Human growth hormone variants having enhanced affinity for human growth hormone receptor at ...

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US006022711A
United States Patent [19] [11] Patent Number: 6,022,711
Cunningham et al. [45] Date of Patent: Feb. 8,2000
[54] HUMAN GROWTH HORMONE VARIANTS OTHER PUBLICATIONS
HAVING ENHANCED AFFINITY FOR
Queen, C. et al., “A humanized antibody that binds to the
HUMAN GROWTH HORMONE RECEPTOR
interleukin 2 receptor”, Proc. Natl. Acad. Sci. USA,
AT SITE 1
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[75] Inventors: Brian C. Cunningham, Piedmont; Argos, P., “An Investigation of Protein Subunit and Domain
Interfaces”, Protein Eng. 2:101—113 (1988).
Henry Lowman, Hercules; James A.
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Baumann, G. et al., “A Speci?c Growth Hormone—Binding
Protein in Human Plasma: Initial Characterization”,Journal
Related US. Application Data
of Clinical Endocrinology and Metabolism 62:134—141
(1986).
[63] Continuation of application No. 08/067,160, May 25, 1993,
Pat. No. 5,534,617, which is a continuation-in-part of appli Carter, P. et al., “Improved Oligonucleotide Site—directed
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Chawla, R. et al., “Structural Variants of Human Growth
07/428,066, Oct. 26, 1989, abandoned, which is a continu
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Chothia, C., “The Nature of the Accessible and Buried
cation No. 07/743,614, Aug. 9, 1991, abandoned, which is a
continuation-in-part of application No. 07/715,300, Jun. 14, Surfaces in Proteins”, J. Mol. Biol. 105:1—12 (1976).
1991, which is a continuation-in-part of application No. Cunningham, B. et al., “DimeriZation of the Extracellular
07/683,400, Apr. 10, 1991, abandoned, which is a continu Domain of the Human Growth Hormone Receptor by a
ation-in-part of application No. 07/621,667, Dec. 3, 1990.
Single Hormone Molecule”, Science 254:821—825 (1991).
[51] Int. Cl.7 ......................... .. C12N 15/18; C12N 15/63; Cunningham, B. et al., “Rational design of receptor—speci?c
C07K 14/475; A61K 38/27 variants of human growth hormone”, Proc. Natl. Acad. Sci.
USA 88:3407—3411 (1991).
[52] US. Cl. ................... .. 435/69.4; 435/243; 435/320.1;
435/325; 514/12; 530/399; 530/402; 536/2351 Davies, D. et al., “Antibody—Antigen Complexes”, Ann.
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De Vos, A. et al., “Human Growth Hormone and Extracel
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4,670,393 6/1987 Jones et al. .
4,699,897 10/1987 Jones et al. . Primary Examiner—John Ulm
4,871,832 10/1989 Aviv et al. ............................ .. 530/399
Assistant Examiner—Christine Saoud
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Attorney, Agent, or Firm—Merchant & Gould PC.
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5,223,409 6/1993 Ladner et al. ....................... .. 435/697 [57] ABSTRACT
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Growth hormone participates in the regulation of normal
FOREIGN PATENT DOCUMENTS growth and development processes. The binding affinity of
growth hormone for its target receptors is dependent upon
0089666 A3 9/1983 European Pat. Off. .
the interaction of site 1 and site 2 domains of growth
WO 88/07084 9/1988 WIPO .
hormone with the target receptor. Embodiments of the
WO 88/07578 10/1988 WIPO .
WO 90/02809 3/1990 WIPO . present invention include site 1 variants of human growth
WO 90/04788 3/1990 WIPO . hormone which bind to target receptors with a different
WO 90/05185 5/1990 WIPO . affinity than that of the native hormone. Embodiments of the
WO 90/08823 8/1990 WIPO . invention further include components for the production of
WO 92/01047 1/1992 WIPO . isolated human growth hormone variants using a host cell/
WO 92/09690 6/1992 WIPO . vector expression system.
WO 92/19736 11/1992 WIPO .
WO 92/21029 11/1992 WIPO .
WO 93/00109 1/1993 WIPO . 8 Claims, 11 Drawing Sheets
6,022,711
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U.S. Patent Feb. 8,2000 Sheet 1 0f 11 6,022,711
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