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Claims for Patent: 5,958,879

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Claims for Patent: 5,958,879

Title: Growth hormone receptor antagonists and methods of reducing growth hormone activity in a mammal
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 mammals. The antagonists may be used to reduce the activity of growth hormone in a mammal, especially one suffering from diabetes, diabetic retinopathy, diabetic nephropathy, a growth hormone secreting tumor, acromegaly, or gigantism.
Inventor(s): Kopchick; John J. (Athens, OH), Chen; Wen Y. (Athens, OH)
Assignee: Ohio University/Edison Biotechnology Institute (Athens, OH)
Application Number:08/486,794
Patent Claims: 1. An isolated or non-naturally occurring polypeptide which comprises an amino acid sequence which

(A) is at least 50% identical with the amino acid sequence of a first reference vertebrate growth hormone, and

(B) differs therefrom solely in that

(I) the amino acid at the position corresponding to Gly 119 of bovine growth hormone is an amino acid other than glycine or alanine, and

(II) any additional difterences, if any, between said amino acid sequence and the amino acid sequence of said first reference vertebrate growth hormone, are independently selected from the group consisting of

(a) a substitution of a conservative replacement amino acid for the corresponding first reference vertebrate growth hormone residue,

(b) a substitution of a non-conservative replacement amino acid for the corresponding first reference vertebrate growth hormone residue where

(i) a second reference vertebrate growth hormone exists for which the corresponding amino acid is a non-conservative substitution for the corresponding first reference vertebrate growth hormone residue, and/or

(ii) the binding affinity for the first reference vertebrate growth hormone's receptor of a single substitution mutant of the first reference vertebrate growth hormone, wherein said corresponding residue, which is not alanine, is replaced by alanine, is at least 10% of the binding affinity of the wild-type first reference vertebrate growth hormone,

(c) a deletion of a residue which is not part of the alpha helixes of said reference vertebrate growth hormone corresponding to helices 1(7-34), 2(75-87), 3(106-127) and 4(152-183) of porcine growth hormone, such deleted residue furthermore not being a conserved residue in the vertebrate GH family, and

(d) a deletion of a residue found in said first reference vertebrate growth hormone but deleted in a second reference vertebrate growth hormone,

said polypeptide having growth hormone receptor antagonist activity, with the proviso that said polypeptide does not correspond to human growth hormone with all of the following substitutions and no others: Y111V, L113I, K115E, D116O, E118K, E119R, G120L, O122E, T123G, G126L, R127I and E129S.

2. 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 polypeptide which comprises an amino acid sequence which

(A) is at least 50% identical with the amino acid sequence of a first reference vertebrate growth hormone, and

(B) differs therefrom solely in that

(I) the amino acid at the position corresponding to Gly 119 of bovine growth hormone is an amino acid other than glycine or alanine, and

(II) any additional differences, if any, between said amino acid sequence and the amino acid sequence of said first reference vertebrate growth hormone, are independently selected from the group consisting of

(a) a substitution of a conservative replacement amino acid for the corresponding first reference vertebrate growth hormone residue,

(b) a substitution of a non-conservative replacement amino acid for the corresponding first reference vertebrate growth hormone residue where

(i) a second reference vertebrate growth hormone exists for which the corresponding amino acid is a non-conservative substitution for the corresponding first reference vertebrate growth hormone residue, and/or

(ii) the binding affinity for the first reference vertebrate growth hormone's receptor of a single substitution mutant of the first reference vertebrate growth hormone, wherein said corresponding residue, which is not alanine, is replaced by alanine, is at least 10% of the binding affinity of the wild-type first reference vertebrate growth hormone,

(c) a deletion of a residue which is not part of the alpha helixes of said reference vertebrate growth hormone corresponding to helices 1(7-34), 2(75-87), 3(106-127) and 4(152-183) of porcine growth hormone, such deleted residue furthermore not being a conserved residue in the vertebrate GH family, and

(d) a deletion of a residue found in said first reference vertebrate growth hormone but deleted in a second reference vertebrate growth hormone,

said polypeptide having mammalian growth hormone receptor antagonist activity.

3. The method of claim 2 wherein the mammal suffers from diabetes.

4. The method of claim 2 wherein the mammal suffers from diabetic retinopathy.

5. The method of claim 2 wherein the mammal suffers from a growth hormone-secreting tumor.

6. The method of claim 2 wherein the mammal suffers from excessive growth hormone secretion.

7. The method of claim 2 wherein the mammal suffers from acromegaly.

8. The method of claim 2 wherein the mammal suffers from gigantism.

9. The method of claim 2 wherein the mammal suffers from diabetic nephropathy.

10. The polypeptide of claim 1, said polypeptide having mammalian growth hormone receptor antagonist activity.

11. The polypeptide of claim 10, where said first and second reference vertebrate growth hormones are mammalian growth hormones.

12. The polypeptide of claim 10, said polypeptide having human growth hormone receptor antagonist activity.

13. The polypeptide of claim 12 wherein said first vertebrate growth hormone is human growth hormone, and the second is bovine growth hormone, or vice versa.

14. The polypeptide of claim 1 wherein, for all non-conservative substitutions, both of conditions (II)(b)(i) and (II)(b)(ii) apply.

15. The polypeptide of claim 1 wherein all substitutions are conservative substitutions as defined in II(a).

16. The polypeptide of claim 1, said amino acid sequence having at least about a 66% identity with the sequence of said first reference vertebrate growth hormone.

17. The polypeptide of claim 1, said amino acid sequence having at least about a 80% identity with the sequence of said first reference vertebrate growth hormone.

18. The polypeptide of claim 1, wherein the third alpha helix is at least 50% identical to the third alpha helix of said first reference vertebrate growth hormone.

19. The polypeptide of claim 18, wherein the third alpha helix is at least 80% identical to the third alpha helix of said first reference vertebrate growth hormone.

20. The polypeptide of claim 18 in which said first reference vertebrate growth hormone is a mammalian growth hormone.

21. The polypeptide of claim 19 in which said first reference vertebrate growth hormone is a mammalian growth hormone.

22. The polypeptide of claim 1 in which the first and second reference vertebrate growth hormones are mammalian growth hormones.

23. The polypeptide of claim 11, in which the first and second reference vertebrate growth hormones are human or bovine growth hormone.

24. The polypeptide of claim 1, which is an isolated polypeptide.

25. The polypeptide of claim 1, which is a non-naturally occurring polypeptide.
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