PEN-866 exploits the preferential accumulation of HSP90-targeting ligands in tumors to selectively accumulate and release anti-cancer payloads. PEN-866 is a miniature conjugate that comprises an HSP90 targeting ligand linked to SN-38, the active metabolite of irinotecan. The conjugate accumulates and is retained in xenograft tumor tissue and gives a sustained release of SN-38 that leads to prolonged DNA damage and tumor regressions in multiple models of cancer.

HSP90 is a chaperone protein required by many cancer cells to maintain the stability and function of numerous onco-proteins that drive cancer cell growth, survival, and metastasis. Small molecule ligands of HSP90 are retained in tumors for as much as 20 times longer than in blood or normal tissue and have been used to image tumors in patients. These properties are believed to be due to the overexpression and increased level of the active form of HSP90 in cancer cells compared to normal tissues. The HSP90 targeting ligand of PEN-866 has a high affinity for HSP90 to retain the conjugate in tumor cells.

The therapeutic payload of PEN-866 is SN-38, a topoisomerase I inhibitor that interferes with the DNA unwinding functions of topoisomerase I leading to DNA damage, cancer cell apoptosis and death. Topoisomerase I is a validated therapeutic target, however patient benefit has been limited by systemic toxicities that could be overcome by the specific targeting of topoisomerase I inhibitors, such as SN-38, to tumor cells using miniature drug conjugates such as PEN-866.

In contrast to drug conjugates that require binding to cell surface targets, PEN-866 penetrates into the cell by diffusion and other mechanisms due to the design, including hydrophobicity, of the conjugate. Once inside the cell, the specific binding of the conjugate to the HSP90 target, which occurs at a higher affinity than in normal cells, allows the conjugate to be preferentially retained in the cancer cell for multiple days. The HSP90 targeting ligand and SN-38 payload in PEN-866 are joined by a cleavable linker that is designed to break in the tumor cells, releasing the potent SN-38 payload leading to cancer cell death. The extended retention of the conjugate in the cancer allows for the release of the payload in the interior of the cell. Also, similar to PEN-221, the small size of PEN-866 allows for rapid penetration into solid tumors. The accumulation and controlled intratumoral payload release by PEN-866 results in a remarkable degree of efficacy and durability of response in multiple cell line and patient-derived xenograft models. PEN-866 is being developed as a Pentarin® that employs a distinct mechanism of tumor targeting and accumulation to achieve potent and sustained antitumor effects. PEN-866 is currently being evaluatedin a Phase 1/2a clinical trial.