Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates |
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Authors: | Marc‐Andr Kasper Andreas Stengl Philipp Ochtrop Marcus Gerlach Tina Stoschek Dominik Schumacher Jonas Helma Martin Penkert Eberhard Krause Heinrich Leonhardt Christian P R Hackenberger |
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Institution: | Marc‐André Kasper,Andreas Stengl,Philipp Ochtrop,Marcus Gerlach,Tina Stoschek,Dominik Schumacher,Jonas Helma,Martin Penkert,Eberhard Krause,Heinrich Leonhardt,Christian P. R. Hackenberger |
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Abstract: | Requirements for novel bioconjugation reactions for the synthesis of antibody–drug conjugates (ADCs) are exceptionally high, since conjugation selectivity as well as the stability and hydrophobicity of linkers and payloads drastically influence the performance and safety profile of the final product. We report Cys‐selective ethynylphosphonamidates as new reagents for the rapid generation of efficacious ADCs from native non‐engineered monoclonal antibodies through a simple one‐pot reduction and alkylation. Ethynylphosphonamidates can be easily substituted with hydrophilic residues, giving rise to electrophilic labeling reagents with tunable solubility properties. We demonstrate that ethynylphosphonamidate‐linked ADCs have excellent properties for next‐generation antibody therapeutics in terms of serum stability and in vivo antitumor activity. |
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Keywords: | ADCs Antikö rper Biokonjugation Bioorganische Chemie Wirkstoffabgabe |
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