Anti-cathepsin D antibody

Abstract

The inventors generated a novel anti-Cath-D antibody (F1M1) that can reduce tumor growth without apparent toxicity in Cath-D secreting basal-like TNBC cell lines exhibiting strong immune infiltration. The F1M1 antibody inhibited the recruitment of immunosuppressive M2 polarized paratumor macrophages (TAMs) and induced the activation of natural killer cells in tumors. F1M1 also enhanced the activation of antitumor M1 polarized TAMs, the recruitment and maturation of conventional cDC1 dendritic cells in tumors, promoting antigen presentation and CD4 in tumors and regional lymph nodes. + and CD8 + It reduced the expression of exhaustion markers on T cells. Interestingly, antibody F1M1 also showed better affinity for Cath-D than antibody F1 previously produced by the inventors. The inventors also developed a novel Fc-optimized F1M1-Fc + We generated a human antibody that promotes ADCC induction in both cancer cells and CAFs, improving antitumor efficacy and inducing NK cell recruitment, activation, and cytotoxic activity in tumors. F1M1-Fc + F1M1-Fc + This inhibited the proliferation of MDA-MB-231 and SUM159 TNBC cell xenografts, and two TNBC-PDX cells (one of which was resistant to neoadjuvant chemotherapy), without apparent toxicity. Furthermore, this F1M1-Fc + This invention improves the therapeutic efficacy of paclitaxel and enzalutamide when used in combination. Thus, the present invention relates to anticathepsin D antibodies and their use in the treatment of cancer, particularly triple-negative breast cancer.

Claims

1. Isolated anti-cathepsin D antibody: (c) Heavy chain having the following variable domains: H-CDR1 having the sequence shown in SEQ ID NO: 2; H-CDR2 having the sequence shown in SEQ ID NO: 3; H-CDR3 having the sequence shown in SEQ ID NO: 4; (d) Light chain having the following variable domains: L-CDR1 having the sequence shown in SEQ ID NO: 6; L-CDR2 having the sequence shown in YDS; L-CDR3 having the sequence shown in SEQ ID NO: 7; including, Isolated anti-cathepsin D antibody (F1M1).

2. An isolated anti-cathepsin D antibody according to claim 1: (a) A heavy chain having at least 70% identity with the sequence shown in Sequence ID No. 1, and (b) A light chain having at least 70% identity with the sequence shown in Sequence ID No. 5, including, Isolated anti-cathepsin D antibody.

3. An isolated anti-cathepsin D antibody according to claim 1 or 2, (a) A heavy chain having a variable domain with the sequence shown in Sequence ID No. 1 and (b) A light chain having a heavy chain, having a variable domain having the sequence shown in Sequence ID No. 5 including, Isolated anti-cathepsin D antibody.

4. An isolated anti-cathepsin D antibody according to any one of claims 1 to 3, The aforementioned antibody is a monoclonal antibody, and more specifically, a monoclonal IgG antibody. Isolated anti-cathepsin D antibody.

5. An isolated anti-cathepsin D antibody according to any one of claims 1 to 4, The antibody is selected from the group consisting of Fab, F(ab')2, Fab', dsFv, diabody, and scFv. Isolated anti-cathepsin D antibody.

6. An isolated anti-cathepsin D antibody according to any one of claims 1 to 4, The antibody includes an Fc region containing at least one, two, three, or four mutations selected from the group consisting of S239D, H268F, S324T, and I332E. Isolated anti-cathepsin D antibody ("F1M1-Fc+").

7. An isolated anti-cathepsin D antibody according to claim 6, The aforementioned antibody can activate and induce the recruitment of natural killer cells into tumors and induce cytotoxicity. Isolated anti-cathepsin D antibody.

8. An isolated anti-cathepsin D antibody according to any one of claims 1 to 4, The antibody comprises an Fc region containing at least three mutations selected from the group consisting of L234A, L235A, and P329G. Isolated anti-cathepsin D antibody ("F1M1-Fc-").

9. An isolated anti-cathepsin D antibody according to any one of claims 1 to 8, The aforementioned anti-cathepsin D antibody is a human antibody. Isolated anti-cathepsin D antibody.

10. An isolated anti-cathepsin D antibody according to any one of claims 1 to 9, The aforementioned antibody can inhibit the recruitment of immunosuppressive paratumor macrophages (TAMs) M2 to the tumor and enhance the activation of antitumor M1 polarized TAMs, thereby increasing CD4 in the tumor and regional lymph nodes. ＋ and CD8 ＋ It can reduce the expression of fatigue markers on T cells, such as PD-L1 and LAG3, and promote the recruitment and maturation of conventional cDC1 dendritic cells. Isolated anti-cathepsin D antibody.

11. An isolated anti-cathepsin D antibody according to any one of claims 1 to 10, The antibody is conjugated to the therapeutic portion, specifically the cytotoxic portion. Isolated anti-cathepsin D antibody.

12. A cross-competitive antibody that cross-competes with the antibody described in any one of claims 1 to 11 for binding to cathepsin D.

13. A nucleic acid molecule encoding an anti-cathepsin D antibody as described in any one of claims 1 to 12.

14. A vector comprising the nucleic acid molecule described in claim 13.

15. A host cell transfected, infected, or transformed with the nucleic acid described in claim 13 and / or the vector described in claim 14.

16. A pharmaceutical composition comprising an anti-cathepsin D antibody as described in any one of claims 1 to 12.

17. A human isolated human anti-cathepsin D antibody according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 16, for use as a pharmaceutical.

18. A method for treating hyperproliferative disorders or diseases in subjects requiring it, The step of administering to the subject an effective amount of an anti-cathepsin D antibody according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 16, method.

19. A method for treating the hyperproliferative disorder or disease described in claim 18, The aforementioned hyperproliferative disease is cancer, more specifically, cancer selected from the group consisting of breast cancer, melanoma, ovarian cancer, lung cancer, liver cancer, pancreatic cancer, melanoma, squamous cell carcinoma, endometrial cancer, head and neck cancer, bladder cancer, malignant glioma, prostate cancer, colon adenocarcinoma, or gastric cancer. method.

20. A method for treating the hyperproliferative disorder or disease described in claim 18, The aforementioned cancer is triple-negative breast cancer (TNBC). method.

21. A method for treating cancer as described in any one of claims 18 or 19, The aforementioned anti-cathepsin D antibody is administered in combination with anticancer therapy selected from the group consisting of radiotherapy, immune checkpoint inhibitors, anti-androgens, T-cell therapy, M-cell therapy, or CAR therapy such as CAR NK cell therapy, antibody-drug conjugates (ADCs), or chemotherapeutic agents. method.

22. A method for treating cancer as described in claim 19, The aforementioned chemotherapeutic agent is paclitaxel. method.

23. A method for treating cancer as described in claim 19, The aforementioned anti-androgen agent is enzalutamide. method.

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