mRNA encoding of immune receptor-targeting antibodies for the augmentation of vaccine-elicited cellular immunity.

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Project summary. Clinically relevant cellular responses to either experimental or FDA approved vaccine adjuvant formulations have been difficult to generate and/or detect. We have long been investigating a combined adjuvant formulation (composed of a TLR agonist and an agonistic antiCD40 antibody) which generates cellular immunity on par with that observed to infectious challenge. The complexity of this three-part vaccine (antigen plus TLR/CD40) is limiting to its clinical application. However, the success of lipid nanoparticle (LNP) encapsulated mRNA vaccines for Covid provides a possible avenue by which our combination adjuvant might be successfully translated into clinical use against chronic infectious diseases and cancer. Our preliminary results show that we can agonize the CD40 pathway, sufficient to augment CD8 T cell responses, by mRNA- mediated delivery of the heavy and light chains of the agonistic anti-CD40 antibody FGK45. The success of this method for targeting CD40 strongly favors the hypothesis that antibodies specific for other immunotherapeutic molecular targets (eg. CTLA4, PD1) might also be successfully delivered via the mRNA vaccination strategy. Completion of this project would not only identify a new and powerful means by which the established potency of our combined adjuvant might be leveraged for clinical application, they open an entirely new paradigm in the use of mRNA vaccination for targeting immunologically relevant molecules for the purposes oncologic checkpoint therapy and beyond.