CD20-binding polypeptide compositions and methods

• US 8,147,832 B2
• Filed: 08/13/2004
• Issued: 04/03/2012
• Est. Priority Date: 08/14/2003
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Carr, Francis Joseph, Williams, Stephen, Gillies, Stephen D.
• Primary Examiner(s): SCHWADRON, RONALD B
• Application Number:
  US10/917,599
• Publication Number:
  US 20050069545A1
• Time in Patent Office: 2,790 Days
• Field of Search: None
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07K 16/2887 against CD20
• CPC Class Codes: C07K 16/3076 against structure-related tumour-associated moieties
• 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 2317/56 variable (Fv) region, i.e. VH and/or VL
• 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 2319/00 Fusion polypeptide
• CPC Class Codes: Y10S 424/80 Antibody or fragment thereof whose amino acid sequence is disclosed in whole or in part
• CPC Class Codes: Y10S 424/801 involving antibody or fragment thereof produced by recombinant dna technology

Abstract

A CD20-binding polypeptide composition comprising a combination of a modified heavy chain variable region polypeptide and a modified light chain variable region polypeptide. The combination can be (a) a modified 2B8 antibody heavy chain variable region polypeptide of SEQ ID NO: 48; and a modified 2B8 antibody light chain variable region polypeptide of SEQ ID NO: 49; or (b) a modified Leu16 antibody heavy chain variable region polypeptide of SEQ ID NO: 50; and a modified Leu16 antibody light chain variable region polypeptide of SEQ ID NO: 51.

Claims

1. A CD20-binding polypeptide composition comprising a combination of a modified heavy chain variable region polypeptide and a modified ht chain variable region polypeptide, the combination being selected from the group consisting of:

(a) a combination of a modified 2B8 antibody heavy chain variable region polypeptide having the amino acid residue sequence of SEQ ID NO;

48 and which includes at least one of the following amino acid residues;

K at residue 12, P at residue 14, V at residue 20, T at residue 48, T at residue 68, E at residue 82, R at residue 87, T at residue 91, and W at residue 106; and

a modified 2B8 antibody light chain variable region polypeptide having the amino acid residue sequence of SEQ ID NO;

49 and which includes at least one of the following amino acid residues;

I at residue 11, T at residue 12, T at residue 27, A at residue 29, T at residue 40, S at residue 59, T at residue 69, M at residue 72, S at residue 76, and L at residue 77; and

(b) a combination of a modified Leu16 antibody heavy chain variable region polypeptide having the amino acid residue sequence of SEQ ID NO;

50 and which includes at least one of the following amino acid residues;

K at residue 12, V at residue 20, T at residue 68, E at residue 82, Rat residue 87, T at residue 91, V at residue 93, and T at residue 114; and

a modified Leu16 antibody light chain variable region polypeptide having the amino acid residue sequence of SEQ ID NO;

51 and which includes at least one of the following amino acid residues;

I at residue 11, T at residue 12, S at residue 59, T at residue 69, M at residue 72, S at residue 76, and L at residue 77.

2. The CD20-binding polypeptide composition of claim 1 in the form of a chimeric antibody and further including a human heavy chain constant region and a human light chain constant region.

3. The CD20-binding polypeptide composition of claim 2 wherein the human heavy chain constant region is an IgG constant region.

4. The CD20-binding polypeptide composition of claim 3 wherein the IgG constant region is an IgG1 constant region.

5. The CD20-binding polypeptide composition of claim 2 wherein the human light chain constant region is a human kappa light chain constant region.

6. The CD20-binding polypeptide composition of claim 2 in the form of a fusion protein with human IL-2.

7. The CD20-binding polypeptide composition of claim 1, in the form of a fusion protein with human IL-2.

8. The CD20-binding polypeptide composition of claim 1 in the form of a Fab antibody fragment, a single-chain Fv antibody fragment, and minibody.

17. A pharmaceutical composition comprising a CD20-binding polypeptide composition of claim 1, together with a pharmaceutically acceptable carrier, excipient, or diluent.

18. The pharmaceutical composition of claim 17 further comprising an additional pharmacologically effective drug.

9. A CD20-binding polypeptide composition comprising (a) a modified 2B8 antibody heavy chain variable region polypeptide having an amino acid residue sequence selected from the group consisting of SEQ ID NO:

2 and SEQ ID NO;

3; and

a modified 2B8 antibody light chain variable region polypeptide having an amino acid residue sequence selected from the group consisting of SEQ ID NO;

5, SEQ ID NO;

6, SEQ ID NO;

7, and SEQ ID NO;

8;

or (b) a modified Leu16 antibody heavy chain polypeptide having the amino acid residue sequence of SEQ ID NO;

10 and a modified Leu16 antibody light chain variable region polypeptide having the amino acid residue sequence of SEQ ID NO 12.

10. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

2 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

5.

11. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

2 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

6.

12. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

2 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

7.

13. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

2 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

8.

14. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

3 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

6.

15. The CD20-binding polypeptide composition of claim 9 comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

3 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

8.

19. The CD20-binding polypeptide composition of claim 9, designated Leu16VhY/VkZ-IL2, in the form of a fusion protein with human IL2 and comprising a polypeptide which is a Vh polypeptide having amino acid residue sequence of SEQ ID NO:

10 and a polypeptide which is a Vk polypeptide having amino acid residue sequence of SEQ ID NO;

12.

16. A CD20-binding polypeptide composition comprising a polypeptide having an amino acid residue sequence of SEQ ID NO:

10 and a polypeptide having an amino acid residue sequence of SEQ ID NO;

12.