1 research outputs found
Discovery of BT8009: A Nectin‑4 Targeting Bicycle Toxin Conjugate for the Treatment of Cancer
Bicycle toxin conjugates
(BTCs) are a promising new class
of molecules
for targeted delivery of toxin payloads into tumors. Herein we describe
the discovery of BT8009, a Nectin-4 targeting BTC currently under
clinical evaluation. Nectin-4 is overexpressed in multiple tumor types
and is a clinically validated target for selective delivery of cytotoxic
payloads. A Nectin-4 targeting bicyclic peptide was identified by
phage display, which showed highly selective binding for Nectin-4
but suffered from low plasma stability and poor physicochemical properties.
Multiparameter chemical optimization involving introduction of non-natural
amino acids resulted in a lead Bicycle that demonstrated high affinity
for Nectin-4, good stability in biological matrices, and a much-improved
physicochemical profile. The optimized Bicycle was conjugated to the
cytotoxin Monomethyl auristatin E via a cleavable linker to give the
targeted drug conjugate BT8009, which demonstrates potent anticancer
activity in in vivo rodent models