Antibodies against human or mouse IL-21 receptor

• US 7,495,085 B2
• Filed: 03/12/2004
• Issued: 02/24/2009
• Est. Priority Date: 03/14/2003
• Status: Expired due to Fees

• Current Assignee: Cambridge Antibody Technology Ltd (Astrazeneca PLC), Wyeth (Pfizer Inc.)
• Original Assignee: Cambridge Antibody Technology Ltd (Astrazeneca PLC), Wyeth (Pfizer Inc.)
• Inventors: Valge-Archer, Viia, Collins, Mary, Young, Deborah A., Whitters, Matthew J., Williams, Andrew James, Witek, Joann
• Primary Examiner(s): Bunner; Bridget E
• Assistant Examiner(s): STOICA, ELLY GERALD
• Application Number:
  US10/798,380
• Publication Number:
  US 20040265960A1
• Time in Patent Office: 1,810 Days
• Field of Search: None
• US Class Current: 530/387.9
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07K 16/2866 against receptors for cytokines, lymphokines, interferons
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/622 Single chain antibody (scFv)

Abstract

The present application provides human antibodies and antigen binding fragments thereof that specifically bind to the human interleukin-21 receptor (IL-21R). The antibodies can act as antagonists of IL-21R activity, thereby modulating immune responses in general, and those mediated by IL-21R in particular. The disclosed compositions and methods may be used for example, in diagnosing, treating or preventing inflammatory disorders, autoimmune diseases, allergies, transplant rejection, cancer, and other immune system disorders.

Claims

1. An isolated antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs:

65, 66, and 67, wherein the antibody selectively binds to the extracellular domain of a human or a mouse IL-21R.

7. The antibody of claim 1,2,3,4,5, or 6, wherein the antibody selectively binds to an amino acid sequence that is at least 95% identical to a sequence comprising at least 100 contiguous amino acids set forth in SEQ ID NO:

43.

8. The antibody of claim 1,2,3,4,5, or 6, wherein the antibody selectively binds the extracellular domain of the polypeptide set forth in SEQ ID NO:

43.

9. The antibody of claim 1,2,3,4,5, or 6, wherein the antibody inhibits the binding of IL-2 1 to an extracellular domain of a human or a mouse IL-21R.

10. The antibody of claim 1,2,3,4,5, or 6, wherein the antibody is human.

11. The antibody of claim 1,2,3,4,5, or 6, wherein the antibody is an IgG₁ antibody.

12. The antibody of claim 11, wherein the antibody is IgG_1λ

or IgG_1κ

.

13. A pharmaceutical composition comprising the antibody of claim 1, 2, 3, 4, 5, or 6, and a pharmaceutical excipient.

14. A diagnostic kit comprising the antibody of claim 1, 2, 3, 4, 5, or 6, and a reagent for detecting the antibody, wherein the antibody and the reagent are in separate containers.

2. An isolated antibody encoded by a nucleotide sequence which is at least 95% identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs:

74, 75, and 76, wherein the antibody selectively binds to the extracellular domain of a human or a mouse IL-21R.

3. An isolated antibody comprising a V_H domain having an amino acid sequence which is at least 95% identical to the amino acid sequence of SEQ ID NO:

65, and a V_L domain having an amino acid sequence which is at least 95% identical to the amino acid sequence of SEQ ID NO;

66, wherein the antibody selectively binds to the extracellular domain of a human or a mouse IL-21R.

4. An isolated antibody comprising a V_H domain which comprises:

(a) the CDR sequences set forth in SEQ ID NOs;

68, 69, and 70, or

(b) conservative amino acid substitutions thereof, wherein the V_H domain comprises CDR sequences with one conservative amino acid substitution of SEQ ID NO;

68, two or less conservative amino acid substitutions of SEQ ID NO;

69, and/or one conservative amino acid substitution of SEQ ID NO;

70,

wherein the antibody selectively binds the extracellular domain of a human or a mouse IL-21R.

5. An isolated antibody comprising a V_L domain which comprises:

(a) the CDR sequences set forth in SEQ ID NOs;

71, 72, and 73, or

(b) conservative amino acid substitutions thereof, wherein the V_L domain comprises CDR sequences with two or less conservative amino acid substitutions of SEQ ID NO;

71, one conservative amino acid substitution of SEQ ID NO;

72, and/or two or less conservative amino acid substitutions of SEQ ID NO;

73,

wherein the antibody selectively binds to the extracellular domain of a human or a mouse IL-21R.

6. An isolated antibody that competes with an antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:

65, 66, and 67 for binding to the extracellular domain of a human or a mouse IL-21R.

15. An antibody or an antigen-binding fragment that binds to the extracellular domain of a human or a mouse IL-21R, produced by a method comprising:

(a) providing a repertoire of nucleic acids encoding a V_H domain that either includes CDR 1, 2 and 3 to be replaced or lacks CDR 1, 2 and 3 encoding regions;

(b) combining the repertoire with donor nucleic acids encoding amino acid sequences as set forth in SEQ ID NOs;

68, 69, and 70 such that the donor nucleic acids are inserted into the CDR 1,2 and 3 region in the repertoire, so as to provide a product repertoire of nucleic acids encoding a V_H domain;

(c) expressing the nucleic acids of the product repertoire;

(d) selecting an antibody or an antigen-binding fragment expressed from the product repertoire of nucleic acids, wherein the antibody or antigen-binding fragment is specific for the extracellular domain of a human or a mouse IL-21R.

16. An antibody or an antigen-binding fragment that binds to the extracellular domain of a human or a mouse IL-21R, produced by a method comprising:

(a) providing a repertoire of nucleic acids encoding a variable domain that either includes a V_H to be replaced, or lacks a V_H encoding region;

(b) combining the repertoire with a donor nucleic acid encoding an amino acid sequence as set forth in SEQ ID NOs;

65, such that the donor nucleic acid is inserted into the V_H region in the repertoire, so as to provide a product repertoire of nucleic acids encoding a variable domain;

(c) expressing the nucleic acids of the product repertoire; and

(d) selecting an antibody or an antigen-binding fragment expressed from the product repertoire of nucleic acids, wherein the antibody or antigen-binding fragment is specific for the extracellular domain of a human or a mouse IL-21R.

17. An antibody or an antigen-binding fragment that binds to the extracellular domain of a human or a mouse IL-21R, produced by a method comprising:

(a) providing a repertoire of nucleic acids encoding a V_L domain that either includes CDR 1, 2 and 3 to be replaced or lacks CDR 1, 2 and 3 encoding regions;

(b) combining the repertoire with donor nucleic acids encoding amino acid sequences as set forth in SEQ ID NOs;

71, 72, and 73, such that the donor nucleic acids are inserted into the CDR 1, 2 and 3 region in the repertoire, so as to provide a product repertoire of nucleic acids encoding a V_L domain;

(c) expressing the nucleic acids of the product repertoire;

(d) selecting an antibody or an antigen-binding fragment expressed from the product repertoire of nucleic acids, wherein the antibody or antigen-binding fragment is specific for the extracellular domain of a human or a mouse IL-21R.

18. An antibody or an antigen-binding fragment that binds to the extracellular domain of a human or a mouse IL-21R, produced by a method comprising:

(a) providing a repertoire of nucleic acids encoding a variable domain that either includes a or V_L to be replaced, or lacks a or V_L encoding region;

(b) combining the repertoire with a donor nucleic acid encoding an amino acid sequence as set forth in SEQ ID NOs;

66, such that the donor nucleic acid is inserted into the or V_L region in the repertoire, so as to provide a product repertoire of nucleic acids encoding a variable domain;

(c) expressing the nucleic acids of the product repertoire; and

(d) selecting an antibody or an antigen-binding fragment expressed from the product repertoire of nucleic acids, wherein the antibody or antigen-binding fragment is specific for the extracellular domain of a human or a mouse IL-21R.