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Publication : Nature-inspired design and evolution of anti-amyloid antibodies.

First Author  Julian MC Year  2019
Journal  J Biol Chem Volume  294
Issue  21 Pages  8438-8451
PubMed ID  30918024 Mgi Jnum  J:348426
Mgi Id  MGI:6368220 Doi  10.1074/jbc.RA118.004731
Citation  Julian MC, et al. (2019) Nature-inspired design and evolution of anti-amyloid antibodies. J Biol Chem 294(21):8438-8451
abstractText  Antibodies that recognize amyloidogenic aggregates with high conformational and sequence specificity are important for detecting and potentially treating a wide range of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. However, these types of antibodies are challenging to generate because of the large size, hydrophobicity, and heterogeneity of protein aggregates. To address this challenge, we developed a method for generating antibodies specific for amyloid aggregates. First, we grafted amyloidogenic peptide segments from the target polypeptide [Alzheimer's amyloid-beta (Abeta) peptide] into the complementarity-determining regions (CDRs) of a stable antibody scaffold. Next, we diversified the grafted and neighboring CDR sites using focused mutagenesis to sample each WT or grafted residue, as well as one to five of the most commonly occurring amino acids at each site in human antibodies. Finally, we displayed these antibody libraries on the surface of yeast cells and selected antibodies that strongly recognize Abeta-amyloid fibrils and only weakly recognize soluble Abeta. We found that this approach enables the generation of monovalent and bivalent antibodies with nanomolar affinity for Abeta fibrils. These antibodies display high conformational and sequence specificity as well as low levels of nonspecific binding and recognize a conformational epitope at the extreme N terminus of human Abeta. We expect that this systematic approach will be useful for generating antibodies with conformational and sequence specificity against a wide range of peptide and protein aggregates associated with neurodegenerative disorders.
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