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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Lindstedt, Philip R 
Aprile, Francesco A 
Rakoto, Robertinah 
Dobson, Christopher M 

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.

Description

Keywords

antibody maturation, chemical mutagenesis, non-natural amino acids, protein aggregation, Alzheimer Disease, Amino Acids, Humans, Protein Processing, Post-Translational, Single-Domain Antibodies, Structure-Activity Relationship

Journal Title

Cell Chem Biol

Conference Name

Journal ISSN

2451-9456
2451-9448

Volume Title

28

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (203249/Z/16/Z)
Wellcome Trust grant no. 203249/Z/16/Z