Compositions useful as ligands for the formyl peptide receptor like 1 receptor and methods of use thereof

• US 20030096260A1
• Filed: 05/07/2002
• Published: 05/22/2003
• Est. Priority Date: 10/09/2001
• Status: Abandoned Application

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Premack, Brett, Schall, Thomas J., Miao, Zhenhua
• Application Number:
  US10/141,620
• Publication Number:
  US 20030096260A1
• Time in Patent Office: Days
• US Class Current: 435/6.16
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/02 Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/04 Amoebicides
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/521 Chemokines

Abstract

The inventors have discovered that a CKβ8-1 truncation variant, CKβ8-1 (25-116), is a bifunctional ligand for two distinct GPCRs, chemokine receptor CCR1 and formyl peptide receptor like 1 (FPRL1). Hence, the inventors have discovered that, in addition to its functional activity on CCR1, CKβ8-1 (25-116) is also a functional ligand for the GPCR receptor FPRL1 that is involved in inflammatory reactions and innate immunity by recruiting monocytes and neutrophils. In addition, the inventors have discovered an alternatively spliced exon of CKβ8-1, named SHAAGtide. SHAAGtide, along with its parent chemokine CKβ8-1 (25-116), is fully functional on both monocytes and neutrophils that are known to express FPRL1.

Claims

1. An isolated protein or polypeptide comprising a N-terminal sequence having at least 80% identity to SEQ ID NO:

1, excluding the sequence of SEQ ID NO;

16.

2. The isolated protein or polypeptide of claim 1, wherein the protein or polypeptide is a ligand for FPRL1.

3. The isolated protein or polypeptide of claim 1, wherein said N-terminal sequence has at least 90% sequence identity to SEQ ID NO:

1.

4. The isolated protein or polypeptide of claim 1, wherein said N-terminal sequence has at least 95% sequence identity to SEQ ID NO:

1.

5. The isolated protein or polypeptide of claim 1, wherein said N-terminal sequence has 100% sequence identity to SEQ ID NO:

1.

6. The isolated protein or polypeptide of claim 1, wherein said N-terminal sequence is SEQ ID NO:

1;

SEQ ID NO;

3;

SEQ ID NO;

5 or SEQ ID NO;

6.

19. An antibody that specifically binds to the peptide of claim 1.

20. A fusion protein comprising a non-SHAAGtide polypeptide fused to the peptide of claim 1.

21. A kit comprising a pharmaceutical composition comprising the polypeptide of claim 1 and a pharmaceutically acceptable carrier, and a syringe.

7. An isolated polypeptide at least 80% identity to SEQ ID NO:

1.

8. The isolated polypeptide of claim 7 having at least 90% identity to SEQ ID NO:

1.

9. The isolated polypeptide of claim 7 having at least 95% identity to SEQ ID NO:

1.

10. The isolated polypeptide of claim 7 having a sequence of SEQ ID NO:

1;

SEQ ID NO;

3;

SEQ ID NO;

5 or SEQ ID NO;

6.

11. An isolated nucleic acid comprising a nucleic acid sequence comprising at least 80% identity with SEQ ID NO:

20.

12. The isolated nucleic acid of claim 11 comprising at least 90% identity to SEQ ID NO:

20.

13. The isolated nucleic acid of claim 11 comprising at least 95% identity to SEQ ID NO:

20.

14. The isolated nucleic acid of claim 11 comprising at least 99% identity to SEQ ID NO:

20.

15. An isolated nucleic acid having a sequence complementary to the nucleic acid of claim 11.

16. The isolated nucleic acid of claim 11 comprising SEQ ID NO:

20, SEQ ID NO;

22, SEQ ID NO;

24, SEQ ID NO;

25, SEQ ID NO;

27, or SEQ ID NO;

30.

17. The isolated nucleic acid of claim 15 comprising SEQ ID NO:

20.

18. The isolated nucleic acid of claim 15 comprising SEQ ID NO:

25.

22. A method of identifying a FPRL1 receptor antagonist comprising:

contacting a cell expressing a FPRL1 receptor with a protein or polypeptide comprising a N-terminal sequence having at least 80% identity to SEQ ID NO;

1;

wherein the receptor is stimulated;

contacting the receptor with a candidate antagonist compound; and

detecting to the FPRL1 receptor.

23. The method of claim 22, wherein the candidate compound is an antibody, peptide, nucleic acid or small molecule.

24. The method claim 22, wherein the cell is a neutrophil, monocyte, T-lymphocyte or dendritic cell.