ANTI-CD38 HUMAN ANTIBODIES AND USES THEREOF
The present invention provides recombinant antigen-binding regions and antibodies and functional fragments containing such antigen-binding regions that are specific for CD38, which plays an integral role in various disorders or conditions. These antibodies, accordingly, can be used to treat, for example, hematological malignancies such as multiple myeloma. Antibodies of the invention also can be used in the diagnostics field, as well as for investigating the role of CD38 in the progression of disorders associated with malignancies. The invention also provides nucleic acid sequences encoding the foregoing antibodies, vectors containing the same, pharmaceutical compositions and kits with instructions for use. The invention also provides isolated novel epitopes of CD38 and methods of use therefore.
1 - 114 . (canceled)
115 . An isolated monoclonal non-chimeric, non-CDR grafted antibody based on a human sequence that binds human CD38 (SEQ ID NO: 22),
(a) wherein said antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 1 nM or less when a human PBMC cell is employed as the effector cell, wherein said CD38+ target cell is selected from LP-1 (DSMZ: ACC41) or RPMI-8226 (ATCC: CCL-155), and wherein the ratio of effector cells to target cells is from 30:1 to 50:1,
(b) wherein said antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 3.2 nM or less,
(c) wherein said antibody comprises a VH3 variable heavy chain and kappa variable light chain, and
(d) wherein the antibody comprises an IgG1 constant region.
116 . The antibody according to claim 115 , wherein the variable heavy chain comprises a framework 1 region comprising SGGGLVQPGGSLRLSC, a framework 2 region comprising VRQAPGKGLEW, a framework 3 region comprising FTISRDNSKNTLYLQMNSLRAEDTAV and a framework 4 region comprising GQGTLVTV.
117 . The antibody according to claim 116 , wherein the variable light chain comprises a framework 1 region comprising TQSP, a framework 2 region comprising QKPG, a framework 3 region comprising RFSGSGSGTDFTL and a framework 4 region comprising TFGQGTKVEIK.
118 . The antibody according to claim 115 , wherein the antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.60 nM or less.
119 . The antibody according to claim 118 , wherein the antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.28 nM or less.
120 . The antibody according to claim 119 , wherein the antibody mediates killing of a CD38+ target cell by antibody dependent cellular cytotoxicity with an EC50 of 0.17 nM or less.
121 . The antibody according to claim 115 , wherein the antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 0.94 nM or less.
122 . The antibody according to claim 121 , wherein the antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 of 0.41 nM or less.
123 . The antibody according to claim 115 , wherein the antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 in the range of 3.2 nM to 0.94 nM.
124 . The antibody according to claim 115 , wherein the antibody mediates killing of a CD38-transfected CHO cell by complement dependent cytotoxicity with an EC50 in the range of 3.2 nM to 0.41 nM.
125 . The antibody according to claim 115 , wherein the antibody has a CDRH1 having a length about 5, CDRH2 having a length about 17, CDRH3 having a length about 13, a CDRL1 having a length about 11, CDRL2 having a length about 7, and CDRL3 having a length about 9.
126 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acid residues within amino acids 44-66 of CD38 (SEQ ID NO: 22).
127 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 110-122 of CD38 (SEQ ID NO: 22).
128 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 148-164 of CD38 (SEQ ID NO: 22).
129 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 186-200 of CD38 (SEQ ID NO: 22).
130 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 202-224 of CD38 (SEQ ID NO: 22).
131 . The antibody according to claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO:13.
132 . The antibody according to claim 131 , wherein said antibody binds to the same epitope of CD38 of an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 5 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 13.
133 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 192-206 of CD38 (SEQ ID NO: 22).
134 . The antibody according to claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 14.
135 . The antibody according to claim 134 , wherein said antibody binds to the same epitope of CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 6 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 14.
136 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 82-94 of CD38 (SEQ ID NO: 22).
137 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 158-170 of CD38 (SEQ ID NO: 22).
138 . The antibody according to claim 115 , wherein said antibody competes in binding to CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 15.
139 . The antibody according to claim 138 , wherein said antibody binds to the same epitope of CD38 with an antibody comprising an H-CDR1, H-CDR2 and H-CDR3 depicted in SEQ ID NO: 7 and an L-CDR1, L-CDR2 and L-CDR3 depicted in SEQ ID NO: 15.
140 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 82-94 of CD38 (SEQ ID NO: 22).
141 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 142-154 of CD38 (SEQ ID NO: 22).
142 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 158-170 of CD38 (SEQ ID NO: 22).
143 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 188-200 of CD38 (SEQ ID NO: 22).
144 . The antibody according to claim 115 , wherein said antibody binds an epitope of CD38 that contains one or more amino acids residues within amino acids 280-296 of CD38 (SEQ ID NO: 22).