NOVEL ANTI-CD38 ANTIBODIES FOR THE TREATMENT OF CANCER
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 cytotoxicity (CDC).
2 : An 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 : An 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 : An 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 - 13 . (canceled)
14 . An 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 - 37 . (canceled)
38 : An antibody or epitope-binding fragment thereof according to claim 1 , characterized in that said antibody or epitope-binding fragment thereof comprises at least one human constant region.
39 . (canceled)
40 : An antibody or epitope-binding fragment thereof according to claim 1 , characterized in that said antibody or epitope-binding fragment thereof is a humanized or resurfaced antibody.
41 : A 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 gf SEQ ID NOS: 1, 2, and 3, and wherein said light chain comprises three sequential complementarity-determining regions of SEQ ID NOS: 4, 5, and 6; or
wherein said heavy chain comprises three sequential complementarity-determining regions of SEQ ID NOS: 7, 8, and 9, and wherein said light chain comprises three sequential complementarity-determining regions of SEQ ID NOS: 10, 11, and 12.
42 - 45 . (canceled)
46 : A 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 of SEQ ID NOS: 19, 20, and 21, and wherein said light chain comprises three sequential complementarity-determining regions SEQ ID NOS: 22, 23, and 24.
47 : A 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 of SEQ ID NOS: 25, 26, and 27, and wherein said light chain comprises three sequential complementarity-determining regions of SEQ ID NOS: 28, 29, and 30.
48 : A 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 comprising SEQ ID NO: 72 and a light chain variable region comprising SEQ ID NO: 68 or SEQ ID NO: 70.
49 . (canceled)
50 : A 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 of SEQ ID NOS: 31, 32, and 33, and wherein said light chain comprises three sequential complementarity-determining regions of SEQ ID NOS: 34, 35, and 36.
51 : An antibody or epitope-binding fragment thereof according to claim 1 , characterized in that said antibody or epitope-binding fragment thereof is a Fab, Fab′, F(ab′)2 or Fv fragment.
52 : A conjugate comprising the antibody or epitope-binding fragment thereof according to claim 1 linked to a cytotoxic agent.
53 - 60 . (canceled)
61 : A pharmaceutical composition comprising (a) the n antibody or epitope-binding fragment thereof according to claim 1 or the conjugate according to claim 52 , and (a pharmaceutically acceptable carrier or excipients.
62 - 64 . (canceled)
65 : A method of treating cancer or autoimmune disease comprising administering to a patient the antibody or epitope-binding fragment thereof according to claim 1 .
66 - 71 . (canceled)
72 : 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.
73 - 75 . (canceled)
76 : One or more polynucleotides encoding an antibody or epitope-binding fragment thereof, wherein the antibody or epitope-binding fragment thereof comprises:
a) a heavy chain variable region (V H ) comprising SEQ ID NO: 50 and a light chain variable region (V L ) comprising SEQ ID NO: 38;
b) a heavy chain variable region (V H ) comprising SEQ ID NO: 52 and a light chain variable region (V L ) comprising SEQ ID NO: 40;
e) a heavy chain variable region (V H ) comprising SEQ ID NO: 66 and a light chain variable region (V L ) comprising SEQ ID NO: 62 or 64;
d) a heavy chain variable region (V H ) comprising SEQ ID NO: 56 and a light chain variable region (V L ) comprising 44;
e) a heavy chain variable region (V H ) comprising SEQ ID NO: 72 and a light chain variable region (V L ) comprising SEQ ID NO: 68 or 70;
f) a heavy chain variable region (V H ) comprising SEQ ID NO: 60 and a light chain variable region (V L ) comprising 48.
77 . (canceled)
78 : A recombinant vector comprising the one or more polynucleotides of claim 76 .
79 : A host cell comprising a vector of claim 78 .