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.
