(270b) Design of Antibodies Specific for Misfolded Proteins

Antibodies that recognize toxic aggregated proteins associated with neurodegenerative disorders (e.g., Parkinson’s disease) are valuable for therapeutic and diagnostic applications. We have developed a novel approach for designing domain antibodies specific for misfolded proteins that is inspired by the molecular interactions that mediate protein aggregation. We find that grafting small hydrophobic peptides from several amyloidogenic polypeptides (e.g., Alzheimer’s and Parkinson’s polypeptides) into the complementarity-determining regions of domain antibodies generates Grafted AMyloid-Motif AntiBODIES (gammabodies) that recognize aggregated proteins with nanomolar binding affinity (Perchiacca et al., PNAS, 2012; Ladiwala et al., PNAS, 2012). Gammabodies bind preferentially to aggregates containing the grafted peptides via homotypic interactions. We are currently optimizing the length, location and number of grafted amyloid peptides within single- and multidomain gammabodies to further enhance binding affinity and specificity.