CD37 IMMUNOTHERAPEUTIC AND COMBINATION WITH BIFUNCTIONAL CHEMOTHERAPEUTIC THEREOF

• US 20090274692A1
• Filed: 04/13/2009
• Published: 11/05/2009
• Est. Priority Date: 04/11/2008
• Status: Active Grant

• Current Assignee: Aptevo Reseach And Development LLC
• Original Assignee: Trubion Pharmaceuticals Inc.
• Inventors: Tan, Phillip, Ledbetter, Jeffrey A., Brady, William, Hayden-Ledbetter, Martha S., Cerveny, Charles G., Morales, Cecile, Nilsson, Christy Anne, Thompson, Peter A., Simon, Sandy A.
• Granted Patent: US 9,101,609 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 39/39541 against normal tissues, cells
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/2896 against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/3061 Blood cells
• CPC Class Codes: C07K 16/461 : Igs containing Ig-regions, -domains or -residues form different species
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/50 : characterized by immunoglobulin fragments

Abstract

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.

Claims

1. A humanized CD37-specific binding molecule, comprising 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 comprises 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.

2. The humanized CD37-specific binding molecule of claim 1, wherein the human heavy chain FR1 comprises SEQ ID NO:

144, the human heavy chain FR2 comprises SEQ ID NO;

151, the human heavy chain FR3 comprises SEQ ID NO;

158, and the human heavy chain FR4 comprises SEQ ID NO;

161 or 162.

3. The humanized CD37-specific binding molecule of claim 1, wherein the human light chain FR1 comprises SEQ ID NO:

171, the human light chain FR2 comprises SEQ ID NO;

182, the human light chain FR3 comprises SEQ ID NO;

195, and the human light chain FR4 comprises SEQ ID NO;

206.

6. An isolated nucleic acid molecule, comprising a nucleotide sequence encoding a humanized CD37-specific binding molecule according to claim 1.

7. A vector comprising a nucleic acid molecule according to claim 6.

8. A host cell comprising a vector according to claim 7.

9. A composition comprising a humanized CD37-specific binding molecule according to claim 1 and a pharmaceutically acceptable carrier.

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 humanized CD37-specific binding molecule according to claim 1.

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 10, 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 chronic lymphocytic leukemia (CLL).

30. The humanized CD37-specific binding molecule of claim 1, wherein the human heavy chain FR1 comprises SEQ ID NO:

144, the human heavy chain FR2 comprises SEQ ID NO;

151, the human heavy chain FR3 comprises SEQ ID NO;

158, and the human heavy chain FR4 comprises SEQ ID NO;

161 or 162, the human light chain FR1 comprises SEQ ID NO;

171, the human light chain FR2 comprises SEQ ID NO;

182, the human light chain FR3 comprises SEQ ID NO;

195, and the human light chain FR4 comprises SEQ ID NO;

206.

4. A CD37-specific binding molecule, comprising an amino acid sequence as set forth in SEQ ID NO:

253.

5. The CD37-specific binding molecule of claim 4, consisting of the amino acid sequence set forth in SEQ ID NO:

253.

14. A composition comprising a CD37-specific binding molecule and bendamustine.

15. The composition of claim 14, wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP.

16. The composition of claim 14, wherein the CD37-specific molecule is a humanized antibody or humanized SMIP.

17. The composition of any one of claims 14 to 16, wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding.

18. The composition of claim 14, 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 comprises 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.

19. 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.

20. The method of claim 19, 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.

21. The method of claim 20, 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.

22. The method of claim 20, wherein the disease associated with aberrant B-cell activity is chronic lymphocytic leukemia (CLL).

23. The method of claim 19, wherein the CD37-specific binding molecule and bendamustine are administered concurrently.

24. The method of claim 19, wherein the CD37-specific binding molecule and bendamustine are administered sequentially.

25. The method of claim 19, wherein the CD37-specific binding molecule and bendamustine are formulated together.

26. The method of claim 19, wherein the CD37-specific binding molecule is a CD37-specific antibody or SMIP.

27. The method of claim 19, wherein the CD37-specific molecule is a humanized antibody or a humanized SMIP.

28. The method of claim 19, wherein the CD37-specific binding molecule competes with G28-1 mAb in CD37-specific binding.

29. The method of claim 19, 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 comprises 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.