DTS-108, A Novel Peptidic Prodrug of SN38: In vivo Efficacy and Toxicokinetic Studies

Abstract

Purpose: Irinotecan is a prodrug converted to the active cytotoxic molecule SN38 predominantly by the action of liver carboxylesterases. The efficacy of irinotecan is limited by this hepatic activation that results in a low conversion rate, high interpatient variability, and dose-limiting gastrointestinal toxicity. The purpose of this study was to evaluate a novel peptidic prodrug of SN38 (DTS-108) developed to bypass this hepatic activation and thus reduce the gastrointestinal toxicity and interpatient variability compared with irinotecan. Experimental Design: SN38 was conjugated to a cationic peptide (Vectocell) via an esterase cleavable linker.The preclinical development plan consisted of toxicity and efficacy evaluation in a number of different models and species. Results: The conjugate (DTS-108) is highly soluble, with a human plasma half-life of 400 minutes in vitro. Studies in the dog showed that DTS-108 liberates significantly higher levels of free SN38 than irinotecan without causing gastrointestinal toxicity. In addition, the ratio of the inactive SN38-glucuronide metabolite compared with the active SN38 metabolite is significantly lower following DTS-108 administration, compared with irinotecan, which is consistent with reduced hepatic metabolism. In vivo efficacy studies showed that DTS-108 has improved activity compared with irinotecan. A significant dose-dependent antitumoral efficacy was observed in all models tested and DTS-108 showed synergistic effects in combination with other clinically relevant therapeutic agents. Conclusions: DTS-108 is able to deliver significantly higher levels of SN38 than irinotecan, without the associated toxicity of irinotecan, resulting in an increased therapeutic window for DTS-108 in preclinical models. These encouraging data merit further preclinical and clinical investigation.Irinotecan is an effective chemotherapeutic agent that is widely prescribed for advanced colorectal cancer as a first-or secondline treatment. Irinotecan has also been shown to be active in gastric cancer, non -small cell lung cancer, and small-cell lung cancer, alone or in combination with other cytotoxic agents (1). Currently, irinotecan is used in combination with 5-fluorouracil (5-FU) in first-line treatment for metastatic colorectal cancer (2). Irinotecan is also used with other agents, including the anti -vascular endothelial growth factor antibody bevacizumab (Avastin; refs. 3,4). Following administration of irinotecan, the active metabolite SN38 (7-ethyl-10-hydroxycamptothecin) is formed by the action of carboxylesterases that are predominantly present in the liver (5, 6). SN38 is a topoisomerase I inhibitor with an activity a thousand times greater than irinotecan, but that cannot be administered directly as it is highly insoluble (1).Several limitations to the clinical use of irinotecan arise due to its mechanism of activation, metabolism, and elimination. The first limitation is caused by the complexity of irinotecan metabolism, which results in high interpatient variabil...

Pharmacokinetics and safety of DTS-108, a human oligopeptide bound to SN-38 with an esterase-sensitive cross-linker in patients with advanced malignancies: a Phase I study

“…DTS-108 is cleaved chemically by esterases that are found in the blood allowing a higher diffusion and taking advantage of the PK of the highly soluble oligopeptide in the plasma and reduces the SN-38 toxicity by lowering the systemic exposure of SN-38, especially in the bone marrow and gut. 21 Our study reinforced the preclinical models and identified the reduced incidence of digestive toxicity while it identified skin toxicity. In animal models, DTS-108 has been identified to induce immediate effects resembling the symptoms of an infusion reaction.…”

“…21 DTS-108 is a soluble prodrug of the topoisomerase inhibitor SN-38, the active metabolite of irinotecan. In DTS-108, the SN-38 moiety is covalently linked to a 20-amino acid peptide through a specific cross-linker, which allows the release of SN-38 through esterase bond cleavage.…”

“…This technology sought to enhance tumor delivery properties by taking advantage of the PK of the highly soluble oligopeptide in the plasma and reducing SN-38 toxicity by lowering the systemic exposure of SN-38 especially in the bone marrow and gut. 21 In preclinical models, DTS-108 was able to deliver significantly higher plasma levels of SN-38 with lower toxicity compared to irinotecan, resulting in a broader therapeutic potential. Based on these encouraging preclinical results, we conducted a Phase I study based on PK …”

“…Novel drug delivery techniques also sought to limit gastrointestinal toxicity and interpatient pharmacokinetic (PK) variability. 21 Based on this rationale, a novel water-soluble conjugate (DTS-108) was developed by linking SN-38 to a highly charged 20-amino acid oligopeptide of human origin (Figure 1). 22 The SN-38 oligopeptide cross-linker can be cleaved chemically by esterases that are primarily found in blood, in contrast to irinotecan, which is cleaved primarily by hepatic carboxylesterases releasing SN-38 in the liver where it is subsequently glucuronidated and secreted in bile as SN-38G.…”

SN-38-Cyclodextrin Complexation and Its Influence on the Solubility, Stability, and In Vitro Anticancer Activity Against Ovarian Cancer

“…However, only about 2-8% of the prodrug is converted to SN-38 by carboxylesterases present in liver and cancer cells, and therefore, a high dose of irinotecan needs to be administered to get the desired therapeutic effect (1,2). For example Camptosar ® has to be injected at a high dose of 150-180 mg/m 2 intravenously over a period of 90 min to treat colorectal cancer.…”