One-pot stapling of interchain disulfides of antibodies using an isobutylene motif.
View / Open Files
Authors
Akkapeddi, Padma
Marques, Marta C
Martínez-Sáez, Nuria
Torres, Vukosava M
Cordeiro, Carlos
Boutureira, Omar
Bernardes, Gonçalo JL
Publication Date
2019-02-13Journal Title
Org Biomol Chem
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.. Org Biomol Chem, 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 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.
Keywords
1107 Immunology, Biotechnology
Sponsorship
The Royal Society (uf110046)
European Research Council (676832)
Royal Society (URF\R\180019)
Engineering and Physical Sciences Research Council (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
Rights
Licence:
http://www.rioxx.net/licenses/all-rights-reserved
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.
Recommended or similar items
The current recommendation prototype on the Apollo Repository will be turned off on 03 February 2023. Although the pilot has been fruitful for both parties, the service provider IKVA is focusing on horizon scanning products and so the recommender service can no longer be supported. We recognise the importance of recommender services in supporting research discovery and are evaluating offerings from other service providers. If you would like to offer feedback on this decision please contact us on: support@repository.cam.ac.uk