Allometric Scaling Approaches for Predicting Human Pharmacokinetic of a Locked Nucleic Acid Oligonucleotide Targeting Cancer-Associated miR-221.

Maria Teresa Di Martino,Francesca Scionti,Daniele Caracciolo,Mariamena Arbitrio,Pierosandro Tagliaferri,Claudio Alberto Erratico,Massimiliano Fonsi,Pierfrancesco Tassone

doi:10.3390/cancers12010027

Maria Teresa Di Martino, Francesca Scionti + Show 6 more

Open Access

https://doi.org/10.3390/cancers12010027

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Abstract

LNA-i-miR-221 is a novel phosphorothioate backbone 13-mer locked nucleic acid oligonucleotide-targeting microRNA-221 designed for the treatment of human malignancies. To understand the pharmacokinetic 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 (Cynomolgus), and human. To this end, 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 was high and ranged 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 was then used to draw inferences about LNA-i-miR-221 pharmacokinetics in humans, thereby providing a framework for definition of safe starting and escalation doses and moving towards a first human clinical trial of LNA-i-miR-221.

Highlights

A rising body of evidence indicates that microRNAs can provide valuable therapeutic targets because of their potential to functionally regulate key oncogenic/tumor suppressor genes by simultaneous regulation of multiple-related pathways
In our previous studies on locked nucleic acid (LNA)-i-miR-221 PK properties in different animal species [2,4], we found that it reaches the targeted biphase already described for these “second generation” antisense oligonucleotides (ASOs), which relies on their systemic distribution and retention by tissues
Definition of an initial dose for first-in-human studies is complex, and a case-by-case approach may be appropriate depending on the product category (i.e., new chemical entities (NCE) or new biological entities (NBE))

Summary

Introduction

A rising body of evidence indicates that microRNAs (miRNAs) can provide valuable therapeutic targets because of their potential to functionally regulate key oncogenic/tumor suppressor genes by simultaneous regulation of multiple-related pathways. In our previous studies on LNA-i-miR-221 PK properties in different animal species [2,4], we found that it reaches the targeted biphase already described for these “second generation” antisense oligonucleotides (ASOs), which relies on their systemic distribution and retention by tissues. Such processes involve surface protein interactions and endocytosis, which lead to cell internalization and excretion [7]

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