Abstract
Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available to achieve this strategy, we describe here the use of dibromomaleimides designed to undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve to 'lock' the conjugates as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration is also shown to infer significant improvements in homogeneity, as demonstrated by mass spectrometry analysis.
Highlights
Antibody bioconjugation is a key technological challenge in chemical biology, enabling a broad range of applications from targeted therapeutics to radioimmunoconjugates and immunoassays.[1]
We have recently described the use of a class of modified maleimide reagents, known as generation maleimides (NGMs),[11] which are able to achieve efficient disulfide bridging and represent a platform for site-selective ADC development (Fig. 1).[12]
Whilst reoxidation was highly efficient, the product was formed as Dibromomaleimide (DBM) reagent selection and synthesis
Summary
Antibody bioconjugation is a key technological challenge in chemical biology, enabling a broad range of applications from targeted therapeutics (e.g. antibody–drug conjugates; ADCs) to radioimmunoconjugates and immunoassays.[1]. Loading each of the cysteines with a reactive reagent, most commonly achieved using classical maleimides, still affords a heterogeneous mixture of products with drug-to-antibody ratios (DARs) of 0, 2, 4, 6 and 8 as the major components.[4] The higher loaded species present have been identified as having reduced stability,[5] and poorer outcomes in vivo due to their accelerated clearance.[4,6]
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