CD37 immunotherapeutics and uses thereof

• US 10,307,481 B2
• Filed: 07/25/2006
• Issued: 06/04/2019
• Est. Priority Date: 07/25/2005
• Status: Active Grant

• Current Assignee: Aptevo Reseach And Development LLC
• Original Assignee: Aptevo Reseach And Development LLC
• Inventors: Grosmaire, Laura S., Hayden-Ledbetter, Martha S., Ledbetter, Jeffrey A., Thompson, Peter A., Simon, Sandy A., Brady, William
• Primary Examiner(s): Dahle, Chun W
• Application Number:
  US11/493,132
• Publication Number:
  US 20070059306A1
• Time in Patent Office: 4,697 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 27/02 Ophthalmic agents
• 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 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2887 : against CD20
• CPC Class Codes: C07K 16/2896 : against molecules with a "CD"-designation, not provided for elsewhere
• CPC Class Codes: C07K 16/30 : from tumour cells
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/53 : Hinge
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/622 : Single chain antibody (scFv)
• CPC Class Codes: C07K 2317/72 : Increased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/75 : Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The present invention generally provides methods for B-cell reduction in an individual using CD37-specific binding molecules. In particular, the invention provides methods for B-cell reduction using CD37-specific binding molecules alone, or a combination of CD37-specific binding molecules and CD20-specific binding molecules, in some instances a synergistic combination. The invention further provides materials and methods for treatment of diseases involving aberrant B-cell activity. In addition, the invention provides humanized CD37-specific binding molecules.

Claims

1. A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:

(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

66, and a fourth framework region; and

(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

69, and a fourth framework region;

wherein the binding protein binds human CD37.

4. The CD37-specific binding protein according to claim 1, 2, or 3 wherein the binding protein comprises a single chain Fv (scFv) polypeptide, an antibody or a binding fragment thereof, or a polypeptide that comprises, from amino to carboxy terminus, an scFv, a human immunoglobulin hinge region, and human immunoglobulin CH2 and CH3 domains.

5. The CD37-specific binding protein according to claim 1, 2, or 3 wherein the light chain variable region is attached to the heavy chain variable region by a linker peptide comprising (Gly₄Ser)_n, wherein n is 1, 2, 3, 4, 5, or 6, as set forth in SEQ ID NO:

221, 222, 223, 224, 225 or 226.

6. The CD37-specific binding protein according to claim 4, wherein the light and heavy chain variable regions are connected to the CH2 and CH3 domains via a hinge region comprised of an amino acid sequence selected from the group consisting of SEQ ID NOS:

90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 115, 116, 118, 120, 122, 124, 126, and 127.

7. The CD37-specific binding protein according to claim 6, wherein the hinge region comprises the amino acid sequence of SEQ ID NO:

92 or SEQ ID NO;

106.

8. The CD37-specific binding protein according to claim 4, wherein the CH2 and CH3 domains are IgG1CH2 and CH3 domains.

9. The CD37-specific binding protein according to claim 1, 2, or 3 wherein the binding protein has a binding affinity for human CD37 of about 0.5 nM to about 10 nM.

10. A composition comprising a CD37-specific immunoglobulin binding protein according to claim 1, 2, or 3 and a pharmaceutically acceptable carrier.

13. The CD37-specific binding protein of claim 1, 2, or 3, wherein

(a) the first light chain framework region comprises the amino acid sequence set forth in SEQ ID NO:

171, the second light chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

182, the third light chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

195, and the fourth light chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

206; and

(b) the first heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

144, the second heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

151, the third heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

158, and the fourth heavy chain framework region comprises the amino acid sequence set forth in SEQ ID NO;

161 or 162.

14. The CD37-specific binding protein of claim 1, 2, or 3, wherein the binding protein is a dimer.

2. A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:

(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

66, and a fourth framework region; and

(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

67, and a fourth framework region;

wherein the binding protein binds human CD37.

3. A humanized or chimeric CD37-specific immunoglobulin binding protein, comprising:

(a) a light chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a light chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

61, a second framework region, a light chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

64, a third framework region, a light chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

66; and

(b) a heavy chain variable region comprising, from amino terminus to carboxy terminus, a first framework region, a heavy chain CDR1 comprising the amino acid sequence set forth in SEQ ID NO;

63, a second framework region, a heavy chain CDR2 comprising the amino acid sequence set forth in SEQ ID NO;

65, a third framework region, a heavy chain CDR3 comprising the amino acid sequence set forth in SEQ ID NO;

68;

wherein the binding protein binds human CD37.

11. The CD37-specific binding protein of claim 3, wherein the light chain variable region comprises amino acids 21-127 of SEQ ID NO:

52, and the heavy chain variable region comprises amino acids 144-259 of SEQ ID NO;

52.

12. The CD37-specific binding protein of claim 3, wherein the binding protein comprises a polypeptide according to SEQ ID NO:

52.