利用nanoprimer技术最大化全身性LNP-DNA递送以实现免疫治疗药物的癌症激活型表达

Earli is developing a platform technology that utilizes lipid nanoparticle (LNP)-delivered recombinant DNA constructs containing cancer-activated synthetic promoters that drive the selective expression of therapeutic proteins such as cytokines to treat the tumor. Our approach demonstrated robust therapeutic impact in vivo via tumor-specific secretion of IL-2 and IL-12 which are uniquely produced in cancer cells, but not normal tissues to control syngeneic tumors growth. While LNP-DNA vehicles often offer advantages over viral vectors, their efficacy can be limited by rapid clearance via the mononuclear phagocyte system (MPS). Although modifications to the surface of LNPs, like pegylation, can extend circulation time, the hepatic clearance remains a challenge that reduces LNPs systemic bioavailability, hinders tumor accumulation, and can contribute to toxicity. In addition, LNP-DNA may produce transient acute inflammation primarily via the intracellular activation of the cGAS/STING pathway, a major host defense mechanism. To address this challenge, Nanobiotix's Nanoprimer technology, engineered biocompatible lipid-based nanoparticles that transiently occupy MPS clearance pathways, was utilized to extend blood circulation time of subsequently administered therapeutics. We investigated the impact of Nanoprimer pre-treatment on the pharmacokinetics , biodistribution, and tolerability of two Earli proprietary extrahepatic LNP formulations, longer-circulating FRM177 and fast clearing FRM146, which encapsulate a recombinant DNA comprised of a strong constitutive promoter to drive firefly luciferase expression in tumor naive mice. The pre-treatment improved the blood bioavailability of FRM146-DNA by 8-fold, while having a minor effect on the delivery of FRM177-DNA. Furthermore, a 2-fold decrease in hepatic DNA accumulation at 48h post dose for both LNP-DNA was observed as well as reduced hepatotoxicity as evidenced by normal levels of liver enzymes. Finally, both LNP-DNA produced a transient mouse body weight loss and serum cytokine elevation, effects that were ameliorated by the Nanoprimer, revealing improved tolerability. Our data demonstrates that the Nanobiotix technology can be a successful strategy to significantly improve the extrahepatic biodistribution and tolerability of LNP-DNA, even those already engineered for extrahepatic delivery. These results expand the known potential of the compound in MPS blockade for clinically relevant LNP-DNA constructs for cancer immunotherapy applications and confirms the relevance of further clinical development for systemically administered LNP-nucleic acid therapeutics. Ongoing studies are focused on determining the impact of Nanoprimer on the anti-tumor efficacy of our cancer-activated cytokine-expressing DNA constructs in syngeneic cancer models.