preparation of drugs for treating neuroendocrine tumors;

[0036] (2) An anti-DLL3 antibody-drug conjugate for the treatment of neuroendocrine tumors, wherein the anti-DLL3 antibody-drug conjugate is administered to a subject;

[0037] (3) A pharmaceutical composition, kit or article for treating neuroendocrine tumors, wherein the pharmaceutical composition, kit or article comprises an anti-DLL3 antibody-drug conjugate;

[0038] (4) Use of a pharmaceutical composition, kit or article in the preparation of a medicament for treating neuroendocrine tumors, wherein the pharmaceutical composition, kit or article comprises an anti-DLL3 antibody-drug conjugate.

[0039] In some implementations, this disclosure provides a method as shown in any of the following:

[0040] (1) Methods of treating neuroendocrine tumors, including administering a therapeutically effective amount of an anti-DLL3 antibody-drug conjugate to subjects in need;

[0041] (2) A method of treating neuroendocrine tumors, comprising administering a pharmaceutical composition, kit, or article to a subject in need, wherein the pharmaceutical composition, kit, or article comprises an anti-DLL3 antibody-drug conjugate.

[0042] In some implementations, this disclosure provides a product represented by any of the following:

[0043] (1) A pharmaceutical composition comprising an anti-DLL3 antibody-drug conjugate;

[0044] (2) A kit containing an anti-DLL3 antibody-drug conjugate;

[0045] (3) Products containing anti-DLL3 antibody-drug conjugates.

[0046] In some embodiments, the kit or article also includes one or more containers containing an anti-DLL3 antibody-drug conjugate.

[0047] In some embodiments, the anti-DLL3 antibody drug conjugate in the pharmaceutical composition is present in individually packaged form.

[0048] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma (NEC).

[0049] In some embodiments, the neuroendocrine tumor is a recurrent and / or metastatic neuroendocrine carcinoma.

[0050] In some embodiments, the neuroendocrine tumor is small cell lung cancer, or a neuroendocrine carcinoma other than small cell lung cancer that is positive for DLL3 expression (e.g., large cell neuroendocrine carcinoma of the lung, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, urinary tract neuroendocrine carcinoma, etc.).

[0051] In some embodiments, the neuroendocrine tumor is a recurrent and / or metastatic small cell lung cancer, large cell pulmonary neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma.

[0052] In some embodiments, the neuroendocrine tumor is recurrent and / or metastatic small cell lung cancer, or recurrent and / or metastatic neuroendocrine carcinoma that is positive for DLL3 expression other than small cell lung cancer (e.g., large cell neuroendocrine carcinoma of the lung, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, urinary tract neuroendocrine carcinoma, etc.).

[0053] In some implementations, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or recurred after previous standard treatment.

[0054] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy.

[0055] In some embodiments, the neuroendocrine tumor is small cell lung cancer that has progressed or relapsed after prior chemotherapy and / or immunotherapy, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma.

[0056] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0057] In some embodiments, the neuroendocrine tumor is small cell lung cancer, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that has progressed or relapsed after prior chemotherapy and / or immunotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0058] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or recurred after receiving at least one, two, three, or four lines of prior therapy.

[0059] In some implementations, the neuroendocrine tumor is a progressive or recurrent neuroendocrine carcinoma that has received no more than two lines of prior systemic chemotherapy.

[0060] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or relapsed after prior chemotherapy and / or immunotherapy, and has received no more than two lines of prior systemic chemotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0061] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or relapsed after prior platinum-based chemotherapy and / or immunotherapy, and has received no more than two lines of prior systemic chemotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0062] In some embodiments, the neuroendocrine tumor is a DLL3-positive neuroendocrine carcinoma (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0063] In some embodiments, the neuroendocrine tumor is a DLL3-positive neuroendocrine carcinoma that has progressed or relapsed after receiving at least one, two, three, or four lines of prior therapy (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0064] In some implementations, the neuroendocrine tumor is a DLL3-positive neuroendocrine carcinoma that has progressed or relapsed after no more than two lines of prior systemic chemotherapy (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0065] In some implementations, the neuroendocrine tumor is a DLL3-positive neuroendocrine carcinoma that has progressed or relapsed after prior standard treatment (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0066] In some embodiments, the neuroendocrine tumor is a DLL3-positive neuroendocrine carcinoma that has progressed or relapsed after previous chemotherapy (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0067] In some implementations, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or relapsed after previous chemotherapy and has received no more than two lines of previous systemic chemotherapy and is positive for DLL3 expression (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0068] In some embodiments, the neuroendocrine tumor is a neuroendocrine carcinoma that has progressed or relapsed after receiving at least one platinum-based chemotherapy and has received no more than two lines of systemic chemotherapy and is positive for DLL3 expression (e.g., large cell neuroendocrine carcinoma of the lung, neuroendocrine carcinoma of the cervix, neuroendocrine carcinoma of the esophagus, neuroendocrine carcinoma of the stomach, neuroendocrine carcinoma of the prostate, neuroendocrine carcinoma of the rectum, neuroendocrine carcinoma of the urinary tract, etc.).

[0069] In some implementations, the neuroendocrine tumor is small-cell lung cancer (SCLC).

[0070] In some embodiments, the neuroendocrine tumor is small cell lung cancer that has progressed or relapsed after receiving at least one, two, three, or four lines of prior therapy.

[0071] In some implementations, the neuroendocrine tumor is a progressive or recurrent small cell lung cancer that has received no more than two lines of prior systemic chemotherapy.

[0072] In some implementations, the neuroendocrine tumor is small cell lung cancer that has progressed or relapsed after prior standard treatment.

[0073] In some embodiments, the neuroendocrine tumor is small cell lung cancer that has progressed or relapsed after prior chemotherapy and / or immunotherapy.

[0074] In some embodiments, the neuroendocrine tumor is small cell lung cancer that has progressed or relapsed after prior chemotherapy and / or immunotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0075] In some embodiments, the neuroendocrine tumor is a small cell lung cancer that has progressed or relapsed after prior chemotherapy and / or immunotherapy, and has received no more than two lines of prior systemic chemotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0076] In some embodiments, the neuroendocrine tumor is a small cell lung cancer that has progressed or relapsed after prior treatment with at least one platinum-based chemotherapy and / or immunotherapy, and has received no more than two lines of prior systemic chemotherapy, wherein the immunotherapy is a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0077] In some embodiments, the neuroendocrine tumor is a small cell lung cancer that is DLL3-positive or DLL3-non-expressing.

[0078] In some embodiments, the neuroendocrine tumor is a small cell lung cancer that is DLL3-positive or DLL3-negative.

[0079] In some implementations, the neuroendocrine tumor is extensive-stage small cell lung cancer.

[0080] In some implementations, the neuroendocrine tumor is a localized or extensive-stage small cell lung cancer.

[0081] In some implementations, the neuroendocrine tumor is small cell lung cancer that has failed previous treatment with PD-L1 inhibitors combined with platinum-based chemotherapy.

[0082] In some embodiments, the neuroendocrine tumor is extensive-stage small cell lung cancer that has failed previous treatment with PD-L1 inhibitors combined with platinum-based chemotherapy.

[0083] In some embodiments, the neuroendocrine tumor is a limited-stage or extensive-stage small cell lung cancer that has failed previous treatment with PD-L1 inhibitors combined with platinum-based chemotherapy.

[0084] In some implementations, the effects of administering an anti-DLL3 antibody-drug conjugate, a drug containing an anti-DLL3 antibody-drug conjugate, or a drug composition containing an anti-DLL3 antibody-drug conjugate are selected from those of delaying tumor growth, reducing the number of tumor cells, tumor regression, prolonging survival, partial remission, and complete remission.

[0085] In some implementations, after one or more treatment cycles, the tumor volume is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% following the administration of an anti-DLL3 antibody-drug conjugate, a drug containing an anti-DLL3 antibody-drug conjugate, or a drug composition containing an anti-DLL3 antibody-drug conjugate.

[0086] Anti-DLL3 antibody-drug conjugates

[0087] In some embodiments, the anti-DLL3 antibody drug conjugate described in any of the preceding claims is derived from any structure of the anti-DLL3 antibody drug conjugate in WO2024179470A1. This disclosure incorporates, by reference, the structure, preparation method and other related contents of the anti-DLL3 antibody drug conjugate in the above-mentioned patent.

[0088] In some embodiments, the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments comprises the structure shown below:

[0089] Where: n is 1 to 10; Pc is anti-DLL3 antibody.

[0090] In some embodiments, such as the anti-DLL3 antibody-drug conjugate described in any of the preceding embodiments, where n is the average number of drug modules per anti-DLL3 antibody, which may be an integer or a decimal. In some embodiments, n is 1-10, or 2-10, or 3-10, or 4-10, or 5-10, or 6-10, or 7-10, or 8-10, or 1-9, or 2-9, or 3-9, or 4-9, or 5-9, or 6-9, or 7-9, or 1-8, or 2-8, or 3-8, or 4-8, or 5-8, or 6-8, or 1-7, or 2-7, or 3-7, or 4-7, or 5-7, or 1-6, or 2-6, or 3-6, or 4-6, or 1-5, or 2-5, or 3-5, or 1-4, or 2-4, or 1-3. In some implementations, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0091] In some embodiments, such as the anti-DLL3 antibody-drug conjugate described in any of the preceding embodiments, wherein n is 3 to 8. In some embodiments, n is 4 to 8. In some embodiments, n is 6 to 8. In some embodiments, n is 3 to 9. In some embodiments, n is 5 to 9. In some embodiments, n is about 8. In some embodiments, n is 8.

[0092] In some implementations, the anti-DLL3 antibody is derived from any type of anti-DLL3 antibody in WO2024179470A1. This disclosure incorporates the antibody sequence, preparation method and other related contents of the aforementioned patent by reference.

[0093] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

[0094] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain variable region and a light chain variable region, wherein the amino acid sequence of the heavy chain variable region HCDR1 is shown in SEQ ID NO: 1, the amino acid sequence of HCDR2 is shown in SEQ ID NO: 2, and the amino acid sequence of HCDR3 is shown in SEQ ID NO: 3, and the amino acid sequence of the light chain variable region LCDR1 is shown in SEQ ID NO: 4, the amino acid sequence of LCDR2 is shown in SEQ ID NO: 5, and the amino acid sequence of LCDR3 is shown in SEQ ID NO: 6.

[0095] Note: The amino acid residues of the CDR in the variable region are determined and annotated by the Kabat numbering system.

[0096] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments 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.

[0097] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 of the amino acid sequence shown in SEQ ID NO: 7, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 of the amino acid sequence shown in SEQ ID NO: 8.

[0098] In some embodiments, such as the anti-DLL3 antibody described in any of the preceding embodiments, the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to a numbering rule selected from Kabat, IMGT, Chothia, AbM, and Contact. In some embodiments, the HCDR1, HCDR2, and HCDR3 of the heavy chain variable regions and the LCDR1, LCDR2, and LCDR3 of the light chain variable regions are defined according to a Kabat numbering rule.

[0099] Heavy chain variable region sequence of anti-DLL3 antibody

[0100] Light chain variable region sequence of anti-DLL3 antibody

[0101] Note: The sequence is FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, where the underlined part is the CDR sequence (the amino acid residues of the CDR are determined and annotated by the Kabat numbering system).

[0102] In some implementations, the anti-DLL3 antibody, as described in any of the preceding embodiments, is a chimeric antibody, a humanized antibody, or a fully human antibody.

[0103] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments 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% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in or related to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in or related to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100%) sequence identity as shown in or related to SEQ ID NO: 8, and the light chain variable region comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100%) sequence identity as shown in or related to SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 96%, 97%, 98%, 9 The sequence shown in NO:8 has at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity.

[0104] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain variable region as shown in SEQ ID NO: 7 and a light chain variable region as shown in SEQ ID NO: 8.

[0105] In some embodiments, the amino acid sequence of the heavy chain variable region of the anti-DLL3 antibody as described in any of the preceding claims is as shown in SEQ ID NO: 7 or has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the sequence shown in SEQ ID NO: 7; and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO: 8 or has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the sequence shown in SEQ ID NO: 8.

[0106] In some embodiments, the anti-DLL3 antibody, as described in any of the preceding embodiments, is an antibody fragment. In some embodiments, the antibody fragment is selected from Fab, Fab′, F(ab′)2, Fd, Fv, scFv, dsFv, and dAb.

[0107] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments, wherein the anti-DLL3 antibody comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is a heavy chain constant region of human IgG1, IgG2, IgG3, IgG4, or variants thereof, and the light chain constant region is a light chain constant region of human κ chain, λ chain, or variants thereof. In some embodiments, the heavy chain constant region is a human IgG1 heavy chain constant region or a variant thereof, and the light chain constant region is a human κ light chain constant region or a variant thereof. In some embodiments, the heavy chain constant region is a human IgG1 heavy chain constant region, and the light chain constant region is a human κ light chain constant region. In some embodiments, the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 9, and the light chain constant region comprises the amino acid sequence of SEQ ID NO: 10.

[0108] Heavy chain constant region sequence of anti-DLL3 antibody

[0109] Light chain constant region sequence of anti-DLL3 antibody

[0110] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in SEQ ID NO: 11, and the light chain comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in SEQ ID NO: 11, and the light chain comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100%) sequence identity as shown in SEQ ID NO: 12, and the light chain comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100%) sequence identity as shown in SEQ ID NO: 11, and the light chain comprises an amino acid sequence having at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 96%, 97%, 98%, 99%, or 100%) sequence identity as shown in SEQ ID NO: 12, The sequence shown in NO:12 has at least 80% (e.g., at least 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) amino acid sequence identity.

[0111] In some embodiments, the anti-DLL3 antibody as described in any of the preceding embodiments comprises a heavy chain as shown in SEQ ID NO: 11 and a light chain as shown in SEQ ID NO: 12.

[0112] In some embodiments, the amino acid sequence of the heavy chain of the anti-DLL3 antibody as described in any of the preceding claims is as shown in SEQ ID NO: 11 or has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the sequence shown in SEQ ID NO: 11; and the amino acid sequence of the light chain is as shown in SEQ ID NO: 12 or has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with the sequence shown in SEQ ID NO: 12.

[0113] Heavy chain sequence of anti-DLL3 antibody

[0114] Light chain sequence of anti-DLL3 antibody

[0115] Note: The underlined portion is the antibody variable region sequence; the ununderlined portion is the antibody constant region sequence.

[0116] <Dosage Regimen>

[0117] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is 0.01 mg / kg to 50 mg / kg; or 0.1 mg / kg to 20 mg / kg; or 0.5 mg / kg to 10 mg / kg; or 0.6 mg / kg to 6 mg / kg;

[0118] The dosage may be 0.8 mg / kg to 5 mg / kg; or 0.8 mg / kg to 4.2 mg / kg; or 0.8 mg / kg to 3.5 mg / kg; or 0.8 mg / kg to 2.4 mg / kg; or 2.4 mg / kg to 5 mg / kg; or 2.4 mg / kg to 4.2 mg / kg; or 2.4 mg / kg to 3.5 mg / kg; or 3.5 mg / kg to 5 mg / kg; or 3.5 mg / kg to 4.2 mg / kg; or 4.2 mg / kg to 5 mg / kg.

[0119] Or 1.5 mg / kg to 5 mg / kg;

[0120] Or 2 mg / kg to 4.5 mg / kg; 2 mg / kg to 4 mg / kg;

[0121] The dosage may be 2 mg / kg to 3 mg / kg; or 1.9 mg / kg to 2.9 mg / kg; or 2 mg / kg to 2.8 mg / kg; or 2.1 mg / kg to 2.7 mg / kg; or 2.2 mg / kg to 2.6 mg / kg; or 2.3 mg / kg to 2.5 mg / kg.

[0122] The dosage may be 2.4 mg / kg to 3.6 mg / kg; or 2.5 mg / kg to 3.5 mg / kg; or 2.6 mg / kg to 3.4 mg / kg; or 2.7 mg / kg to 3.3 mg / kg; or 2.8 mg / kg to 3.2 mg / kg; or 2.9 mg / kg to 3.1 mg / kg.

[0123] The dosage may be 2.8 mg / kg to 4.2 mg / kg; or 3 mg / kg to 4 mg / kg; or 3.1 mg / kg to 3.9 mg / kg; or 3.2 mg / kg to 3.8 mg / kg; or 3.3 mg / kg to 3.7 mg / kg; or 3.4 mg / kg to 3.6 mg / kg.

[0124] The dosage may be 3.5 mg / kg to 5 mg / kg; or 3.4 mg / kg to 5 mg / kg; or 3.5 mg / kg to 4.9 mg / kg; or 3.6 mg / kg to 4.9 mg / kg; or 3.7 mg / kg to 4.7 mg / kg; or 3.8 mg / kg to 4.6 mg / kg; or 3.9 mg / kg to 4.5 mg / kg; or 4 mg / kg to 4.4 mg / kg; or 4.1 mg / kg to 4.3 mg / kg.

[0125] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 0.01 mg / kg, about 0.02 mg / kg, about 0.03 mg / kg, about 0.04 mg / kg, about 0.05 mg / kg, about 0.06 mg / kg, about 0.07 mg / kg, about 0.08 mg / kg, about 0.09 mg / kg, about 0.1 mg / kg, about 0.2 mg / kg, about 0.3 mg / kg, about 0.4 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.7 mg / kg, about 0 mg / kg, or about 0 mg / kg. 0.8 mg / kg, approximately 0.9 mg / kg, approximately 1 mg / kg, approximately 1.1 mg / kg, approximately 1.2 mg / kg, approximately 1.3 mg / kg, approximately 1.4 mg / kg, approximately 1.5 mg / kg, approximately 1.6 mg / kg, approximately 1.7 mg / kg, approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2 mg / kg, approximately 2.1 mg / kg, approximately 2.2 mg / kg, approximately 2.3 mg / kg, approximately 2.4 mg / kg, approximately 2.5 mg / kg, approximately 2.6 mg / kg, approximately 2.7 mg / kg, approximately 2.8 mg / kg, approximately 2. 9 mg / kg, approximately 3 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approximately 3.3 mg / kg, approximately 3.4 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.7 mg / kg, approximately 3.8 mg / kg, approximately 3.9 mg / kg, approximately 4 mg / kg, approximately 4.1 mg / kg, approximately 4.2 mg / kg, approximately 4.3 mg / kg, approximately 4.4 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.7 mg / kg, approximately 4.8 mg / kg, approximately 4.9 mg / kg, approximately 5 mg / kg, approximately 5.1mg / kg, approximately 5.2mg / kg, approximately 5.3mg / kg, approximately 5.4mg / kg, approximately 5.5mg / kg, approximately 5.6mg / kg, approximately 5.7mg / kg, approximately 5.8mg / kg, approximately 5.9mg / kg, approximately 6mg / kg, approximately 7mg / kg, approximately 8mg / kg, approximately 9mg / kg, approximately 10mg / kg, approximately 15mg / kg, approximately 20mg / kg, approximately 25mg / kg, approximately 30mg / kg, approximately 35mg / kg, approximately 40mg / kg, approximately 45mg / kg, or approximately 50mg / kg.

[0126] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is 0.01 mg / kg, 0.02 mg / kg, 0.03 mg / kg, 0.04 mg / kg, 0.05 mg / kg, 0.06 mg / kg, 0.07 mg / kg, 0.08 mg / kg, 0.09 mg / kg, 0.1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0. 8mg / kg, 0.9mg / kg, 1mg / kg, 1.1mg / kg, 1.2mg / kg, 1.3mg / kg, 1.4mg / kg, 1.5mg / kg, 1.6mg / kg, 1.7mg / kg, 1.8mg / kg, 1.9mg / kg, 2mg / kg, 2.1mg / kg, 2.2mg / kg, 2.3mg / kg, 2.4mg / kg, 2.5mg / kg, 2.6mg / kg, 2.7mg / kg, 2.8mg / kg, 2.9mg / k g, 3mg / kg, 3.1mg / kg, 3.2mg / kg, 3.3mg / kg, 3.4mg / kg, 3.5mg / kg, 3.6mg / kg, 3.7mg / kg, 3.8mg / kg, 3.9mg / kg, 4mg / k g, 4.1mg / kg, 4.2mg / kg, 4.3mg / kg, 4.4mg / kg, 4.5mg / kg, 4.6mg / kg, 4.7mg / kg, 4.8mg / kg, 4.9mg / kg, 5mg / kg, 5.1mg / kg, 5.2mg / kg, 5.3mg / kg, 5.4mg / kg, 5.5mg / kg, 5.6mg / kg, 5.7mg / kg, 5.8mg / kg, 5.9mg / kg, 6mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 15mg / kg, 20mg / kg, 25mg / kg, 30mg / kg, 35mg / kg, 40mg / kg, 45mg / kg or 50mg / kg, or any range between these values.

[0127] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 0.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg, 2.4 mg / kg, 3 mg / kg, 3.5 mg / kg, 4.2 mg / kg, or 5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3 mg / kg, 3.5 mg / kg, 4.2 mg / kg, or 5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 0.8 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 1.8 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 2.4 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3.5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 4.2 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 1.8 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 2.4 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 3 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 3.5 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 4.2 mg / kg. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 5 mg / kg.

[0128] In some embodiments, the anti-DLL3 antibody-drug conjugate is administered once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks. In some embodiments, the anti-DLL3 antibody-drug conjugate is administered once every two weeks or once every three weeks. In some embodiments, the anti-DLL3 antibody-drug conjugate is administered once every two weeks. In some embodiments, the anti-DLL3 antibody-drug conjugate is administered once every three weeks.

[0129] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 0.8 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 1.8 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 2.4 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3.5 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 4.2 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 5 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 1.8 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 2.4 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 3 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 3.5 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 4.2 mg / kg, administered once every 3 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is 5 mg / kg, administered once every 3 weeks.

[0130] In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 0.8 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is about 1.8 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 2.4 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 3.5 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 4.2 mg / kg, administered once every 2 weeks. In some embodiments, the dosage of the anti-DLL3 antibody-drug conjugate is about 5 mg / kg, administered once every 2 weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 1.8 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 2.4 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 3 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 3.5 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 4.2 mg / kg, administered once every two weeks. In some embodiments, the dose of the anti-DLL3 antibody-drug conjugate is 5 mg / kg, administered once every two weeks.

[0131] In some embodiments, the dosing period of the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments may also be referred to as the treatment period, and may be 1 week (or 7 days), 2 weeks (or 14 days), 3 weeks (or 21 days), 4 weeks (or 28 days), 5 weeks (or 35 days), 6 weeks (or 42 days), 7 weeks (or 49 days), 8 weeks (or 56 days), 9 weeks (or 63 days), or 10 weeks (or 70 days). In some embodiments, the dosing period of the anti-DLL3 antibody-drug conjugate is 2 weeks (or 14 days). In some embodiments, the dosing period of the anti-DLL3 antibody-drug conjugate is 3 weeks (or 21 days).

[0132] In some embodiments, the anti-DLL3 antibody-drug conjugate is administered orally, parenterally, or transdermally; the parenterial administration includes, but is not limited to, intravenous injection, intravenous infusion, subcutaneous injection, or intramuscular injection. In some embodiments, the anti-DLL3 antibody-drug conjugate is administered via intravenous injection. In some embodiments, the anti-DLL3 antibody-drug conjugate is administered via intravenous infusion.

[0133] In some embodiments, the anti-DLL3 antibody-drug conjugate as described in any of the preceding embodiments is configured in an injectable form. Exemplarily, the injectable form of the anti-DLL3 antibody-drug conjugate is an injection solution or lyophilized powder for injection, comprising the anti-DLL3 antibody-drug conjugate and one or more pharmaceutically acceptable excipients. In some embodiments, the anti-DLL3 antibody-drug conjugate is formulated as any composition selected from CN202411179425.3.

[0134] In some implementations, such as the anti-DLL3 antibody-drug conjugate described in any of the preceding embodiments, certain clinical benefits have been demonstrated in the treatment of neuroendocrine tumors, bringing patients clinical benefits superior to existing treatments, and controlling or alleviating the disease.

[0135] In this disclosure, the standard systemic anti-tumor treatment regimens are well known to those skilled in the art, such as those disclosed in regulatory-approved treatment guidelines. These include, but are not limited to, detailed and up-to-date information on standard treatment regimens for various cancers provided in the NCCN and CSCO guidelines. Attached Figure Description

[0136] Figure 1: CT scan of the subject's lungs. Detailed Implementation

[0137] the term

[0138] 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.

[0139] The singular forms “a,” “an,” and “the” used in this disclosure include plural references unless the context clearly indicates otherwise.

[0140] Unless the context clearly requires otherwise, the words “comprising,” “having,” “including,” etc., in the patent specification and claims should be understood as “including but not limited to,” rather than as exclusive or exhaustive.

[0141] "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.

[0142] 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.

[0143] Those skilled in the art will understand that when used as a reference range, cutoff value, or specific value, "about" can mean within one or more standard deviations. Alternatively, "about" can mean a range with a difference of up to 20% (i.e., ±20%). Since many of the values ​​used herein were determined experimentally, those skilled in the art will understand that such determinations can vary between different experiments and are generally true across experiments. Due to this inherent variability, the values ​​used herein should not be unduly restricted. Therefore, the term "about" is used to cover variations of ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% or less from a specified value.

[0144] Although this disclosure provides content ranges or content values, those skilled in the art will understand that the content ranges or content values ​​cover the acceptable range of error for the specific values ​​measured.

[0145] The three-letter and single-letter codes for amino acids used in this disclosure are as described in J. Biol. Chem., 243, p3558 (1968).

[0146] The term "amino acid" refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimics that function in a manner similar to naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those that are subsequently modified, such as hydroxyproline, γ-carboxyglutamic acid, and O-phosphoserine. Amino acid analogs are compounds that have the same basic chemical structure as naturally occurring amino acids (i.e., the α-carbon bound to hydrogen, carboxyl, amino, and R groups), such as homoserine, ortholeucine, methionine sulfoxide, and methionine methylsulfonium. These analogs have modified R groups (e.g., ortholeucine) or modified peptide backbones but retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimics are chemical compounds that have a structure different from the general chemical structure of amino acids but function in a manner similar to naturally occurring amino acids.

[0147] The term "antibody" is used in the broadest sense and encompasses a wide variety of antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, antibody fragments, and antigen-binding fragments (or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. "Natural antibody" refers to a naturally occurring immunoglobulin molecule. For example, a natural IgG antibody is a heterotetraglycoprotein of approximately 150,000 Daltons, composed of two identical light chains and two identical heavy chains bound by disulfide bonds. From the N to C terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable region, followed by a heavy chain constant region. The IgG heavy chain constant region (CH) typically contains three constant domains (CH1, CH2, and CH3); similarly, from the N to C terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light domain (light chain constant region, CL).

[0148] The term "variable region" or "variable domain" refers to the domain in the antibody heavy or light chain involved in antibody-antigen binding. In this paper, the antibody heavy chain variable region (VH) and light chain variable region (VL) each contain four conserved frame regions (FRs) and three complementarity-determining regions (CDRs). The term "complementarity-determining region" or "CDR" refers to the region within the variable domain that primarily facilitates antigen binding; "frame" or "FR" refers to the variable domain residues other than the CDR residues. The VH contains three CDR regions: HCDR1, HCDR2, and HCDR3; the VL contains three CDR regions: LCDR1, LCDR2, and LCDR3. Each VH and VL consists of three CDRs and four FRs arranged in the following order from the amino terminus (also called the N-terminus) to the carboxyl terminus (also called the C-terminus): FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. A single VH or VL may be sufficient to confer antigen-binding specificity.

[0149] 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. The correspondence between various numbering systems is well known to those skilled in the art and is exemplified as shown in Table A below.

[0150] Table A. Relationships between CDR numbering systems

[0151] Unless otherwise stated, the variable regions and CDR sequences in this disclosure embodiment are subject to the "Kabat" numbering rule.

[0152] The term "monoclonal antibody" refers to a group of substantially homogeneous antibodies, meaning that the antibody molecules contained in this group have the same amino acid sequence, except for the possible small number of naturally occurring mutations. In contrast, polyclonal antibody formulations typically contain multiple different antibodies with different amino acid sequences in their variable structural domains, and they generally specifically target different epitopes. "Monoclonal" indicates the characteristic of an antibody obtained from a substantially homogeneous group of antibodies and should not be construed as requiring the antibody to be produced by any particular method. In some embodiments, the antibodies provided in this disclosure are monoclonal antibodies.

[0153] The antibodies disclosed herein may be derived from animals (such as antibodies from mice, birds, rabbits, camels, monkeys, etc.), chimeric antibodies, or humanized antibodies.

[0154] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a specific source or species, while the remaining portion of the heavy and / or light chain is derived from another different source or species.

[0155] The term "humanized" antibody refers to an antibody that retains the reactivity of a non-human antibody while exhibiting lower immunogenicity in humans. For example, this can be achieved by retaining the non-human CDR region and replacing the rest of the antibody with its human counterpart (i.e., the frame region portion of the constant region and the variable region).

[0156] The term "affinity" refers to the overall strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding ligand (e.g., an antigen). Unless otherwise specified, as used herein, binding "affinity" refers to internal binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of molecule X for its ligand Y can typically be represented by the dissociation constant (KD). Affinity can be measured using conventional methods known in the art.

[0157] The term "antigen" refers to a molecule or molecular moiety that can be bound by a selective binder of an antigen-binding protein (such as an antibody). An antigen may have one or more epitopes that can interact with different antigen-binding proteins (such as antibodies).

[0158] The term "epitope" refers to a region on an antigen that can specifically bind to an antibody or its antigen-binding fragment. Epitopes can be formed from consecutive amino acids (linear epitopes) or contain non-consecutive amino acids (conformal epitopes), for example, due to the folding of the antigen (i.e., tertiary folding of the antigen as a protein), which allows non-consecutive amino acids to be spatially close. The difference between conformational and linear epitopes is that antibody binding to a conformational epitope is lost in the presence of a denaturing solvent. An epitope contains at least 3, at least 4, at least 5, at least 6, at least 7, or 8-10 amino acids in a unique spatial conformation. Screening for antibodies that bind to a specific epitope (i.e., those that bind the same epitope) can be performed using methods routine in the art, such as, but not limited to, alanine scanning, Western blotting, peptide cleavage analysis, epitope excision, epitope extraction, chemical modification of the antigen, and cross-blocking.

[0159] The terms "capable of specific binding," "specific binding," or "binding" refer to the ability of an antibody to bind to a specific antigen or epitope with a higher affinity than other antigens or epitopes. Typically, antibodies bind at an affinity of approximately 1 × 10⁻⁶. -7 An equilibrium dissociation constant (KD) of M or less binds to an antigen or epitope. In some embodiments, the KD of antibody binding to an antigen is 10% or less (e.g., 1%) of the KD of the antibody binding to a nonspecific antigen (e.g., BSA, casein). KD can be measured using known methods, such as by FACS or surface plasmon resonance assays. However, antibodies that specifically bind to an antigen or an epitope within an antigen may be cross-reactive to other related antigens, for example, to corresponding antigens from other species (homologous), such as humans or monkeys, such as the cynomolgus (cyno), the chimpanzee (chimp), or the common marmoset (marmoset).

[0160] Antibody drug conjugates (ADCs) are conjugates obtained by linking an antibody (or its antigen-binding fragment) directly or through a linker to a drug.

[0161] A "drug" (abbreviated as D) is any substance that has biological or detectable activity (e.g., therapeutic agents, detectable markers, binders, etc.) and its prodrugs, which are metabolized in the body to become active agents. Examples of therapeutic agents include cytotoxic agents, chemotherapeutic agents, cell growth inhibitors, and immunomodulators. Chemotherapeutic agents are chemical compounds that can be used to treat cancer. Representative therapeutic agents include cytotoxins, cytotoxic agents, and cell growth inhibitors.

[0162] Cytotoxicity refers to the loss, elimination, and / or killing of target cells. Cytotoxic agents are drugs that have cytotoxic and / or cell growth-inhibiting effects on cells. Cell growth inhibition refers to the inhibition of cell proliferation. Cell growth inhibitors are drugs that have a cell growth-inhibiting effect on cells, thereby inhibiting the growth and / or expansion of specific subgroups of cells.

[0163] Additional representative therapeutic agents include radioisotopes, chemotherapeutic agents, immunomodulators, anti-angiogenic agents, antiproliferative agents, apoptosis-promoting agents, and cell-lysing enzymes (e.g., RNase). These drug descriptive terms are not mutually exclusive, and therefore, one or more of the aforementioned terms may be used to describe a therapeutic agent. For example, the selected radioisotope may also be a cytotoxic agent. Therapeutic agents can be prepared as pharmaceutically acceptable salts, acids, or derivatives of any of the above. Generally, conjugates containing a radioisotope as a drug are called radioimmunoconjugates, and those containing a chemotherapeutic agent as a drug are called chemoimmunoconjugates.

[0164] Examples of cytotoxic agents include, but are not limited to, anthracycline, orrisstatin, CC-1065, dolastatin, docalmicin, enediyne, geldanamycin, maytansine, puromycin, taxane, vinca alkaloids, SN-38, tubulolysin, hemiasterlin, eribulin, trabectedin, lurbinectedin, and their stereoisomers, isosteres, analogues, or derivatives. Chemotherapy agents, phytotoxicants, other bioactive proteins, enzymes (i.e., ADEPT), radioactive isotopes, and photosensitizers (i.e., for photodynamic therapy) may also be used.

[0165] The terms "connector unit" and "connector" refer to a chemical structural fragment or bond that is linked to an antibody at one end and a drug at the other. Connectors can also be attached to other connectors before being linked to an antibody or drug. Connector attachment to antibodies can be accomplished in various ways, such as via surface lysine residues, reductive coupling to oxidized carbohydrates, release of cysteine ​​residues via reducing interchain disulfide bonds, modification of reactive cysteine ​​residues at specific sites, and tags containing acyl donor glutamine, or modification of peptides to make them reactive endogenous glutamine in the presence of transglutaminase and amines. Various ADC linker systems are known in the art, including hydrazone-, disulfide-, and peptide-based links.

[0166] The connector may comprise one or more connector elements. Exemplary connector elements include 6-maleiminohexanoyl (“MC”), maleiminopropionyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe”), p-aminobenzyloxycarbonyl (“PAB”), N-succinimino-4-(2-pyridylthio)valerate (“SPP”), N-succinimino-4-(N-maleiminomethyl)cyclohexane-1-carboxylate (“SMCC”, also referred to herein as “MCC”), and N-succinimino-(4-iodo-acetyl)aminobenzoate (“SIAB”).

[0167] The linker can be selected from the following elements or combinations thereof: extensions, spacers, and amino acid units. Linkers can be synthesized by methods known in the art, such as those described in US20050238649A1. The linker can be a “cleavable linker” that facilitates drug release into cells. For example, acid-labile linkers (e.g., hydrazones), protease-sensitive linkers (e.g., peptidase-sensitive linkers), light-labile linkers, dimethyl linkers, or disulfide-containing linkers can be used.

[0168] “LD” is the connector-drug section formed when the drug (D) is connected to the connector (L).

[0169] "Drug loading," also known as drug-to-antibody ratio (DAR), refers to the average number of drugs conjugated to each antibody in an ADC. It can range from about 1 to about 10 drugs per antibody, and in some embodiments, from about 1 to about 8 drugs per antibody, or selected from the ranges of 2-8, 2-7, 2-6, 2-5, 2-4, 1-3, 3-4, 3-5, 5-6, 5-7, 5-8, and 6-8. The general formula of the ADC disclosed herein includes a set of antibody-drug conjugates within the aforementioned range. In embodiments disclosed herein, drug loading may be expressed as n, which can be a decimal or an integer. Drug loading can be determined using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays, HIC, and RP-HPLC.

[0170] "Pharmaceutical composition" means a mixture containing one or more antibody-drug conjugates or their physiologically / pharmacologically acceptable salts or prodrugs described herein, 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 the exertion of its biological activity.

[0171] "Pharmaceutically acceptable carriers" or "pharmaceutically acceptable excipients" include any material that, when combined with an active ingredient, allows the ingredient to retain its biological activity and does not react with the subject's immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solutions, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods.

[0172] "Administration," "giving," and "treatment," when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, 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. "Administration," "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. "Administration," "giving," and "treatment" also mean, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo, such as cells. "Treatment," when applied to humans, veterinary, or research subjects, refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0173] "Treatment" means administering an oral or topical therapeutic agent, such as a pharmaceutical composition comprising any of the substances 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, in order to induce the regression of such symptoms or inhibit their progression to any clinically measurable degree. 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 test method commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments disclosed herein (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.

[0174] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate a diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects disclosed herein may be animal or human subjects.

[0175] Details of one or more embodiments of this disclosure are set forth in the foregoing description. While any methods and materials similar to or the same as those described herein may be used to implement or test this disclosure, preferred methods and materials are described below. Other features, objects, and advantages of this disclosure will be apparent from the description and claims. In the description and claims, the singular form includes plural references unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have their general meaning as understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in the description are incorporated herein by reference. The following embodiments are presented to illustrate preferred embodiments of this disclosure more fully. These embodiments should not be construed in any way as limiting the scope of this disclosure, which is defined by the claims.

[0176] Non-restrictive implementation scheme

[0177] Implementation Plan 1. Use of anti-DLL3 antibody-drug conjugates in the preparation of drugs for treating cancer.

[0178] Implementation Scheme 2. The use according to Implementation Scheme 1, wherein the cancer is a neuroendocrine neoplasm (NEN).

[0179] Implementation Scheme 3. Use of anti-DLL3 antibody-drug conjugates in the preparation of medicaments for the treatment of neuroendocrine neoplasms (NEN).

[0180] Implementation Scheme 4. A method for treating cancer, comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need.

[0181] Implementation Scheme 5. The method according to Implementation Scheme 4, wherein the cancer is a neuroendocrine neoplasm (NEN).

[0182] Implementation Scheme 6. A method for treating neuroendocrine tumors, comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need.

[0183] Implementation Scheme 7. The use or method according to any one of Implementation Schemes 1 to 6, wherein the anti-DLL3 antibody drug conjugate comprises the structure shown below:

[0184] in:

[0185] n is 1 to 10; or 3 to 9; or 5 to 9; or about 8;

[0186] Pc is an anti-DLL3 antibody.

[0187] Implementation Scheme 8. The use or method according to any one of Implementation Schemes 1 to 7, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain variable region comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; and / or

[0188] The anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8; and / or

[0189] The anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0190] Implementation Scheme 9. A method for using an anti-DLL3 antibody-drug conjugate to treat or inhibit the growth of neuroendocrine tumors, the method comprising administering a therapeutically effective amount of the anti-DLL3 antibody-drug conjugate to a subject in need, the conjugate comprising the structure shown below:

[0191] in:

[0192] n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and

[0193] Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

[0194] Implementation Scheme 10. The anti-DLL3 antibody-drug conjugate used according to Implementation Scheme 9, wherein the cancer is a neuroendocrine tumor.

[0195] Implementation Scheme 11. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 10, wherein the subject is further selected according to one or more of the following criteria:

[0196] (i) Age 18 to 75 years old, gender not limited;

[0197] (ii) Histologically or cytologically confirmed inoperable recurrent or metastatic solid tumors that have progressed or recurred after prior standard treatment, as shown below:

[0198] (a) Small-cell lung cancer (SCLC): Prior to receiving at least one standard treatment

[0199] Progression or relapse, and previous systemic chemotherapy not exceeding two lines;

[0200] (b) Other DLL3-positive neuroendocrine carcinomas: failure of prior standard treatment, or treatment received at least one

[0201] Progression or relapse after platinum-based treatment regimens, and prior systemic chemotherapy not exceeding two lines;

[0202] (iii) An ECOG score of 0 or 1;

[0203] (iv) Expected survival of more than 3 months; and

[0204] (v) Has sufficient bone marrow and organ function.

[0205] Implementation Scheme 12. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 11, wherein the subject has failed prior treatment with a PD-L1 inhibitor in combination with platinum-based chemotherapy for neuroendocrine tumors.

[0206] Implementation Scheme 13. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 12, wherein the tumor of the subject is inoperable.

[0207] Implementation Scheme 14. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 13, wherein the subject has received no more than two lines of prior systemic chemotherapy.

[0208] Implementation Scheme 15. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is about 0.01 mg / kg to 50 mg / kg, about 0.8 mg / kg to 5 mg / kg, about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg or about 5 mg / kg.

[0209] Implementation Scheme 16. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is 0.01 mg / kg to 50 mg / kg, 0.8 mg / kg to 5 mg / kg, 0.8 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3 mg / kg, 3.5 mg / kg, 4.2 mg / kg or 5 mg / kg.

[0210] Implementation Scheme 17. A method for treating or inhibiting the growth of neuroendocrine tumors, the method comprising:

[0211] (1) Select subjects with inoperable tumors; and

[0212] (2) The dosage of the anti-DLL3 antibody-drug conjugate administered to the subject was approximately 2.4 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4.2 mg / kg, or approximately 5 mg / kg;

[0213] The anti-DLL3 antibody-drug conjugate described herein comprises the structure shown below:

[0214] in:

[0215] n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and

[0216] Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

[0217] Implementation Scheme 18. A method for treating or inhibiting the growth of neuroendocrine tumors, the method comprising:

[0218] (1) Subjects selected had failed prior PD-L1 inhibitor therapy for neuroendocrine tumors; and

[0219] (2) The dosage of the anti-DLL3 antibody-drug conjugate administered to the subject was approximately 1.8 mg / kg, approximately 2.4 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4.2 mg / kg, or approximately 5 mg / kg;

[0220] The anti-DLL3 antibody-drug conjugate described herein comprises the structure shown below:

[0221] in:

[0222] n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and

[0223] Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

[0224] Implementation Scheme 19. A method for treating or inhibiting the growth of neuroendocrine tumors, the method comprising:

[0225] (1) Subjects selected for prior PD-L1 inhibitor combined with platinum-based chemotherapy for neuroendocrine tumors had failed; and

[0226] (2) The dosage of the anti-DLL3 antibody-drug conjugate administered to the subject was approximately 0.8 mg / kg, approximately 1.8 mg / kg, approximately 2.4 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, approximately 4.2 mg / kg, or approximately 5 mg / kg;

[0227] The anti-DLL3 antibody-drug conjugate described herein comprises the structure shown below:

[0228] in:

[0229] n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and

[0230] Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

[0231] Implementation Scheme 20. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 19, wherein the anti-DLL3 antibody-drug conjugate is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.

[0232] Implementation Scheme 21. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosing frequency is once a week.

[0233] Implementation Scheme 22. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 20, wherein the dosing frequency is once every 2 weeks.

[0234] Implementation Scheme 23. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 20, wherein the dosing frequency is once every 3 weeks.

[0235] Implementation Scheme 24. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the anti-DLL3 antibody-drug conjugate is administered intravenously, subcutaneously or intraperitoneally.

[0236] Implementation Scheme 25. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the anti-DLL3 antibody-drug conjugate is administered intravenously.

[0237] Implementation Scheme 26. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 24, wherein the anti-DLL3 antibody-drug conjugate is administered subcutaneously.

[0238] Implementation Scheme 27. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 24, wherein the anti-DLL3 antibody-drug conjugate is administered intraperitoneally.

[0239] Implementation Scheme 28. According to any of the preceding uses, the method or the anti-DLL3 antibody-drug conjugate used therein, after one or more treatment cycles, the tumor volume of the subject is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, or 70%.

[0240] Implementation Scheme 29. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 27, wherein the tumor burden of the subject is reduced by at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% after one or more treatment cycles.

[0241] Implementation Scheme 30. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein administration of the anti-DLL3 antibody-drug conjugate produces an effect selected from: delayed tumor growth, reduced tumor cell number, tumor regression, prolonged survival, partial remission, complete remission, and combinations thereof.

[0242] Implementation Scheme 31. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is from about 0.01 mg / kg to 50 mg / kg.

[0243] Implementation Scheme 32. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is from 0.01 mg / kg to 50 mg / kg.

[0244] Implementation Scheme 33. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is from about 0.8 mg / kg to 5 mg / kg.

[0245] Implementation Scheme 34. The method or the anti-DLL3 antibody-drug conjugate used according to any of the preceding uses, wherein the dosage of the anti-DLL3 antibody-drug conjugate is from 0.8 mg / kg to 5 mg / kg.

[0246] Implementation Scheme 35. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 33, wherein the dosage of the anti-DLL3 antibody drug conjugate is about 0.8 mg / kg.

[0247] Implementation Scheme 36. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 35, wherein the dosage of the anti-DLL3 antibody-drug conjugate is 0.8 mg / kg.

[0248] Implementation Scheme 37. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 34, wherein the dosage of the anti-DLL3 antibody-drug conjugate is about 1.8 mg / kg.

[0249] Implementation Scheme 38. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34 and 37, wherein the dosage of the anti-DLL3 antibody drug conjugate is 1.8 mg / kg.

[0250] Implementation Scheme 39. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 32, wherein the dosage of the anti-DLL3 antibody drug conjugate is about 2.4 mg / kg.

[0251] Implementation Scheme 40. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34 and 39, wherein the dosage of the anti-DLL3 antibody drug conjugate is 2.4 mg / kg.

[0252] Implementation Scheme 41. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 34, wherein the dosage of the anti-DLL3 antibody-drug conjugate is about 3 mg / kg.

[0253] Implementation Scheme 42. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34 and 41, wherein the dosage of the anti-DLL3 antibody drug conjugate is 3 mg / kg.

[0254] Implementation Scheme 43. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34, wherein the dosage of the anti-DLL3 antibody drug conjugate is about 3.5 mg / kg.

[0255] Implementation Scheme 44. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34 and 43, wherein the dosage of the anti-DLL3 antibody drug conjugate is 3.5 mg / kg.

[0256] Implementation Scheme 45. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34, wherein the dosage of the anti-DLL3 antibody drug conjugate is about 4.2 mg / kg.

[0257] Implementation Scheme 46. The method or the anti-DLL3 antibody drug conjugate used according to any one of Implementation Schemes 1 to 34 and 45, wherein the dosage of the anti-DLL3 antibody drug conjugate is 4.2 mg / kg.

[0258] Implementation Scheme 47. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 33, wherein the dosage of the anti-DLL3 antibody-drug conjugate is about 5 mg / kg.

[0259] Implementation Scheme 48. The method or the anti-DLL3 antibody-drug conjugate used according to any one of Implementation Schemes 1 to 33 and 47, wherein the dosage of the anti-DLL3 antibody-drug conjugate is 5 mg / kg.

[0260] Implementation Scheme 49. The use, method, or application of the anti-DLL3 antibody as described in any of the preceding embodiments, wherein the neuroendocrine tumor is a neuroendocrine carcinoma (NEC).

[0261] Implementation Scheme 50. The use, method, or application of the anti-DLL3 antibody according to Implementation Scheme 49, wherein the neuroendocrine carcinoma is a recurrent and / or metastatic neuroendocrine carcinoma.

[0262] Implementation Scheme 51. The use, method, or application of the anti-DLL3 antibody according to Implementation Scheme 50, wherein the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after prior standard treatment.

[0263] Implementation Scheme 52. The use, method, or application of the anti-DLL3 antibody according to Implementation Scheme 50 or 51, wherein the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy.

[0264] Implementation Scheme 53. The use, method, or application of the anti-DLL3 antibody according to any one of Implementation Schemes 50 to 52, wherein the recurrent and / or metastatic neuroendocrine carcinoma is small cell lung cancer, large cell pulmonary neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy.

[0265] Implementation Scheme 54. Use, method or application of the anti-DLL3 antibody according to any one of Implementation Schemes 1 to 53, wherein the neuroendocrine tumor is small-cell lung cancer (SCLC) or a neuroendocrine carcinoma other than small-cell lung cancer that is positive for DLL3 expression.

[0266] Implementation Scheme 55. Use, method or application of the anti-DLL3 antibody according to any one of Implementation Schemes 50 to 53, wherein the neuroendocrine tumor is a recurrent and / or metastatic small cell lung cancer, or a recurrent and / or metastatic neuroendocrine carcinoma other than small cell lung cancer that is positive for DLL3 expression.

[0267] Additional non-restrictive implementation schemes

[0268] Implementation Plan 1. Use of anti-DLL3 antibody drug conjugate in the preparation of a medicament for the treatment of recurrent and / or metastatic neuroendocrine carcinoma (NEC);

[0269] The anti-DLL3 antibody-drug conjugate comprises the structure shown below:

[0270] in:

[0271] n is 1 to 10; preferably 3 to 9; more preferably 5 to 9; most preferably about 8;

[0272] Pc is an anti-DLL3 antibody.

[0273] Implementation Scheme 2. According to the use described in Implementation Scheme 1, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0274] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0275] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0276] Implementation Scheme 3. According to the use described in Implementation Scheme 1 or 2, the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg; even more preferably about 2.4 mg / kg; and / or

[0277] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0278] Implementation Scheme 4. The use according to any one of Implementation Schemes 1 to 3, wherein the dosage of the anti-DLL3 antibody drug conjugate is about 2.4 mg / kg; and the dosing frequency is once every 3 weeks.

[0279] Implementation Scheme 5. The use according to any one of Implementation Schemes 1 to 4, wherein the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after prior standard treatment;

[0280] Preferably, the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after previous chemotherapy and / or immunotherapy;

[0281] Most preferably, the recurrent and / or metastatic neuroendocrine carcinoma is small cell lung cancer, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy.

[0282] Implementation Scheme 6. A method for treating recurrent and / or metastatic neuroendocrine carcinoma (NEC), comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need;

[0283] The anti-DLL3 antibody-drug conjugate comprises the structure shown below:

[0284] in:

[0285] n is 1 to 10; preferably 3 to 9; more preferably 5 to 9; most preferably about 8;

[0286] Pc is an anti-DLL3 antibody.

[0287] Implementation Scheme 7. The method according to Implementation Scheme 6, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0288] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0289] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0290] Implementation Scheme 8. The method according to Implementation Scheme 6 or 7, wherein the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg or about 5 mg / kg; even more preferably about 2.4 mg / kg; and / or

[0291] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0292] Implementation Scheme 9. The method according to any one of Implementation Schemes 6 to 8, wherein the dose of the anti-DLL3 antibody drug conjugate is about 2.4 mg / kg; and the dosing frequency is once every 3 weeks.

[0293] Implementation Scheme 10. The method according to any one of Implementation Schemes 6 to 9, wherein the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after prior standard treatment;

[0294] Preferably, the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after previous chemotherapy and / or immunotherapy;

[0295] Most preferably, the recurrent and / or metastatic neuroendocrine carcinoma is small cell lung cancer, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy.

[0296] Additional non-restrictive implementation schemes

[0297] Implementation Plan 1. Use of anti-DLL3 antibody-drug conjugates in the preparation of drugs for the treatment of neuroendocrine neoplasm (NEN).

[0298] Implementation Scheme 2. According to the use described in Implementation Scheme 1, the anti-DLL3 antibody drug conjugate comprises the structure shown below:

[0299] in:

[0300] n is 1 to 10; preferably 3 to 9; more preferably 5 to 9; most preferably about 8;

[0301] Pc is an anti-DLL3 antibody.

[0302] Implementation Scheme 3. According to the use described in Implementation Scheme 1 or 2, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain variable region comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 3, respectively;

[0303] 4. LCDR1, LCDR2 and LCDR3 shown in SEQ ID NO: 5 and SEQ ID NO: 6;

[0304] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0305] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0306] Implementation Scheme 4. The use according to any one of Implementation Schemes 1 to 3, wherein the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg; and / or

[0307] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0308] Implementation Scheme 5. The use according to any one of Implementation Schemes 1 to 4, wherein the neuroendocrine tumor is a neuroendocrine carcinoma (NEC);

[0309] Preferably, the neuroendocrine tumor is small-cell lung cancer (SCLC), or a neuroendocrine carcinoma other than small-cell lung cancer that expresses DLL3 positively;

[0310] More preferably, the neuroendocrine tumor is a recurrent and / or metastatic small cell lung cancer, or a recurrent and / or metastatic neuroendocrine carcinoma other than small cell lung cancer that is positive for DLL3 expression.

[0311] Implementation Scheme 6. A method for treating neuroendocrine tumors, comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need.

[0312] Implementation Scheme 7. The method according to Implementation Scheme 6, wherein the anti-DLL3 antibody drug conjugate comprises the structure shown below:

[0313] in:

[0314] n is 1 to 10; preferably 3 to 9; more preferably 5 to 9; most preferably about 8;

[0315] Pc is an anti-DLL3 antibody.

[0316] Implementation Scheme 8. The method according to Implementation Scheme 6 or 7, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0317] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0318] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0319] Implementation Scheme 9. The method according to any one of Implementation Schemes 6 to 8, wherein the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg; and / or

[0320] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0321] Implementation Scheme 10. The method according to any one of Implementation Schemes 6 to 9, wherein the neuroendocrine tumor is a neuroendocrine carcinoma (NEC);

[0322] Preferably, the neuroendocrine tumor is small-cell lung cancer (SCLC), or a neuroendocrine carcinoma other than small-cell lung cancer that expresses DLL3 positively;

[0323] More preferably, the neuroendocrine tumor is a recurrent and / or metastatic small cell lung cancer, or a recurrent and / or metastatic neuroendocrine carcinoma other than small cell lung cancer that is positive for DLL3 expression.

[0324] Additional non-restrictive implementation schemes

[0325] Implementation Plan 1. Use of anti-DLL3 antibody-drug conjugates in the preparation of drugs for the treatment of neuroendocrine neoplasm (NEN).

[0326] Implementation Scheme 2. According to the use described in Implementation Scheme 1, the anti-DLL3 antibody drug conjugate comprises the structure shown below:

[0327] in:

[0328] n is 1 to 10; preferably 3 to 8; more preferably 6 to 8; most preferably about 8;

[0329] Pc is an anti-DLL3 antibody.

[0330] Implementation Scheme 3. The use according to Implementation Scheme 1 or 2, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0331] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0332] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0333] Implementation Scheme 4. The use according to any one of Implementation Schemes 1 to 3, wherein the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 2.4 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg or about 5 mg / kg; and / or

[0334] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0335] Implementation Scheme 5. The use according to any one of Implementation Schemes 1 to 4, wherein the neuroendocrine tumor is a poorly differentiated neuroendocrine carcinoma (NEC);

[0336] Preferably, the neuroendocrine tumor is small-cell lung cancer (SCLC).

[0337] Implementation Scheme 6. A method for treating neuroendocrine tumors, comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need.

[0338] Implementation Scheme 7. The method according to Implementation Scheme 6, wherein the anti-DLL3 antibody drug conjugate comprises the structure shown below:

[0339] in:

[0340] n is 1 to 10; preferably 3 to 8; more preferably 6 to 8; most preferably about 8;

[0341] Pc is an anti-DLL3 antibody.

[0342] Implementation Scheme 8. The method according to Implementation Scheme 6 or 7, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively;

[0343] Preferably, the anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8 or the sequence shown in SEQ ID NO: 8.

[0344] More preferably, the anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 12.

[0345] Implementation Scheme 9. The method according to any one of Implementation Schemes 6 to 8, wherein the dosage of the anti-DLL3 antibody drug conjugate is from 0.01 mg / kg to 50 mg / kg; preferably from 0.8 mg / kg to 5 mg / kg; more preferably about 0.8 mg / kg, about 2.4 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg or about 5 mg / kg; and / or

[0346] The administration frequency of the anti-DLL3 antibody-drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks; preferably once every 2 weeks or once every 3 weeks; more preferably once every 3 weeks.

[0347] Implementation Scheme 10. The method according to any one of Implementation Schemes 6 to 9, wherein the neuroendocrine tumor is a poorly differentiated neuroendocrine carcinoma (NEC);

[0348] Preferably, the neuroendocrine tumor is small-cell lung cancer (SCLC).

[0349] Example

[0350] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the invention.

[0351] Experimental methods not specifically described in the examples or test cases disclosed herein are generally performed under standard conditions or as recommended by the raw material or product manufacturer. Reagents not specifically named are commercially available, standard reagents. Example 1: A multicenter, open-label phase I clinical study of the safety, tolerability, pharmacokinetics, and efficacy of an anti-DLL3 antibody-drug conjugate in patients with advanced malignant solid tumors.

[0352] 1. Drug Information

[0353] The preparation of the anti-DLL3 antibody-drug conjugate can be referenced in WO2024179470A1 (incorporated herein by reference in its entirety), and its structure is as follows:

[0354] n is approximately 8;

[0355] The heavy chain amino acid sequence of the anti-DLL3 antibody Hu100 is shown in SEQ ID NO: 11, and the light chain amino acid sequence is shown in SEQ ID NO: 12.

[0356] Dosage form: Injectable (injection solution).

[0357] Specifications: 5 mL: 0.1 g / bottle.

[0358] Route of administration: Intravenous infusion.

[0359] 2. Study population

[0360] 2.1 Selection Criteria

[0361] Participants must meet all of the following criteria to be eligible for this study:

[0362] 1) Voluntarily participate in this clinical study, understand the study procedures, and be able to sign an informed consent form in writing.

[0363] 2) Age 18 to 75 years old, gender not limited.

[0364] 3) Patients with histologically or cytologically confirmed inoperable recurrent or metastatic solid tumors who have progressed or relapsed after previous standard treatment, specifically as follows:

[0365] i. Small-cell lung cancer (SCLC): Patients must have received at least one standard treatment prior to diagnosis, including platinum-based and PD-1 / PD-L1 inhibitor therapy (excluding cases where the patient refused or the investigator determined that the patient was unsuitable for immunotherapy).

[0366] If the disease progresses or relapses, the patient has received no more than two lines of previous systemic chemotherapy.

[0367] ii. Other DLL3-positive neuroendocrine carcinomas: failure of previous standard treatment, or progression or recurrence after receiving at least one platinum-based treatment regimen, and prior systemic chemotherapy not exceeding two lines.

[0368] 4) ECOG score is 0 or 1.

[0369] 5) Expected survival period of more than 3 months.

[0370] 6) Has sufficient bone marrow and organ function.

[0371] 7) Male subjects whose partners are women of childbearing age and female subjects of childbearing age must use effective contraception from the time they sign the informed consent form until 6 months after the last dose of the investigational drug.

[0372] 3. Research Design

[0373] 3.1 Dosage escalation phase

[0374] This phase assesses the tolerability, safety, PK characteristics, and immunogenicity of the anti-DLL3 antibody-drug conjugate to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD).

[0375] The anti-DLL3 antibody-drug conjugate was administered in a sequentially increasing dose from low to high, with an initial dose of 0.8 mg / kg, administered intravenously every 3 weeks (Q3W), for a 21-day treatment cycle.

[0376] Accelerated Titration Phase: Considering the possibility that the starting dose of 0.8 mg / kg is too low and may result in no therapeutic benefit for the subjects, only one subject will be enrolled initially. If no DLT occurs during the DLT observation period and no grade 2 or higher study drug-related adverse events occur, no new subjects will be enrolled at this dose level, and the study will immediately proceed to the BOIN design phase, with 2.4 mg / kg set as the starting dose. If an adverse event occurs, 0.8 mg / kg will be converted to the starting dose for the BOIN phase, and 2–5 more subjects will be enrolled to begin the dose escalation study.

[0377] BOIN Design Phase: Four dose groups were pre-designed (2.4 mg / kg, 3.5 mg / kg, 4.2 mg / kg, and 5 mg / kg). Subjects were enrolled starting with the initial trial dose, with 3-6 subjects per cohort and no more than 12 subjects per dose group. After the completion of the DLT observation period (i.e., the first cycle of study dosing) safety assessment in each cohort, the dose for the next cohort was determined according to the BOIN design dose escalation decision table, up to the maximum sample size for a single dose group (12 subjects) or the maximum total sample size (approximately 30 subjects) specified in the protocol, or the dose escalation was terminated early by the Safety Monitoring Committee (SMC).

[0378] If necessary, the SMC will jointly discuss and decide, based on the obtained safety, tolerability, PK, and preliminary efficacy data, whether it is necessary to increase the dose of other anti-DLL3 antibody drug conjugates (higher or intermediate doses), explore other dosing frequencies (such as Q2W), and conduct expansion phase dose groups and timing.

[0379] 3.2 Dosage expansion phase

[0380] The dose expansion phase aims to increase the sample size of each dose group to further observe the safety, tolerability, pharmacokinetic (PK) characteristics, immunogenicity, and efficacy of anti-DLL3 antibody-drug conjugates at specific doses. Based on the safety, tolerability, and PK data of different dose groups in the dose escalation phase, the SMC will discuss and select 2–4 anti-DLL3 antibody-drug conjugate dose groups for dose expansion. The expanded dose groups can be intermediate doses determined by the SMC (e.g., 1.8 mg / kg, 2.8 mg / kg, 3.0 mg / kg). The plan is to enroll approximately 12–35 subjects in each dose group (including subjects from the same dose group in the dose escalation phase). Dose expansion can begin once the selected dose groups are confirmed to be tolerable and safe in the dose escalation phase. Each dose group in the dose expansion phase will use the same administration method and study procedures as in the dose escalation phase or those selected by the SMC.

[0381] 3.3 Therapeutic Effect Expansion Stage

[0382] The dosage of anti-DLL3 antibody-drug conjugates in this phase will be determined by the SMC based on safety, pharmacokinetic (PK), and efficacy data from the dose escalation and dose expansion phases. One or more dose groups will be selected, and preliminary efficacy assessments will be conducted according to different tumor types, including but not limited to: (1) recurrent / metastatic small cell lung cancer; (2) other recurrent / metastatic neuroendocrine carcinomas with positive DLL3 expression. Based on preliminary data, other cohorts for efficacy expansion may be added or the efficacy expansion of the above cohorts may be terminated. Each cohort is planned to enroll 10–30 subjects. If preliminary data suggests that more patients need to be enrolled for certain tumor types or dose groups, the number of enrolled cases may be increased after discussion and decision by the SMC. The research steps and treatment regimens for efficacy expansion are similar to those in the dose escalation and dose expansion phases.

[0383] 4. Administration method

[0384] Anti-DLL3 antibody-drug conjugate: Intravenous infusion, pre-set doses: 0.8 mg / kg, 1.8 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.2 mg / kg and 5 mg / kg, administered once every 3 weeks (Q3W), with a cycle of 21 days; other dosages or frequencies may be explored in the study.

[0385] Treatment duration: Continue medication until the treatment ends as specified in the treatment plan.

[0386] 5. Evaluation Indicators

[0387] 5.1 Effectiveness Evaluation

[0388] Tumor assessment was performed using RECIST criteria version 1.1, and all subjects underwent baseline tumor imaging assessment during the screening period. Efficacy parameters are as follows:

[0389] 1) Objective response rate (ORR): The proportion of subjects who achieved a complete response (CR) or a partial response (PR) according to RECIST v1.1 criteria.

[0390] 2) Progression-free survival (PFS): According to RECIST v1.1 criteria, it is defined as the time from the start of the first dose of medication to the occurrence of objective tumor progression or all-cause death, whichever occurs first.

[0391] 3) Disease control rate (DCR): The proportion of subjects with a disease control rate (BOR) of CR, PR, or stable disease (SD) that has persisted for at least 6 weeks (±7 days) since the first dose, as assessed by RECIST v1.1 criteria.

[0392] 4) Duration of Response (DoR): Defined according to RECIST v1.1 criteria from the date of first recorded tumor response to the date of first recorded tumor progression or death from any cause, whichever comes first.

[0393] 5) Overall survival (OS): refers to the time from the start of the first dose of medication to death from any cause.

[0394] As of December 2024, there were 11 evaluable small cell lung cancer patients in the ≥2.4 mg / kg dose group (who had undergone at least one post-baseline tumor assessment according to RECIST 1.1), of whom 8 achieved partial response (PR), with an overall response rate (ORR) of approximately 73%.

[0395] As shown in Figure 1, a 70-year-old male patient with extensive-stage small cell lung cancer had failed previous treatment with PD-L1 inhibitors combined with platinum-based chemotherapy. He received anti-DLL3 antibody-drug conjugate therapy, and at week 6, he achieved a partial response (PR), with a 70.6% reduction in mediastinal lymph nodes.

[0396] As of February 2025, a total of 54 subjects (median age: 59.5 years; smoking history: 59.3%; ECOG PS1: 98.1%; SCLC: 96.3%; brain / liver metastases: 24.1% / 25.9%; median number of prior treatment lines: 2 [range 1-4]; prior platinum / immunotherapy history: 98.1% / 77.8%) were enrolled and received treatment in 5 dose groups (0.8, 2.4, 3.0, 3.5 and 4.2 mg / kg).

[0397] Of the 42 evaluable SCLC patients, the objective response rate (ORR) and disease control rate (DCR) were 59.5% (25 / 42) and 90.5% (38 / 42), respectively. 25 patients achieved partial response (PR). Among the 26 evaluable SCLC patients who completed ≥12 weeks of follow-up, the ORR was 69.2% (18 / 26), with the ORR in the 2.4 mg / kg dose group being 77.8% (7 / 9).

[0398] One NEC subject (3.5 mg / kg) achieved PR; the subject had cervical neuroendocrine carcinoma.

[0399] As of June 2025, a total of 87 SCLC subjects were enrolled, of whom 72.4% (63 / 87) had a history of prior immunotherapy. Preliminary efficacy was evaluated in 71 SCLC subjects, with dose groups including 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, and 4.2 mg / kg. Results are shown in Table 1.

[0400] Table 1. Efficacy evaluation results of 71 subjects with SCLC

[0401] In all SCLC patients receiving first-line treatment, an ORR of 73.2% (52 / 71) and a confirmed ORR of 47.9% (34 / 71) were observed; in SCLC patients receiving second-line treatment, an ORR of 77.1% (27 / 35) and a confirmed ORR of 60.0% (21 / 35) were observed.

[0402] In the 2.4 mg / kg dose group, 73.7% (14 / 19) ORR and 57.9% (11 / 19) confirmed ORR were observed in all SCLC subjects receiving first-line treatment; in SCLC subjects receiving second-line treatment, 80.0% (8 / 10) ORR and 70.0% (7 / 10) confirmed ORR were observed.

[0403] In SCLC patients with baseline brain metastases at a dose ≥2.4 mg / kg, the confirmed ORR was 66.7% (12 / 18) and the DCR was 100% (18 / 18). In SCLC patients with baseline brain metastases at a dose of 2.4 mg / kg, the confirmed ORR was 83.3% (5 / 6) and the DCR was 100% (6 / 6).

[0404] In SCLC subjects with doses ≥2.4 mg / kg, the median progression-free survival (mPFS) was 6.7 months.

[0405] As of November 2025, excluding SCLC, 18 other neuroendocrine carcinoma patients were enrolled (including: large cell lung cancer, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, and urinary tract neuroendocrine carcinoma). Based on the efficacy evaluable set (EES), the ORR was 47.1% (8 / 17) and the DCR was 82.4% (14 / 17).

[0406] 5.2 Safety Evaluation

[0407] Safety assessment includes collecting adverse events (AEs) and severe acute exacerbations (SAEs), as well as laboratory tests, vital signs, physical examinations, and 12-lead electrocardiograms.

[0408] As of December 2024, most treatment-related adverse events (TRAEs) were grade 1-2, with no drug-induced discontinuation events and the maximum tolerated dose not yet reached. The most common TRAEs included decreased white blood cell count, anemia, decreased neutrophil count, nausea, and decreased platelet count.

[0409] As of February 2025, during the dose escalation phase, one dose-limiting toxicity (grade 4 thrombocytopenia) occurred in the 4.2 mg / kg dose group. The overall incidence and ≥3 incidence of treatment-related adverse events (TRAEs) were 96.3% and 37.0%, respectively; the most common adverse reactions included leukopenia, anemia, decreased neutrophil count, decreased platelet count, nausea, decreased lymphocyte count, decreased appetite, and increased serum bilirubin. In the 2.4 mg / kg and 3.5 mg / kg dose extension groups, the incidence of serious TRAEs was 4.8% and 17.9%, respectively. No TRAEs leading to discontinuation or death occurred.

[0410] 5.3 Pharmacokinetics (PK)

[0411] Blood samples were collected for pharmacokinetic analysis to detect anti-DLL3 antibody-drug conjugates, total antibodies, and free toxins.

[0412] Non-compartmental model analysis will be used to estimate the pharmacokinetic (PK) parameters of anti-DLL3 antibody-drug conjugates, total antibody, and free toxin. The PK parameters will be calculated according to the actual sampling time points.

[0413] As of February 2025, after systemic exposure to anti-DLL3 antibody-drug conjugates, the levels of total antibodies and free toxins increased proportionally with increasing dose; plasma toxin exposure remained at low levels in all dose groups.

[0414] 5.4 Immunogenicity

[0415] Immunogenicity assessment includes anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs, if applicable) against the investigational drug.

[0416] The samples will be analyzed using validated analytical methods, in accordance with the central laboratory's SOP.

[0417] In summary, the aforementioned anti-DLL3 antibody-drug conjugates exhibit tolerable and manageable safety profiles and demonstrate promising antitumor activity in various neuroendocrine carcinomas.

Claims

1. Use of the anti-DLL3 antibody-drug conjugate in the preparation of a medicament for the treatment of neuroendocrine neoplasm (NEN); wherein the neuroendocrine neoplasm is a recurrent and / or metastatic neuroendocrine carcinoma (NEC); The anti-DLL3 antibody-drug conjugate comprises the structure shown below: in: n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and Pc is an anti-DLL3 antibody.

2. The use according to claim 1, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain variable region comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; and / or The anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8; and / or The anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO:

12.

3. The use according to claim 1 or 2, wherein the dosage of the anti-DLL3 antibody-drug conjugate is 0.01 mg / kg to 50 mg / kg, 0.8 mg / kg to 5 mg / kg, about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg; and / or The anti-DLL3 antibody-drug conjugate is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

4. The use according to any one of claims 1 to 3, wherein the recurrent and / or metastatic neuroendocrine carcinoma is a neuroendocrine carcinoma that has progressed or recurred after prior standard treatment; and / or The recurrent and / or metastatic neuroendocrine carcinoma refers to neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy; and / or The recurrent and / or metastatic neuroendocrine carcinomas are small cell lung cancer, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that have progressed or recurred after prior chemotherapy and / or immunotherapy.

5. A method for treating neuroendocrine neoplasm (NEN), comprising administering an anti-DLL3 antibody-drug conjugate to a subject in need; wherein the neuroendocrine neoplasm is a recurrent and / or metastatic neuroendocrine carcinoma (NEC); The anti-DLL3 antibody-drug conjugate comprises the structure shown below: in: n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and Pc is an anti-DLL3 antibody.

6. The method of claim 5, wherein the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively; and the light chain variable region comprising LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively; and / or The anti-DLL3 antibody 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% sequence identity as shown in SEQ ID NO: 7 or the sequence shown in SEQ ID NO: 7, and the light chain variable region comprises an amino acid sequence having at least 80% sequence identity as shown in SEQ ID NO: 8; and / or The anti-DLL3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 11 or having at least 80% sequence identity with the sequence shown in SEQ ID NO: 11, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 12 or having at least 80% sequence identity with the sequence shown in SEQ ID NO:

12.

7. The method according to claim 5 or 6, wherein the dosage of the anti-DLL3 antibody drug conjugate is 0.01 mg / kg to 50 mg / kg, 0.8 mg / kg to 5 mg / kg, about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg.

8. The method according to any one of claims 5 to 7, wherein the anti-DLL3 antibody drug conjugate is administered once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, or once every 6 weeks.

9. A method for treating or inhibiting the growth of neuroendocrine tumors, the method comprising: (1) Select subjects with inoperable tumors; and (2) The dosage of the anti-DLL3 antibody-drug conjugate administered to the subject was approximately 0.8 mg / kg, approximately 1.8 mg / kg, approximately 2.4 mg / kg, approximately 3 mg / kg, approximately 3.5 mg / kg, or approximately 4.2 mg / kg; The anti-DLL3 antibody-drug conjugate described herein comprises the structure shown below: in: n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

10. A method of using an anti-DLL3 antibody-drug conjugate for treating or inhibiting the growth of neuroendocrine tumors, the method comprising administering a therapeutically effective amount of the anti-DLL3 antibody-drug conjugate to a subject in need, the conjugate comprising the structure shown below: in: n is 1 to 10; or 3 to 9; or 5 to 9; or about 8; and Pc is an anti-DLL3 antibody; the anti-DLL3 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 respectively; and the light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 respectively.

11. The anti-DLL3 antibody-drug conjugate according to claim 10, wherein the method comprises administering the anti-DLL3 antibody-drug conjugate to the subject at a dose of about 0.8 mg / kg, about 1.8 mg / kg, about 2.4 mg / kg, about 3 mg / kg, about 3.5 mg / kg, about 4.2 mg / kg, or about 5 mg / kg.

12. The method according to any one of claims 8 to 11, or the anti-DLL3 antibody-drug conjugate used, wherein the dosing frequency is once every 2 weeks or once every 3 weeks.

13. The method according to any one of claims 5 to 12, or the anti-DLL3 antibody-drug conjugate used therein, wherein the subject has received no more than two lines of prior systemic chemotherapy.

14. The use according to any one of claims 1 to 13, the method, or the anti-DLL3 antibody-drug conjugate used, wherein the anti-DLL3 antibody-drug conjugate is administered intravenously, subcutaneously, or intraperitoneally.

15. The method according to any one of claims 1 to 14, or the anti-DLL3 antibody-drug conjugate used therein, wherein the effect produced by the anti-DLL3 antibody-drug conjugate is selected from the group consisting of delaying tumor growth, reducing the number of tumor cells, tumor regression, prolonging survival, partial remission, complete remission, or a combination thereof; and / or After one or more treatment cycles, the tumor volume shrinks by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, or 70%.

16. The method according to any one of claims 5 to 15, or the anti-DLL3 antibody-drug conjugate used therein, wherein the neuroendocrine tumor is a neuroendocrine carcinoma (NEC); and / or The neuroendocrine carcinoma is a recurrent and / or metastatic neuroendocrine carcinoma; and / or The recurrent and / or metastatic neuroendocrine carcinoma refers to neuroendocrine carcinoma that has progressed or recurred after prior standard treatment; and / or The recurrent and / or metastatic neuroendocrine carcinoma refers to neuroendocrine carcinoma that has progressed or recurred after prior chemotherapy and / or immunotherapy; and / or The recurrent and / or metastatic neuroendocrine carcinomas are small cell lung cancer, large cell lung neuroendocrine carcinoma, cervical neuroendocrine carcinoma, esophageal neuroendocrine carcinoma, gastric neuroendocrine carcinoma, prostate neuroendocrine carcinoma, rectal neuroendocrine carcinoma, or urinary tract neuroendocrine carcinoma that have progressed or recurred after prior chemotherapy and / or immunotherapy.

17. The method or the anti-DLL3 antibody-drug conjugate used according to any one of claims 1 to 16, wherein the neuroendocrine tumor is small-cell lung cancer (SCLC) or a neuroendocrine carcinoma other than small-cell lung cancer that is positive for DLL3 expression.

18. The method of claim 17, or the anti-DLL3 antibody-drug conjugate used therein, wherein the neuroendocrine tumor is recurrent and / or metastatic small cell lung cancer, or recurrent and / or metastatic neuroendocrine carcinoma other than small cell lung cancer that is positive for DLL3 expression.

19. The method according to any one of claims 5 to 18, or the anti-DLL3 antibody-drug conjugate used therein, wherein the subject is further selected according to one or more of the following criteria: (i) Age 18 to 75 years old, gender not limited; (ii) Histologically or cytologically confirmed inoperable recurrent or metastatic solid tumors that have progressed or recurred after prior standard treatment, as shown below: (a) Small-cell lung cancer (SCLC): Progression or recurrence after receiving at least one standard treatment, and prior systemic chemotherapy not exceeding two lines; (b) Other DLL3-positive neuroendocrine carcinomas: failure of previous standard treatment, or progression or recurrence after receiving at least one platinum-based treatment regimen, and prior systemic chemotherapy not exceeding two lines; (iii) An ECOG score of 0 or 1; (iv) Expected survival of more than 3 months; and (v) Has sufficient bone marrow and organ function.

20. The method of any one of claims 1 to 19, or the anti-DLL3 antibody-drug conjugate used therein, wherein the dose of the anti-DLL3 antibody-drug conjugate is about 2.4 mg / kg.

Images