(47a) Design of Potent Antibody Inhibitors of Amyloid Fibrillization

Antibodies hold significant potential for specifically inhibiting toxic protein aggregation associated with conformational disorders such as Alzheimer’s and prion disease. Unfortunately, conventional antibodies are poor inhibitors of protein aggregation. We aim to harness the homotypic interactions between hydrophobic peptide segments that mediate amyloid fibrillization to design 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 antibody variants that potently inhibit amyloid formation. Grafted AMyloid-Motif AntiBODIES (gammabodies) presenting hydrophobic peptide segments from amyloidogenic proteins inhibit aggregation of the corresponding polypeptide at substoichiometric concentrations. In contrast, sequence- and conformation-specific antibodies obtained via immunization are unable to prevent aggregation at substoichiometric concentrations. We expect that our antibody design approach – which eliminates the need for immunization or screening to identify sequence-specific antibodies – can be readily extended to generate potent antibody inhibitors for other amyloidogenic polypeptides linked to human diseases.