Structure-Based Design of Antibodies Specific for Misfolded Proteins

Conformation-specific antibodies that recognize aggregated proteins associated with several conformational disorders (e.g., Parkinson’s disease) are invaluable for diagnostic and therapeutic applications. We have developed a novel approach for designing conformation- and sequence-specific antibodies against misfolded proteins that is inspired by the homotypic interactions governing protein aggregation. We demonstrate that grafting small hydrophobic peptides from several amyloidogenic polypeptides (e.g., the beta-amyloid peptide associated with Alzheimer’s disease) into the complementarity determining regions of antibody fragments generates antibody variants that selectively recognize aggregated proteins containing the cognate peptide motifs (Perchiacca et al., PNAS, 2012). We refer to these antibodies as gammabodies for Grafted AMyloid-Motif AntiBODIES. Gammabodies display strict sequence specificity and scrambling their grafted sequences eliminates antibody reactivity. We also find that gammabodies inhibit the cytotoxicity of protein aggregates. We will discuss how gammabodies can be designed against diverse misfolded proteins, as well as how they can be used as site-specific probes to analyze the structures of toxic misfolded proteins.