Combination Therapies with Anti-CD38 Antibodies

Abstract

The present invention relates to combination therapies with anti-CD38 antibodies and all-trans retinoic acid.

1 . A method of treating a subject having a CD38-positive hematological malignancy, comprising administering to the subject in need thereof an anti-CD38 antibody in combination with all-trans retinoic acid (ATRA). 
     
     
         2 . The method of  claim 1 , wherein the anti-CD38 antibody induces killing of CD38-expressing cells in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). 
     
     
         3 . The method of  claim 2 , wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by CDC in vitro. 
     
     
         4 . The method of  claim 2 , wherein the anti-CD38 antibody induces killing of the CD38-expressing cells by ADCC in vitro. 
     
     
         5 . The method of any one of  claims 1 ,  2   3  or  4 , wherein the CD38-positive hematological malignancy is multiple myeloma (MM), acute lymphoblastic leukemia (ALL), non-Hodgkin's lymphoma (NHL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL), follicular lymphoma (FL) or mantle-cell lymphoma (MCL). 
     
     
         6 . The method of  claim 5 , wherein the CD38-positive hematological malignancy is MM. 
     
     
         7 . The method of  claim 6 , wherein the subject is resistant to or has acquired resistance to treatment with at least one chemotherapeutic agent, an anti-CD38 antibody, or a combination of at least one chemotherapeutic agent and an anti-CD38 antibody. 
     
     
         8 . The method of  claim 7 , wherein the at least one chemotherapeutic agent is lenalidomide, bortezomib, melphalan, dexamethasone or thalidomide. 
     
     
         9 . The method of  claim 8 , wherein the at least one chemotherapeutic agent is lenalidomide or bortezomib. 
     
     
         10 . The method of  claim 1 ,  2 ,  3  or  4 , wherein the anti-CD38 antibody is of IgG1, IgG2, IgG3 or IgG4 isotype. 
     
     
         11 . The method of  claim 10 , wherein the anti-CD38 antibody is of IgG1 isotype. 
     
     
         12 . The method of  claim 1 , wherein the anti-CD38 antibody competes for binding to CD38 with an antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 4 and a light chain variable region (VL) of SEQ ID NO: 5. 
     
     
         13 . The method of  claim 12 , wherein the antibody binds to the region SKRNIQFSCKNIYR (SEQ ID NO: 2) and the region EKVQTLEAWVIHGG (SEQ ID NO: 3) of human CD38 (SEQ ID NO: 1). 
     
     
         14 . The method of  claim 13 , wherein the anti-CD38 antibody comprises the heavy chain complementarity determining regions (HCDR) 1 (HCDR1), 2 (HCDR2) and 3 (HCDR3) sequences of SEQ ID NOs: 6, 7 and 8, respectively. 
     
     
         15 . The method of  claim 14 , wherein the anti-CD38 antibody comprises the light chain complementarity determining regions (LCDR) 1 (LCDR1), 2 (LCDR2) and 3 (LCDR3) sequences of SEQ ID NOs: 9, 10 and 11, respectively. 
     
     
         16 . The method of  claim 15 , wherein the anti-CD38 antibody comprises the heavy chain variable region (VH) of SEQ ID NO: 4 and the light chain variable region (VL) of SEQ ID NO: 5. 
     
     
         17 . The method of  claim 1 , wherein the anti-CD38 antibody comprises a heavy chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 12 and a light chain comprising an amino acid sequence that is 95%, 96%, 97%, 98% or 99% identical to that of SEQ ID NO: 13. 
     
     
         18 . The method of  claim 1 , wherein the anti-CD38 antibody comprises the heavy chain of SEQ ID NO: 12 and the light chain of SEQ ID NO: 13. 
     
     
         19 . The method of  claim 1 , wherein the anti-CD38 antibody comprises the VH of SEQ ID NO: 14 and the VL of SEQ ID NO: 15. 
     
     
         20 . The method of  claim 1 , wherein the anti-CD38 antibody comprises the VH of SEQ ID NO: 16 and the VL of SEQ ID NO: 17. 
     
     
         21 . The method of  claim 1 , wherein the anti-CD38 antibody comprises the VH of SEQ ID NO: 18 and the VL of SEQ ID NO: 19. 
     
     
         22 . The method of  claim 1 , wherein the anti-CD38 antibody comprises the VH of SEQ ID NO: 20 and the VL of SEQ ID NO: 21.