In vivo expression of an mRNA encoded multi-mechanistic mAb combination against Staphylococcus aureus and protection in disease model

Single monoclonal antibodies (mAbs) can be expressed in vivo through gene delivery of their mRNA formulated with liponanoparticles (mRNA/LNP). However, delivery of a mAb combination could be challenging due to risk of heavy and light variable chain mispairing. We evaluated the pharmacokinetics of a three mAb combination against Staphylococcus aureus first in single chain variable fragment scFv-Fc and then in immunoglobulin G 1 (IgG1) format in mice. Intravenous delivery of each mRNA/LNP or the trio (1 mg/kg each) induced functional antibody expression after 24 hours (10-100 μg/ml) with 64 to 78% cognate-chain paired IgG expression after 3 days, and an absence of non-cognate chain pairing for scFv-Fc. We did not observe reduced neutralizing activity for each mAb compared to the level of expression of chain-paired mAbs. Delivery of the trio mRNA protected mice in a S. aureus induced dermonecrosis model. Intravenous administration of the three mRNA in non-human primates achieved peak serum IgG levels ranging between 2.9-13.7 μg/ml with a half-life of 11.8-15.4 days. These results suggest nucleic acid delivery of mAb combinations holds promise and may be a viable option to streamline development of therapeutic antibodies.