CUED Publications database

Systematic Activity Maturation of a Single-Domain Antibody with Non-canonical Amino Acids through Chemical Mutagenesis

Lindstedt, PR and Aprile, FA and Sormanni, P and Rakoto, R and Dobson, CM and Bernardes, GJL and Vendruscolo, M (2021) Systematic Activity Maturation of a Single-Domain Antibody with Non-canonical Amino Acids through Chemical Mutagenesis. Cell Chemical Biology, 28. 70-77.e5. ISSN 2451-9456

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Abstract

Great advances have been made over the last four decades in therapeutic and diagnostic applications of antibodies. The activity maturation of antibody candidates, however, remains a significant challenge. To address this problem, we present a method that enables the systematic enhancement of the activity of a single-domain antibody through the post-translational installation of non-canonical side chains by chemical mutagenesis. We illustrate this approach by performing a structure-activity relationship study beyond the 20 naturally occurring amino acids on a single-domain antibody designed in silico to inhibit the aggregation of the amyloid-β peptide, a process closely linked to Alzheimer's disease. We found that this approach can improve, by five orders of magnitude, the anti-aggregation activity of the starting single-domain antibody, without affecting its stability. These results show that the expansion of the chemical space available to antibodies through chemical mutagenesis can be exploited for the systematic enhancement of the activity of these molecules.

Item Type: Article
Uncontrolled Keywords: antibody maturation chemical mutagenesis non-natural amino acids protein aggregation
Subjects: UNSPECIFIED
Divisions: UNSPECIFIED
Depositing User: Cron Job
Date Deposited: 22 Nov 2020 20:11
Last Modified: 06 Apr 2021 01:46
DOI: 10.1016/j.chembiol.2020.11.002