Abstract 578: Pharmacokinetic proprieties of a locked nucleic acid oligonucleotide targeting miR-221
Authors: Di Martino Maria Teresa 
Published: September 2020

Abstract
MiR-221 is overexpressed in several malignancies where it promotes tumor growth and survival by interfering with gene transcripts, including p27Kip1, PUMA, PTEN, and p57Kip2. We previously demonstrated that a novel 13-mer miR-221 inhibitor (LNA-i-miR-221) exerts antitumor activity against human cancer with a pilot favorable pharmacokinetics and safety profile in mice and non-naive monkeys. Next we performed and here report a non-GLP/GLP dose-finding investigation of LNA-i-miR-221 in Sprague Dawley rats. The safety of the intravenous dose (125 mg/kg/day) for four consecutive days, two treatment cycles, was investigated by a first non-GLP study. Toxicokinetics profile of LNA-i-miR-221 was next explored in a GLP study at three different doses (5, 12.5 and 125 mg/kg/day). Slight changes in blood parameters and histological findings in kidney were observed at the highest dose. These effects were reversible and consistent with in vivo ASO class effect. Based on these findings the NOAEL was established at 5 mg/kg/day. The plasma exposure of LNA-i-miR-221, based on C0 and AUC, suggested no differential sex effect. Slight accumulation occurred between cycles one and two but was not observed after four consecutive administrations. These findings demonstrate a safety profile of LNA-i-miR-221 in Sprague Dawley rats and provide a reference translational framework and path for the development of other LNA miR inhibitors in Phase I clinical study. In addition to understand the pharmacokinetics properties of this new agent, including unbound/total clearance, we investigated the LNA-i-miR-221 protein binding in three different species including rat (Sprague Dawley), monkey (Macaca fascicularis) and human. To this aim, we generated a suitable ultrafiltration method to study the binding of LNA-i-miR-221 to plasma proteins. We identified that the fraction of LNA-i-miR-221 (at concentration of 1 and 10 µM) bound to rat, monkey and human plasma proteins is high and ranges from 98.2 to 99.05%. This high protein binding of LNA-i-miR-221 to plasma proteins in all the species tested translates into a pharmacokinetic advantage by preventing rapid renal clearance. The integration of these results into multiple allometric interspecies scaling methods have been then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, therefore providing a framework for definition of safe starting and escalation doses toward a first-in-human clinical trial of LNA-i-miR-221.
This work was supported by the Italian Association for Cancer Research (AIRC), PI: PT. “Special Program Molecular Clinical Oncology - 5 per mille" n. 9980, 2010/15 and its Extension Program 2016/17 n.9980.
Citation Format: Maria Teresa Di Martino. Pharmacokinetic proprieties of a locked nucleic acid oligonucleotide targeting miR-221 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 578.