Read by QxMD icon Read

Nature-inspired design and evolution of anti-amyloid antibodies

Mark C Julian, Lilia A Rabia, Alec A Desai, Ammar Arsiwala, Julia E Gerson, Henry L Paulson, Ravi S Kane, Peter M Tessier
Journal of Biological Chemistry 2019 March 27
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 Aβ 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 wild-type 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 Aβ amyloid fibrils and only weakly recognize soluble Aβ. We found that this approach enables the generation of monovalent and bivalent antibodies with nanomolar affinity for Aβ 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 amino terminus of human Aβ. 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.


You need to log in or sign up for an account to be able to comment.

No comments yet, be the first to post one!

Trending on Read

Available on the App Store

Available on the Play Store
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"