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|Title:||Human growth hormone variants|
|Abstract:||A method for selecting novel proteins such as growth hormone and antibody fragment variants having altered binding properties for their respective receptor molecules is provided. The method comprises fusing a gene encoding a protein of interest to the carboxy terminal domain of the gene III coat protein of the filamentous phage M13. The gene fusion is mutated to form a library of structurally related fusion proteins that are expressed in low quantity on the surface of a phagemid particle. Biological selection and screening are employed to identify novel ligands useful as drug candidates. Disclosed are preferred phagemid expression vectors and selected human growth hormone variants.|
|Inventor(s):||Lowman; Henry B. (Hercules, CA), Wells; James A. (Burlingame, CA)|
|Assignee:||Genentech, Inc. (South San Francisco, CA)|
|Filing Date:||Jun 05, 1995|
|Claims:||1. A human growth hormone variant wherein hGH amino acids 10, 14, 18, and 21 respectively are as a group sequentially selected from the group consisting of: |
(1)H,G,N,N; (2)A,W,D,N; (3)Y,T,V,N and (4)I,N,I,N.
2. A human growth hormone (hGH) variant wherein hGH amino acid glutamate.sub.174 is replaced by serine.sub.174 and phenlalanine.sub.176 is replaced by tyrosine.sub.176 and one or more of the eight naturally occurring hGH amino acids F10, M14, H18, H21, R167, D171, T175 and I179 are replaced by another natural amino acid, said variant capable of binding to human growth hormone binding protein.
3. The hGH variant of claim 2 wherein the eight naturally occurring hGH amino acids F10, M14, H18, H21, R167, D171, T175 and I179 respectively are as a group replaced with a corresponding amino acid sequentially selected from the group consisting of:
4. The variant of claim 3 wherein said human growth hormone variant (11) further contains leucine.sub.15 replaced by arginine.sub.15 and lysine.sub.168 replaced by arginine.sub.168.
5. The variant of claim 3 wherein said human growth hormone variant (40) further contains phenylalanine.sub.176.