# US 6,849,718 B2 · Muteins of hypoxia inducible factor alpha and methods of use thereof

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- Number: US 6,849,718 B2
- Document ID: US6849718B2
- Status: Granted
- Kind: B2
- Application number: 10/101,816
- Filed: 2002-03-19
- Published: 2003-03-06
- Granted: 2005-02-01
- Earliest claimed: 2001-03-20
- Assignees: Dana-Farber Cancer Institute, Inc.
- Inventors: William G. Kaelin, Jr.; Mircea Ivan
- Web page: https://patentgrep.com/patent/US6849718B2

## CPC

- C12Q 1/26: involving oxidoreductase
- A61K 38/1709: {from mammals}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- C07K 14/4702: {Regulators; Modulating activity}
- G01N 33/573: for enzymes or isoenzymes
- G01N 2333/90245: acting on paired donors with incorporation of molecular oxygen (1.14)
- 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)
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## 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

### Claim 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.

### Claim 2 (depends on 1)

The HIF mutein polypeptide of claim 1, wherein amino acid 562 when numbered in accordance with SEQ ID NO: 2 is not a leucine.

### Claim 3 (depends on 1)

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.

### Claim 4

A HIF mutein polypeptide comprising the amino acid sequence of SEQ ID NO: 7.