bc0c00357_si_001.pdf (1.71 MB)
Tailored Linker Chemistries for the Efficient and Selective Activation of ADCs with KSPi Payloads
journal contribution
posted on 2020-07-22, 15:46 authored by Hans-Georg Lerchen, Beatrix Stelte-Ludwig, Anette Sommer, Sandra Berndt, Anne-Sophie Rebstock, Sarah Johannes, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah JörißenSeveral
antibody–drug conjugates (ADCs) have failed to achieve
a sufficiently large therapeutic window in patients due to toxicity
induced by unspecific payload release in the circulation or ADC uptake
into healthy organs. Herein, we describe the successful engineering
of ADCs consisting of novel linkers, which are efficiently and selectively
cleaved by the tumor-associated protease legumain. ADCs generated
via this approach demonstrate high potency and a preferential activation
in tumors compared to healthy tissue, thus providing an additional
level of safety. A remarkable tolerance of legumain for different
linker peptides, including those with just a single asparagine residue,
together with a modifier of the physicochemical metabolite profile,
proves the broad applicability of this approach for a tailored design
of ADCs.