One-pot stapling of interchain disulfides of antibodies using an isobutylene motif.
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Authors
Akkapeddi, Padma
Marques, Marta C
Martínez-Sáez, Nuria
Torres, Vukosava M
Cordeiro, Carlos
Lopes Bernardes, Goncalo
Publication Date
2019-02Journal Title
Organic & biomolecular chemistry
ISSN
1477-0520
Publisher
Royal Society of Chemistry (RSC)
Volume
17
Issue
7
Pages
2005-2012
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
Metadata
Show full item recordCitation
Sun, S., Akkapeddi, P., Marques, M. C., Martínez-Sáez, N., Torres, V. M., Cordeiro, C., Boutureira, O., & et al. (2019). One-pot stapling of interchain disulfides of antibodies using an isobutylene motif.. Organic & biomolecular chemistry, 17 (7), 2005-2012. https://doi.org/10.1039/c8ob02877j
Abstract
Monoclonal antibodies have emerged as an important class of therapeutics in oncological and autoimmune diseases due to several attractive properties, such as high binding affinity and specificity. However, it has recently become clear that antibodies recovered from serum show 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 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 IgG, 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 effectors functions and behaved similarly as its native form in vivo. This work provides a straightforward and scalable method for the stabilisation antibodies in various formats.
Sponsorship
Royal Society (uf110046)
European Commission Horizon 2020 (H2020) ERC (676832)
Royal Society (URF\R\180019)
EPSRC (EP/M003647/1)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (675007)
Identifiers
External DOI: https://doi.org/10.1039/c8ob02877j
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287420
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