Engineering the surface properties of a human monoclonal antibody prevents self-association and rapid clearance in vivo.

ABSTRACT: Uncontrolled self-association is a major challenge in the exploitation of proteins as therapeutics. Here we describe the development of a structural proteomics approach to identify the amino acids responsible for aberrant self-association of monoclonal antibodies and the design of a variant with reduced aggregation and increased serum persistence in vivo. We show that the human monoclonal antibody, MEDI1912, selected against nerve growth factor binds with picomolar affinity, but undergoes reversible self-association and has a poor pharmacokinetic profile in both rat and cynomolgus monkeys. Using hydrogen/deuterium exchange and cross-linking-mass spectrometry we map the residues responsible for self-association of MEDI1912 and show that disruption of the self-interaction interface by three

SUBMITTER: Dobson CL 

PROVIDER: S-EPMC5171805 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature