Discovery of an SSTR2-Targeting Maytansinoid Conjugate (PEN-221) with Potent Activity in Vitro and in Vivo

Somatostatin receptor 2 (SSTR2) is
frequently overexpressed on
several types of solid tumors, including neuroendocrine tumors and
small-cell lung cancer. Peptide agonists of SSTR2 are rapidly internalized
upon binding to the receptor and linking a toxic payload to an SSTR2
agonist is a potential method to kill SSTR2-expressing tumor cells.
Herein, we describe our efforts towards an efficacious SSTR2-targeting
cytotoxic conjugate; examination of different SSTR2-targeting ligands,
conjugation sites, and payloads led to the discovery of 22 (PEN-221),
a conjugate consisting of microtubule-targeting agent DM1 linked to
the C-terminal side chain of Tyr3–octreotate. PEN-221
demonstrates in vitro activity which is both potent (IC50 = 10 nM) and receptor-dependent (IC50 shifts 90-fold
upon receptor blockade). PEN-221 targets high levels of DM1 to SSTR2-expressing
xenograft tumors, which has led to tumor regressions in several SSTR2-expressing
xenograft mouse models. The safety and efficacy of PEN-221 is currently
under evaluation in human clinical trials.