Synthetic chemokine receptor ligands and methods of use thereof

• US 20070172446A1
• Filed: 05/13/2004
• Published: 07/26/2007
• Est. Priority Date: 05/16/2003
• Status: Abandoned Application

• Current Assignee: Intermune Incorporated (Roche Holding AG)
• Original Assignee: Intermune Incorporated (Roche Holding AG)
• Inventors: Blatt, Lawrence
• Application Number:
  US10/555,735
• Publication Number:
  US 20070172446A1
• Time in Patent Office: Days
• US Class Current: 424/85.100
• 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 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• 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 17/00 Drugs for dermatological disorders
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/00 Antiparasitic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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
• CPC Class Codes: C07K 14/522 Alpha-chemokines, e.g. NAP-2, ENA-78, GRO-alpha/MGSA/NAP-3, GRO-beta/MIP-2alpha, GRO-gamma/MIP-2beta, IP-10, GCP-2, MIG, PBSF, PF-4, KC

Abstract

The present invention provides synthetic CXCR3 ligands, including consensus CXCR3 ligands and hybrid CXCR3 ligands; and compositions comprising the ligands. The present invention provides polynucleotides encoding the synthetic CXCR3 ligands; expression vectors comprising the polynucleotides; and host cells comprising the polynucleotidess. The present invention provides methods of treating fibrotic disorders; methods of treating angiogenic disorders; methods of treating cancer; and methods of treating bacterial infections. The methods generally involve administering to an individual in need thereof an effective amount of a subject synthetic CXCR3 ligand.

(SEQ ID NO: 15)MKKSGVLFLLGIILLVLIGVQGFPMFKRGRCLCIGPGVKPVNPRSLEKLE IIPASQFCPRIEIIATLKNGVQTCLNPDSKQARLIIKKVSKEMSKRSP

Claims

1. A synthetic CXCR3 polypeptide ligand comprising a polypeptide of from about 70 to about 125 amino acids in length, optionally further including an additional methionine attached to the ordinarily first amino acid at the N-terminus, the amino acid sequence of the polypeptide comprising, in sequence, discrete sub-sequences corresponding in amino acid identity and number to sub-sequences of different, naturally occurring CXCR3 ligands selected from IP-10, I-TAC, and Mig, where the amino acid sequence of the synthetic CXCR3 polypeptide differs from the amino acid sequence of naturally occurring CXCR3 ligands IP-10, I-TAC, and Mig.

2. The synthetic CXCR3 polypeptide ligand of claim 1, wherein the CXCR3 ligand comprises the amino acid sequence as set forth in any one of SEQ ID NOs:

15-20.

5. A composition comprising the synthetic CXCR3 ligand of any of claims 1-4.

6. A polynucleotide comprising a nucleotide sequence encoding a synthetic CXCR3 ligand of any of claims 1-4.

7. The polynucleotide of claim 6, wherein-said synthetic CXCR3 ligand comprises the amino acid sequence set forth in any one of SEQ ID NO:

01, 02, 03, 15, 16, 17, 18, 19, and 20.

8. An expression vector comprising the polynucleotide of claim 6 operably linked to a promoter.

9. A host cell comprising the polynucleotide of claim 6.

10. A host cell comprising the expression vector of claim 8.

11. A method for producing a synthetic CXCR3 ligand, the method comprising:

culturing the host cell of claim 10 under conditions that favor production of the synthetic CXCR3 ligand; and

isolating the synthetic CXCR3 ligand from the culture.

12. An antibody that specifically binds a synthetic CXCR3 ligand of any one of claims 1-4.

3. A synthetic CXCR3 ligand comprising a polypeptide of from about 70 to about 125 amino acids in length, optionally further including an additional methionine attached to the ordinarily first amino acid at the N-terminus, the amino acid sequence of the polypeptide comprising those amino acid residues that are common to IP-10, Mig, and I-TAC, and which comprises, at one or more of those positions where there is no amino acid common to IP-10, Mig, and I-TAC, an amino acid which predominantly occurs at that position.

4. The synthetic CXCR3 polypeptide ligand of claim 3, wherein the CXCR3 ligand comprises the amino acid sequence as set forth in any one of SEQ ID NO:

01, 02, and 03.

13. A method of treating a fibrotic disease in an individual, the method comprising administering to an individual suffering from a fibrotic disease an amount of a synthetic CXCR3 ligand that is effective in the treatment or prophylaxis of the fibrotic disease in the individual.

14. The method of claim 13, wherein the fibrotic disease is pulmonary fibrosis.

15. The method of claim 13, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

16. The method of claim 13, wherein the pulmonary fibrosis is from a known etiology.

17. The method of claim 13, wherein the fibrotic disease is selected from liver fibrosis, renal fibrosis, cardiac fibrosis, and scleroderma.

20. The method of any of claims 13-19, wherein the individual is a human.

18. A method of reducing tumor growth in an individual having a tumor, the method comprising administering to the individual an effective amount of a synthetic CXCR3 ligand.

19. The method of claim 18, further comprising administering an effective amount of an anti-neoplastic agent selected from an alkylating agent, a nitrosourea, an antimetabolite, an antitumor antibiotic, a plant (vinca) alkaloid, a taxane, and a steroid hormone.