Lipid nanoparticle delivery of unmodified mRNAs encoding multiple monoclonal antibodies targeting poxviruses in rabbits

Poxviruses are a large and complex family of viruses with members such as monkeypox virus and variola virus. The possibility of an outbreak of monkeypox virus (or a related poxvirus) or the misuse of variola virus justifies the development of countermeasures. Furthermore, poxviruses can be a useful surrogate for developing technology involving antibody therapies. In our experiments, we explored the feasibility of utilizing unmodified mRNA that encodes three previously described monoclonal antibodies, c8A, c6C, and c7D11, as countermeasures to smallpox in a relatively large (>3 kg) laboratory animal (rabbits). We confirmed in vitro translation, secretion, and biological activity of mRNA constructs and identified target monoclonal antibody levels from a murine vaccinia virus model that provided a clinical benefit. Individually, we were able to detect c7D 11, c8A, and c6C in the serum of rabbits within 1 day of an intramuscular jet injection of lipid nanoparticle (LNP)-formulated mRNA. Injection of a combination of three LNP -formulated mRNA constructs encoding the three different antibodies produced near equivalent serum levels compared with each individual construct administered alone. These data are among the first demonstrating the feasibility of launching multiple antibodies using mRNA constructs in a large, nonrodent species. Based on empirically derived target serum level and the observed decay rate, the antibody levels attained were unlikely to provide protection.

Automated summary

This study explored the feasibility of using unmodified mRNA encoding three previously described monoclonal antibodies as countermeasures against smallpox in rabbits. The researchers confirmed the translation, secretion, and biological activity of the mRNA constructs in vitro and found that injecting a combination of the three mRNA constructs produced similar serum levels as individual injections. This is the first evidence of launching multiple antibodies using mRNA constructs in a large nonrodent species.