CBTF: New Amine-to-Thiol Coupling Reagent for Preparation
of Antibody Conjugates with Increased Plasma Stability
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Abstract
Amine-to-thiol
coupling is the most common route for the preparation
of antibody–drug conjugates (ADC). It is usually achieved by
using heterobifunctional reagents possessing an activated ester at
one end and a maleimide group at the other. However, maleimide-based
conjugates were recently revealed to have limited stability in blood
circulation, which can compromise therapeutic efficacy of the conjugate.
To address this issue, we have developed a heterobifunctional reagent,
sodium 4-((4-(cyanoethynyl)benzoyl)oxy)-2,3,5,6-tetrafluorobenzenesulfonate
(CBTF), for amine-to-thiol coupling. It comprises a recently described
3-arylpropionitrile (APN) function in replacement of maleimide and
allows for the preparation of remarkably stable conjugates. A series
of antibody–dye conjugates have been prepared using this reagent
and shown superior stability in human blood plasma compared to maleimide-derived
conjugates