DEVELOPMENT OF GM-CSF ANTOGONISTS

由于分子技术的发展，药物开发正在迅速发展

Pharmaceutic development is rapidly evolving due to molecular techniques and their application to analysis of ligand-receptor interactions. Antibodies can serve as molecular probes to study structural aspects receptor binding and activation. This has recently been extended to the development of biologically active peptides based on structural analysis of antibody variable regions. These techniques may now be applied to clinically relevant biomolecules with the ultimate goal of developing novel therapeutics. Granulocyte/macrophage colony stimulating factor (GM-CSF) plays a critical role in myeloid differentiation, and has been implicated in several immune and inflammatory processes. GM-CSF binds to specific cellular receptors (GM-CSFR) which belong to a recently described supergene family. These receptors are potential targets for pharmacologic agents designed for a variety of therapeutic applications. Design of such pharmacologic agents depends on a molecular understanding of ligand-receptor interactions. The overall aim of this grant is to utilize monoclonal antibodies and recombinant antibodies as molecular tools to analyze the GM-CSF - GM-CSFR interaction. This will follow the general approach of developing biologically active peptides based on antibody structures. Specifically, monoclonal antibodies (mAbs) and recombinant antibodies (rAbs) that bind GM-CSF and neutralize GM-CSF activity will be developed. Subsequently, anti-GM-CSFR mAbs and rAbs will be developed that bind to the same site on the GM-CSFR that GM-CSF binds. Direct anti-receptor antibodies and anti-idiotypic analogs of GM-CSF will be developed. The molecular structure of these mAbs/rAbs will be analyzed in a comparative fashion with the GM-CSFR and GM-CSF. This will allow analysis of potential binding strategies shared by the GM-CSFR and the neutralizing antibodies, and by GM-CSF and the antireceptor antibodies. This information will allow the development of peptides that specifically bind to GM-CSF and the GM-CSFR. These peptides can serve as powerful tools to analyze intermolecular interactions critical in GM-CSF activity. Such peptides with biological activity in vitro will allow design of pharmaceutics with potential clinical utility.