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, wherein:
(i) 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;
(ii) 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;
(iii) 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;
(iv) 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;
(v) 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;
(vi) 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;
(vii) 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;
(viii) 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;
(ix) 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;
(x) 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
(xi) 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, 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, wherein:
(i) 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;
(ii) 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;
(iii) 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;
(iv) 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;
(v) 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;
(vi) 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;
(vii) 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;
(viii) 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;
(ix) 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;
(x) 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
(xi) 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, 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, or set of nucleic acids, 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 comprising the nucleic acid, or set of nucleic acids, of claim 90 .
92 . A host cell comprising the nucleic acid, or set of nucleic acids, of claim 90 , or a vector comprising the nucleic acid, or set of nucleic acids.
93 . A method of treating a disease or disorder involving cells expressing CD38 comprising administering to a subject in need thereof an effective amount of 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.
94 . The method of claim 93 , wherein the disease or disorder is rheumatoid arthritis.
95 . The method of claim 93 , wherein the disease or disorder is multiple myeloma.
96 . The method of claim 93 , wherein the method comprises administering one or more further therapeutic agents to the subject.
97 . The method of claim 96 , wherein the one or more further therapeutic agents are selected from the group consisting of: a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressive agent, and an immunomodulatory agent.
98 . The method of claim 96 , 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.
99 . A method of preventing a disease or disorder involving cells expressing CD38 comprising administering to a subject in need thereof an effective amount of 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.
100 . The method of claim 99 , wherein the disease or disorder is rheumatoid arthritis.
101 . The method of claim 99 , wherein the disease or disorder is multiple myeloma.
102 . The method of claim 99 , wherein the method comprises administering one or more further therapeutic agents to the subject.
103 . An immunogenic peptide consisting essentially of the amino acid sequence SKRNIQFSCKNIRY (SEQ ID NO: 35) or EKVQTLEAWVIHGG (SEQ ID NO: 36).
104 . A fusion protein comprising the immunogenic peptide of claim 103 and a fusion partner comprising a sequence or polypeptide that (a) improves the half-life of the fusion protein, (b) facilitates detection and/or purification of the fusion protein, (c) promotes the targeting of the fusion protein, (d) promotes induction of a distinct immune response, or (e) is a cytotoxic agent.
105 . A nucleic acid encoding the immunogenic peptide of claim 103 .
106 . A method of inducing a CD38-specific immune response comprising administering to a subject in need thereof an effective amount of the immunogenic peptide of claim 103 .
107 . The method of claim 106 , which is part of an immunotherapy regimen.
108 . A vaccine comprising the immunogenic peptide of claim 103 .