Abstract 3794: Developing an mRNA nanomedicine platform to democratise therapeutic antibodies

Abstract The manufacturing of therapeutic antibodies requires expensive, complex, and frequently challenging production that keeps the cost of treatment in the clinic high. Alternatively, leveraging novel modalities such as mRNA to encode therapeutics circumvents many of the problems associated with the large-scale production of biologics, and instead relies on in vivo expression of antibodies within patients. Importantly, recent work demonstrates that therapeutic antibodies translated from mRNA in pre-clinical models can be readily detected within hours and persist up to several weeks. Peak levels of circulating mRNA-encoded antibodies are comparable to recombinant protein equivalents and have been shown to be within favorable therapeutic ranges in first-in-human phase I trials. Here we outline an mRNA-LNP based roadmap to encode and deliver therapeutic antibodies, using the standard-of-care anti-HER2 antibody Trastuzumab as a case study, and harness a plethora of pre-clinical models to validate the platform. Characterization of mRNA-expressed Trastuzumab in vitro showed robust translation in producer cell lines, retention of antigen specificity and maintenance of heavy chain-light chain integrity as expected. To evaluate in vivo expression of mRNA encoded Trastuzumab, antibody levels were measured in serum after infusing mRNA-LNPs in translational pharmacology models. Plasma concentrations of secreted mRNA-encoded trastuzumab were benchmarked against circulating levels of infused recombinant antibody equivalents and demonstrated superior pharmacokinetics as well as tolerability at lower doses compared to protein-infused groups. Additionally, bioluminescence imaging was utilized to dissect whole-animal biodistribution and sites of mRNA-translation of ALC-0315 containing LNP formulations used for mRNA antibody delivery. To demonstrate anti-tumor potency, mRNA-encoded trastuzumab was purified from producer cell lines and tested in cytotoxicity assays using human NK cells and HER2-positive tumor cell lines. mRNA-encoded trastuzumab robustly induced antibody-dependent cell cytotoxicity (ADCC) to the same magnitude as recombinant biosimilars. In mouse tumor xenograft models infused with LNPs, mRNA-encoded trastuzumab displayed superior in vivo efficacy at comparatively lower doses relative to recombinant formats by persistently reducing tumor growth and volume as well as enhancing overall survival. Overall, the case study data demonstrate that mRNA-encoded therapeutic antibodies could provide a cost effective, alternate strategy for solid tumor immunotherapy and may unlock an approach to democratize and accelerate patient access to biologics in the clinic. Citation Format: Dan Rocca, Roxana Redis, Phillipp Meyer, Ina Rohleff, Eva Oswald, Sarah L. Martin, Rachel Pooley, Matthew Benson, Namrata Jayanth, Maxim Mashrick, Christian Cobaugh, Michael Shaw, Julia Schueler, Louise S. Brackenbury, Justin Bryans. Developing an mRNA nanomedicine platform to democratise therapeutic antibodies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3794.