Muteins of hypoxia inducible factor alpha and methods of use thereof

• US 6,849,718 B2
• Filed: 03/19/2002
• Issued: 02/01/2005
• Est. Priority Date: 03/20/2001
• Status: Expired due to Term

• Current Assignee: Dana-Farber Cancer Institute
• Original Assignee: Dana-Farber Cancer Institute
• Inventors: Kaelin, William G. Jr., Ivan, Mircea
• Primary Examiner(s): Chan, Christina
• Assistant Examiner(s): HADDAD, MAHER M
• Application Number:
  US10/101,816
• Publication Number:
  US 20030045686A1
• Time in Patent Office: 1,050 Days
• Field of Search: 530/350, 530/402
• US Class Current: 530/350
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/4702 Regulators; Modulating activity
• CPC Class Codes: C12Q 1/26 involving oxidoreductase
• CPC Class Codes: G01N 2333/90245 acting on paired donors with incorporation of molecular oxygen (1.14)
• CPC Class Codes: G01N 2500/02 Screening involving studying the effect of compounds C on the interaction between interacting molecules A and B (e.g. A = enzyme and B = substrate for A, or A = receptor and B = ligand for the receptor)
• CPC Class Codes: G01N 33/573 for enzymes or isoenzymes

Abstract

The present invention provides hypoxia inducible factor alpha muteins, DNA sequences encoding these hypoxia inducible factor alpha muteins, recombinant DNA molecules containing those DNA sequences operatively linked to expression control sequences and capable of inducing expression of an hypoxia inducible factor alpha muteins, hosts transformed with those recombinant DNA molecules, pharmaceutical compositions containing hypoxia inducible factor alpha muteins and methods of using those compositions to treat hypoxia and ischemic related tissue damage.

Claims

1. A hypoxia inducible factor (HIF) mutein polypeptide comprising SEQ ID NO:

2, except that amino acid residue at position 402 of SEQ ID NO;

2 of said HIF mutein is not proline, said HIF mutein displaying decreased binding to VHL, and increased resistance to degradation in the presence of oxygen.

2. The HIF mutein polypeptide of claim 1, wherein amino acid 562 when numbered in accordance with SEQ ID NO:

2 is not a leucine.

3. The HIF mutein polypeptide of claim 1, with an additional substitution such that the amino acid at position 564 of SEQ ID NO:

2 is not a proline.

4. A HIF mutein polypeptide comprising the amino acid sequence of SEQ ID NO:

7.