Synfacts 2019; 15(10): 1189
DOI: 10.1055/s-0039-1690935
Chemistry in Medicine and Biology
© Georg Thieme Verlag Stuttgart · New York

Ethynylphosphonamidates in the Synthesis of Antibody–Drug Conjugates

Dirk Trauner
Andrej Shemet
Kasper M.-A, Stengl A, Ochtrop P, Gerlach M, Stoschek T, Schumacher D, Helma J, Penkert M, Krause E, Leonhardt H. * Hackenberger CP. R. * Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Humboldt Universität zu Berlin, and Ludwig-Maximilians-Universität München, Germany
Ethynylphosphonamidates for the Rapid and Cysteine-Selective Generation of Efficacious Antibody–Drug Conjugates.

Angew. Chem. Int. Ed. 2019;
58: 11631-11636
Further Information

Publication History

Publication Date:
17 September 2019 (online)



Antibody–drug conjugates (ADCs) have emerged as a new class of targeted therapeutics. They combine the high potency of cytotoxic drugs with the tumor specificity of monoclonal antibodies. However, the insufficient stability in serum and undesired aggregation often lead to off-target toxicity.



The researchers report the conjugation of antimitotic agent monomethyl auristantin F (MMAF) to the Her2-targeting antibody trastuzumab by using ethynylphosphonamidate functionalized linker B. The resulting ADC showed a drug-to-antibody ratio of 4.6. Furthermore, the use of a phosphonamidate linker bearing diethyleneglycol improved the polarity of the whole linker system. The ADCs had in vivo antitumor activity.