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
Key words
antibodies - bioconjugation - drug delivery
Significance
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.
Comment
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.
