Antibodies hold significant potential for inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer's disease. Unfortunately, conventional antibodies require near-stoichiometric concentrations to completely inhibit aggregation. We aim to harness the molecular interactions mediating amyloid formation to design domain antibodies with potent anti-aggregation activity. We have discovered that grafting small hydrophobic peptides from amyloidogenic polypeptides into the complementarity-determining regions of single-domain antibodies yields potent aggregation inhibitors (Ladiwala et al., PNAS, 2012). Grafted AMyloid-Motif AntiBODIES (gammabodies) specific for A� (Alzheimer's disease), aSynuclein (Parkinson's disease) and IAPP (type 2 diabetes) inhibit aggregation at low substoichiometric concentrations (1:10 gammabody:monomer molar ratio). In contrast, conventional antibodies obtained via immunization fail to prevent aggregation at the same substoichiometric concentrations. We expect that our antibody design approach � which eliminates the need for immunization or screening � can be readily extended to generate potent aggregation inhibitors of other amyloidogenic polypeptides linked to human diseases.

Design of potent domain antibody inhibitors of amyloid fibril assembly

245th National Meeting (2013)

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