EGFR BINDING PEPTIDES AND USES THEREOF

• US 20100151003A1
• Filed: 12/20/2007
• Published: 06/17/2010
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Biotech, Inc. (Johnson & Johnson)
• Inventors: Trikha, Mohit, Kehoe, John, Shi, Frank, Bryan, Wang
• Granted Patent: US 8,536,113 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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

Abstract

Short oligopeptides are provided which are capable of binding to the epidermal growth factor receptor on the surface of human tumor cells. Methods for using the peptides as targeting moieties in more complex compositions, such as conjugates of cytoxins, and/or structures, such as liposomal structures, for the purposes of drug delivery are also provided.

Claims

1. A peptide which exhibits one or more properties selected from a) competitive binding with known EGFR ligands, EGF and TGF-α

;

b) ability to compete with the neutralizing monoclonal antibody cetuximab for binding to EGFR;

c) binding to a non-ligand binding domain on EGFR; and

d) ability to bind to extracellular domain of EGFR in the presence of EGF.

2. A peptide according to claim 1 comprising the sequence LCXXΦ

Φ

HPLC, where Φ

is F or Y (SEQ ID NO;

     9).

3. A peptide according to claim 2 comprising at least one sequence selected from SEQ ID NOs:

6, 7, or 8.

4. A peptide according to claim 1 comprising the sequence SLPXLLC, where X is any amino acid (SEQ ID NO:

22).

5. A peptide according to claim 4 comprising at least one sequence selected from SEQ ID NOs:

10-20, or 21.

6. A peptide according to claim 1 comprising the sequence DC(I/V)XFGXX(L/V)YC, where the amino acids at position 3 is either I or V and the amino acid at position 9 is either L or V and X represents any amino acid (SEQ ID NO:

36).

7. A peptide according to claim 6 comprising at least one sequence selected from SEQ ID NOs:

23-34, or 35.

8. A peptide according to claim 1 comprising the sequence CXLXXDXXL/IL/IC where the amino acids at position 9 is either L or I and the amino acid at position 10 is either L or I and X represents any amino acid (SEQ ID NO:

42).

9. A peptide according to claim 8 comprising at least one sequence selected from SEQ ID NOs:

37-40, or 41.

10. A peptide according to claim 1 comprising the sequence XXCXXTXFDXWXVCXX where X represents any amino acid (SEQ ID NO:

50).

11. A peptide according to claim 10 comprising at least one sequence selected from SEQ ID NOs:

43-48, or 49.

12. A peptide according to claim 1 comprising the sequence DPCTWEVWGRECLQ (SEQ. ID. No. 55).

13. A peptide according to claim 1 wherein the peptide is conjugated by chemical bond to a non-protein polymer, a reporter group, or an active.

14. A peptide conjugate according to claim 13, wherein the active is a cytotoxin, a immunomodulator, or a radioisotope.

15. A peptide conjugate according to claim 13, wherein the polymer comprises a hydrophilic component and a lipid component.

16. A nucleic acid encoding the peptide according to one of claims 1-2.

17. A composition comprising a fusion protein according to the formula:

V1_o-Pep_a-Flex_n-V2_m-Hinge-CH2-CH3 

 

(I)

wherein Pep represents a peptide of claim 1, Flex is an optional flexible linker polypeptide that provides structural flexibility, V1 and V2 are bracketing sequences, Hinge is at least a portion of an immunoglobulin hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region;

m, n and o can be zero or can be an integer between 1 and 10, and a can be an integer from 1 to 10.

18. A composition comprising a fusion protein according to the formula:

V1_o-Pep_a-Flex_n-V2_m-Hinge-CH2-CH3 

 

(I)

wherein Pep represents a peptide of claim 2, Flex is an optional flexible linker polypeptide that provides structural flexibility, V1 and V2 are bracketing sequences, Hinge is at least a portion of an immunoglobulin hinge region, CH2 is at least a portion of an immunoglobulin CH2 constant region, CH3 is at least a portion of an immunoglobulin CH3 constant region;

m, n and o can be zero or can be an integer between 1 and 10, and a can be an integer from 1 to 10.

19. The composition of claim 18, comprising the protein of SEQ ID NO:

60.

20. A pharmaceutical composition comprising a peptide or peptide conjugate according to any of claims 1, 13 or 17.

21. The pharmaceutical composition of claim 20 which comprises the peptide associated with a lipid structure.

22. The pharmaceutical composition of claim 21 wherein the lipid structure further comprises a therapeutic or prophylactic agent.

23. The pharmaceutical composition of claim 22 wherein the lipid structure is a liposomal drug formulation having an inner lipid surface and an outer surface, and the peptide is associated with the liposomal outer surface.

24. A method of treating, preventing or managing a hyperproliferative cell disease associated with cells that express EGFR in a subject in need thereof, said method comprising administering to said subject a therapeutically or prophylactically effective amount of a composition comprising:

(a) a peptide of claim 1;

(b) a therapeutic or prophylactic agent that treats, prevents or manages said hyperproliferative cell disease; and

(c) a pharmaceutically acceptable carrier.

25. The method of claim 21 wherein the hyperproliferative disease is cancer.

26. A method of treating, preventing or managing an infectious disease associated with viral agents which attack cells that express EGFR in a subject in need thereof, said method comprising administering to said subject a therapeutically or prophylactically effective amount of a composition comprising:

(a) a peptide of claim 1;

(b) a therapeutic or prophylactic agent that treats, prevents or manages said infectious disease; and

(c) a pharmaceutically acceptable carrier.