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Mechanistic insights into the rational design of masked antibodies.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Bersellini, Manuela 

Abstract

Although monoclonal antibodies have greatly improved cancer therapy, they can trigger side effects due to on-target, off-tumor toxicity. Over the past decade, strategies have emerged to successfully mask the antigen-binding site of antibodies, such that they are only activated at the relevant site, for example, after proteolytic cleavage. However, the methods for designing an ideal affinity-based mask and what parameters are important are not yet well understood. Here, we undertook mechanistic studies using three masks with different properties and identified four critical factors: binding site and affinity, as well as association and dissociation rate constants, which also played an important role. HDX-MS was used to identify the location of binding sites on the antibody, which were subsequently validated by obtaining a high-resolution crystal structure for one of the mask-antibody complexes. These findings will inform future designs of optimal affinity-based masks for antibodies and other therapeutic proteins.

Description

Keywords

Masked antibodies, off-tumor cytotoxicity, pro-antibody, pro-biologics, pro-drug, protein design, protein-protein interaction, Antibodies, Monoclonal, Antibody Affinity, Binding Sites

Journal Title

MAbs

Conference Name

Journal ISSN

1942-0862
1942-0870

Volume Title

14

Publisher

Informa UK Limited
Sponsorship
Engineering and Physical Sciences Research Council (EP/L015889/1)