Next Generation Stealth Lipid for the Delivery of mRNA

Project Summary This proposal will develop a lipid nanoparticle (LNP) with a proprietary polyethylene glycol (PEG) alternative as a new PEG-free LNP for the delivery of mRNA payloads. This proposal is motivated by increasing concerns surrounding anti-PEG antibodies, PEG allergies, and reduced effectiveness of PEGylated carriers of drugs and vaccines. As severe PEG allergies are expected to escalate with increasing PEG exposure in the population, the importance of addressing this issue is magnified, especially in light of the extensive clinical pipeline of more than 150 PEG-LNP formulations under development for diverse therapeutic payloads. To address these concerns, Gateway Bio has developed poly(oligoethylene glycol) methyl ether methacrylate (POEGMA), a next- generation polymer that resembles PEG but is tailored to address the existing limitations of PEG. POEGMA comprises a brush polymer structure with tri(ethylene glycol) side-chains along a poly(methyl methacrylate) backbone. The high density of tri(ethylene glycol) side-chains fully maintains the stealth properties of PEG, but this unique architecture also limits the number of consecutive ethylene glycol units to just 3 repeats, which eliminates PEG antigenicity—the binding of pre-existing anti-PEG antibodies to POEGMA, and mitigates anti- POEGMA immune reactions—the formation of new antibodies which recognize POEGMA. Prior studies have demonstrated the promising attributes of POEGMA-modified biologics, including long circulation in blood, elimination of antigenicity—recognition by anti-PEG antibodies, and minimal immunogenicity—the induction of anti-POEGMA antibodies. In Preliminary Studies for this proposal, evaluation of POEGMA in an LNP—employing a wild type SARS CoV-2 spike protein encoded mRNA payload as a case study—reveals superior antigen expression of POEGMA-modified LNPs compared to their PEGylated counterparts in vitro, with both model and therapeutically relevant mRNAs. This proposal builds upon these studies by further evaluating POEGMA LNPs for in vitro stability, in vitro toxicity, in vivo efficacy, anti-PEG antigenicity, and anti-POEGMA immunogenicity. We anticipate that POEGMA-LNPs will exhibit superior antigen expression of the mRNA payload and reduced immunogenicity compared to a PEG-LNP control, and will thereby pave the way for the adoption of this technology across the diverse spectrum of nucleic acid based LNP formulations—vaccines, drugs, and genomic medicines—that are currently under development. 1