Developing An mRNA-Encoded Antibody Platform To Accelerate Therapies To Clinic

By Roxana Redis, Dan Rocca, *Maria Blanca Torroba, Rachel Pooley, Sarah L. Martin, Matt Benson, Namrata Jayanth, Valerie Ferreira, Alex Hale, Eva Oswald, Philipp Meyer, Julia Schueler, Christian Cobaugh#, Michael Shaw#, Maxim Mashrick#, Henry Leonard, Tina Rea-Davies, Matt Miller, Louise Brackenbury, and Justin Bryans

The manufacturing of therapeutic antibodies is complex and costly, involving expensive production processes, challenging purification, lengthy stability optimization, and intricate protein characterization, all of which contribute to high treatment costs. In contrast, mRNA nanomedicine approaches offer a promising alternative by enabling in vivo antibody production within patients, bypassing many of these manufacturing hurdles and reducing both costs and time to clinical application.

Recent studies have shown that therapeutic antibodies translated in vivo from mRNA can be detected within hours following infusion into preclinical models and can persist for several days or even weeks. Peak levels of mRNA-encoded antibodies are comparable to those of infused recombinant antibodies and have been shown to fall within therapeutic ranges in recent Phase I trials (August et al., 2021, Nat. Med. 27:2224).

In this paper, we present the foundation of an mRNA-LNP platform for encoding and expressing therapeutic antibodies in vivo, eliminating the need for costly and time-consuming manufacturing. Additionally, we also provide a roadmap for encoding the standard-of-care anti-HER2 antibody, Trastuzumab, using LNP-encapsulated modified mRNA, followed by validation steps in preclinical models to demonstrate robust pharmacokinetics, pharmacodynamics, and anti-tumor efficacy.