Binding protein-3-selective insulin-like growth factor I variants: engineering, biodistributions, and clearance.

Abstract

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.

• Authors: Y Dubaquié, D L Mortensen, A Intintoli, D A Hogue, G Nakamura, P Rancatore, P Lester, M D Sadick, E Filvaroff, P J Fielder, H B Lowman
• Journal: Endocrinology (Endocrinology) Vol. 142 Issue 1 Pg. 165-73 (Jan 2001) ISSN: 0013-7227 [Print] United States
• PMID: 11145579 (Publication Type: Journal Article)

Chemical References

• Insulin-Like Growth Factor Binding Protein 1
• Insulin-Like Growth Factor Binding Protein 3
• Recombinant Proteins
• Sulfates
• Insulin-Like Growth Factor I
• Receptor, IGF Type 1

Topics

• Aged
• Amino Acid Substitution
• Animals
• Breast Neoplasms
• Cartilage, Articular (drug effects, metabolism)
• Female
• Genetic Variation
• Humans
• Insulin-Like Growth Factor Binding Protein 1 (metabolism)
• Insulin-Like Growth Factor Binding Protein 3 (genetics, metabolism)
• Insulin-Like Growth Factor I (genetics, metabolism, pharmacokinetics)
• Kinetics
• Metabolic Clearance Rate
• Mutagenesis, Site-Directed
• Organ Culture Techniques
• Rats
• Rats, Sprague-Dawley
• Receptor, IGF Type 1 (metabolism)
• Recombinant Proteins (metabolism, pharmacokinetics)
• Substrate Specificity
• Sulfates (metabolism)
• Tissue Distribution
• Tumor Cells, Cultured