Modified growth hormones

• US 20070249532A9
• Filed: 11/03/2005
• Published: 10/25/2007
• 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
• Granted Patent: US 7,998,930 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 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 modified growth hormone polypeptide, comprising:

one to five amino acid replacements at positions corresponding to any of amino acid positions 1-55, 57, 58, 60-63, 67-87, 89-91, 93, 95-100, 102-128, 131-132, 135-139, 141, 142, 144, 148-182, 184, 185 and 187-191 of mature human growth hormone polypeptide compared to an unmodified growth hormone polypeptide, wherein;

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

1; and

the modified growth hormone polypeptide exhibits increased protein stability compared to the unmodified growth hormone polypeptide of SEQ ID NO;

1 or SEQ ID No. 712.

2. The modified growth hormone polypeptide of claim 1, wherein:

the amino acid replacement or replacements correspond to positions selected from among positions 1, 2, 5, 6, 8, 9, 10, 11, 14, 15, 16, 19, 20, 23, 25, 26, 28, 30, 31, 32, 33, 35, 37, 38, 39, 41, 42, 44, 45, 48, 52, 54, 61, 70, 73, 74, 75, 76, 77, 80, 81, 82, 86, 87, 89, 93, 97, 103, 107, 111, 112, 113, 114, 115, 116, 117, 118, 119, 124, 125, 127, 128, 139, 153, 154, 156, 157, 158, 160, 162, 163, 164, 166, 167, 168, 169, 170, 171, 172, 174, 176, 177, 178, and 191 of mature human growth hormone.

3. The modified growth hormone polypeptide of claim 2, wherein:

the amino acid replacement or replacements correspond to positions selected from among positions F1, P2, P5, L6, R8, L9, F10, D11, M14, L15, R16, R9, L20, L23, F25, D26, Y28, E30, F31, E32, E33, Y35, P37, K38, E39, K41, Y42, F44, L45, P48, L52, F54, P61, K70, L73, E74, L75, L76, R77, L80, L81, L82, W86, L87, P89, L93, F97, Y103, D107, Y111, D112, L113, L114, K115, D116, L117, E118, E119, L124, M125, R127, L128, F139, D153, D154, L156, L157, K158, Y160, L162, L163, Y164, F166, R167, K168, D169, M170, D171, K172, E174, F176, L177, R178, and F191 of mature human growth hormone polypeptide.

4. The modified growth hormone polypeptide of claim 3, wherein:

the amino acid replacement or replacements is (are) selected from among replacing R by H or Q, replacing E by H, Q or N, replacing K by Q or N, replacing D by N or Q, replacing M by I or V, replacing P by A or S, replacing Y by I or H, replacing F by I or V, replacing W by H or S, and replacing L by I or V.

5. The modified growth hormone polypeptide of claim 4, wherein:

the amino acid replacement or replacements is (are) selected from among F1I, F1V, P2A, P2S, P5A, P5S, L6I, L6V, R8H, R8Q, L9I, L9V, F10I, F10V, D11N, D11Q, M14I, M14V, L15I, L15V, R16H, R16Q, R19H, R19Q, L20I, L20V, L23I, L23V, F25I, F25V, D26N, D26Q, Y28H, Y28I, E30Q, E30H, E30N, F31I, F31V, E32Q, E32H, E32N, E33Q, E33H, E33N, Y35H, Y35I, P37A, P37S, K38N, K38Q, E39Q, E39H, E39N, K41N, K41Q, Y42H, Y42I, F44I, F44V, L45I, L45V, P48A, P48S, L52I, L52V, F54I, F54V, P61A, P61S, K70N, K70Q, L73I, L73V, E74Q, E74H, E74N, L75I, L75V, L76I, L76V, R77H, R77Q, L80I, L80V, L81I, L81V, L82I, L82V, W86H, W86S, L87I, L87V, P89A, P89S, L93I, L93V, F97I, F97V, Y103H, Y103I, D107N, D107Q, Y111H, Y111I, D112N, D112Q, L113I, L113V, L114I, L114V, K115N, K115Q, D116N, D116Q, L117I, L117V, E118Q, E118H, E118N, E119Q, E119H, E119N, L124I, L124V, M125I, M125V, R127H, R127Q, L128I, L128V, F139I, F139V, D153N, D153Q, D154N, D154Q, L156I, L156V, L157I, L157V, K158N, K158Q, Y160H, Y160I, L162I, L162V, L163I, L163V, Y164H, Y164I, F166I, F166V, R167H, R167Q, K168N, K168Q, D169N, D169Q, M170I, M170V, D171N, D171Q, K172N, K172Q, E174Q, E174H, E174N, F176I, F176V, L177I, L177V, R178H, R178Q, F191I and F191V.

6. The modified growth hormone polypeptide of claim 5, wherein:

the amino acid replacement or replacements is (are) positions corresponding to positions selected from among positions F1I, P2A, P5S, L9V, D11N, M14V, R16H, L23I, L23V, D26N, K38N, K41Q, Y42H, Y42I, L73V, E74N, L81V, L87V, Y111I, D112N, D116Q, E119Q, L124V, M125I, M125V, D153N, L156I, L157I, K158N, L162I, F166I, R167H, R167Q, K168N, K168Q, D169Q, D171N, D171Q, K172Q, E174Q, E174N, E174H, L177V, L177I, R178Q and F191I.

7. The modified growth hormone polypeptide of claim 6, wherein:

the amino acid replacement or replacements is (are) selected from among D11N, M14V, L23I, L23V, Y42H, Y42I, L81V, E119Q, M125I and E174N.

8. The modified growth hormone polypeptide of claim 1, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 6, 9, 13, 15, 17, 20, 23, 24, 105, 110, 113, 114, 117, 121, 124 and 128 of mature human growth hormone polypeptide.

9. The modified growth hormone polypeptide of claim 8, wherein:

the one or more single amino acid replacements correspond to one or more of positions selected from among positions L6, L9, A13, L15, A17, L20, L23, A24, A105, V110, L113, L114, L117, I121, L124 and L128.

10. The modified growth hormone polypeptide of claim 9, wherein the one or more amino acid replacements is (are) selected from among E, D, K, R, N, Q, S and T.

11. The modified growth hormone polypeptide of claim 10, wherein:

the one or more single amino acid replacements are selected from among L6E, L6D, L6K, L6R, L6N, L6Q, L6S, L6T, L9E, L9D, L9K, L9R, L9N, L9Q, L9S, L9T, A13E, A13D, A13K, A13R, A13N, A13Q, A13S, A13T, L15E, L15D, L15K, L15R, L15Q, L15N, L15S, L15T, A17E, A17D, A17K, A17R, A17N, A17Q, A17S, A17T, L20E, L20D, L20K, L20R, L20N, L20Q, L20S, L20T, L23E, L23D, L23K, L23R, L23N, L23Q, L23S, L23T, A24E, A24D, A24K, A24R, A24N, A24Q, A24S, A24T, A105E, A105D, A105K, A105R, A105N, A105Q, A105S, A105T, V110E, V110D, V110K, V110R, V110N, V110Q, V110S, V110T, L113E, L113D, L113K, L113R, L113N, L113Q, L113S, L113T, L114E, L114D, L114K, L114R, L114N, L114Q, L114S, L114T, L117E, L117D, L117K, L117R, L117N, L117Q, L117S, L117T, I121E, I121D, I121K, I121R, I121N, I121Q, I121S, I121T, L124E, L124D, L124K, L124R, L124N, L124Q, L124S, L124T, L128E, L128D, L128K, L128R, L128Q, L128N, L128S and L128T.

12. The modified growth hormone polypeptide of claim 1, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 56, 59, 64, 65, 66, 88, 92, 94, 101, 129, 130, 133, 134, 140, 143, 145, 146, 147, 183, and 186 of a mature human growth hormone polypeptide comprising the sequence of amino acids set forth in SEQ ID NO;

1.

13. The modified growth hormone polypeptide of claim 12, wherein:

the amino acid replacements correspond to one or more of positions selected from among positions E56, P59, R64, E65, E66, E88, F92, R94, L101, E129, D130, P133, R134, K140, Y143, K145, F146, D147, R183 and E186.

14. The modified growth hormone polypeptide of claim 13, wherein:

the one or more amino acid replacement(s) is (are) selected from among replacing E with any of Q, N and H, replacing P with S or A, replacing R with H or Q, replacing L or F with I or V, replacing K or D with Q or N, and replacing Y with H or I.

15. The modified growth hormone polypeptide of claim 14, wherein:

the one or more single amino acid replacement(s) is (are) selected from among E56Q, E56N, E56H, P59S, P59A, R64H, R64Q, E65Q, E65N, E65H, E66Q, E66N, E66H, E88Q, E88N, E88H, F92I, F92V, R94H, R94Q, L101V, L101I, E129Q, E129N, E129H, D130Q, D130N, P133S, P133A, R134H, R134Q, K140Q, K140N, Y143H, Y143I, K145Q, K145N, F146I, F146V, D147Q, D147N, R183H, R183Q, E186Q, E186N and E186H.

16. The modified growth hormone polypeptide of claim 1, that is a human growth hormone (hGH) polypeptide.

17. The modified growth hormone polypeptide of claim 1, wherein the amino acid replacements are made in a human pituitary growth hormone polypeptide or human placental growth hormone polypeptide.

18. The modified growth hormone polypeptide of claim 1, that is a mature growth hormone polypeptide.

19. The modified growth hormone polypeptide of claim 1, that is a precursor growth hormone polypeptide.

20. The modified growth hormone polypeptide of claim 1, wherein the growth hormone is pegylated, albuminated, or glycosylated.

21. The modified growth hormone polypeptide of claim 1, wherein the increased stability is manifested as an increased half-life in vivo or in vitro compared to an unmodified growth hormone polypeptide.

22. The modified growth hormone polypeptide of claim 21, wherein the increased stability is manifested as an increased half-life when administered to a subject.

23. A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified growth hormone polypeptide of claim 1.

24. A vector, comprising the nucleic acid molecule of claim 23.

25. A cell, comprising the vector of claim 24.

26. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a nucleic acid of claim 23 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

27. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a vector of claim 24 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

28. A pharmaceutical composition, comprising the modified growth hormone polypeptide of claim 1.

29. The pharmaceutical composition of claim 28, further comprising a pharmaceutically acceptable excipient.

30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is formulated for oral administration.

31. The pharmaceutical composition of claim 28, wherein the modified growth hormone polypeptide exhibits increased protein half-life or bioavailability in the gastrointestinal tract.

32. The pharmaceutical composition of claim 28, further comprising a pharmaceutically-acceptable additive.

33. A pharmaceutical composition, comprising a nucleic acid molecule of claim 23.

34. A pharmaceutical composition, comprising a vector of claim 24.

35. A method, comprising treating a subject by administering the pharmaceutical composition of claim 28, wherein the subject has a disease or condition that is treated by the administration of growth hormone.

36. The method of claim 35, wherein the disease or condition is selected from among a growth deficiency disorder, AIDS wasting, aging, impaired immune function of HIV-infected subjects, a catabolic illness, surgical recovery, a congestive cardiomyopathy, liver transplantation, liver regeneration after hepatectomy, chronic renal failure, renal osteodystrophy, osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia, a chronic inflammatory or nutritional disorder such as Crohn'"'"'s disease, short bowel syndrome, juvenile chronic arthritis, cystic fibrosis, male infertility, X-linked hypophosphatemic rickets, Down'"'"'s syndrome, Spina bifida, Noonan Syndrome, obesity, impaired muscle strength and fibromyalgia.

37. The method of claim 36, wherein the growth deficiency disorder is selected from among Turner'"'"'s syndrome, intrauterine growth retardation, idiopathic short stature, Prader Willi syndrome, and thalassaemia.

38. A modified growth hormone polypeptide, comprising:

one or more single amino acid replacements at positions corresponding to any of amino acid positions 1-12, 14-26, 29-53, 57, 58, 60-63, 67-78, 80-84, 86, 87, 89, 91, 93, 95-100, 102-113, 115-128, 131, 132, 135-139, 141, 142, 144, 148-160, 162-182, 185 and 187-191 of mature human growth hormone polypeptide compared to unmodified growth hormone, wherein;

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

1; and

the modified growth hormone polypeptide exhibits increased protein stability compared to the unmodified mature human growth hormone polypeptide of SEQ ID NO;

1.

39. The modified growth hormone polypeptide of claim 38, wherein:

the amino acid replacements correspond to one or more of positions selected from among positions F1, P2, P5, L6, R8, L9, F10, D11, M14, L15, R16, R19, L20, L23, F25, D26, E30, F31, E32, E33, Y35, P37, K38, E39, K41, Y42, F44, L45, P48, L52, P61, K70, L73, E74, L75, L76, R77, L80, L81, L82, W86, L87, P89, L93, F97, Y103, D107, Y111, D112, L113, K115, D116, L117, E118, E119, L124, M125, R127, L128, F139, D153, D154, L156, L157, K158, Y160, L162, L163, Y164, F166, R167, K168, D169, M170, D171, K172, E174, F176, L177, R178 and F191.

40. The modified growth hormone polypeptide of claim 39, wherein:

the amino acid replacement or replacements is (are) selected from among replacing R by H or Q, replacing E by H, Q or N, replacing K by Q or N, replacing D by N or Q, replacing M by I or V, replacing P by A or S, replacing Y by I or H, replacing F by I or V, replacing W by H or S, and replacing L by I or V.

41. The modified growth hormone polypeptide of claim 40, wherein:

the amino acid replacement or replacements is (are) selected from among F1I, F1V, P2A, P2S, P5A, P5S, L6I, L6V, R8H, R8Q, L9I, L9V, F10I, F10V, D11N, D11Q, M14I, M14V, L15I, L15V, R16H, R16Q, R19H, R19Q, L20I, L20V, L23I, L23V, F25I, F25V, D26N, D26Q, E30Q, E30H, E30N, F31I, F31V, E32Q, E32H, E32N, E33Q, E33H, E33N, Y35H, Y35I, P37A, P37S, K38N, K38Q, E39Q, E39H, E39N, K41N, K41Q, Y42H, Y42I, F44I, F44V, L45I, L45V, P48A, P48S, L52I, L52V, P61A, P61S, K70N, K70Q, L73I, L73V, E74Q, E74H, E74N, L75I, L75V, L76I, L76V, R77H, R77Q, L80I, L80V, L81I, L81V, L82I, L82V, W86H, W86S, L87I, L87V, P89A, P89S, L93I, L93V, F97I, F97V, Y103H, Y103I, D107N, D107Q, Y111H, Y111I, D112N, D112Q, L113I, L113V, K115N, K115Q, D116N, D116Q, L117I, L117V, E118Q, E118H, E118N, E119Q, E119H, E119N, L124I, L124V, M125I, M125V, R127H, R127Q, L128I, L128V, F139I, F139V, D153N, D153Q, D154N, D154Q, L156I, L156V, L157I, L157V, K158N, K158Q, Y160H, Y160I, L162I, L162V, L163I, L163V, Y164H, Y164I, F166I, F166V, R167H, R167Q, K168N, K168Q, D169N, D169Q, M170I, M170V, D171N, D171Q, K172N, K172Q, E174Q, E174H, E174N, F176I, F176V, L177I, L177V, R178H, R178Q, F191I and F191V.

42. The modified growth hormone polypeptide of claim 41, wherein:

the amino acid replacement or replacements is (are) selected from among F1I, P2A, P5S, L9V, D11N, M14V, R16H, L23I, L23V, D26N, K38N, K41Q, Y42H, Y42I, L73V, E74N, L81V, L87V, Y111I, D112N, D116Q, E119Q, L124V, M125I, M125V, D153N, L156I, L157I, K158N, L162I, F166I, R167H, R167Q, K168N, K168Q, D169Q, D171N, D171Q, K172Q, E174Q, E174N, E174H, L177V, L177I, R178Q and F191I.

43. The modified growth hormone polypeptide of claim 42, wherein:

the amino acid replacement(s) is (are) positions corresponding to positions selected from among D11N, M14V, L23I, L23V, Y42H, Y42I, L81V, E119Q, M125I and E174N.

44. The modified growth hormone polypeptide of claim 38, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 6, 9, 13, 15, 17, 20, 23, 24, 105, 110, 113, 114, 117, 121, 124 and 128 of mature human growth hormone polypeptide.

45. The modified growth hormone polypeptide of claim 44, wherein:

the one or more single amino acid replacements correspond to one or more of positions selected from among positions L6, L9, A13, L15, A17, L20, L23, A24, A105, V110, L113, L114, L117, I121, L124 and L128.

46. The modified growth hormone polypeptide of claim 45, wherein the one or more amino acid replacements is (are) selected from among E, D, K, R, N, Q, S and T.

47. The modified growth hormone polypeptide of claim 46, wherein:

the one or more single amino acid replacements are selected from among L6E, L6D, L6K, L6R, L6N, L6Q, L6S, L6T, L9E, L9D, L9K, L9R, L9N, L9Q, L9S, L9T, A13E, A13D, A13K, A13R, A13N, A13Q, A13S, A13T, L15E, L15D, L15K, L15R, L15Q, L15N, L15S, L15T, A17E, A17D, A17K, A17R, A17N, A17Q, A17S, A17T, L20E, L20D, L20K, L20R, L20N, L20Q, L20S, L20T, L23E, L23D, L23K, L23R, L23N, L23Q, L23S, L23T, A24E, A24D, A24K, A24R, A24N, A24Q, A24S, A24T, A105E, A105D, A105K, A105R, A105N, A105Q, A105S, A105T, V110E, V110D, V110K, V110R, V110N, V110Q, V110S, V110T, L113E, L113D, L113K, L113R, L113N, L113Q, L113S, L113T, L114E, L114D, L114K, L114R, L114N, L114Q, L114S, L114T, L117E, L117D, L117K, L117R, L117N, L117Q, L117S, L117T, I121E, I121D, I121K, I121R, I121N, I121Q, I121S, I121T, L124E, L124D, L124K, L124R, L124N, L124Q, L124S, L124T, L128E, L128D, L128K, L128R, L128Q, L128N, L128S and L128T.

48. The modified growth hormone polypeptide of claim 38, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 56, 59, 64, 65, 66, 88, 92, 94, 101, 129, 130, 133, 134, 140, 143, 145, 146, 147, 183, and 186 of a mature human growth hormone polypeptide comprising the sequence of amino acids set forth in SEQ ID NO;

1.

49. The modified growth hormone polypeptide of claim 48, wherein the amino acid replacements are selected from among E56, P59, R64, E65, E66, E88, F92, R94, L101, E129, D130, P133, R134, K140, Y143, K145, F146, D147, R183 and E186.

50. The modified growth hormone polypeptide of claim 49, wherein:

the one or more amino acid replacement(s) is (are) selected from among replacing E with any of Q, N and H, replacing P with S or A, replacing R with H or Q. replacing L or F with I or V, replacing K or D with Q or N, and replacing Y with H or I.

51. The modified growth hormone polypeptide of claim 50, wherein:

the one or more single amino acid replacement(s) is (are) selected from among E56Q, E56N, E56H, P59S, P59A, R64H, R64Q, E65Q, E65N, E65H, E66Q, E66N, E66H, E88Q, E88N, E88H, F92I, F92V, R94H, R94Q, L101V, L101I, E129Q, E129N, E129H, D130Q, D130N, P133S, P133A, R134H, R134Q, K140Q, K140N, Y143H, Y143I, K145Q, K145N, F146I, F146V, D147Q, D147N, R183H, R183Q, E186Q, E186N and E186H.

52. The modified growth hormone polypeptide of claim 38, that is a human growth hormone (hGH) polypeptide.

53. The modified growth hormone polypeptide of claim 38, wherein the amino acid replacements are made in a human pituitary growth hormone polypeptide or human placental growth hormone polypeptide.

54. The modified growth hormone polypeptide of claim 38, that is a mature growth hormone polypeptide.

55. The modified growth hormone polypeptide of claim 38, that is a precursor growth hormone polypeptide.

56. The modified growth hormone polypeptide of claim 38, wherein the growth hormone is pegylated, albuminated, or glycosylated.

57. The modified growth hormone polypeptide of claim 38, wherein the increased stability is manifested as an increased half-life in vivo or in vitro compared to an unmodified growth hormone polypeptide.

58. The modified growth hormone polypeptide of claim 57, wherein the increased stability is manifested as an increased half-life when administered to a subject.

59. A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified growth hormone polypeptide of claim 38.

60. A vector, comprising the nucleic acid molecule of claim 59.

61. A cell, comprising the vector of claim 60.

62. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a nucleic acid of claim 59 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

63. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a vector of claim 60 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

64. A pharmaceutical composition, comprising the modified growth hormone polypeptide of claim 38.

65. The pharmaceutical composition of claim 64, further comprising a pharmaceutically acceptable excipient.

66. The pharmaceutical composition of claim 64, wherein the pharmaceutical composition is formulated for oral administration.

67. The pharmaceutical composition of claim 64, wherein the modified growth hormone polypeptide exhibits increased protein half-life or bioavailability in the gastrointestinal tract.

68. The pharmaceutical composition of claim 64, further comprising a pharmaceutically-acceptable additive.

69. A pharmaceutical composition, comprising a nucleic acid molecule of claim 59.

70. A pharmaceutical composition, comprising a vector of claim 60.

71. A method, comprising treating a subject by administering the pharmaceutical composition of claim 64, wherein the subject has a disease or condition that is treated by the administration of growth hormone.

72. The method of claim 71, wherein the disease or condition is selected from among a growth deficiency disorder, AIDS wasting, aging, impaired immune function of HIV-infected subjects, a catabolic illness, surgical recovery, a congestive cardiomyopathy, liver transplantation, liver regeneration after hepatectomy, chronic renal failure, renal osteodystrophy, osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia, a chronic inflammatory or nutritional disorder such as Crohn'"'"'s disease, short bowel syndrome, juvenile chronic arthritis, cystic fibrosis, male infertility, X-linked hypophosphatemic rickets, Down'"'"'s syndrome, Spina bifida, Noonan Syndrome, obesity, impaired muscle strength and fibromyalgia.

73. The method of claim 72, wherein the growth deficiency disorder is selected from among Turner'"'"'s syndrome, intrauterine growth retardation, idiopathic short stature, Prader Willi syndrome, and thalassaemia.

74. A modified growth hormone polypeptide, comprising:

one or more single amino acid replacements compared to an unmodified growth hormone polypeptide, wherein;

the replacement positions are not positions that correspond to any of positions 56, 59, 64-66, 88, 92, 94, 101, 129, 130, 133, 134, 140, 143, 145-147, 183 and 186 of mature human growth hormone polypeptide comprising a sequence of amino acids set forth in SEQ ID NO;

1; and

the modified growth hormone polypeptide exhibits increased protein stability compared to the unmodified growth hormone.

75. The modified growth hormone polypeptide of claim 74, wherein:

the amino acid replacement(s) is (are) positions corresponding to positions selected from among positions 1, 2, 5, 6, 8, 9, 10, 11, 14, 15, 16, 19, 20, 23, 25, 26, 28, 30, 31, 32, 33, 35, 37, 38, 39, 41, 42, 44, 45, 48, 52, 54, 61, 70, 73, 74, 75, 76, 77, 80, 81, 82, 86, 87, 89, 93, 97, 103, 107, 111, 112, 113, 114, 115, 116, 117, 118, 119, 124, 125, 127, 128, 139, 153, 154, 156, 157, 158, 160, 162, 163, 164, 166, 167, 168, 169, 170, 171, 172, 174, 176, 177, 178, and 191.

76. The modified growth hormone polypeptide of claim 75, wherein:

the amino acid replacement(s) is (are) positions corresponding to positions selected from among positions F1, P2, P5, L6, R8, L9, F10, D11, M14, L15, R16, R19, L20, L23, F25, D26, Y28, E30, F31, E32, E33, Y35, P37, K38, E39, K41, Y42, F44, L45, P48, L52, F54, P61, K70, L73, E74, L75, L76, R77, L80, L81, L82, W86, L87, P89, L93, F97, Y103, D107, Y111, D112, L113, L114, K115, D116, L117, E118, E119, L124, M125, R127, L128, F139, D153, D154, L156, L157, K158, Y160, L162, L163, Y164, F166, R167, K168, D169, M170, D171, K172, E174, F176, L177, R178,and F191.

77. The modified growth hormone polypeptide of claim 76, wherein:

the amino acid replacement(s) is (are) selected from among replacing R by H or Q, replacing E by H, Q or N, replacing K by Q or N, replacing D by N or Q, replacing M by I or V, replacing P by A or S, replacing Y by I or H, replacing F by I or V, replacing W by H or S, and replacing L by I or V.

78. The modified growth hormone polypeptide of claim 77, wherein:

the amino acid replacement(s) is (are) selected from among F1I, F1V, P2A, P2S, P5A, P5S, L6I, L6V, R8H, R8Q, L9I, L9V, F10I, F10V, D11N, D11Q, M14I, M14V, L15I, L15V, R16H, R16Q, R19H, R19Q, L20I, L20V, L23I, L23V, F25I, F25V, D26N, D26Q, Y28H, Y28I, E30Q, E30H, E30N, F31I, F31V, E32Q, E32H, E32N, E33Q, E33H, E33N, Y35H, Y35I, P37A, P37S, K38N, K38Q, E39Q, E39H, E39N, K41N, K41Q, Y42H, Y42I, F44I, F44V, L45I, L45V, P48A, P48S, L52I, L52V, F54I, F54V, P61A, P61S, K70N, K70Q, L73I, L73V, E74Q, E74H, E74N, L75I, L75V, L76I, L76V, R77H, R77Q, L80I, L80V, L81I, L81V, L82I, L82V, W86H, W86S, L87I, L87V, P89A, P89S, L93I, L93V, F97I, F97V, Y103H, Y103I, D107N, D107Q, Y111H, Y111I, D112N, D112Q, L113I, L113V, L114I, L114V, K115N, K115Q, D116N, D116Q, L117I, L117V, E118Q, E118H, E118N, E119Q, E119H, E119N, L124I, L124V, M125I, M125V, R127H, R127Q, L128I, L128V, F139I, F139V, D153N, D153Q, D154N, D154Q, L156I, L156V, L157I, L157V, K158N, K158Q, Y160H, Y160I, L162I, L162V, L163I, L163V, Y164H, Y164I, F166I, F166V, R167H, R167Q, K168N, K168Q, D169N, D169Q, M170I, M170V, D171N, D171Q, K172N, K172Q, E174Q, E174H, E174N, F176I, F176V, L177I, L177V, R178H, R178Q, F191I and F191V.

79. The modified growth hormone polypeptide of claim 78, wherein:

the amino acid replacement(s) is (are) selected from among F1I, P2A, P5S, L9V, D11N, M14V, R16H, L23I, L23V, D26N, K38N, K41Q, Y42H, Y42I, L73V, E74N, L81V, L87V, Y111I, D112N, D116Q, E119Q, L124V, M125I, M125V, D153N, L156I, L157I, K158N, L162I, F166I, R167H, R167Q, K168N, K168Q, D169Q, D171N, D171Q, K172Q, E174Q, E174N, E174H, L177V, L177I, R178Q and F191I.

80. The modified growth hormone polypeptide of claim 79, wherein:

the amino acid replacement or replacements is (are) selected from among D11N, M14V, L23I, L23V, Y42H, Y42I, L81V, E119Q, M125I and E174N.

81. The modified growth hormone polypeptide of claim 74, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 6, 9, 13, 15, 17, 20, 23, 24, 105, 110, 113, 114, 117, 121, 124 and 128 of mature human growth hormone polypeptide.

82. The modified growth hormone polypeptide of claim 81, wherein:

the one or more single amino acid replacements correspond to one or more of positions selected from among positions L6, L9, A13, L15, A17, L20, L23, A24, A105, V110, L113, L114, L117, I121, L124 and L128.

83. The modified growth hormone polypeptide of claim 82, wherein the one or more amino acid replacement(s) is (are) selected from among E, D, K, R, N, Q, S and T.

84. The modified growth hormone polypeptide of claim 83, wherein:

the one or more single amino acid replacement(s) is (are) selected from among L6E, L6D, L6K, L6R, L6N, L6Q, L6S, L6T, L9E, L9D, L9K, L9R, L9N, L9Q, L9S, L9T, A13E, A13D, A13K, A13R, A13N, A13Q, A13S, A13T, L15E, L15D, L15K, L15R, L15Q, L15N, L15S, L15T, A17E, A17D, A17K, A17R, A17N, A17Q, A17S, A17T, L20E, L20D, L20K, L20R, L20N, L20Q, L20S, L20T, L23E, L23D, L23K, L23R, L23N, L23Q, L23S, L23T, A24E, A24D, A24K, A24R, A24N, A24Q, A24S, A24T, A105E, A105D, A105K, A105R, A105N, A105Q, A105S, A105T, V110E, V110D, V110K, V110R, V110N, V110Q, V110S, V110T, L113E, L113D, L113K, L113R, L113N, L113Q, L113S, L113T, L114E, L114D, L114K, L114R, L114N, L114Q, L114S, L114T, L117E, L117D, L117K, L117R, L117N, L117Q, L117S, L117T, I121E, I121D, I121K, I121R, I121N, I121Q, I121S, I121T, L124E, L124D, L124K, L124R, L124N, L124Q, L124S, L124T, L128E, L128D, L128K, L128R, L128Q, L128N, L128S and L128T.

85. The modified growth hormone polypeptide of claim 74, further comprising:

one or more single amino acid replacements corresponding to selected from among positions 56, 59, 64, 65, 66, 88, 92, 94, 101, 129, 130, 133, 134, 140, 143, 145, 146, 147, 183, and 186 of a mature human growth hormone polypeptide comprising the sequence of amino acids set forth in SEQ ID NO;

1.

86. The modified growth hormone polypeptide of claim 85, wherein the amino acid replacements correspond to one or more of positions selected from among positions E56, P59, R64, E65, E66, E88, F92, R94, L101, E129, D130, P133, R134, K140, Y143, K145, F146, D147, R183 and E186.

87. The modified growth hormone polypeptide of claim 86, wherein:

the one or more amino acid replacement(s) is (are) selected from among replacing E with any of Q, N and H, replacing P with S or A, replacing R with H or Q, replacing L or F with I or V, replacing K or D with Q or N, and replacing Y with H or I.

88. The modified growth hormone polypeptide of claim 87, wherein:

the one or more single amino acid replacement(s) is (are) selected from among E56Q, E56N, E56H, P59S, P59A, R64H, R64Q, E65Q, E65N, E65H, E66Q, E66N, E66H, E88Q, E88N, E88H, F92I, F92V, R94H, R94Q, L101V, L101I, E129Q, E129N, E129H, D130Q, D130N, P133S, P133A, R134H, R134Q, K140Q, K140N, Y143H, Y143I, K145Q, K145N, F146I, F146V, D147Q, D147N, R183H, R183Q, E186Q, E186N and E186H.

89. The modified growth hormone polypeptide of claim 74, that is a human growth hormone (hGH) polypeptide.

90. The modified growth hormone polypeptide of claim 74, wherein the amino acid replacements are made in a human pituitary growth hormone polypeptide or human placental growth hormone polypeptide.

91. The modified growth hormone polypeptide of claim 74, that is a mature growth hormone polypeptide.

92. The modified growth hormone polypeptide of claim 74, that is a precursor growth hormone polypeptide.

93. The modified growth hormone polypeptide of claim 74, wherein the growth hormone is pegylated, albuminated, or glycosylated.

94. The modified growth hormone polypeptide of claim 74, wherein the increased stability is manifested as an increased half-life in vivo or in vitro compared to an unmodified growth hormone polypeptide.

95. The modified growth hormone polypeptide of claim 94, wherein the increased stability is manifested as an increased half-life when administered to a subject.

96. A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified growth hormone polypeptide of claim 74.

97. A vector, comprising the nucleic acid molecule of claim 96.

98. A cell, comprising the vector of claim 97.

99. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a nucleic acid of claim 96 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

100. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a vector of claim 97 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

101. A pharmaceutical composition, comprising the modified growth hormone polypeptide of claim 74.

102. The pharmaceutical composition of claim 101, further~comprising a pharmaceutically acceptable excipient.

103. The pharmaceutical composition of claim 101, wherein the pharmaceutical composition is formulated for oral administration.

104. The pharmaceutical composition of claim 101, wherein the modified growth hormone polypeptide exhibits increased protein half-life or bioavailability in the gastrointestinal tract.

105. The pharmaceutical composition of claim 101, further comprising a pharmaceutically-acceptable additive.

106. A pharmaceutical composition, comprising a nucleic acid molecule of claim 96.

107. A pharmaceutical composition, comprising a vector of claim 97.

108. A method, comprising treating a subject by administering the pharmaceutical composition of claim 101, wherein the subject has a disease or condition that is treated by the administration of growth hormone.

109. The method of claim 108, wherein the disease or condition is selected from among a growth deficiency disorder, AIDS wasting, aging, impaired immune function of HIV-infected subjects, a catabolic illness, surgical recovery, a congestive cardiomyopathy, liver transplantation, liver regeneration after hepatectomy, chronic renal failure, renal osteodystrophy, osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia, a chronic inflammatory or nutritional disorder such as Crohn'"'"'s disease, short bowel syndrome, juvenile chronic arthritis, cystic fibrosis, male infertility, X-linked hypophosphatemic rickets, Down'"'"'s syndrome, Spina bifida, Noonan Syndrome, obesity, impaired muscle strength and fibromyalgia.

110. The method of claim 109, wherein the growth deficiency disorder is selected from among Turner'"'"'s syndrome, intrauterine growth retardation, idiopathic short stature, Prader Willi syndrome, and thalassaemia.

111. A modified growth hormone polypeptide, comprising:

one or more single amino acid replacements compared with the unmodified growth hormone polypeptide, wherein;

the amino acid replacement(s) correspond to positions selected from among positions 1-55, 57, 58, 60-63, 67-87, 89-91, 93, 95-100, 102-128, 131, 132, 135-139, 141, 142, 144, 148-182, 184, 185 and 187-191 of mature human growth hormone polypeptide comprising a sequence of amino acids set forth in SEQ ID NO;

1, wherein;

if position 9 is replaced, the replacing amino acid is not proline;

if position 14 is replaced, the replacing amino acid is not serine;

if position 13 or 27 is replaced, the replacing amino acid is not valine;

if position 28 is replaced, the replacing amino acid is not phenylalanine;

if position 54 is replaced, the replacing amino acid is not tyrosine;

if position 55, 79, 85 or 184 is replaced, the replacing amino acid is not alanine;

if position 90 is replaced, the replacing amino acid is not isoleucine;

if position 114 or 161 is replaced, the replacing amino acid is not methionine; and

if position 120 or 126 is replaced, the replacing amino acid is not arginine; and

the modified growth hormone polypeptide exhibits increased protein stability compared to the unmodified growth hormone polypeptide.

112. The modified growth hormone polypeptide of claim 111, wherein:

the amino acid replacement(s) correspond to positions selected from among positions 1, 2, 5, 6, 8, 9, 10, 11, 14, 15, 16, 19, 20, 23, 25, 26, 28, 30, 31, 32, 33, 35, 37, 38, 39, 41, 42, 44, 45, 48, 52, 54, 61, 70, 73, 74, 75, 76, 77, 80, 81, 82, 86, 87, 89, 93, 97, 103, 107, 111, 112, 113, 114, 115, 116, 117, 118, 119, 124, 125, 127, 128, 139, 153, 154, 156, 157, 158, 160, 162, 163, 164, 166, 167, 168, 169, 170, 171, 172, 174, 176, 177, 178, and 191 of mature human growth hormone.

113. The modified growth hormone polypeptide of claim 112, wherein:

the amino acid replacement(s) correspond to positions selected from among positions F1, P2, P5, L6, R8, L9, F10, D11, M14, L15, R16, R19, L20, L23, F25, D26, Y28, E30, F31, E32, E33, Y35, P37, K38, E39, K41, Y42, F44, L45, P48, L52, F54, P61, K70, L73, E74, L75, L76, R77, L80, L81, L82, W86, L87, P89, L93, F97, Y103, D107, Y111, D112, L113, L114, K115, D116, L117, E118, E119, L124, M125, R127, L128, F139, D153, D154, L156, L157, K158, Y160, L162, L163, Y164, F166, R167, K168, D169, M170, D171, K172, E174, F176, L177, R178, and F191 of mature human growth hormone polypeptide.

114. The modified growth hormone polypeptide of claim 113, wherein:

the amino acid replacement(s) is (are) selected from among replacing R by H or Q, replacing E by H, Q or N, replacing K by Q or N, replacing D by N or Q, replacing M by I or V, replacing P by A or S, replacing Y by I or H, replacing F by I or V, replacing W by H or S, and replacing L by I or V.

115. The modified growth hormone polypeptide of claim 114, wherein:

the amino acid replacement(s) is (are) selected from among F1I, F1V, P2A, P2S, P5A, P5S, L6I, L6V, R8H, R8Q, L9I, L9V, F10I, F10V, D11N, D11Q, M14I, M14V, L15I, L15V, R16H, R16Q, R19H, R19Q, L20I, L20V, L23I, L23V, F25I, F25V, D26N, D26Q, Y28H, Y28I, E30Q, E30H, E30N, F31I, F31V, E32Q, E32H, E32N, E33Q, E33H, E33N, Y35H, Y35I, P37A, P37S, K38N, K38Q, E39Q, E39H, E39N, K41N, K41Q, Y42H, Y42I, F44I, F44V, L45I, L45V, P48A, P48S, L52I, L52V, F54I, F54V, P61A, P61S, K70N, K70Q, L73I, L73V, E74Q, E74H, E74N, L75I, L75V, L76I, L76V, R77H, R77Q, L80I, L80V, L81I, L81V, L82I, L82V, W86H, W86S, L87I, L87V, P89A, P89S, L93I, L93V, F97I, F97V, Y103H, Y103I, D107N, D107Q, Y111H, Y111I, D112N, D112Q, L113I, L113V, L114I, L114V, K115N, K115Q, D116N, D116Q, L117I, L117V, E118Q, E118H, E118N, E119Q, E119H, E119N, L124I, L124V, M125I, M125V, R127H, R127Q, L128I, L128V, F139I, F139V, D153N, D153Q, D154N, D154Q, L156I, L156V, L157I, L157V, K158N, K158Q, Y160H, Y160I, L162I, L162V, L163I, L163V, Y164H, Y164I, F166I, F166V, R167H, R167Q, K168N, K168Q, D169N, D169Q, M170I, M170V, D171N, D171Q, K172N, K172Q, E174Q, E174H, E174N, F176I, F176V, L177I, L177V, R178H, R178Q, F191I and F191V.

116. The modified growth hormone polypeptide of claim 115, wherein:

the amino acid replacement(s) is (are) selected from among F1I, P2A, P5S, L9V, D11N, M14V, R16H, L23I, L23V, D26N, K38N, K41Q, Y42H, Y42I, L73V, E74N, L81V, L87V, Y111I, D112N, D116Q, E119Q, L124V, M125I, M125V, D153N, L156I, L157I, K158N, L162I, F166I, R167H, R167Q, K168N, K168Q, D169Q, D171N, D171Q, K172Q, E174Q, E174N, E174H, L177V, L177I, R178Q and F191I.

117. The modified growth hormone polypeptide of claim 116, wherein:

the amino acid replacement(s) is (are) selected from among D11N, M14V, L23I, L23V, Y42H, Y42I, L81V, E119Q, M125I and E174N.

118. The modified growth hormone polypeptide of claim 111, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 6, 9, 13, 15, 17, 20, 23, 24, 105, 110, 113, 114, 117, 121, 124 and 128 of mature human growth hormone polypeptide.

119. The modified growth hormone polypeptide of claim 118, wherein:

the one or more single amino acid replacements correspond to one or more of positions selected from among positions L6, L9, A13, L15, A17, L20, L23, A24, A105, V110, L113, L114, L117, I121, L124 and L128.

120. The modified growth hormone polypeptide of claim 119, wherein the one or more amino acid replacement(s) is (are) selected from among amino acid residues E, D, K, R, N, Q, S and T.

121. The modified growth hormone polypeptide of claim 120, wherein:

the one or more single amino acid replacement(s) is (are) selected from among L6E, L6D, L6K, L6R, L6N, L6Q, L6S, L6T, L9E, L9D, L9K, L9R, L9N, L9Q, L9S, L9T, A13E, A13D, A13K, A13R, A13N, A13Q, A13S, A13T, L15E, L15D, L15K, L15R, L15Q, L15N, L15S, L15T, A17E, A17D, A17K, A17R, A17N, A17Q, A17S, A17T, L20E, L20D, L20K, L20R, L20N, L20Q, L20S, L20T, L23E, L23D, L23K, L23R, L23N, L23Q, L23S, L23T, A24E, A24D, A24K, A24R, A24N, A24Q, A24S, A24T, A105E, A105D, A105K, A105R, A105N, A105Q, A105S, A105T, V110E, V110D, V110K, V110R, V110N, V110Q, V110S, V110T, L113E, L113D, L113K, L113R, L113N, L113Q, L113S, L113T, L114E, L114D, L114K, L114R, L114N, L114Q, L114S, L114T, L117E, L117D, L117K, L117R, L117N, L117Q, L117S, L117T, I121E, I121D, I121K, I121R, I121N, I121Q, I121S, I121T, L124E, L124D, L124K, L124R, L124N, L124Q, L124S, L124T, L128E, L128D, L128K, L128R, L128Q, L128N, L128S and L128T.

122. The modified growth hormone polypeptide of claim 111, further comprising:

one or more single amino acid replacements corresponding to positions selected from among positions 56, 59, 64, 65, 66, 88, 92, 94, 101, 129, 130, 133, 134, 140, 143, 145, 146, 147, 183, and 186 of a mature human growth hormone polypeptide comprising the sequence of amino acids set forth in SEQ ID NO;

1.

123. The modified growth hormone polypeptide of claim 122, wherein the amino acid replacements correspond to one or more of positions selected from among positions E56, P59, R64, E65, E66, E88, F92, R94, L101, E129, D130, P133, R134, K140, Y143, K145, F146, D147, R183 and E186.

124. The modified growth hormone polypeptide of claim 123, wherein:

the one or more amino acid replacement(s) is (are) selected from among replacing E with any of Q, N and H, replacing P with S or A, replacing R with H or Q, replacing L or F with I or V, replacing K or D with Q or N, and replacing Y with H or I.

125. The modified growth hormone polypeptide of claim 124, wherein:

the one or more single amino acid replacement(s) is (are) selected from among E56Q, E56N, E56H, P59S, P59A, R64H, R64Q, E65Q, E65N, E65H, E66Q, E66N, E66H, E88Q, E88N, E88H, F92I, F92V, R94H, R94Q, L101V, L101I, E129Q, E129N, E129H, D130Q, D130N, P133S, P133A, R134H, R134Q, K140Q, K140N, Y143H, Y143I, K145Q, K145N, F146I, F146V, D147Q, D147N, R183H, R183Q, E186Q, E186N and E186H.

126. The modified growth hormone polypeptide of claim 111, that is a human growth hormone (hGH) polypeptide.

127. The modified growth hormone polypeptide of claim 111, wherein the amino acid replacements are made in a human pituitary growth hormone polypeptide or human placental growth hormone polypeptide.

128. The modified growth hormone polypeptide of claim 111, that is a mature growth hormone polypeptide.

129. The modified growth hormone polypeptide of claim 111, that is a precursor growth hormone polypeptide.

130. The modified growth hormone polypeptide of claim 111, wherein the growth hormone is pegylated, albuminated, or glycosylated.

131. The modified growth hormone polypeptide of claim 111, wherein the increased stability is manifested as an increased half-life in vivo or in vitro compared to an unmodified growth hormone polypeptide.

132. The modified growth hormone polypeptide of claim 131, wherein the increased stability is manifested as an increased half-life when administered to a subject.

133. A nucleic acid molecule, comprising a sequence of nucleotides encoding a modified growth hormone polypeptide of claim 111.

134. A vector, comprising the nucleic acid molecule of claim 133.

135. A cell, comprising the vector of claim 134.

136. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a nucleic acid of claim 133 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

137. A method for expressing a modified growth hormone polypeptide, comprising:

i) introducing a vector of claim 134 into a cell, and

ii) culturing the cell under conditions in which the encoded modified growth hormone polypeptide is expressed.

138. A pharmaceutical composition, comprising the modified growth hormone polypeptide of claim 111.

139. The pharmaceutical composition of claim 138, further comprising a pharmaceutically acceptable excipient.

140. The pharmaceutical composition of claim 138, wherein the pharmaceutical composition is formulated for oral administration.

141. The pharmaceutical composition of claim 138, wherein the modified growth hormone polypeptide exhibits increased protein half-life or bioavailability in the gastrointestinal tract.

142. The pharmaceutical composition of claim 138, further comprising a pharmaceutically-acceptable additive.

143. A pharmaceutical composition, comprising a nucleic acid molecule of claim 133.

144. A pharmaceutical composition, comprising a vector of claim 134.

145. A method, comprising treating a subject by administering the pharmaceutical composition of claim 138, wherein the subject has a disease or condition that is treated by the administration of growth hormone.

146. The method of claim 145, wherein the disease or condition is selected from among a growth deficiency disorder, AIDS wasting, aging, impaired immune function of HIV-infected subjects, a catabolic illness, surgical recovery, a congestive cardiomyopathy, liver transplantation, liver regeneration after hepatectomy, chronic renal failure, renal osteodystrophy, osteoporosis, achondroplasia/hypochondroplasia, skeletal dysplasia, a chronic inflammatory or nutritional disorder such as Crohn'"'"'s disease, short bowel syndrome, juvenile chronic arthritis, cystic fibrosis, male infertility, X-linked hypophosphatemic rickets, Down'"'"'s syndrome, Spina bifida, Noonan Syndrome, obesity, impaired muscle strength and fibromyalgia.

147. The method of claim 146, wherein the growth deficiency disorder is selected from among Turner'"'"'s syndrome, intrauterine growth retardation, idiopathic short stature, Prader Willi syndrome, and thalassaemia.

148. A modified growth hormone polypeptide comprising any of the sequences of amino acids set forth in SEQ ID NOS:

2-69, 75, 76, 85-107, 111, 112, 115, 116, 119, 120, 123-154, 164, 165, 176-216, 222-351 or an active portion thereof.

149. The modified growth hormone polypeptide of claim 148, wherein the modified growth hormone polypeptide comprises any of the sequences of amino acids set forth in SEQ ID NOS:

16, 19, 28, 29, 58, 59, 101, 144, 149 and 210.