Combination treatment of cd38-expressing tumors

Abstract

The invention relates to novel method for the treatment of cancer using a combination therapy comprising an antibody that binds CD38, a corticosteroid and a non-corticosteroid chemotherapeutic agent.

1 - 108 . (canceled) 
     
     
         109 . A method for inhibiting growth and/or proliferation of tumor cells expressing CD38 in an individual in need thereof, which method comprises administration to the said individual of
 i) a non-agonistic antibody which binds to CD38,   ii) at least one corticosteroid, and   iii) at least one non-corticosteroid chemotherapeutic agent selected from the group consisting of a proteasome inhibitor and a glutamic acid derivative.   
     
     
         110 . A method for treating cancer involving tumor cells expressing CD38 in an individual in need thereof, which method comprises administration to the said individual of:
 i) a non-agonistic antibody which binds to CD38,   ii) optionally at least one corticosteroid, and   iii) optionally at least one non-corticosteroid chemotherapeutic agent, followed by autologous peripheral stem cell or bone marrow transplantation.   
     
     
         111 . The method of  claim 109 , wherein said antibody is a full length IgG1 or IgM antibody. 
     
     
         112 . The method of  claim 109 , wherein said antibody does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells. 
     
     
         113 . The method of  claim 109 , wherein said antibody does not induce release of detectable IFN-γ by human T cells or peripheral blood mononuclear cells. 
     
     
         114 . The method of  claim 109 , wherein said antibody is internalized by CD38-expressing cells. 
     
     
         115 . The method of  claim 109 , wherein said antibody induces ADCC of CD38 expressing cells. 
     
     
         116 . The method of  claim 115 , wherein said antibody induces ADCC with an EC50 value of below 15 ng/ml in multiple myeloma cells. 
     
     
         117 . The method of  claim 109 , wherein said antibody induces CDC of CD38 expressing cells in the presence of complement. 
     
     
         118 . The method of  claim 117 , wherein said antibody induces CDC with an EC50 value of below 5 μg/ml in Daudi-luc or CD38-CHO cells. 
     
     
         119 . The method of  claim 109 , wherein said antibody inhibits the synthesis of cGDPR. 
     
     
         120 . The method of  claim 119 , wherein said antibody inhibits the synthesis of cGDPR by at least 25 after 90 minutes at a concentration of 3 μg/ml. 
     
     
         121 . The method of  claim 109 , wherein said antibody inhibits the synthesis of cADPR. 
     
     
         122 . The method of  claim 121 , wherein said antibody inhibits the synthesis of cADPR by at least 25% after 90 minutes at a concentration of 3 μg/ml. 
     
     
         123 . The method of  claim 109 , wherein said antibody competes with an antibody having a VL sequence of SEQ ID No:2 and a VH sequence of SEQ ID No:7; an antibody having a VL sequence of SEQ ID No:12 and a VH sequence of SEQ ID No:17 or an antibody having a VL sequence of SEQ ID No:22 and a VH sequence of SEQ ID No:27, for binding to CD38. 
     
     
         124 . The method of  claim 109 , wherein said antibody is an antibody that specifically binds to a CD38 epitope that also is specifically bound by an antibody having a VL sequence of SEQ ID No:2 and a VH sequence of SEQ ID No:7; an antibody having a VL sequence of SEQ ID No:12 and a VH sequence of SEQ ID No:17; or an antibody having a VL sequence of SEQ ID No:22 and a VH sequence of SEQ ID No:27. 
     
     
         125 . The method of  claim 124 , wherein said antibody binds to the regions SKRNIQFSCKNIYR and EKVQTLEAWVIHGG of human CD38 (SEQ ID NO:31). 
     
     
         126 . The method of  claim 124 , wherein the binding of said antibody to human CD38 is sensitive to mutations at positions 272 and 274 of human CD38. 
     
     
         127 . The method of  claim 124 , wherein said antibody is not able to bind to mutant CD38 wherein serine at position 274 is replaced by phenylalanine. 
     
     
         128 . The method of  claim 109 , wherein said at least one corticosteroid comprises dexamethasone. 
     
     
         129 . The method of  claim 109 , wherein said at least one corticosteroid comprises prednisone. 
     
     
         130 . The method of  claim 109 , wherein said glutamic acid derivative is thalidomide or a thalidomide analog. 
     
     
         131 . The method of  claim 130 , wherein said thalidomide analog is lenalidomide. 
     
     
         132 . The method of  claim 128 , wherein said glutamic acid derivative is thalidomide or a thalidomide analog. 
     
     
         133 . The method of  claim 132 , wherein said thalidomide analog is lenalidomide. 
     
     
         134 . The method of  claim 109 , wherein said proteasome inhibitor is bortezomib. 
     
     
         135 . The method of  claim 134 , wherein said at least one non-corticosteroid chemotherapeutic agent further comprises one or more agents selected from the group consisting of: melphalan, mechlorethamine, thioepa, chlorambucil, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine (DTIC), procarbazine, mitomycin C, cisplatin and other platinum derivatives, such as carboplatin. 
     
     
         136 . The method of  claim 128 , wherein said proteasome inhibitor is bortezomib. 
     
     
         137 . The method of  claim 136 , wherein said at least one corticosteroid comprises a glutamic acid derivative which is thalidomide or lenalidomide. 
     
     
         138 . The method of  claim 109 , wherein said non-agonistic antibody, said at least one corticosteroid and said at least one non-corticosteroid chemotherapeutic agent are administered sequentially. 
     
     
         139 . The method of  claim 109 , wherein said non-agonistic antibody, said at least one corticosteroid and said at least one non-corticosteroid chemotherapeutic agent are administered separately. 
     
     
         140 . The method  claim 109 , wherein said antibody is administered in a dose of from 1 to 20 mg/kg. 
     
     
         141 . The method of  claim 109 , wherein said antibody is administered once weekly for 2 to 12 weeks. 
     
     
         142 . The method of  claim 109 , wherein said tumor cells expressing CD38 are from a B cell lymphoma, plasma cell malignancy, T/NK cell lymphoma or a myeloid malignancy. 
     
     
         143 . The method of  claim 142 , wherein said tumor cells expressing CD38 are multiple myeloma cells. 
     
     
         144 . The method of  claim 142 , wherein said tumor cells expressing CD38 are chronic lymhocytic leukemia cells. 
     
     
         145 . The method of  claim 109 , wherein said tumor cells are recurrent or refractory tumor cells. 
     
     
         146 . The method of  claim 109 , wherein said individual has not responded to a previous anti-cancer treatment for multiple myeloma.