期刊
ORGANIC & BIOMOLECULAR CHEMISTRY
卷 17, 期 7, 页码 2005-2012出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c8ob02877j
关键词
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资金
- Royal Society [UF110046, URF\R\180019]
- FCT Portugal (iFCT) [IF/00624/2015, SFRH/BPD/118731/2016]
- ERC StG [676832]
- Marie Sklodowska-Curie ITN ProteinConjugates [675007]
- European Commission (Marie Curie IEF)
- Cambridge Trust
- China Scholarship Council
- Portuguese Mass Spectrometry Network [LISBOA-01-0145-FEDER-022125]
- Project EU_FT-ICR_MS - European Union [731077]
- EPSRC [EP/M003647/1]
- EPSRC [EP/M003647/1] Funding Source: UKRI
- Royal Society [UF110046] Funding Source: Royal Society
- Marie Curie Actions (MSCA) [675007] Funding Source: Marie Curie Actions (MSCA)
- European Research Council (ERC) [676832] Funding Source: European Research Council (ERC)
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.
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