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Enhancement of Insulin-Like Growth Factor I Activity by Novel Antisera: Potential Structure/Function Interactions¹

The Babraham Institute, Cambridge, United Kingdom CB2 4AT

Address all correspondence and requests for reprints to: Dr. J. M. Pell, The Babraham Institute, Cambridge, United Kingdom CB2 4AT. E-mail: jenny.pell{at}bbsrc.ac.uk

Insulin-like growth factor I (IGF-I) is essential for normal growth and development, regulating cell proliferation, differentiation, and survival. Little IGF-I exists in the free form; rather, it is bound to one of a family of six specific IGF-binding proteins (IGFBPs). Usually, IGFBPs have a high affinity for IGF-I and inhibit its activity. Intriguingly, some IGFBPs also potentiate IGF-I action; the precise mechanism of this is unclear, but it is thought to include modification of the IGFBP to lower its affinity for IGF-I. We have previously generated a novel antihuman (h) IGF-I antiserum that, instead of inhibiting IGF-I activity, enhances it in vivo. As the enhancing anti-IGF-I antiserum and potentiating IGFBPs share several properties with regard to IGF action, the antibody may provide a model for examining the actions of enhancing IGFBPs. In this study we demonstrate that the antiserum can also enhance IGF-I activity in vitro, assessed as cell number of a bovine fibroblast cell line, suggesting that its actions might not merely be confined to changing the kinetics of IGF-I clearance or degradation. Epitope scanning using overlapping octamer and hexamer peptides spanning the entire sequence of IGF-I indicates that the enhancing antiserum recognizes a specific linear region spanning the C-terminal region of the C domain and the proximal A domain (residues Ser³³ to Cys⁴⁷), and that this recognition is not present in nonenhancing antisera. Further, this region is located on the opposite surface of IGF-I from putative type 1 receptor-binding residues, allowing the possibility that the antiserum might be able to modulate IGF-I receptor binding. Antibodies raised against a synthetic peptide corresponding to Ser³³ to Cys⁴⁷ of IGF-I also potentiated IGF-I activity in vivo. As IGF-I may be beneficial in various clinical conditions associated with catabolism or cell repair, we suggest that this potentiating anti-IGF-I antiserum has favorable properties that could form a basis for therapeutic strategy.

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