Alteration of immune response using pan DR-binding peptides

• US 5,736,142 A
• Filed: 09/14/1994
• Issued: 04/07/1998
• Est. Priority Date: 09/14/1993
• Status: Expired due to Term

• Current Assignee: Epimmune, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: Cytyc Corporation (Hologic Incorporated)
• Inventors: Alexander, Jeffrey L., Gaeta, Federico, Sette, Alessandro, Sidney, John, Grey, Howard M.
• Primary Examiner(s): Cunningham, Thomas M.
• Application Number:
  US08/305,871
• Time in Patent Office: 1,301 Days
• Field of Search: 424/185.1, 424/186.1, 424/193.1, 530/300, 530/326-328, 530/402, 530/403, 530/868, 530/327, 530/332, 514/2, 514/15
• US Class Current: 424/185.1
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07K 14/001 by chemical synthesis
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 14/70539 MHC-molecules, e.g. HLA-molecules
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: C12N 2730/10122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: Y10S 530/868 involving autoimmunity, allergy, immediate hypersensitivity, delayed hypersensitivity, immunosuppression, or immunotolerance

Abstract

The present invention provides compositions and methods of inhibiting or inducing activation of T cells in a patient. The methods comprise administering a therapeutically effective dose of pharmaceutical compositions comprising a pharmaceutically acceptable carrier and peptides of between about 4 and about 20 residues, that bind antigen binding sites on MHC molecules encoded by substantially all alleles of a DR locus. These peptides are referred to as pan DR binding peptides. The pan DR binding peptides can be used to inhibit immune responses associated with immunopathologies, such as autoimmunity, allograft rejection and allergic responses. The peptides can also be used in combination with CTL peptides to enhance a CTL response.

Claims

1. A composition comprising a peptide capable of binding antigen binding sites on MHC molecules encoded by substantially all alleles of a DR locus, the peptide consisting of 2 D-amino acids and 11 L-amino acids, said peptide having the formula R₁ --R₂ --R₃ --R₄ --R₅, proceeding from the amino-terminus to the carboxy-terminus, wherein:

R₁ is a D-amino acid followed by alanine or lysine;

R₂ is selected from the group consisting of cyclohexylalanine, tyrosine, and phenylalanine;

R₃ is 3 or 4 amino acids, wherein each amino acid is independently selected from the group consisting of alanine, isoleucine, serine, glutamic acid and valine;

R₄ is selected from the group consisting of threonine-leucine-lysine, lysine-threonine, and tryptophan-threonine-leucine-lysine; and

R₅ consists of 2 or 4 amino acids followed by a D-amino acid, wherein each of the 2 or 4 amino acids is independently selected from the group consisting of alanine, serine and valine.

2. The composition of claim 1 wherein:

R₁ is D-alanine followed by alanine or lysine;

R₂ is cyclohexylalanine or phenylalanine;

R₃ is 3 or 4 amino acid, wherein each of the 3 or 4 amino acids is selected from the group comprising alanine, isoleucine, and valine; and

R₅ is 2 or 4 alanines followed by D-alanine.

3. The composition of claim 2 wherein the peptide is selected from the group consisting of aAXAAAKTAAAAa, aAXAAAATLKAAa, aAXVAAATLKAAa, aAXIAAATLKAAa, aKXVAAWTLKAAa, aKFVAAWTLKAAa, aAXAEAATLKAAa, aAXAVAATLKAAa, aAXAAEATLKAAa, aAXAAVATLKAAa, aAXAAAETLKAAa, and aAXAAAVTLKAAa, wherein α

is D-alanine, A is alanine, X is cyclohexylalanine, K is lysine, T is threonine, L is leucine, V is valine, E is glutamic acid, l is isoleucine, W is tryptophan, and F is phenylalanine.

4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the peptide of claim 1.

5. A composition comprising a CTL inducing peptide and a T helper peptide, wherein the T helper peptide is a peptide of claim 1.

6. The composition of claim 5, wherein the CTL inducing peptide is acetylated, palmitylated, or acylated with a fatty acid.

7. The composition of claim 5, wherein the CTL inducing peptide is linked to the T helper peptide to form a CTL/T helper peptide conjugate.

8. The composition of claim 7, wherein the CTL/T helper peptide conjugate is linked to a carrier.

9. The composition of claim 6, wherein the CTL inducing peptide is linked to the T helper peptide by a spacer molecule.

10. The composition of claim 9, wherein the spacer is Ala-Ala-Ala.

11. A method of inhibiting MHC Class II mediated activation of T cells in a patient, the method comprising administering to the patient a therapeutically effective dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a peptide of claim 1.

12. The method of claim 11 wherein the peptide is the peptide of claim 1.

13. The method of claim 11 wherein the peptide is a peptide of claim 3.

14. A method of inducing MHC Class II mediated activation of T cell clones in a patient, the method comprising administering to the patient a therapeutically effective dose of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a peptide of claim 1.

15. The method of claim 14 wherein the peptide is conjugated to a CTL inducing peptide.

16. The method of claim 14 wherein the peptide is the peptide of claim 1.

17. The method of claim 14 wherein the peptide is a peptide of claim 3.

18. The method of claim 11 wherein the peptide binds with high affinity to antigen binding sites on MHC Class II molecules encoded by at least about 7 DR alleles selected from the group consisting of DR alleles DR1, 2w2b, 2w2a, 3, 4w4, 4w14, 5, 7, 52a, 52b, 52c, and 53.

19. The method of claim 14 wherein the peptide binds with high affinity antigen to binding sites on MHC Class II molecules encoded by at least about 7 DR alleles selected from the group consisting of DR alleles DR1, 2w2b, 2w2a, 3, 4w4, 4w14, 5, 7, 52a, 52b, 52c, and 53.

20. The method of claim 14, wherein the peptide is linked to a carrier.

21. The method of claim 20, wherein the carrier is tetanus toxoid.

22. The composition of claim 3, wherein the peptide is aAXAAAKTAAAAa.

23. The composition of claim 3, wherein the peptide is aAXAAAATLKAAa.

24. The composition of claim 3, wherein the peptide is a AXVAAATLKAAa.

25. The composition of claim 3, wherein the peptide is aAXIAAATLKAAa.

26. The composition of claim 3, wherein the peptide is aKXVAAWTLKAAa.

27. The composition of claim 3, wherein the peptide is aKFVAAWTLKAAa.

28. The composition of claim 3, wherein the peptide is aAXAEAATLKAAa.

29. The composition of claim 3, wherein the peptide is aAXAVAATLKAAa.

30. The composition of claim 3, wherein the peptide is aAXAAEATLKAAa.

31. The composition of claim 3, wherein the peptide is aAXAAVATLKAAa.

32. The composition of claim 3, wherein the peptide is aAXAAAETLKAAa.

33. The composition of claim 3, wherein the peptide is aAXAAAVTLKAAa.

34. A peptide which binds more than one DR allele, the peptide consisting of the formula R₁ --R₂ --R₃ --R₄ --R₅, proceeding from the amino-terminus to the carboxy-terminus, wherein:

R₁ is a D- or an L-amino acid residue followed by alanine or lysine;

R₂ is selected from the group consisting of tyrosine, and phenylalanine;

R₃ is 3 or 4 amino acids, wherein each amino acid is independently selected from the group consisting of alanine, isoleucine, serine, glutamic acid, and valine;

R₄ is selected from the group consisting of threonine-leucine-lysine, lysine threonine, and tryptophan-threonine-leucine-lysine; and

R₅ consists of 2 or 4 amino acids followed by a D- or an L-amino acid residue, wherein each of the 2 or 4 amino acids is independently selected from the group consisting of alanine, serine and valine.

35. The peptide of claim 34, wherein the peptide is selected from the group consisting of AAXAAAKTAAAAA (SEQ. ID. No. 18), AAXAAAATLKAAA (SEQ. ID. No. 19), AAXVAAATLKAAA (SEQ, ID. No. 20), AAXIAAATLKAAA (SEQ. ID. No. 21), AKXVAAWTLKAAA (SEQ. ID. No. 22), AKFVAAWTLKAAA (SEQ. ID. No. 23), AAXAEAATLKAAA (SEQ. ID. No. 24), AAXAVAATLKAAA (SEQ. ID. No. 25), AAXAAEATLKAAA (SEQ. ID. No, 26), AAXAAVATLKAAA (SEQ. ID. No. 27), AAXAAAETLKAAA (SEQ, ID. No. 28), AAXAAAVTLKAAA (SEQ. ID. No. 29), wherein A is alanine, X is tyrosine or phenylalanine, K is lysine, T is threonine, L is leucine, V is valine, I is isoleucine, W is tryptophan, E is glutamic acid and F is phenylalanine.

36. The peptide of claim 35, wherein the peptide is AAXAAAKTAAAAA (SEQ. ID. No. 18).

37. The peptide of claim 35, wherein the peptide is AAXAAAATLKAAA (SEQ. ID. No. 19).

38. The peptide of claim 35, wherein the peptide is AAXVAAATLKAAA (SEQ. ID. No. 20).

39. The peptide of claim 35, wherein the peptide is AAXIAAATLKAAA (SEQ. ID. No. 21).

40. The peptide of claim 35, wherein the peptide is AKXVAAWTLKAAA (SEQ. ID. No. 22).

41. The peptide of claim 35, wherein the peptide is AKFVAAWTLKAAA (SEQ. ID. No. 23).

42. The peptide of claim 35, wherein the peptide is AAXAEAATLKAAA (SEQ. ID. No. 24).

43. The peptide of claim 35, wherein the peptide is AAXAVAATLKAAA (SEQ. ID. No. 25).

44. The peptide of claim 35, wherein the peptide is AAXAAEATLKAAA (SEQ. ID. No. 26).

45. The peptide of claim 35, wherein the peptide is AAXAAVATLKAAA (SEQ. ID. No. 27).

46. The peptide of claim 35, wherein the peptide is AAXAAAETLKAAA (SEQ. ID. No. 28).

47. The peptide of claim 35, wherein the peptide is AAXAAAVTLKAAA SEQ. ID. No. 29).

48. The peptide of claim 34, wherein the peptide is linked to a carrier.

49. The peptide of claim 48, wherein the carrier is tetanus toxoid.

50. A cell comprising a peptide of claim 34.

51. The cell of claim 50, wherein the peptide is associated with an MHC Class II molecule on the surface of the cell.

52. A cell comprising the peptide of claim 48.

53. A method of inducing MHC Class II mediated activation of T helper cells, the method comprising contacting a peptide of claim 34 with the T helper cells.

54. The method of claim 53, wherein the peptide is contacted with T helper cells in vitro.

55. The method of claim 53, wherein the T helper cells mediate a CTL response.

56. The method of claim 53, wherein the T helper cells mediate an antibody response.