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 a CD70-expressing cancer 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 to the CD70 and wherein the drug is a cytotoxic agent;    wherein the cancer is multiple myeloma, Hodgkin's disease, a diffuse large B-cell lymphoma, a follicular lymphoma, a mantle cell lymphoma, an Epstein Barr Virus positive B cell lymphomas, a glioblastoma, a neuroblastoma, an astrocytoma, a meningioma or Waldenstrom macroglobulinemia;    wherein the cytotoxic or cytostatic agent is not a peptide toxin.    
     
     
         2 . The method of  claim 1 , wherein the antibody competes for binding to CD70 with monoclonal antibody 1F6 or 2F2.  
     
     
         3 . The method of  claim 2 , wherein the antibody comprises at least one polypeptide region selected from the group consisting of 
 (a) an H1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:6;    (b) an H2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:8;    (c) an H3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:10;    (d) an L1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:16;    (e) an L2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:18;    (f) an L3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:20;    (g) an H1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:26;    (h) an H2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:28;    (i) an H3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:30;    (j) an L1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:36;    (k) an L2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:38; and    (l) an L3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:40.    
     
     
         4 . The method of  claim 3 , wherein the antibody comprises 
 the H1, H2, and H3 regions of (a), (b), and (c); or    the H1, H2, and H3 regions of (g), (h), and (i).    
     
     
         5 . The method of  claim 4 , wherein the polypeptide regions of (a), (b), (c), (d), (e), and (f) have, 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.  
     
     
         6 . The method of  claim 4 , wherein 
 the antibody comprising the H1, H2, and H3 regions of (a), (b), and (c) further comprises the L1, L2, and L3 regions of (d), (e), and (f); or    the antibody comprising the H1, H2, and H3 regions of (g), (h), and (i) further comprises the L1, L2, and L3 regions of (j), (k), and (l).    
     
     
         7 . The method of  claim 4 , wherein the antibody comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO 22.  
     
     
         8 . The method of  claim 7 , wherein the heavy chain variable region has the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:22.  
     
     
         9 . The method of  claim 7 , wherein the antibody, comprising the heavy chain variable region having at least 80% sequence identity to SEQ ID NO:2 or SEQ ID NO:22, further comprises, respectively, a light chain variable region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:12 or SEQ ID NO:32.  
     
     
         10 . The method of  claim 9 , wherein the light chain variable region has the amino acid sequence set forth in SEQ ID NO:12 or SEQ ID NO:32.  
     
     
         11 . The method of  claim 10 , wherein the antibody is monoclonal antibody 1F6 or 2F2.  
     
     
         12 . The method of  claim 11 , wherein the antibody-drug conjugate is selected from the group consisting of humanized 1F6-val-cit-MMAE, humanized 1F6-val-cit-MMAF, humanized 1F6-val-cit-AFP, humanized 2F2-val-cit-MMAE, humanized 2F2-val-cit-MMAF, and humanized 2F2-val-cit-AFP.  
     
     
         13 . The method of  claim 1 , wherein the antibody is a chimeric, humanized, or human antibody.  
     
     
         14 . The method of  claim 13 , wherein the chimeric antibody comprises a human constant region.  
     
     
         15 . The method of  claim 1 , wherein the antibody is multivalent.  
     
     
         16 . 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 lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid.  
     
     
         17 . The method of  claim 1 , wherein the cytotoxic agent is AFP, MMAF, MMAE, AEB, AEVB, auristatin E, paclitaxel, docetaxel, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin-10, echinomycin, combretatstatin, chalicheamicin, maytansine, DM-1, or netropsin.  
     
     
         18 . The method of  claim 1 , wherein the cytotoxic agent is an anti-tubulin agent.  
     
     
         19 . The method of  claim 18 , wherein the anti-tubulin agent is an auristatin, a vinca alkaloid, a podophyllotoxin, a taxane, a baccatin derivative, a cryptophysin, a maytansinoid, a combretastatin, or a dolastatin.  
     
     
         20 . The method of  claim 18 , wherein the antitubulin agent is AFP, MMAF, MMAE, AEB, AEVB, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, paclitaxel, docetaxel, epothilone A, epothilone B, nocodazole, colchicines, colcimid, estramustine, cemadotin, discodermolide, maytansine, DM-1, or eleutherobin.  
     
     
         21 . The method of  claim 20 , wherein the cytotoxic agent is AFP, MMAF, or MMAE.  
     
     
         22 . The method of  claim 1 , wherein the antibody is conjugated to the cytotoxic agent via a linker.  
     
     
         23 . The method of  claim 22 , wherein the linker is cleavable under intracellular conditions.  
     
     
         24 . The method of  claim 23 , wherein the cleavable linker is a peptide linker cleavable by an intracellular protease.  
     
     
         25 . The method of  claim 24 , wherein the peptide linker is a dipeptide linker.  
     
     
         26 . The method of  claim 25 , wherein the dipeptide linker comprises a val-cit or a phe-lys dipeptide.  
     
     
         27 . The method of  claim 23 , wherein the cleavable linker is hydrolyzable at a pH of less than 5.5.  
     
     
         28 . The method of  claim 27 , wherein the hydrolyzable linker is a hydrazone linker.  
     
     
         29 . The method of  claim 23 , wherein the cleavable linker is a disulfide linker.  
     
     
         30 . The method of  claim 1 , wherein the subject is human.  
     
     
         31 . A method for the treatment of a cancer in a subject, the method comprising: 
 administering to the subject in need thereof from about one to about ten suboptimal dosages, over a period of about four to about ten days, of an antibody-drug conjugate comprising an antibody that binds CD70 expressed on the cancer and wherein the antibody is conjugated to a cytotoxic agent or an immunosuppressive agent.    thymic carcinoma, a nasopharyngeal carcinoma, and a brain tumor.    
     
     
         32 . The method of  claim 30 , wherein the kidney tumor is a renal cell carcinoma.  
     
     
         33 . The method of  claim 35 , wherein the suboptimal dosage is from about 0.05 to 1 mg/kg.  
     
     
         34 . The method of  claim 1 , wherein the antibody competes for binding to CD70 with monoclonal antibody 1F6 or 2F2.  
     
     
         35 . 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 to CD70 and wherein the antibody is conjugated to a cytotoxic agent or an immunosuppressive agent.    
     
     
         36 . The method of  claim 35 , wherein the antibody competes for binding to CD70 with monoclonal antibody 1F6 or 2F2.  
     
     
         37 . The method of  claim 36 , wherein the antibody comprises at least one polypeptide region selected from the group consisting of 
 (a) an H1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:6;    (b) an H2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:8;    (c) an H3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:10;    (d) an L1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:16;    (e) an L2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:18;    (f) an L3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:20;    (g) an H1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:26;    (h) an H2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:28;    (i) an H3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:30;    (j) an L1 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:36;    (k) an L2 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:38; and    (l) an L3 region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:40.    
     
     
         38 . The method of  claim 37 , wherein the antibody comprises 
 the H1, H2, and H3 regions of (a), (b), and (c); or    the H1, H2, and H3 regions of (g), (h), and (i).    
     
     
         39 . The method of  claim 38 , wherein the polypeptide regions of (a), (b), (c), (d), (e), and (f) have, 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.  
     
     
         40 . The method of  claim 38 , wherein 
 the antibody comprising the H1, H2, and H3 regions of (a), (b), and (c) further comprises the L1, L2, and L3 regions of (d), (e), and (f); or    the antibody comprising the H1, H2, and H3 regions of (g), (h), and (i) further comprises the L1, L2, and L3 regions of (j), (k), and (l).    
     
     
         41 . The method of  claim 38 , wherein the antibody comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO 22.  
     
     
         42 . The method of  claim 41 , wherein the heavy chain variable region has the amino acid sequence set forth in SEQ ID NO:2 or SEQ ID NO:22.  
     
     
         43 . The method of  claim 41 , wherein the antibody, comprising the heavy chain variable region having at least 80% sequence identity to SEQ ID NO:2 or SEQ ID NO:22, further comprises, respectively, a light chain variable region having at least 80% sequence identity to the amino acid sequence set forth in SEQ ID NO:12 or SEQ ID NO:32.  
     
     
         44 . The method of  claim 43 , wherein the light chain variable region has the amino acid sequence set forth in SEQ ID NO:12 or SEQ ID NO:32.  
     
     
         45 . The method of  claim 44 , wherein the antibody is monoclonal antibody 1F6 or 2F2.  
     
     
         46 . The method of  claim 45 , wherein the antibody-drug conjugate is selected from the group consisting of humanized 1F6-val-cit-AFP, humanized 1F6-val-cit-MMAF, humanized 1F6-val-cit-MMAE, humanized 2F2-val-cit-AFP, humanized 2F2-val-cit-MMAF, and humanized 2F2-val-cit-MMAE.  
     
     
         47 . The method of  claim 35 , wherein the antibody is a chimeric, humanized, or human antibody.  
     
     
         48 . The method of  claim 47 , wherein the chimeric antibody comprises a human constant region.  
     
     
         49 . The method of  claim 35 , wherein the antibody is multivalent.  
     
     
         50 . The method of  claim 35 , 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 lexitropsin, a duocarmycin, a taxane, a puromycin, a dolastatin, a maytansinoid, and a vinca alkaloid.  
     
     
         51 . The method of  claim 35 , wherein the cytotoxic agent is AFP, MMAF, MMAE, AEB, AEVB, auristatin E, paclitaxel, docetaxel, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, dolastatin-10, echinomycin, combretatstatin, chalicheamicin, maytansine, DM-1, or netropsin.  
     
     
         52 . The method of  claim 35 , wherein the cytotoxic agent is an anti-tubulin agent.  
     
     
         53 . The method of  claim 52 , wherein the anti-tubulin agent is an auristatin, a vinca alkaloid, a podophyllotoxin, a taxane, a baccatin derivative, a cryptophysin, a maytansinoid, a combretastatin, or a dolastatin.  
     
     
         54 . The method of  claim 52 , wherein the antitubulin agent is AFP, MMAF, MMAE, AEB, AEVB, auristatin E, vincristine, vinblastine, vindesine, vinorelbine, VP-16, camptothecin, paclitaxel, docetaxel, epothilone A, epothilone B, nocodazole, colchicines, colcimid, estramustine, cemadotin, discodermolide, maytansine, DM-1, or eleutherobin.  
     
     
         55 . The method of  claim 54 , wherein the cytotoxic agent is AFP, MMAF, or MMAE.  
     
     
         56 . The method of  claim 35 , wherein the immunosuppressive agent is 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.  
     
     
         57 . The method of  claim 35 , wherein the antibody is conjugated to the cytotoxic agent or the immunosuppressive agent via a linker.  
     
     
         58 . The method of  claim 57 , wherein the linker is cleavable under intracellular conditions.  
     
     
         59 . The method of  claim 58 , wherein the cleavable linker is a peptide linker cleavable by an intracellular protease.  
     
     
         60 . The method of  claim 58 , wherein the intracellular protease is a lysosomal protease or an endosomal protease.  
     
     
         61 . The method of  claim 58 , wherein the peptide linker is a dipeptide linker.  
     
     
         62 . The method of  claim 61 , wherein the dipeptide linker comprises a val-cit linker or a phe-lys dipeptide.  
     
     
         63 . The method of  claim 57 , wherein the cleavable linker is hydrolyzable at a pH of less than 5.5.  
     
     
         64 . The method of  claim 63 , wherein the hydrolyzable linker is a hydrazone linker.  
     
     
         65 . The method of  claim 57 , wherein the cleavable linker is a disulfide linker.  
     
     
         66 . The method of  claim 35 , wherein the immunological disorder is a T cell-mediated immunological disorder.  
     
     
         67 . The method of  claim 66 , wherein the T cell mediated immunological disorder is a T-cell mediated and include activated T cell expressing CD70.  
     
     
         68 . The method of  claim 67 , wherein resting T cells are not substantially depleted by administration of the antibody-drug conjugate.  
     
     
         69 . The method of  claim 66 , 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.  
     
     
         70 . The method of  claim 35 , wherein the immunological disorder is an activated B-lymphocyte disorder.  
     
     
         71 . The method of  claim 35 , wherein the subject is human.