Anti-cd70 antibody-drug conjugates and their use for the treatment of cancer and immune disorders

Abstract

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, 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, a cytostatic agent or an immunosuppressive agent.   
     
     
         2 . The method of  claim 1 , wherein the antibody-drug conjugate is internalized into a CD70+ immune cells, where the agent exerts a cytotoxic, cytostatic or immunosuppressive effect upon the immune cell. 
     
     
         3 . 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 an amino acid sequence set forth in SEQ ID NO:2, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO:12, or   (b) a heavy chain variable region having an amino acid sequence set forth in SEQ ID NO:22, and a light chain variable region having an amino acid sequence set forth in SEQ ID NO:32.   
     
     
         4 . The method of  claim 3 , wherein the antibody is a human, humanized, or chimeric antibody. 
     
     
         5 . The method of  claim 3 , wherein the antibody is multivalent. 
     
     
         6 . 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;
 (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; or   (c) has a heavy chain variable region and a light chain variable region having at least 90% sequence identity to the amino acid sequence set forth in (i) SEQ ID NO:2 and SEQ ID NO:12, respectively, or (ii) SEQ ID NO:22 and SEQ ID NO:32, respectively.   
     
     
         7 . 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. 
     
     
         8 . The method of  claim 7 , wherein the cytotoxic agent is an anti-tubulin agent. 
     
     
         9 . The method of  claim 8 , wherein the anti-tubulin agent is an auristatin, an enediyne, vinca alkaloid, or a maytansinoid. 
     
     
         10 . The method of  claim 8 , wherein the anti-tubulin agent is MMAE. 
     
     
         11 . 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. 
     
     
         12 . The method of  claim 1 , wherein the antibody-drug conjugate comprises an immunosuppressive agent selected from the group consisting of gancyclovir, etanercept, cyclosporine, tacrolimus, rapamycin, cyclophosphamide, azathioprine, mycophenolate mofetil, methotrexate, cortisol, aldosterone, dexamethasone, a cyclooxygenase inhibitor, a 5-lipoxygenase inhibitor, or a leukotriene receptor antagonist. 
     
     
         13 . The method of  claim 1 , wherein the antibody is conjugated to the cytotoxic, cytostatic or immunosuppressive agent via a linker. 
     
     
         14 . The method of  claim 13 , wherein the linker is cleavable under intracellular conditions. 
     
     
         15 . The method of  claim 14 , wherein the peptide linker comprises a dipeptide. 
     
     
         16 . The method of  claim 15 , wherein the dipeptide is val-cit or phe-lys. 
     
     
         17 . The method of  claim 14 , wherein the cleavable linker is hydrolyzable at a pH of less than 5.5. 
     
     
         18 . The method of  claim 17 , wherein the hydrolyzable linker is a hydrazone linker. 
     
     
         19 . The method of  claim 14 , wherein the cleavable linker is a disulfide linker. 
     
     
         20 . The method of  claim 2 , wherein the antibody-drug conjugate exerts a cytotoxic effect upon internalization into an activated CD70+ T cell. 
     
     
         21 . The method of  claim 1 , wherein the immunological disorder is a T-cell-mediated immunological disorder. 
     
     
         22 . The method of  claim 21 , wherein the immunological disorder is mediated by activated T cells expressing CD70. 
     
     
         23 . The method of  claim 22 , wherein resting T cells are not substantially depleted by administration of the antibody-drug conjugate. 
     
     
         24 . The method of  claim 21 , 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. 
     
     
         25 . The method of  claim 1 , wherein the immunological disorder is an activated B-lymphocyte disorder. 
     
     
         26 . The method of  claim 1 , wherein the subject is human.