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 a CD70-expressing cancer in a subject, the method comprising:
administering to the subject, in an amount effective for the treatment thereof, an antibody-drug conjugate comprising an antibody that binds to CD70, wherein:
(i) the drug is a cytotoxic agent,
(ii) the antibody is a mouse antibody comprising a heavy chain variable region having the amino acid sequence set forth in residues 20 to 137 of SEQ ID NO:2, and a light chain variable region having the amino acid sequence set forth in residues 21 to 132 of SEQ ID NO:12, or a chimeric or humanized form of the mouse antibody, and
(iii) the antibody-drug conjugate is internalized into cells, where it exerts a therapeutic effect.
2. The method of claim 1 , wherein the antibody is a humanized antibody.
3. The method of claim 1 , wherein the antibody is a chimeric antibody.
4. The method of claim 3 , wherein the chimeric antibody comprises a human constant region.
5. The method of claim 1 , wherein the antibody is multivalent.
6. The method of claim 1 , wherein the cytotoxic agent is selected from the group consisting of an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a duocarmycin, a maytansinoid, and a vinca alkaloid.
7. The method of claim 1 , wherein the cytotoxic agent is an anti-tubulin agent.
8. The method of claim 7 , wherein the cytotoxic agent is AFP, MMAF, or MMAE.
9. The method of claim 1 , wherein the antibody is conjugated to the cytotoxic agent via a linker.
10. The method of claim 9 , wherein the linker is cleavable under intracellular conditions.
11. The method of claim 10 , wherein the cleavable linker is a peptide linker cleavable by an intracellular protease.
12. The method of claim 11 , wherein the peptide linker comprises a dipeptide.
13. The method of claim 12 , wherein the dipeptide is val-cit or phe-lys.
14. The method of claim 10 , wherein the cleavable linker is hydrolyzable at a pH of less than 5.5.
15. The method of claim 14 , wherein the hydrolyzable linker is a hydrazone linker.
16. The method of claim 10 , wherein the cleavable linker is a disulfide linker.
17. The method of claim 1 , wherein the CD70-expressing cancer is selected from the group consisting of a kidney tumor, a B cell lymphoma, a thymic carcinoma, and a nasopharyngeal carcinoma.
18. The method of claim 1 , wherein the subject is human.
19. The method of claim 13 , wherein the antibody is a humanized antibody, and the cytotoxic agent is AFP, MMAF or MMAE.
20. The method of claim 1 , wherein the antibody blocks binding of said CD70 to CD27.
21. A method for the treatment of a CD70-expressing non-Hodgkin's lymphoma in a human subject, the method comprising:
administering to the subject, in an amount effective for the treatment thereof an antibody-drug conjugate comprising an antibody that binds to CD70, wherein:
(i) the drug is a cytotoxic agent, and
(ii) the antibody-drug conjugate is internalized into cells, where it exerts a therapeutic effect.
22. The method of claim 21 , wherein the antibody is a humanized antibody.
23. The method of claim 21 , wherein the cytotoxic agent is selected from the group consisting of an auristatin, a DNA minor groove binding agent, a DNA minor groove alkylating agent, an enediyne, a duocarmycin, a maytansinoid, and a vinca alkaloid.
24. The method of claim 21 , wherein the cytotoxic agent is an anti-tubulin agent.
25. The method of claim 24 , wherein the cytotoxic agent is AFP or MMAE.
26. The method of claim 21 , wherein the antibody is conjugated to the cytotoxic agent via a linker.
27. The method of claim 26 , wherein the linker is cleavable under intracellular conditions.
28. The method of claim 27 , wherein the cleavable linker is cleavable by an intracellular protease.
29. The method of claim 28 , wherein the linker comprises a dipeptide.