Anti-CD70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders
View Patent ↗Disclosed are anti-CD70 antibodies and derivatives thereof conjugated to cytotoxic, immunosuppressive, or other therapeutic agents, as well as pharmaceutical compositions and kits comprising the antibody- and antibody derivative-drug conjugates. Also disclosed are methods, for the treatment of CD70-expressing cancers and immunological disorders, comprising administering to a subject the disclosed pharmaceutical compositions.
1. A method for the treatment of an immunological disorder in a subject, wherein the immune disorder is mediated by cells that express CD70, the method comprising:
administering to the subject, in an amount effective for the treatment, an antibody-drug conjugate comprising an antibody that binds CD70 and is conjugated to a cytotoxic agent, wherein the antibody-drug conjugate is internalized into immune cells that express CD70, where it exerts a therapeutic effect.
2. The method of claim 1 , wherein the antibody competes for binding to CD70 with a monoclonal antibody that comprises:
(a) a heavy chain variable region having the amino acid sequence set forth in residues 20-137 of SEQ ID NO:2, and a light chain variable region having the amino acid sequence set forth in residues 21-132 of SEQ ID NO:12, or
(b) a heavy chain variable region having the amino acid sequence set forth in residues 20-137 of SEQ ID NO:22, and a light chain variable region having the amino acid sequence set forth in residues 21-132 SEQ ID NO:32.
3. The method of claim 2 , wherein the antibody is a humanized, or chimeric antibody.
4. The method of claim 2 , wherein the antibody is multivalent.
5. The method of claim 1 , wherein the antibody is a chimeric or humanized antibody and
(a) comprises H1, H2, H3, L1, L2 and L3 complementarity determining regions having, respectively, the amino acid sequences set forth in SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10; SEQ ID NO:16, SEQ ID NO:18, and SEQ ID NO:20; or
(b) comprises H1, H2, H3, L1, L2 and L3 complementarity determining regions having, respectively, the amino acid sequences set forth in SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30; SEQ ID NO:36, SEQ ID NO:38, and SEQ ID NO:40.
6. The method of claim 1 , wherein the antibody-drug conjugate comprises a cytotoxic agent selected from the group consisting of an anti-tubulin agent, a DNA minor groove binding agent, and a DNA minor groove alkylating agent.
7. The method of claim 6 , wherein the cytotoxic agent is an anti-tubulin agent.
8. The method of claim 7 , wherein the anti-tubulin agent is an auristatin, an enediyne, a vinca alkaloid, or a maytansinoid.
9. The method of claim 7 , wherein the anti-tubulin agent is MMAE.
10. The method of claim 1 , wherein the antibody-drug conjugate comprises a cytotoxic agent selected from the group consisting of an enediyne, a lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid.
11. The method of claim 1 , wherein the antibody is conjugated to the cytotoxic agent via a linker.
12. The method of claim 11 , wherein the linker is cleavable under intracellular conditions.
13. The method of claim 12 , wherein the linker comprises a dipeptide.
14. The method of claim 13 , wherein the dipeptide is val-cit or phe-lys.
15. The method of claim 12 , wherein the cleavable linker is hydrolyzable at a pH of less than 5.5.
16. The method of claim 15 , wherein the hydrolyzable linker is a hydrazone linker.
17. The method of claim 12 , wherein the cleavable linker is a disulfide linker.
18. The method of claim 1 , wherein the immunological disorder is a T-cell-mediated immunological disorder.
19. The method of claim 18 , wherein resting T cells are not substantially depleted by administration of the antibody-drug conjugate.
20. The method of claim 18 , wherein the T cell-mediated immunological disorder is rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren's syndrome, Hashimoto's thyroiditis, Grave's disease, primary biliary cirrhosis, Wegener's granulomatosis, tuberculosis, or acute graft versus host disease.
21. The method of claim 1 , wherein the immunological disorder is an activated B-lymphocyte disorder.
22. The method of claim 1 , wherein the subject is human.
23. The method of claim 3 , wherein the antibody is a humanized antibody.
24. The method of claim 3 , wherein the antibody is a chimeric antibody.
25. The method of claim 3 , wherein the antibody comprises a human constant region.