ANTIBODIES AGAINST CD38 FOR TREATMENT OF MULTIPLE MYELOMA
Isolated human monoclonal antibodies which bind to human CD38, and related antibody-based compositions and molecules, are disclosed. Also disclosed are pharmaceutical compositions comprising the human antibodies, and therapeutic and diagnostic methods for using the human antibodies.
1 - 87 . (canceled)
88 . An in vitro method for detecting the presence of CD38 antigen, or a cell expressing CD38, in a sample comprising:
(a) contacting the sample with an antibody that binds to human CD38 encoded by: (i) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 1 and SEQ ID NO: 6, respectively; (ii) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 11 and SEQ ID NO: 16, respectively; (iii) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 21 and SEQ ID NO: 26, respectively; or (iv) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions, which are conservative sequence modifications of the sequences as set forth in (i), (ii) or (iii), under conditions that allow formation of a complex between the antibody and CD38; and
(b) detecting the formation of the complex.
89 . An in vivo method for detecting the presence of CD38 antigen, or a cell expressing CD38, in a subject comprising:
(a) administering to the subject an antibody that binds to human CD38 encoded by: (i) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 1 and SEQ ID NO: 6, respectively; (ii) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 11 and SEQ ID NO: 16, respectively; (iii) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions as set forth in SEQ ID NO: 21 and SEQ ID NO: 26, respectively; or (iv) human light chain and human heavy chain nucleic acids comprising nucleotide sequences in their variable regions, which are conservative sequence modifications of the sequences as set forth in (i), (ii) or (iii), under conditions that allow formation of a complex between the peptide and CD38; and
(b) detecting the formation of the complex.
90 . An isolated nucleic acid encoding an antibody which binds to human CD38 (SEQ ID NO: 31), wherein:
(a) the antibody does not bind to a mutant human CD38, wherein in the mutant human CD38, the serine residue in position 274 has been substituted with a phenylalanine residue (SEQ ID NO: 34), and wherein the antibody inhibits the synthesis of cGDPR by at least 25% after 90 minutes at a concentration of 3 μg/ml;
(b) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7 or encoded by the nucleotide sequence set forth in SEQ ID NO: 6;
(c) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 or encoded by the nucleotide sequence set forth in SEQ ID NO: 16;
(d) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27 or encoded by the nucleotide sequence set forth in SEQ ID NO: 26;
(e) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2 or encoded by the nucleotide sequence set forth in SEQ ID NO: 1;
(f) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 or encoded by the nucleotide sequence set forth in SEQ ID NO: 11
(g) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22 or encoded by the nucleotide sequence set forth in SEQ ID NO: 21;
(h) the antibody comprises heavy and light chain variable region amino acid sequences as set forth in (i) SEQ ID NOs: 7 and 2, respectively; (ii) SEQ ID NOs: 17 and 12, respectively; or (iii) SEQ ID NOs: 27 and 22, respectively;
(i) the antibody comprises heavy and light chain variable regions encoded by the nucleotide sequence as set forth in (i) SEQ ID NOs: 6 and 1, respectively; (ii) SEQ ID NOs: 16 and 11, respectively; or (iii) SEQ ID NOs: 26 and 21, respectively;
(j) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively;
(k) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively; or
(l) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, and 30, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively.
91 . A vector encoding the nucleic acid of claim 90 .
92 . A method of treating a disease or disorder involving cells expressing CD38 comprising administering to a subject in need thereof an antibody which binds to human CD38 (SEQ ID NO: 31), wherein:
(a) the antibody does not bind to a mutant human CD38, wherein in the mutant human CD38, the serine residue in position 274 has been substituted with a phenylalanine residue (SEQ ID NO: 34), and wherein the antibody inhibits the synthesis of cGDPR by at least 25% after 90 minutes at a concentration of 3 μg/ml;
(b) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 7 or encoded by the nucleotide sequence set forth in SEQ ID NO: 6;
(c) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 17 or encoded by the nucleotide sequence set forth in SEQ ID NO: 16;
(d) the antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 27 or encoded by the nucleotide sequence set forth in SEQ ID NO: 26;
(e) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2 or encoded by the nucleotide sequence set forth in SEQ ID NO: 1;
(f) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 12 or encoded by the nucleotide sequence set forth in SEQ ID NO: 11
(g) the antibody comprises a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 22 or encoded by the nucleotide sequence set forth in SEQ ID NO: 21;
(h) the antibody comprises heavy and light chain variable region amino acid sequences as set forth in (i) SEQ ID NOs: 7 and 2, respectively; (ii) SEQ ID NOs: 17 and 12, respectively; or (iii) SEQ ID NOs: 27 and 22, respectively;
(i) the antibody comprises heavy and light chain variable regions encoded by the nucleotide sequence as set forth in (i) SEQ ID NOs: 6 and 1, respectively; (ii) SEQ ID NOs: 16 and 11, respectively; or (iii) SEQ ID NOs: 26 and 21, respectively;
(j) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively;
(k) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively; or
(l) the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, and 30, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively.
93 . The method of claim 92 , wherein the disease or disorder is rheumatoid arthritis.
94 . The method of claim 92 , wherein the disease is multiple myeloma.
95 . The method of claim 92 , wherein the method comprises administering one or more further therapeutic agents to the subject.
96 . The method of claim 95 , wherein the one or more further therapeutic agents are selected from the group consisting of: a chemotherapeutic agent, an anti-inflammatory agent, and an immunosuppressive and/or immunomodulatory agent.
97 . The method of claim 95 , wherein the one or more therapeutic agents are selected from the group consisting of: cisplatin, gefitinib, cetuximab, rituximab, bevacizumab, erlotinib, bortezomib, thalidomide, pamidronate, zoledronic acid, clodronate, risendronate, ibandronate, etidronate, alendronate, tiludronate, arsenic trioxide, lenalidomide, filgrastim, pegfilgrastim, sargramostim, suberoylanilide hydroxamic acid, and SCIO-469.
98 . The method of claim 92 , wherein the antibody possesses one or more of the following characteristics:
(i) acts as an antagonist of CD38;
(ii) does not induce significant proliferation of peripheral blood mononuclear cells;
(iii) does not induce release of significant IL-6 by human monocytes or peripheral blood mononuclear cells;
(iv) does not induce release of detectable IFN-gamma by human T cells or peripheral blood mononuclear cells;
(v) is internalized by CD38 expressing cells;
(vi) induces ADCC;
(vii) induces CDC in the presence of complement;
(viii) inhibits the synthesis of cGDPR;
(ix) inhibits the synthesis of cADPR;
(x) binds to human CD38 with an affinity (K D ) of below 10 −8 M;
(xi) binds to a mutant human CD38 with an EC 50 that is less than 50% compared to the EC 50 of the binding of the antibody to human CD38 (SEQ ID No:31), wherein the serine residue in position 274 of the mutant human CD38 has been substituted with a phenylalanine residue (SEQ ID No:34);
(xii) binds to a mutant human CD38 with an EC 50 that is less than 50% compared to the EC 50 of the binding of the antibody to human CD38 (SEQ ID No:31), wherein the glutamine residue in position 272 of the mutant human CD38 has been substituted with an arginine residue (SEQ ID No:33); or
(xiii) binds to a mutant human CD38 with an EC 50 that is 75%-125% of the EC 50 of the binding of the antibody to human CD38 (SEQ ID No:31), wherein the threonine residue in position 237 of the mutant human CD38 has been substituted with an alanine residue (SEQ ID No:32).
99 . The method of claim 92 , wherein the antibody is a human monoclonal antibody.
100 . The method of claim 92 , wherein the antibody is a full-length IgG1, IgG2, IgG3, IgG4, IgD, IgA, IgE, or IgM antibody.
101 . The method of claim 92 , wherein the antibody is glycosylated in a eukaryotic cell.
102 . The method of claim 92 , wherein the antibody is an antibody fragment or single chain antibody.
103 . The method of claim 92 , wherein the antibody further comprises a chelator linker for attaching a radioisotope.
104 . The method of claim 92 , wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 3, 4, and 5, respectively.
105 . The method of claim 92 , wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 18, 19, and 20, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 13, 14, and 15, respectively.
106 . The method of claim 92 , wherein the antibody comprises a heavy chain variable region comprising CDR1, CDR2, and CDR3 sequences comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, and 30, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 sequences set forth in SEQ ID NOs: 23, 24, and 25, respectively.