Specific Inhibitor of Placental Alkaline Phosphatase Isolated from a DNA-Encoded Chemical Library Targets Tumor of the Female Reproductive Tract
Gabriele Bassi, Nicholas Favalli, Christian Pellegrino, Yuichi Onda, Jörg Scheuermann, Samuele Cazzamalli, Markus G. Manz, Dario Neri
Abstract
Placental alkaline phosphatase (PLAP) is an abundant surface antigen in the malignancies of the female reproductive tract. Nevertheless, the discovery of PLAP-specific small organic ligands for targeting applications has been hindered by ligand cross-reactivity with the ubiquitous tissue non-specific alkaline phosphatase (TNAP). In this study, we used DNA-encoded chemical libraries to discover a potent (IC50 = 32 nM) and selective PLAP inhibitor, with no detectable inhibition of TNAP activity. Subsequently, the PLAP ligand was conjugated to fluorescein; it specifically bound to PLAP-positive tumors in vitro and targeted cervical cancer in vivo in a mouse model of the disease. Ultimately, the fluorescent derivative of the PLAP inhibitor functioned as a bispecific engager redirecting the killing of chimeric antigen receptor-T cells specific to fluorescein on PLAP-positive tumor cells.