AN ANTI-IDIOTYPE-BASED STRATEGY FOR DRUG DISCOVERY

THE OVERALL GOAL OF THIS RESEARCH IS TO DEVELOP A GROUP OF POLYCLONAL ANTI-IDIOTYPE ANTIBODIES THAT PROVIDE A STRUCTURAL REPRESENTATION OF RECEPTOR-BINDING DETERMINANTS ON THE C5A COMPONENT OF THE COMPLEMENT. THIS WILL BE ACCOMPLISHED BY FIRST GENERATING ANTIBODIES THAT BIND TO THEDETERMINANTS ON C5A THAT ARE INVOLVED IN THE BINDING OF C5A TO ITS RECEPTOR. POLYCLONAL ANTI-IDIOTYPE ANTIBODIES WILL THEN BE GENERATED IN RESPONSE TO THESE IDIOTYPES. THESE ANTI-IDIOTYPE ANTIBODIES WILL BE SCREENED FOR THEIR ABILITY TO PROVIDE A STRUCTURAL IMAGE OF THE RECEPTOR-BINDING DETERMINANTS OF C5A BY ASCERTAINING THEIR ABILITY TO BIND TO THE C5A RECEPTOR. THESE RECEPTOR-BINDING ANTI-IDIOTYPES WILL BE USEFUL REAGENTS FOR PROBING THE PHYSIOLOGY OF C5A INTERACTIONS WITHITS RECEPTOR, FOR TRACKING THE SUBCELLULAR AND TISSUE LOCALIZATION OF THE RECEPTOR, AND FOR ISOLATING AND PURIFYING THE RECEPTOR. THE IDIOTYPE ANTIBODIES SPECIFIC FOR THE RECEPTOR-BINDING DOMAINS ON C5A WILL THEMSELVES BE VALUABLE REAGENTS FOR IDENTIFYING THE BINDING EPITOPES ON C5A. IN PHASE II, AN EXTENSIVE FAMILY OF MONOCLONAL ANTI-IDIOTYPEANTIBODIES WILL BE GENERATED IN RESPONSE TO THOSE IDIOTYPES THAT DEMONSTRATE UTILITY IN PHASE I EFFORTS TO PRODUCE POLYCLONAL ANTI-IDIOTYPES. THE GENES FOR THESE MONOCLONAL ANTI-IDIOTYPE ANTIBODIES WILL THEN BE CLONED, SEQUENCED, MUTATED, AND EXPRESSED AS PART OF THE BASIS OF A NOVEL APPROACH TO DRUG DISCOVERY, BASED ON ANALYSIS OF THE PRIMARYSEQUENCES OF THE ANTIBODIES THAT MIMIC LIGAND-RECEPTOR BINDING.