Modified growth hormones

• US 7,998,930 B2
• Filed: 11/03/2005
• Issued: 08/16/2011
• Est. Priority Date: 11/04/2004
• Status: Active Grant

• Current Assignee: HanAll Biopharma Co. Ltd.
• Original Assignee: HanAll Biopharma Co. Ltd.
• Inventors: Guyon, Thierry, Drittanti, Lila, Borrelly, Gilles, Vega, Manuel
• Primary Examiner(s): Saoud; Christine J
• Application Number:
  US11/267,871
• Publication Number:
  US 20060094655A1
• Time in Patent Office: 2,112 Days
• Field of Search: None
• US Class Current: 514/11.3
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: C07K 14/61 : Growth hormone [GH], i.e. somatotropin

Abstract

Provided are modified growth hormone polypeptides, nucleic acid molecules encoding modified growth hormone polypeptides and methods of generating modified growth hormone polypeptides. Also provided are methods of treatment using modified growth hormone polypeptides.

Claims

1. A pharmaceutical composition, comprising a modified growth hormone polypeptide containing an amino acid replacement in an unmodified growth hormone polypeptide at a position corresponding to amino acid Y42 of a mature human growth hormone polypeptide, wherein:

the growth hormone polypeptide is modified in its primary sequence only by the amino acid replacement at Y42;

the amino acid replacement is Y42H, whereby the modified growth hormone polypeptide retains an activity and exhibits increased resistance to proteolysis in the serum or gastrointestinal tract compared to the unmodified growth hormone polypeptide that does not comprise the amino acid replacement, and is rendered orally available;

the unmodified human growth hormone polypeptide comprises the sequence of amino acids set forth in SEQ ID NO;

1 or the sequence of amino acid residues set forth as amino acid residues 27-217 in SEQ ID NO;

712, or allelic or species variants, alternative splice variants or an active portion thereof that includes the position corresponding to Y42; and

the pharmaceutical composition is formulated for oral administration.

2. The pharmaceutical composition of claim 1, wherein the modified growth hormone polypeptide is a human growth hormone (hGH) polypeptide.

3. The pharmaceutical composition of claim 1, wherein the amino acid replacement is made in a human pituitary growth hormone polypeptide or human placental growth hormone polypeptide.

4. The pharmaceutical composition of claim 3, wherein the unmodified growth hormone is a pituitary growth hormone comprising a sequence of amino acids set forth in SEQ ID NO:

1 or SEQ ID NO;

713, allelic or species variants, alternative splice variants, or an active portion thereof that includes the position corresponding to Y42.

5. The pharmaceutical composition of claim 3, wherein the unmodified growth hormone is a placental growth hormone comprising a sequence of amino acids set forth in SEQ ID NO:

712, or a mature form thereof, allelic or species variants, alternative splice variants, or an active portion thereof that includes the position corresponding to Y42.

6. The pharmaceutical composition of claim 1, wherein the modified growth hormone polypeptide is a mature growth hormone polypeptide.

7. The pharmaceutical composition of claim 1, wherein the modified growth hormone polypeptide is a precursor growth hormone polypeptide.

8. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 1, further comprising a pharmaceutically-acceptable additive.

10. The pharmaceutical composition of claim 1, wherein the modified growth hormone polypeptide comprises the sequence of amino acids set forth in SEQ ID NO:

58 or an active portion thereof that contains Y42H.

11. The pharmaceutical composition of claim 1 that is a tablet or capsule.

12. The pharmaceutical composition of claim 1, wherein the modified growth hormone comprises the sequence of amino acids set forth in SEQ ID NO:

58 or allelic or species variants, alternative splice variants or an active portion thereof that includes the position and mutation corresponding to Y42H.