Novel anti-cd38 antibodies for the treatment of cancer

Abstract

Antibodies, humanized antibodies, resurfaced antibodies, antibody fragments, derivatized antibodies, and conjugates of same with cytotoxic agents, which specifically bind to CD38, are capable of killing CD38 + cells by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and/or complement-dependent cytotoxicity (CDC). Said antibodies and fragments thereof may be used in the treatment of tumors that express CD38 protein, such as multiple myeloma, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, or acute lymphocytic leukemia, or the treatment of autoimmune and inflammatory diseases such as systemic lupus, rheumatoid arthritis, multiple sclerosis, erythematosus, and asthma. Said derivatized antibodies may be used in the diagnosis and imaging of tumors that express elevated levels of CD38. Also provided are cytotoxic conjugates comprising a cell binding agent and a cytotoxic agent, therapeutic compositions comprising the conjugate, methods for using the conjugates in the inhibition of cell growth and the treatment of disease, and a kit comprising the cytotoxic conjugate. In particular, the cell binding agent is a monoclonal antibody, and epitope-binding fragments thereof, that recognizes and binds the CD38 protein.

1 ) An antibody or epitope-binding fragment thereof that specifically binds CD38, characterized in that said antibody or epitope-binding fragment thereof is capable of killing a CD38 +  cell by apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytoxicity (CDC). 
     
     
         2 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing said CD38 +  cell by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         3 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is a monoclonal antibody. 
     
     
         4 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said CD38 +  cell is a lymphoma cell, a leukemia cell, or a multiple myeloma cell. 
     
     
         5 ) The antibody or epitope-binding fragment thereof of  claim 4 , characterized in that said CD38 +  cell is a non-Hodgkin's lymphoma (NHL) cell, a Burkitt's lymphoma (BL) cell, a multiple myeloma (MM) cell, a B chronic lymphocytic leukemia (B-CLL) cell, a B and T acute lymphocytic leukemia (ALL) cell, a T cell lymphoma (TCL) cell, an acute myeloid leukemia (AML) cell, a hairy cell leukemia (HCL) cell, a Hodgkin's Lymphoma (HL) cell, or a chronic myeloid leukemia (CML) cell. 
     
     
         6 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing at least 24% of Daudi lymphoma cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         7 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 7% of Ramos lymphoma cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         8 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 11% of MOLP-8 multiple myeloma cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         9 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 36% of SU-DHL-8 lymphoma cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         10 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 62% of DND-41 leukemia cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         11 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 27% NU-DUL-1 lymphoma cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         12 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 9% of JVM-13 leukemia cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         13 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof is capable of killing more than 4% of HC-1 leukemia cells by apoptosis in the absence of stroma cells or stroma-derived cytokines. 
     
     
         14 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof binds CD38 with a k D  of 3×10 −9  M or lower. 
     
     
         15 ) The antibody or epitope-binding fragment thereof according to  claim 1 , characterized in that said antibody or epitope-binding fragment thereof comprises one or more complementarity-determining region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36. 
     
     
         16 ) The antibody or epitope-binding fragment thereof according to  claim 15 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, and said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs:1, 2, 3, 7, 8, 9, 13, 14, 15, 19, 20, 21, 25, 26, 27, 31, 32, and 33, and said light chain comprises three sequential complementarity-determining regions having amino acid sequences selected from the group consisting of SEQ ID NOs: 4, 5, 6, 10, 11, 12, 16, 17, 18, 22, 23, 24, 28, 29, 30, 34, 35, and 36. 
     
     
         17 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 38, 40, 42, 44, 46, and 48. 
     
     
         18 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence selected from the group consisting of SEQ ID NOS: 50, 52, 54, 56, 58, 60. 
     
     
         19 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 1, 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 4, 5, and 6. 
     
     
         20 ) The antibody or epitope-binding fragment thereof according to  claim 19 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 38. 
     
     
         21 ) The antibody or epitope-binding fragment thereof according to  claim 19 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 50. 
     
     
         22 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 10, 11, and 12. 
     
     
         23 ) The antibody or epitope-binding fragment thereof according to  claim 22 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 40. 
     
     
         24 ) The antibody or epitope-binding fragment thereof according to  claim 22 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 52. 
     
     
         25 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18. 
     
     
         26 ) The antibody or epitope-binding fragment thereof according to  claim 25 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 42. 
     
     
         27 ) The antibody or epitope-binding fragment thereof according to  claim 25 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 54. 
     
     
         28 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 19, 20, and 21, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 22, 23, and 24. 
     
     
         29 ) The antibody or epitope-binding fragment thereof according to  claim 28 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 44. 
     
     
         30 ) The antibody or epitope-binding fragment thereof according to  claim 28 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 56. 
     
     
         31 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30. 
     
     
         32 ) The antibody or epitope-binding fragment thereof according to  claim 31 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 46. 
     
     
         33 ) The antibody or epitope-binding fragment thereof according to  claim 31 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 58. 
     
     
         34 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 31, 32, and 33, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 34, 35, and 36. 
     
     
         35 ) The antibody or epitope-binding fragment thereof according to  claim 34 , characterized in that said antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence consisting of SEQ ID NO: 48. 
     
     
         36 ) The antibody or epitope-binding fragment thereof according to  claim 34 , characterized in that said antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence consisting of SEQ ID NO: 60. 
     
     
         37 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof is produced by a hybridoma cell line selected from the group of hybridoma cell lines deposited at the American Type Culture Collection (10801 University Bld, Manassas, Va., 20110-2209, USA), on Jun. 21, 2006, under the deposit numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671. 
     
     
         38 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one human constant region. 
     
     
         39 ) The antibody or epitope-binding fragment thereof according to  claim 38 , characterized in that said constant region is the human IgG1/IgKappa constant region. 
     
     
         40 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof is a humanized or resurfaced antibody. 
     
     
         41 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 1, 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 4, 5, and 6. 
     
     
         42 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 10, 11, and 12. 
     
     
         43 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 13, 14, and 15, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 16, 17, and 18. 
     
     
         44 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 43 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence represented by SEQ ID NO: 66. 
     
     
         45 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 43 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence selected from the group of SEQ ID NOS: 62 and 64. 
     
     
         46 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 19, 20, and 21, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 22, 23, and 24. 
     
     
         47 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 25, 26, and 27, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 28, 29, and 30. 
     
     
         48 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 47 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a heavy chain variable region having an amino acid sequence represented by SEQ ID NO: 72. 
     
     
         49 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 47 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises a light chain variable region having an amino acid sequence selected from the group of SEQ ID NOS: 68 and 70. 
     
     
         50 ) The humanized or resurfaced antibody or epitope-binding fragment thereof according to  claim 40 , characterized in that said humanized or resurfaced antibody or epitope-binding fragment thereof comprises at least one heavy chain and at least one light chain, wherein said heavy chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 31, 32, and 33, and wherein said light chain comprises three sequential complementarity-determining regions having amino acid sequences represented by SEQ ID NOS: 34, 35, and 36. 
     
     
         51 ) The antibody or epitope-binding fragment thereof according to  claim 16 , characterized in that said antibody or epitope-binding fragment thereof is a Fab, Fab′, F(ab′)2 or Fv fragment. 
     
     
         52 ) The antibody or epitope-binding fragment thereof according to  claim 1  wherein the antibody or epitope-binding fragment is linked to a cytotoxic agent thereby forming a conjugate. 
     
     
         53 ) The conjugate of  claim 52 , characterized in that said cytotoxic agent is selected from the group consisting of a maytansinoid, a small drug, a tomaymycin derivative, a leptomycin derivative, a prodrug, a taxoid, CC-1065 and a CC-1065 analog. 
     
     
         54 ) The conjugate of  claim 53 , characterized in that said cytotoxic agent is the maytansine DM1 of formula: 
       
         
           
           
               
               
           
         
       
     
     
         55 ) The conjugate of  claim 53 , characterized in that said cytotoxic agent is the maytansine DM4 of formula: 
       
         
           
           
               
               
           
         
       
     
     
         56 ) The conjugate of  claim 53 , characterized in that said cytotoxic agent is a tomaymycin derivative selected from the group consisting of:
 8,8′-[1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-methoxy-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[1,5-pentanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[1,4-butanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[3-methyl-1,5-pentanediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[2,6-pyridinediylbis(oxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′44-(3-tert-butoxycarbonylaminopropyloxy)-2,6-pyridinediylbis-(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(3-aminopropyloxy)-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(N-methyl-3-tert-butoxycarbonylaminopropyl)-1,3-benzenediylbis-(methyleneoxy)]-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-{5-[3-(4-methyl-4-methyldisulfanyl-pentanoylamino)propyloxy]-1,3-benzenediylbis(methyleneoxy)}-bis[(S)-2-eth-(E)-ylidene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-acetylthiomethyl-1,3-benzenediylbis(methyleneoxy)]-bis[(S)-2-methylene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   bis-{2-[(S)-2-methylene-7-methoxy-5-oxo-1,3,,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy]-ethyl}-carbamic acid tert-butyl ester   8,8′-[3-(2-acetylthioethyl)-1,5-pentanediylbis(oxy)]-bis[(S)-2-methylene-7-methoxy-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(N-4-mercapto-4,4-dimethylbutanoyl)amino-1,3-benzenediylbis(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(N-4-methyldithio-4,4-dimethylbutanoyl)-amino-1,3-benzenediylbis(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(N-methyl-N-(2-mercapto-2,2-dimethylethyl)amino-1,3-benzenediyl(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[5-(N-methyl-N-(2-methyldithio-2,2-dimethylethyl)amino-1,3-benzenediyl(methyleneoxy)]-bis[7-methoxy-2-methylene-1,2,3,11a-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(2-(4-mercapto-4-methyl)-pentanamido-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(2-(4-methyl-4-methyldisulfanyl)-pentanamido-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(3-(4-methyl-4-methyldisulfanyl)-pentanamido-propoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(4-(4-methyl-4-methyldisulfanyl)-pentanamido-butoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(3-[4-(4-methyl-4-methyldisulfanyl-pentanoyl)-piperazin-1-yl]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(3-[4-(4-methyl-4-methyldisulfanyl-pentanoyl)-piperazin-1-yl]-propyl)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(2-{2-[2-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(2-{2-[2-(2-{2-[2-(4-methyl-4-methyldisulfanyl-pentanoylamino)-ethoxy]-ethoxy}-ethoxy)-ethoxy]ethoxy}-ethoxy)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(2-[methyl-(2-methyl-2-methyldisulfanyl-propyl)-amino]-ethoxy)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(3-[methyl-(4-methyl-4-methyldisulfanyl-pentanoyl)-amino]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(4-(3-[methyl-(2-methyl-2-methyldisulfanyl-propyl)-amino]-propyl)-pyridin-2,6-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one]   8,8′-[(1-(4-methyl-4-methyldisulfanyl)-pentanamido)-benzene-3,5-dimethyl)-dioxy]-bis[(S)-2-eth-(E)-ylidene-7-dimethoxy-1,2,3,11a-tetrahydro-pyrrolo[2,1-c][1,4]benzodiazepin-5-one].   
     
     
         57 ) The conjugate of  claim 53 , characterized in that the cytotoxic agent is a leptomycin derivative selected from the group consisting of:
 (2-Methylsulfanyl-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-Hydroxy-3,5, 7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid (2-methylsulfanyl-ethyl)-amid   Bis-[(2-mercaptoethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9, 11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid]   (2-Mercapto-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11, 15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid   (2-Methyldisulfanyl-ethyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid   (2-Methyl-2-methyldisulfanyl-propyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid   (2-Mercapto-2-methyl-propyl)-amid of (2E,10E,12E,16Z,18E)-(R)-6-hydroxy-3,5,7,9,11,15,17-heptamethyl-19-((2S,3S)-3-methyl-6-oxo-3,6-dihydro-2H-pyran-2-yl)-8-oxo-nonadeca-2,10,12,16,18-pentaenoic acid.   
     
     
         58 ) The antibody or epitope-binding fragment thereof according to  claim 1  or the conjugate according to  claim 52 , for use as a medicament. 
     
     
         59 ) A pharmaceutical composition comprising the antibody or epitope-binding fragment thereof according to  claim 1  or the conjugate according to  claim 52 , and a pharmaceutically acceptable carrier or excipients. 
     
     
         60 ) The pharmaceutical composition of  claim 59 , characterized in that said composition contains a further therapeutic agent. 
     
     
         61 ) The pharmaceutical composition of  claim 60 , characterized in that the further therapeutic agent is an antagonist of epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP) or vascular endothelial growth factor (VEGF), or an antagonist of a receptor for epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP), or vascular endothelial growth factor (VEGF), including HER2 receptor, HER3 receptor, c-MET, and other receptor tyrosine kinases. 
     
     
         62 ) The pharmaceutical composition of  claim 60 , characterized in that the further therapeutic agent is an antibody directed against a cluster of differentiation antigen selected from a group comprising CD3, CD14, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD36, CD40, CD44, CD52, CD55, CD59, CD56, CD70, CD79, CD80, CD103, CD134, CD137, CD138, and CD152. 
     
     
         63 ) A method of treating cancer or autoimmune disease comprising administering a medicament comprising a pharmaceutical composition comprising the antibody or epitope-binding fragment thereof according to  claim 1  or the conjugate according to  claim 52 , to make a medicament to treat cancer or autoimmune disease. 
     
     
         64 ) The method of  claim 63 , characterized in that said cancer is selected from the group consisting of carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarama, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma. 
     
     
         65 ) The method of  claim 63 , characterized in that said cancer is hematopoietic tumors of lymphoid lineage, including leukemia, non-Hodgkin's lymphoma, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, multiple myeloma, chronic lymphocytic leukemia; hematopoietic tumors of myeloid lineage, including acute and chronic myeloid leukemias and promyelocytic leukemia. 
     
     
         66 ) The method of  claim 63 , characterized in that said autoimmune or inflammatory disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Crohn's diasease, ulcerative colitis, gastritis, Hashimoto's thyroiditis, ankylosing spondylitis, hepatitis C-associated cryoglobulinemic vasculitis, chronic focal encephalitis, bullous pemphigoid, hemophilia A, membranoproliferative glomerulnephritis, Sjogren's syndrome, adult and juvenile dermatomyositis, adult polymyositis, chronic urticaria, primary biliary cirrhosis, idiopathic thrombocytopenic purpura, neuromyelitis optica, Graves' dysthyroid disease, bullous pemphigoid, membranoproliferative glonerulonephritis, Churg-Strauss syndrome, and asthma. 
     
     
         67 ) The method according to  claim 63 , further comprising the use of a further therapeutic agent in the manufacture of the same or different composition. 
     
     
         68 ) The method according to  claim 67 , characterized in that the further therapeutic agent is an antagonist of fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP) or vascular endothelial growth factor (VEGF), or an antagonist of a receptor for epidermal-growth factor (EGF), fibroblast-growth factor (FGF), hepatocyte growth factor (HGF), tissue factor (TF), protein C, protein S, platelet-derived growth factor (PDGF), heregulin, macrophage-stimulating protein (MSP), or vascular endothelial growth factor (VEGF), including HER2 receptor, HER3 receptor, c-MET, and other receptor tyrosine kinases. 
     
     
         69 ) The method according to  claim 67 , characterized in that the further therapeutic agent is an antibody directed against a cluster of differentiation antigen selected from a group comprising CD3, CD14, CD19, CD20, CD22, CD25, CD28, CD30, CD33, CD36, CD40, CD44, CD52, CD55, CD59, CD56, CD70, CD79, CD80, CD103, CD134, CD137, CD138, and CD152. 
     
     
         70 ) A method of diagnosing a cancer in a subject known to or suspected to have a cancer, said method comprising:
 a) Contacting cells of said patient with an antibody or epitope-binding fragment thereof according to  claim 1 ,   b) Measuring the binding of said antibody or epitope-binding fragment thereof to said cells, and   c) comparing the expression in part (b) with that of a normal reference subject or standard.   
     
     
         71 ) The method of  claim 70 , characterized in that said cancer is selected from the group consisting of carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, ovary, pancreas, stomach, cervix, thyroid and skin; including squamous cell carcinoma; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyoscarcoma; other tumors, including melanoma, seminoma, tetratocarcinoma, neuroblastoma and glioma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin, including fibrosarcoma, rhabdomyoscarama, and osteosarcoma; and other tumors, including melanoma, xeroderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer and teratocarcinoma. 
     
     
         72 ) The method of  claim 70 , wherein said cancer is hematopoietic tumors of lymphoid lineage, including leukemia, non-Hodgkin's lymphoma, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, multiple myeloma, chronic lymphocytic leukemia; hematopoietic tumors of myeloid lineage, including acute and chronic myeloid leukemias and promyelocytic leukemia. 
     
     
         73 ) The method of  claim 70 , characterized in that the said cells are in frozen or fixed tissue or cells from said patient. 
     
     
         74 ) A polynucleotide encoding a polypeptide selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, and 72. 
     
     
         75 ) The polynucleotide according to  claim 74 , characterized in that said polynucleotide has a sequence sharing at least 80% homology with a polynucleotide selected from the group consisting of SEQ ID NOs: 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, and 71. 
     
     
         76 ) A recombinant vector comprising a nucleic acid of any of  claim 74  or  75 . 
     
     
         77 ) A host cell comprising a vector of  claim 76 . 
     
     
         78 ) An antibody or epitope-binding fragment thereof according to  claim 1  or the conjugate according to  claim 52 , characterized in that said antibody or epitope-binding fragment thereof binds to an epitope of the human CD38 extracellular domain that comprises residues at least 10 residues selected among Pro75, Glu76, His79, Gln107, Pro108, Met110, Lys111, Leu112, Gly113, Thr114, Gln115, Thr116, Val117, Pro118, Cys119, Thr148, Leu150, Arg194, Arg195, Glu198, Ala199, Cys201 and Glu233 or a conservatively substituted form thereof. 
     
     
         79 ) An antibody or epitope-binding fragment thereof, characterized in that said antibody or epitope-binding fragment thereof that specifically binds to the same epitope bound by a monoclonal antibody produced by a hybridoma cell line selected from the group of hybridoma cell lines deposited at the American Type Culture Collection (10801 University Bld, Manassas, Va., 20110-2209, USA), on Jun. 21, 2006, under the deposit numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671.