Delivery of monoclonal antibodies using mRNA lipid nanoparticles confers protection against SARS-CoV-2 and influenza

Monoclonal antibodies (mAbs) are an emerging class of therapeutics for the prevention and treatment of viral infections. Recent advances in mRNA/lipid nanoparticle (LNP) technology provide a promising new modality for the production of mAbs <i>in vivo</i>, potentially bypassing the need for recombinant manufacturing of mAb proteins. In this study, we compared traditional infusion of protein-based neutralizing mAbs targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or influenza viruses to mRNA/LNP-based production of mAbs in treated mice. High serum concentrations of mAbs were achieved upon delivery of a single mRNA encoding both heavy and light chains via intravenous or intramuscular routes using prototypic LNP formulations. However, the pharmacokinetics of mRNA-delivered mAbs were heavily influenced by the induction of anti-drug antibody responses directed against the encoded mAbs, resulting in reduced half-life <i>in vivo</i> and compromised protective capacity against SARS-CoV-2 Omicron BA.1 infection. In contrast, mRNA/LNP delivery of a neutralizing mAb conferred superior protection against lethal influenza challenge compared to equivalent recombinant protein doses. Overall, mRNA/LNP delivery comprises a feasible and attractive pathway to speed the development and deployment of antiviral antibodies. However, optimization of LNP formulation, dosing, and administration routes is required to maximize protective potential.