Receptor modulators

• US 7,851,598 B2
• Filed: 01/10/2005
• Issued: 12/14/2010
• Est. Priority Date: 01/09/2004
• Status: Active Grant

• Current Assignee: Oxford University Innovation Limited (University of Oxford)
• Original Assignee: Isis Innovation Limited
• Inventors: Davis, Simon
• Primary Examiner(s): OUSPENSKI, ILIA I
• Application Number:
  US10/585,491
• Publication Number:
  US 20080044837A1
• Time in Patent Office: 2,164 Days
• Field of Search: None
• US Class Current: 530/387.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: C07K 14/70521 CD28, CD152
• CPC Class Codes: C07K 14/70532 B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 2299/00 Coordinates from 3D structures of peptides, e.g. proteins or enzymes
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: G16B 15/00 ICT specially adapted for analysing two-dimensional or three-dimensional molecular structures, e.g. structural or functional relations or structure alignment
• CPC Class Codes: G16B 15/20 Protein or domain folding
• CPC Class Codes: G16B 20/00 ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
• CPC Class Codes: G16B 20/50 Mutagenesis

Abstract

Method of identifying a modulator of CD28 comprising comparing a structural model of a candidate modulator with a structural model of CD28 to thereby determine whether the modulator will bind to CD28, wherein the structural model is derived from, or comprises, structural coordinates of a crystal of: (i) CD28, (ii) a fragment of CD28, or (iii) a homologue of (i) or (ii). The crystal of CD28 in a soluble form complexed with the Fab fragment of a mitogenic (superagonistic) antibody has been obtained and used for the determination of the 3D-structure of the receptor. The application also relates to modulators of superagonistic signalling for any receptor of the CD28 family, i.e. to superagonistic antibodies and chimeric proteins thereof, and to the screening of the superagonistic modulators. In the methods of screening, the binding of the candidate modulators to a portion of the receptor proximal to the cell membrane is investigated.

Claims

1. An antibody that binds to the extracellular portion of the human PD-1 receptor at a membrane proximal region and said antibody binds to an epitope comprising SEQ ID NO:

44, SEQ ID NO;

46, SEQ ID NO;

48, SEQ ID NO;

50, SEQ ID NO;

52, SEQ ID NO;

54, SEQ ID NO;

56 or SEQ ID NO;

61, wherein;

a) said antibody does not only bind to a peptide consisting of LAAFPEDRSQPGQDCR (SEQ ID NO;

     61), the human PD-1 equivalent of the C′

-D loop of human CD28; and

b) said antibody induces superagonistic signaling of the PD-1 receptor by binding to a membrane proximal region of the human PD-1 receptor that is within 75 Å

of a cell surface or wherein said antibody binds to a membrane proximal region of human PD-1 expressed on the surface of a cell and holds the cell surface within 200 Å

of a substrate to which said antibody is immobilized.

2. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

44.

3. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

46.

4. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

48.

5. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

50.

6. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

52.

7. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

54.

8. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

56.

9. The antibody according to claim 1, wherein said antibody binds to an epitope comprising SEQ ID NO:

61.

10. The antibody according to claim 1, wherein said antibody is a monoclonal antibody.

11. The antibody according to claim 10, wherein said antibody is a humanized antibody.

12. The antibody according to claim 10, wherein said antibody is a complementarity determining region (CDR)-grafted antibody.

13. The antibody according to claim 10, wherein said antibody is a chimeric antibody.

14. The antibody according to claim 1, wherein said antibody induces superagonistic signaling of the PD-1 receptor by binding to a membrane proximal region of the human PD-1 receptor that is within 60 Å

of a cell surface.

15. The antibody according to claim 1, wherein said antibody induces superagonistic signaling of the PD-1 receptor by binding to a membrane proximal region of the human PD-1 receptor that is within 50 Å

of a cell surface.

16. The antibody according to claim 1, wherein said antibody induces superagonistic signaling of the PD-1 receptor by binding to a membrane proximal region of the human PD-1 receptor that is within 40 Å

of a cell surface.

17. The antibody according to claim 1, wherein said antibody binds to a membrane proximal region of human PD-1 expressed on the surface of a cell and holds the cell surface within 180 Å

of a substrate to which said antibody is immobilized.

18. The antibody according to claim 1, wherein said antibody hinds to a membrane proximal region of human PD-1 expressed on the surface of a cell and holds the cell surface within 150 Å

of a substrate to which said antibody is immobilized.

19. The antibody according to claim 1, wherein said antibody binds to a membrane proximal region of human PD-1 expressed on the surface of a cell and holds the cell surface within 120 Å

of a substrate to which said antibody is immobilized.