Issue 7, 2019

One-pot stapling of interchain disulfides of antibodies using an isobutylene motif

Abstract

Monoclonal antibodies have emerged as an important class of therapeutics in oncological and autoimmune diseases due to their several attractive properties, such as high binding affinity and specificity. However, it has recently become clear that antibodies recovered from serum show a significantly decreased potency owing to various reasons, including deamidation, oxidation, fragment antigen binding (Fab) exchange, and disulfide shuffling. Fab exchange and disulfide shuffling result because of the instability of disulfides in serum. Herein, we reported a ‘one-pot’ stapling strategy using isobutylene motifs to stabilise the interchain disulfides of antibodies. This general method was applied to a Fab fragment of the anti-HER2 antibody. The stapled Fab was completely stable in the presence of biological thiols. The approach was further applied to two different full-length IgGs, trastuzumab and rituximab, under mild and biocompatible conditions. The binding affinity of the antibody was enhanced, relative to its native form, after being stapled. The stapled structure maintained its effector functions and behaved similarly to its native form in vivo. This work provides a straightforward and scalable method for the stabilisation of antibodies in various formats.

Graphical abstract: One-pot stapling of interchain disulfides of antibodies using an isobutylene motif

Supplementary files

Article information

Article type
Paper
Submitted
17 Xim 2018
Accepted
27 Xim 2018
First published
10 Kax 2018

Org. Biomol. Chem., 2019,17, 2005-2012

One-pot stapling of interchain disulfides of antibodies using an isobutylene motif

S. Sun, P. Akkapeddi, M. C. Marques, N. Martínez-Sáez, V. M. Torres, C. Cordeiro, O. Boutureira and G. J. L. Bernardes, Org. Biomol. Chem., 2019, 17, 2005 DOI: 10.1039/C8OB02877J

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements