Rapid generation of antibody-drug conjugates (ADCs) is limited by chemistries available for drug attachment. Here, we present diene-containing noncanonical amino acids (ncAAs) capable of undergoing fast and selective Diels-Alder reactions with maleimide following incorporation into antibodies. Diels-Alder bioconjugation (DAB) provides practical and performance-enhancing benefits related to production and the resulting physical properties of bioconjugate therapeutics such as ADCs. Manufacture of ADCs using DAB can be achieved in a one-step process that doesn’t require addition of catalysts, pH adjustment, or chemical activation of antibodies. Since DAB was designed from the perspective of ADC payloads, it utilizes clinically validated drugs and thus eliminates the need for concurrent development of new compounds. DAB brings unique advantages related to conjugate stability and antibody design options that are not realized with current cysteine-based approaches that use the same maleimide payloads. For example, DAB solves position-dependent stability issues that plague thiosuccinimide-linked ADCs due to the retro-Michael reaction at physiological conditions. Also, drug can be attached via DAB at antibody positions where cysteine introduction interferes with natural protein disulfides. While DAB has been successfully applied towards development of ADCs, the technology is poised to enable further applications that expand the scope of protein-based therapeutics such as polymer-, peptide-, nanoparticle-, and nucleic acid-bioconjugates.

Production of antibody-drug conjugates through maleimide-diene coupling to noncanonical amino acids

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.