Abstract 2714: Developing an mRNA encoded therapeutic antibody platform to simplify manufacturing and reduce time to clinic

Abstract The manufacturing of therapeutic antibodies requires expensive production, often challenging purification, lengthy stability optimization and complex protein characterization that despite continual improvement, keeps the cost of treatment in the clinic high. Alternatively, leveraging gene-based approaches such as mRNA to express therapeutics circumvents many of the manufacturing challenges and instead rely on in situ production of antibodies within a patient, improving the developability and cost of sophisticated, disease-modifying antibodies. Crucially, recent work demonstrates that therapeutic antibodies translated in vivo from mRNA can be readily detected within hours following infusion into pre-clinical models and can persist up to several days or weeks. Peak levels of circulating mRNA-encoded antibodies are comparable to infused recombinant equivalents dosed to patients and have been shown to be within favorable therapeutic ranges in phase I trials. Here we outline an mRNA-LNP based platform to encode and deliver therapeutic antibodies in vivo that can overcome costly and challenging manufacturing and that demonstrates both robust PK/PD kinetics and potency. We describe how to effectively encode a standard-of-care anti-HER2 antibody - Trastuzumab - using LNP-encapsulated modified mRNA and validate using in vitro as well as in vivo efficacy models. Initial in vitro characterization of mRNA encoded antibodies demonstrates robust translation in producer cell lines, reproducible expression kinetics, retention of antigen specificity and HC: LC integrity when analyzed by ELISA and WB. To evaluate whether Trastuzumab-encoding mRNA-produced protein is detectable in vivo, antibody levels were measured in mouse serum after IV administration of a single dose of mRNA formulated LNPs. Peak plasma concentrations of mRNA-encoded trastuzumab were benchmarked against circulating recombinant Trastuzumab in parallel groups, and pharmacokinetics interrogated. Of note, the majority of mRNA encoded antibody was likely produced in the liver as shown by bioluminescence imaging. To demonstrate the efficacy of the platform, the potency of mRNA-encoded Trastuzumab isolated from producer cell lines will be assessed using in vitro cytotoxicity assays with human PBMCs and HER2+ tumor lines to dissect ADCC or direct tumor growth inhibition. Additionally, to determine whether mRNA-encoded Trastuzumab is able to retain anti-tumor activity in vivo, a mouse tumor xenograft model will be established and the mRNA antibody-dependent effects on tumor volume, growth and morbidity-free survival will be examined. Overall, the data demonstrate that mRNA-encoded therapeutic antibodies could provide an effective, alternate strategy for solid tumor treatment and may unlock a strategy to deliver lead biologics at reduced cost and with improved developability. Citation Format: Roxana Redis, Dan Rocca, Rachel Pooley, Matthew Benson, Namrata Jayanth, Eva Oswald, Alexander Hale, Louise Brackenbury, Justin Bryans. Developing an mRNA encoded therapeutic antibody platform to simplify manufacturing and reduce time to clinic abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2714.