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Ethynylphosphonamidates for the Rapid and Cysteine‐Selective Generation of Efficacious Antibody–Drug Conjugates
Author(s) -
Kasper MarcAndré,
Stengl Andreas,
Ochtrop Philipp,
Gerlach Marcus,
Stoschek Tina,
Schumacher Dominik,
Helma Jonas,
Penkert Martin,
Krause Eberhard,
Leonhardt Heinrich,
Hackenberger Christian P. R.
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201904193
Subject(s) - bioconjugation , conjugate , chemistry , combinatorial chemistry , reagent , alkylation , solubility , cysteine , monoclonal antibody , drug , selectivity , electrophile , antibody , biochemistry , organic chemistry , pharmacology , catalysis , medicine , mathematical analysis , mathematics , immunology , biology , enzyme
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.