CD37 IMMUNOTHERAPEUTIC AND COMBINATION WITH BIFUNCTIONAL CHEMOTHERAPEUTIC THEREOF
The present disclosure provides a humanized anti-CD37 small modular immunopharmaceutical (SMIP) molecule, as well as synergistic combination therapies of CD37-specific binding molecules (such as anti-CD37 SMIP proteins or antibodies) with bifunctional chemotherapeutics (such as bendamustine) that can be administered concurrently or sequentially, for use in treating or preventing B-cell related autoimmune, inflammatory, or hyperproliferative diseases.
1 . A composition comprising a CD37-specific binding molecule and bendamustine.
2 . The composition of claim 1 , wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP.
3 . The composition of claim 1 , wherein the CD37-specific molecule is a humanized antibody or humanized SMIP.
4 . The composition of any one of claims 1 to 3 , wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding.
5 . The composition of claim 1 , wherein the CD37-specific binding protein comprises a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a light chain CDR2 as set forth in SEQ ID NO:64, and a light chain CDR3 as set forth in SEQ ID NO:66; and
a heavy chain CDR1 as set forth in SEQ ID NO:63, a heavy chain CDR2 as set forth in SEQ ID NO:65, and a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69.
6 . The composition of claim 1 , wherein the CD37-specific binding protein comprises, from amino terminus to carboxy terminus:
(i) a humanized heavy chain variable region,
(ii) a linker,
(iii) a humanized light chain variable region,
(iv) an IgG1 hinge, and
(v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.
7 . The composition of claim 1 , wherein the CD37-specific binding molecule comprises, from amino terminus to carboxy terminus:
(i) a heavy chain variable region comprising a heavy chain CDR3 as set forth in SEQ ID NO:67 or 68;
(ii) a linker;
(iii) a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO:61;
(iv) an IgG1 hinge; and
(v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.
8 . The composition of claim 1 , wherein the CD37-specific binding molecule comprises, from amino terminus to carboxy terminus:
(i) a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO:63, a heavy chain CDR2 as set forth in SEQ ID NO:65, and a heavy chain CDR3 as set forth in SEQ ID NO:67 or 68;
(ii) a linker;
(iii) a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO:61, a light chain CDR2 as set forth in SEQ ID NO:64, and a light chain CDR3 as set forth in SEQ ID NO:66;
(iv) an IgG1 hinge; and
(v) a human IgG1 CH2 region, and (vi) a human IgG1 CH3 region.
9 . The composition of claim 8 , wherein the CD37-specific binding molecule is a humanized CD37-specific binding molecule that comprises from amino terminus to carboxyl terminus:
(i) a humanized heavy chain variable region,
(ii) a linker as set forth in SEQ ID NO:229,
(iii) a humanized light chain variable region,
(iv) an IgG1 hinge,
(v) a human IgG1 CH2 region, and
(vi) a human IgG1 CH3 region, wherein
(a) the humanized heavy chain variable region comprising from amino terminus to carboxyl terminus: a human heavy chain FR1, a heavy chain CDR1 as set forth in SEQ ID NO:63, a human heavy chain FR2, a heavy chain CDR2 as set forth in SEQ ID NO:65, a human heavy chain FR3, a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69, and a human heavy chain FR4, and
(b) the humanized light chain variable region comprises from amino terminus to carboxyl terminus: a human light chain FR1, a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a human light chain FR2, a light chain CDR2 as set forth in SEQ ID NO:64, a human light chain FR3, and a light chain CDR3 as set forth in SEQ ID NO:66, and a human light chain FR4.
10 . A method for reducing B-cells or treating a disease associated with aberrant B-cell activity, comprising administering to a subject in need thereof an effective amount of a CD37-specific binding molecule and bendamustine.
11 . The method of claim 10 , wherein the disease associated with aberrant B-cell activity is a B-cell lymphoma, a B-cell leukemia, a B-cell myeloma, a disease characterized by autoantibody production, or a disease characterized by inappropriate T-cell stimulation associated with a B-cell pathway.
12 . The method of claim 11 , wherein the disease characterized by autoantibody production is idiopathic inflammatory myopathy, rheumatoid arthritis, myasthenia gravis, Grave's disease, type I diabetes mellitus, multiple sclerosis, an autoimmune disease, dermatomyositis, polymyositis, or Waldenstrom's macroglobinemia.
13 . The method of claim 10 , wherein the disease associated with aberrant B-cell activity is selected from the group consisting of chronic lymphocytic leukemia (CLL), non-Hodgkins lymphoma (NHL), and hairy cell leukemia.
14 . The method of claim 10 , wherein the CD37-specific binding molecule and bendamustine are administered concurrently.
15 . The method of claim 10 , wherein the CD37-specific binding molecule and bendamustine are administered sequentially.
16 . The method of claim 10 , wherein the CD37-specific binding molecule and bendamustine are formulated together.
17 . The method of claim 10 , wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP.
18 . The method of claim 10 , wherein the CD37-specific molecule is a humanized antibody or a humanized SMIP.
19 . The method of claim 10 , wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding.
20 . The method of claim 10 , wherein the CD37-specific binding molecule is a humanized CD37-specific binding molecule that comprises from amino terminus to carboxyl terminus:
(i) a humanized heavy chain variable region,
(ii) a linker as set forth in SEQ ID NO:229,
(iii) a humanized light chain variable region,
(iv) an IgG1 hinge,
(v) a human IgG1 CH2 region, and
(vi) a human IgG1 CH3 region, wherein
(a) the humanized heavy chain variable region comprising from amino terminus to carboxyl terminus: a human heavy chain FR1, a heavy chain CDR1 as set forth in SEQ ID NO:63, a human heavy chain FR2, a heavy chain CDR2 as set forth in SEQ ID NO:65, a human heavy chain FR3, a heavy chain CDR3 as set forth in SEQ ID NO:67, 68 or 69, and a human heavy chain FR4, and
(b) the humanized light chain variable region comprises from amino terminus to carboxyl terminus: a human light chain FR1, a light chain CDR1 as set forth in SEQ ID NO:61 or 62, a human light chain FR2, a light chain CDR2 as set forth in SEQ ID NO:64, a human light chain FR3, and a light chain CDR3 as set forth in SEQ ID NO:66, and a human light chain FR4.