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 the corresponding aggregated proteins with submicromolar binding affinity (Perchiacca et al., PNAS, 2012; Ladiwala et al., PNAS, 2012). Moreover, we find that gammabodies can be readily evolved to further enhance their binding affinity and specificity using yeast surface display. We are currently optimizing our design and evolution methods to generate high-affinity single- and multidomain antibodies for applications related to inhibiting and reversing toxic protein aggregation.

Design and evolution of antibody fragments specific for misfolded proteins

247th National Meeting (2014)

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