Reflection on “Site-specific PEGylation of proteins by a Staudinger-phosphite reaction”: from protein modification to ADCs in the clinic

Abstract

Chemoselective or bioorthogonal modification reactions resulted in several breakthrough studies that enabled the incorporation of functional modules into proteins and antibodies for basic and translational research. In 2010, we published a paper in Chemical Science, which described a chemoselective method for synthesizing branched PEGylated peptides and proteins using the Staudinger-phosphite reaction (R. Serwa, P. Majkut, B. Horstmann, J. M. Swiecicki, M. Gerrits, E. Krause and C. P. R. Hackenberger, Chem. Sci., 2010, 1, 596–602, https://doi.org/10.1039/C0SC00324G). We discuss subsequent studies in using the protocol for the intracellular stabilization of peptides and the development of the P5-labeling platform, which we currently use in the generation of antibody–drug-conjugates (ADCs) as next-generation biopharmaceuticals in clinical studies, for which a first proof-of-concept study was also published in Chemical Science (P. Ochtrop, J. Jahzerah, P. Machui, I. Mai, D. Schumacher, J. Helma, M. A. Kasper and C. P. R. Hackenberger, Chem. Sci., 2023, 14, 2259–2266, https://doi.org/10.1039/D2SC05678J).