This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dubaquié, Y. Articles by Lowman, H. B. Search for Related Content PubMed PubMed Citation Articles by Dubaquié, Y. Articles by Lowman, H. B. Pubmed/NCBI databases Substance via MeSH

Binding Protein-3-Selective Insulin-Like Growth Factor I Variants: Engineering, Biodistributions, and Clearance

Departments of Protein Engineering (Y.D., G.N., H.B.L.), Pharmacokinetics and Metabolism (D.L.M., P.J.F.), Bioanalytical Technology (A.I., M.D.S.), Endocrinology (D.A.H., E.F.), and Recovery Sciences (P.R., P.L.), Genentech, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: Dr. Henry B. Lowman, Department of Protein Engineering, 1 DNA Way, Genentech, Inc., South San Francisco, California 94080. E-mail: hbl{at}gene.com

Insulin-like growth factor I (IGF-I) is a potent anabolic peptide that mediates most of its pleiotropic effects through association with the IGF type I receptor. Biological availability and plasma half-life of IGF-I are modulated by soluble binding proteins (IGFBPs), which sequester free IGF-I into high affinity complexes. Elevated levels of specific IGFBPs have been observed in several pathological conditions, resulting in inhibition of IGF-I activity. Administration of IGF-I variants that are unable to bind to the up-regulated IGFBP species could potentially counteract this effect. We engineered two IGFBP-selective variants that demonstrated 700- and 80,000-fold apparent reductions in affinity for IGFBP-1 while preserving low nanomolar affinity for IGFBP-3, the major carrier of IGF-I in plasma. Both variants displayed wild-type-like potency in cellular receptor kinase assays, stimulated human cartilage matrix synthesis, and retained their ability to associate with the acid-labile subunit in complex with IGFBP-3. Furthermore, pharmacokinetic parameters and tissue distribution of the IGF-I variants in rats differed from those of wild-type IGF-I as a function of their IGFBP affinities. These IGF-I variants may potentially be useful for treating disease conditions associated with up-regulated IGFBP-1 levels, such as chronic or acute renal and hepatic failure or uncontrolled diabetes. More generally, these results suggest that the complex biology of IGF-I may be clarified through in vivo studies of IGFBP-selective variants.

This article has been cited by other articles:

				S. M. Firth, F. MCDougall, A. J. MCLachlan, and R. C. Baxter Impaired Blockade of Insulin-Like Growth Factor I (IGF-I)-Induced Hypoglycemia by IGF Binding Protein-3 Analog with Reduced Ternary Complex-Forming Ability Endocrinology, May 1, 2002; 143(5): 1669 - 1676. [Abstract] [Full Text] [PDF]