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Details for Patent: 5,955,346

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Details for Patent: 5,955,346

Title: Variants of human prolactin and human placeatal lactogen
Abstract:The invention provides methods for the systematic analysis of the structure and function of polypeptides by identifying active domains which influence the activity of the polypeptide with a target substance. Such active domains are determined by substituting selected amino acid segments of the polypeptide with an analogous polypeptide segment from an analog to the polypeptide. The analog has a different activity with the target substance as compared to the parent polypeptide. The activities of the segment-substituted polypeptides are compared to the same activity for the parent polypeptide for the target. A comparison of such activities provides an indication of the location of the active domain in the parent polypeptide. The invention also provides methods for identifying the active amino acid residues within the active domain of the parent polypeptide. The method comprises substituting a scanning amino acid for one of the amino acid residues within the active domain of the parent polypeptide and assaying the residue-substituted polypeptide so formed with a target substance. The invention further provides polypeptide variants comprising segment-substituted and residue-substituted growth hormones, prolactins and placental lactogens.
Inventor(s): Wells; James A. (Burlingame, CA), Cunningham; Brian C. (Piedmont, CA)
Assignee: Genentech, Inc. (South San Francisco, CA)
Filing Date:Jun 07, 1995
Application Number:08/476,999
Claims:1. An isolated nucleic acid comprising a nucleotide sequence encoding a variant of human prolactin, wherein said variant binds to the human growth hormone receptor and has the amino acid sequence of the human prolactin as shown in FIG. 2 except that said variant has 1 to 19 amino acid substitutions compared to said human prolactin. and wherein at least one of the amino acid substitutions is an amino acid substitution at an amino acid residue selected from the group consisting of H54, T55, S56, L58, A59, E62, D63, K64, Q66, A67, M70, N71, Q72, K73, D74, H171, N175, Y176, K178, and L179, numbered as shown for said human prolactin in FIG. 2.

2. An expression vector comprising the nucleotide sequence of claim 1.

3. An expression host comprising an expression vector including the nucleotide sequence of claim 1.

4. An isolated nucleic acid comprising a nucleotide sequence encoding a variant of human placental lactogen, wherein said variant binds to the human growth hormone receptor with an affinity different from the affinity of the human placental lactogen for the human growth hormone receptor and has the amino acid sequence of the human placental lactogen as shown in FIG. 2 except that said variant has 1 to 4 amino acid substitutions compared to said human placental lactogen, and wherein at least one of the amino acid substitutions is an amino acid substitution at an amino acid residue selected from the group consisting of Q2, V4, H12, Q16, D56, M64, and M179, numbered as shown for said human placental lactogen in FIG. 2.

5. An expression vector comprising the nucleotide sequence of claim 4.

6. An expression host comprising the expression vector including the nucleotide sequence of claim 4.

7. An isolated variant of human prolactin, wherein said variant binds to the human growth hormone receptor and has the amino acid sequence of the human prolactin shown in FIG. 2 except that said variant has 1 to 19 amino acid substitutions compared to said human prolactin, and wherein at least one of the amino acid substitutions is an amino acid substitution at an amino acid residue selected from the group consisting of H54, T55, S56, L58, A59, E62, D63, K64, Q66, A67, M70, N71, Q72, K73, D74, H171, N175, Y176, K178, and L179, numbered as shown for said human prolactin in FIG. 2.

8. The human prolactin variant of claim 3 wherein said amino acid substitution is selected from the group consisting of H54F, T55S, S56E, L58I, A59P, E62S, D63N, K64R, Q66E, A67T, M70K, N71S, Q72N, K73L, D74E, H171D, N175T, Y176F, and K178R.

9. The human prolactin variant of claim 8 wherein said amino acid substitution comprises H171D, and said human prolactin variant further comprises the following set of amino acid substitutions: N175T: Y176F.

10. The human prolactin variant of claim 9 further comprising the amino acid substitution K178R.

11. The human prolactin variant of claim 10 further comprising the following set of amino acid substitutions: H54F: T55S: S56E: L58I: A59P: E62S: D63N: K64R: Q66E: A67T: M70K: N71S: Q72N: K73L: D74E.

12. The human prolactin variant of claim 10 further comprising the following set of amino acid substitutions: I184S: H185V: N186E: N187G: N188S and the deletion of the isoleucine between I184 and H185.

13. The human prolactin variant of claim 10 further comprising the following set of amino acid substitutions: H54F: S56E: L58I: E62S: D63N: Q66E.

14. The human prolactin variant of claim 10 further comprising the following set of amino acid substitutions: H54F S56E : L58I.

15. The human prolactin variant of claim 10 further comprising the amino acid substitution D174A.

16. The human prolactin variant of claim 15 further comprising the following set of amino acid substitutions: E62S D63N: Q66E.

17. The human prolactin variant of claim 16 further comprising the amino acid substitution H54F.

18. The human prolactin variant of claim 16 further comprising the amino acid substitution S56E.

19. The human prolactin variant of claim 16 further comprising the amino acid substitution L58I.

20. The human prolactin variant of claim 16 further comprising the amino acid substitution A59P.

21. The human prolactin variant of claim 16 further comprising the amino acid substitution N71S.

22. The human prolactin variant of claim 16 further comprising the amino acid substitution L179I.

23. An isolated variant of human placental lactogen, wherein said variant binds to the human growth hormone receptor with an affinity different from the affinity of the human placental lactogen for the human growth hormone receptor, said variant having the amino acid sequence of the human placental lactogen as shown in FIG. 2 except that said variant has 1 to 4 amino acid substitutions compared to said human palcental lactogen, wherein at least one of the amino acid substitutions is an amino acid substitution at an amino acid residue selected from the group consisting of Q2, V4, H12, Q16, D56, M64, and M1 79, numbered as shown for said human palcental lactogen in FIG. 2.

24. The human placental lactogen variant of claim 23 wherein said amino acid substitution is selected from the group consisting of Q2P, V4I, H 12N, Q16R, D56E, M64R and M179I.

25. The human placental lactogen variant of claim 23 wherein said amino acid substitution is selected from the group consisting of V4A, D56A, M64A and M179A.

26. The human placental lactogen variant of claim 23 wherein said amino acid substitution comprises D56E, and said human placental lactogen variant further comprises the amino acid substitution M64R.
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