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

Insulin-like growth factor I(IGF-I) is a potent anabolic peptide that media tes most of its pleiotropic effects through association with the IGF type I receptor. Biological availability and plasma half-life of IGF-I are modula ted by soluble binding proteins (IGFBPs), which sequester free IGF-I into h igh affinity complexes. Elevated levels of specific IGFBPs have been observ ed in several pathological conditions, resulting in inhibition of IGF-I act ivity. Administration of IGF-I variants that are unable to bind to the up-r egulated IGFBP species could potentially counteract this effect. We enginee red two IGFBP selective variants that demonstrated 700- and 80,000-fold app arent reductions in affinity for IGFBP-1 while preserving low nanomolar aff inity for IGFBP-3, the major carrier of IGF-I in plasma. Both variants disp layed 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, pharmaco kinetic parameters and tissue distribution of the IGF-I variants in rats di ffered from those of wild-type IGF-I as a function of their IGFBP affinitie s. These IGF-I variants may potentially be useful for treating disease cond itions associated with up-regulated IGFBP-1 levels, such as chronic or acut e 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.