The overall goal of this Phase I research project is to develop a group of polyclonal anti-idiotype antibodies which provide a structural representation of receptor-binding determinants on the C5a component of complement. This will be accomplished by first generating antibodies which bind to the determinants on C5a which 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 with its 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 efforts, an extensive family of monoclonal anti-idiotype antibodies will be generated in response to those idiotypes which had demonstrated 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 primary sequences of the antibodies which mimic ligand-receptor binding. This innovative strategy for developing therapeutic agents is described in more detail herein.
