Motif-Grafted, Conformation-Specific Antibodies for Selectively Targeting Toxic Misfolded Proteins

Protein aggregation is the seminal event in several neurodegenerative disorders (e.g., Alzheimer’s and Prion disease). Contrary to protein folding, the misfolding of proteins results not in a single folded structure, but rather a spectrum of aggregated conformers with unique secondary and tertiary structures. Antibodies that target specific aggregated protein conformers – such as those that are toxic relative to those that are benign – are of broad interest for both diagnostic and therapeutic applications, yet generating such antibodies is extremely challenging. Much evidence now suggests that protein aggregation is governed by relatively small peptide elements within such proteins rather than their overall sequences. Thus, we posit that grafting peptide segments that regulate protein aggregation into the complementary determining regions (CDRs) of highly stable antibodies will endow such antibodies with the capacity to selectively target toxic aggregated conformers relative to non-toxic ones. Indeed, we find that conformation-specific antibodies can be readily generated using this approach. In this presentation, we will discuss our development of libraries of motif-grafted antibodies specific for targeting toxic aggregates of the amyloid ß peptide associated with Alzheimer’s disease and infectious amyloids of the yeast prion Sup35. We also find that motif-grafted antibodies are powerful structural probes for illuminating the conformational differences between toxic and non-toxic protein aggregates. We expect our motif-grafting approach will be useful for generating conformation-specific antibodies against diverse toxic misfolded proteins.