To avoid the difficulties of ex vivo manufacturing and the poor pharmacokinetics of T cell redirecting bispecific antibodies, Stadler et al. engineered non-immunogenic mRNA that could be translated in vivo over a sustained period of time. The resulting proteins were functional, and were able to recruit TILs and completely eliminate established tumors in murine models.
The potential of bispecific T cell-engaging antibodies is hindered by manufacturing challenges and short serum half-life. We circumvented these limitations by treating mice with in vitro-transcribed pharmacologically optimized, nucleoside-modified mRNA encoding the antibody. We achieved sustained endogenous synthesis of the antibody, which eliminated advanced tumors as effectively as the corresponding purified bispecific antibody. Because manufacturing of pharmaceutical mRNA is fast, this approach could accelerate the clinical development of novel bispecific antibodies.