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CN-122028937-A - Antibody drug conjugate therapy for cancer

CN122028937ACN 122028937 ACN122028937 ACN 122028937ACN-122028937-A

Abstract

The present invention provides methods, dosage regimens and administration of Antibody Drug Conjugates (ADCs) for the treatment of cancer. More specifically, the cancer is advanced or metastatic solid cancer.

Inventors

  • WEI HONGYING
  • HUANG QIQI
  • HUANG YING
  • LI CHUAN
  • LIU JUNHAO
  • ZHOU YUANFENG

Assignees

  • 上海翰森生物医药科技有限公司
  • 常州恒邦药业有限公司

Dates

Publication Date
20260512
Application Date
20241011
Priority Date
20231014

Claims (19)

  1. 1. A method of treating or preventing cancer comprising administering to a human patient a therapeutically effective amount of an anti-B7H 4 antibody drug conjugate, wherein the anti-B7H 4 antibody drug comprises an anti-B7H 4 antibody and an anti-tumor compound linked via a linker.
  2. 2. The method of claim 1, wherein the anti-B7H 4 antibody comprises HCDR1 consisting of amino acid sequence SEQ ID No. 1, HCDR2 consisting of amino acid sequence SEQ ID No. 2 and HCDR3 consisting of amino acid sequence SEQ ID No. 3 in the heavy chain variable region, and LCDR1 consisting of amino acid sequence SEQ ID No. 4, LCDR2 consisting of amino acid sequence SEQ ID No. 5 and LCDR3 consisting of amino acid sequence SEQ ID No. 6 in the light chain variable region; Preferably, the anti-B7H 4 antibody comprises a heavy chain variable region consisting of the amino acid sequence SEQ ID NO. 7 and a light chain variable region consisting of the amino acid sequence SEQ ID NO. 8; More preferably, the anti-B7H 4 antibody comprises a heavy chain consisting of the amino acid sequence SEQ ID NO. 9 and a light chain consisting of the amino acid sequence SEQ ID NO. 10.
  3. 3. The method of claim 1, wherein the anti-tumor compound is SN-38, MMAE, MMAF, or irinotecan, or a derivative or analog thereof.
  4. 4. The method of claim 1, wherein the linker is Or (b) , The anti-B7H 4 antibody Linked and said anti-tumor compound The connection is carried out, Is the connection location.
  5. 5. The method of claim 1, wherein the anti-B7H 4 antibody drug conjugate is a compound of formula (I): (I) Ab is an anti-B7H 4 antibody, wherein the anti-B7H 4 antibody is as defined in claim 2; y is 1 to 10, preferably 4 to 8, more preferably 4,6 or 8.
  6. 6. The method of claims 1 to 5, wherein the dose of the anti-B7H 4 antibody drug conjugate is in the range of 0.5 mg to 20 mg/kg, preferably 1 mg to 10 mg/kg, more preferably 0.7 mg to 7.2 mg/kg, even more preferably 4 mg to 6 mg/kg, preferably 4.5 mg to 6 mg/kg, even more preferably 4.8 mg to 5.8 mg/kg.
  7. 7. The method of claim 6, wherein the dose of the anti-B7H 4 antibody drug conjugate is selected from 0.7 mg/kg, 1.4 mg/kg, 2.8 mg/kg, 4.8 mg/kg, 5.8 mg/kg, or 7.2 mg/kg.
  8. 8. The method of claims 1-7, wherein the anti-B7H 4 antibody drug conjugate is administered by intravenous administration.
  9. 9. The method of claims 1 to 8, wherein the anti-B7H 4 antibody drug conjugate is administered once every 1 to 4 weeks, preferably once every 3 weeks.
  10. 10. The method according to claims 1 to 9, wherein the cancer is selected from breast cancer, ovarian cancer, endometrial cancer, cervical cancer, vulvar cancer, vaginal cancer, renal cancer, liver cancer, lung cancer, prostate cancer, uterine cancer, colorectal cancer and pancreatic cancer, preferably breast cancer, ovarian cancer and endometrial cancer.
  11. 11. The method of claims 1 to 10, wherein the cancer is resistant or refractory, preferably the resistant or refractory is resistant or refractory to cancer obtained as a result of treatment with an anti-cancer drug, the anti-cancer drug being a chemotherapeutic agent, PARP inhibitor, PARP1 inhibitor or PD-1/PD-L1 inhibitor, more preferably the anti-cancer drug is a platinum-based chemotherapeutic agent, PARP inhibitor or PD-1/PD-L1 inhibitor, still more preferably the anti-cancer drug is epirubicin, paclitaxel, docetaxel, cisplatin, gemcitabine, vinorelbine, capecitabine, carboplatin, oxaliplatin, eribulin, irinotecan, olanzapari, nilaparib, pamofaciparli, AZD5305, AZD9574, pembrolizumab, atuzumab, deuzumab, melitumomab, tebub Li Shan, tebufalizumab, aprb, ceritumomab Lu Lishan, perlizumab Shu Geli, panaxbizumab or Wo Lishan.
  12. 12. The method of claims 1 to 10, wherein the cancer is advanced or metastatic solid cancer, preferably the cancer is advanced or metastatic solid cancer that fails or is intolerant to standard treatment.
  13. 13. The method of claims 10 to 12, wherein the breast cancer is a triple negative, HER-2 positive, HR negative/HER-2 negative or HR positive/HER-2 negative breast cancer.
  14. 14. The method of claims 10 to 12, wherein the ovarian cancer is chemotherapy-resistant, preferably platinum-resistant.
  15. 15. The method of claims 1-5, wherein the patient has been previously treated with at least one anti-cancer treatment.
  16. 16. The method of claim 15, wherein the patient has been previously treated with at least one of targeted therapy, chemotherapy, immunotherapy, or endocrine therapy, preferably the patient has been previously treated with at least one of a chemotherapeutic agent, PARP inhibitor, PARP1 inhibitor, or PD-1/PD-L1 inhibitor, more preferably the patient has been previously treated with a platinum-based chemotherapeutic agent, PARP inhibitor, or PD-1/PD-L1 inhibitor, still more preferably the patient has been previously treated with at least one of epirubicin, paclitaxel, docetaxel, cisplatin, gemcitabine, vinorelbine, capecitabine, carboplatin, oxaliplatin, irinotecan, olanzapaline, nipradine, pamphleb, fluxapari, AZD5305, AZD9574, monoclonal antibody, atuzumab, deluzumab, melitumomab, melbinab, saripratzeylantin, aprevigatran, li Shan, cerimab Lu Lishan, monoclonal antibody, panduralumiab, or at least one of the other beads 3525.
  17. 17. The method of claims 1-5, wherein the patient failed prior treatment or the patient's cancer has progressed after treatment with at least one anti-cancer treatment.
  18. 18. The method of claim 17, wherein the patient has failed prior treatment or the patient's cancer has progressed following treatment with at least one of targeted therapy, chemotherapy, immunotherapy, or endocrine therapy, preferably the patient has failed prior treatment or the patient's cancer has progressed following treatment with a platinum-based chemotherapeutic agent, PARP inhibitor, PARP1 inhibitor, or PD-1/PD-L1 inhibitor, more preferably the patient has failed prior treatment or the patient's cancer has progressed following treatment with epirubicin, paclitaxel, docetaxel, cisplatin, gemcitabine, vinorelbine, capecitabine, carboplatin, oxaliplatin, irinotecan, olapari, nilaparine, pamphle, fluxapari, AZD5305, AZD9574, pembrolizumab, atuzumab, deuzumab, melitumomab, tetuzumab, tertuzumab, aprimab, sariglizumab, shu Geli, panaxab, or Wo Lishan.
  19. 19. The method of claim 15, wherein the OC patient has previously received PARP inhibitor or platinum resistance therapy or the TNBC patient has previously received PARP inhibitor or PD-1/PD-L1 inhibitor therapy.

Description

Antibody drug conjugate therapy for cancer Technical Field The present invention relates to therapeutic antibody drug conjugates comprising an anti-tumor compound linked to an antibody or antigen-binding fragment. More specifically, the present invention relates to specific treatment of human subjects using anti-B7 homolog 4 (B7-H4) antibody exenatide analog conjugates. Background Malignant tumors have become one of the major diseases threatening the health of people in China and even worldwide. According to the national cause of death monitoring report in 2019, malignant tumors are discharged as the main cause of death, accounting for 24.09% of all resident causes of death. The incidence and mortality of chinese malignancies has increased continuously over the last decades. Advanced solid tumors refer to solid tumors that have metastasized, and clinical TNM (tumor lymph node metastasis) stage is typically stage III and stage IV. Currently, the prognosis for most advanced solid tumors is poor. Breast and ovarian cancers rank first and ninth among the malignancy morbidity of urban females, respectively, with mortality being third and ninth, respectively, according to the prevalence of malignancy in the middle country published by the national cancer center of 2023. Triple Negative Breast Cancer (TNBC) is an invasive type of breast cancer accounting for about 10% of all breast cancer patients. TNBC is estrogen receptor negative (ER negative), progesterone receptor negative (PR negative) and human epidermal growth factor 2 (HER-2) negative, and is not suitable for endocrine therapy or anti-HER-2 targeted therapy. The prognosis of TNBC is particularly poor, with five-year survival rates of only about 20%. In addition, about 70% of ovarian cancers are clinically advanced at the time of treatment, with five-year survival rates of only 30% to 40% for stage III/IV ovarian cancer patients, most patients dying from cancer recurrence or resistance. Thus, patients with solid tumors such as breast and ovarian cancers require more treatment options. B7-H4 (B7 homolog 4 protein) (also known as B7S1 (B7 superfamily member 1), B7x (B7 homolog x), or VTCN1 (V-set domain containing T cell activation inhibitor 1) was first found by Sica et al to be the seventh member of the B7 family in 2003. Human B7-H4 is a type I transmembrane protein consisting of 282 amino acids its coding gene is located in the p11.1 region of chromosome 1 (Choi IH et al, J immunol.2003 Nov 1; 171 (9): 4650-4): B7-H4 has a negative regulatory effect on the immune response of T cells. B7-H4 plays a broad inhibitory role in the differentiation and development of CD4+ and CD8+ T cells, cell cycle progression and cytokine production (Sica GL et al, immunoy. 2003 Jun; 18 (6): 849-61). Recent studies have found that B7-H4 protein is abundantly expressed in various tumor tissues, enabling tumor cells to evade attack by the body's immune system. Human B7-H4 is currently known to be expressed on cancer cells such as breast cancer, ovarian cancer, lung cancer, cervical cancer, kidney cancer, bladder cancer and liver cancer. B7-H4 mRNA was found to be expressed in spleen, lung, thymus, liver, skeletal muscle, kidney, pancreas, testis, and ovary. At the protein level, it was found that the level of B7-H4 expression was low in tissues such as the breast (ducts and leaflets), oviduct epithelium and endometrial glands. The biological nature of B7-H4, which is not expressed or under expressed in normal cells but over expressed in tumor cells, makes it a target for the development of Antibody Drug Conjugates (ADCs). WO2020244657 discloses an ADC targeting B7-H4. ADC consisted of a humanized IgG1 anti-B7-H4 monoclonal antibody linked to a small molecule cytotoxic drug (topoisomerase I inhibitor) via a protease cleavable linker to exert tumor killing. The B7-H4 molecule is used as a target point of tumor treatment to provide a new method for tumor immunotherapy. Disclosure of Invention The present invention provides a method of treating or preventing cancer by administering a therapeutically effective amount of an anti-B7H 4 drug conjugate comprising an anti-B7H 4 antibody and an anti-tumor compound linked via a linker. In some embodiments, the anti-B7H 4 antibody comprises HCDR1 consisting of amino acid sequence SEQ ID NO. 1, HCDR2 consisting of amino acid sequence SEQ ID NO. 2, and HCDR3 consisting of amino acid sequence SEQ ID NO. 3 in the heavy chain variable region, and LCDR1 consisting of amino acid sequence SEQ ID NO. 4, LCDR2 consisting of amino acid sequence SEQ ID NO. 5, and LCDR3 consisting of amino acid sequence SEQ ID NO. 6 in the light chain variable region. In some embodiments, the anti-B7H 4 antibody comprises a heavy chain variable region consisting of the amino acid sequence SEQ ID NO. 7 and a light chain variable region consisting of the amino acid sequence SEQ ID NO. 8. In some embodiments, the anti-B7H 4 antibody comprises a heavy chain consisting of t