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

Abstract

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.

Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer

“…PEN-221 binds with high affinity (K i of 51 pmol/L) and selectivity to SSTR2 (>420-fold higher than the other 4 SSTR isoforms; ref. 29). The second step is the internalization and accumulation of the PEN-221 receptor complex within the intracellular compartment of the tumor cell.…”

“…The second step is the internalization and accumulation of the PEN-221 receptor complex within the intracellular compartment of the tumor cell. This is especially important due to the low membrane permeability of PEN-221, limiting the passive uptake of PEN-221 (29). In an in vitro assay using CHO cells that overexpress the human SSTR2 receptor, PEN-221 triggered SSTR2-dependent internalization equivalent to the natural ligand, somatostatin-28, with an EC 50 of 0.51 nmol/L (n ¼ 3) and 1.08 nmol/L (n ¼ 3), respectively ( Fig.…”

“…PEN-221 was rationally synthesized through a series of experiments that explored different SSTR2-targeting ligands, conjugation sites, linkers, and payloads. PEN-221 was selected on the basis of its potent in vitro and in vivo activity, including the ability to cause tumor regressions in vivo (29). In the present article, we report on the properties of PEN-221 that include high-affinity binding specifically to SSTR2 and rapid internalization of the receptor resulting in SCLC tumor-specific accumulation of DM1.…”

177Lu-DOTATATE for the treatment of gastroenteropancreatic neuroendocrine tumors

“…One of the compounds that are furthest advanced in development is PEN-221. PEN-221 is a SSA conjugated to the chemotherapeutic agent mertansine (DM1), which is a microtubule inhibitor [51]. Findings from the dose-escalation portion of the phase I/II study of PEN-221 in NET and small cell lung carcinoma (SCLC) patients were presented at ASCO 2018 [52].…”

Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?

“…Peptide display has enabled the rapid isolation of binders through many innovative approaches. The pentarin (pen = penetrate, tar = target) platform consists of small peptides (<2 kDa) that can be made into pentarin-drug conjugates (PDC), developed by Tarveda (formerly Blend) Therapeutics [82]. Their lead compound is PEN-221, a somatostatin receptor-2 (SSTR2) targeting octreotide peptide analogue coupled to DM1 maytansine.…”