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Claims for Patent: 6,583,115

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Claims for Patent: 6,583,115

Title: Methods for treating acromegaly and giantism with growth hormone antagonists
Abstract:The present invention relates to antagonists of vertebrate growth hormones obtained by mutation of the third alpha helix of such proteins (especially bovine or human GHs). These mutants-have growth-inhibitory or other GH-antagonizing effects. These novel hormones may be administered exogenously to animals, or transgenic animals may be made that express the antagonist. Animals have been made which exhibited a reduced growth phenotype. The invention also describes methods of treating acromegaly, gigantism, cancer, diabetes, vascular eye diseases (diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, retinopathy of sickle-cell anemia, etc.) as well as nephropathy and other diseases, by administering an effective amount of a growth hormone antagonist. The invention also provides pharmaceutical formulations comprising one or more growth hormone antagonists.
Inventor(s): Kopchick; John J. (Athens, OH), Chen; Wen Y. (Athens, OH)
Assignee: Ohio University/Edison Biotechnology Institute (Athens, OH)
Application Number:08/486,793
Patent Claims: 1. A non-naturally occurring vertebrate growth hormone variant having an amino acid sequence comprising an amino acid substitution of any amino acid, other glycine or alanine, for the glycine at the position corresponding to position Gly119 of bovine growth hormone, wherein the growth hormone variant has vertebrate growth hormone inhibitory activity, with the proviso that said variant does not correspond to human growth hormone with all of the following substitutions and no others: Y111V, L113I, K115E, D116Q, E118K, E119R, G120L, Q122E, T123G, G126L, R127I and E129S.

2. A vertebrate growth hormone variant of claim 1 where said variant differs from the vertebrate growth hormone solely at said position corresponding to Gly119 of bovine growth hormone.

3. The vertebrate growth hormone variant of claim 1 having an amino acid sequence comprising lysine at the position corresponding to Gly119 of bovine growth hormone.

4. The vertebrate growth hormone variant of claim 1 having an amino acid sequence comprising arginine at the position corresponding to Gly119 of bovine growth hormone.

5. The vertebrate growth hormone variant of claim 1 having an amino acid sequence comprising proline at the position corresponding to Gly119 of bovine growth hormone.

6. The vertebrate growth hormone variant of claim 1 having an amino acid sequence comprising tryptophan at the position corresponding to Gly119 of bovine growth hormone.

7. The vertebrate growth hormone variant of claim 1 having an amino acid sequence comprising leucine at the position corresponding to Gly119 of bovine growth hormone.

8. A method of inhibiting the development of, ameliorating, or otherwise treating a condition, or ameliorating a growth hormone-mediated symptom of a condition, of a mammal caused, hastened, or exacerbated by a mammalian growth hormone activity, said condition or symptom being responsive to a vertebrate growth hormone variant having growth hormone receptor antagonist activity, which comprises administering to a mammal a growth hormone activity-antagonizing and pharmaceutically acceptable amount of a vertebrate growth hormone variant according to any one of claims 1-7.

9. A method of reducing the activity of growth hormone in a mammal, which comprises administering to a mammal a growth hormone activity-antagonizing and pharmaceutically acceptable amount of a vertebrate growth hormone variant according to any one of claims 1-7.
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