mRNA delivery of immunoglobulin A for prevention and treatment of infectious diseases

Monoclonal antibodies (mAbs) represent powerful therapeutic and prophylactic tools since they are safe and effective molecules that can be easily discovered, developed and mass-produced. Until now, immunoglobulins G (IgGs) represent the most studied and used isotype in the infectious disease field. In the last years, there has been a growing appreciation for other antibody isotypes such as immunoglobulin A (IgA), highly abundant in mucosal secretions of the human gastrointestinal tract and upper airways. In these tissues, IgA functions as the first line of defence against pathogenic and opportunistic pathogens. However, the clinical development of IgA-based therapeutics has been hindered by the structural complexity of the protein and the challenges associated with its production and purification. In this context, the messenger RNA (mRNA) technology could bypass the complex and non-standardized IgA purification workflows, leading to accelerated clinical development and success. On these premises, our research explores the potential therapeutic application of IgA in the context of infectious diseases caused by antimicrobial-resistant (AMR) bacteria. Two functional candidate antibodies, the anti-Shigella sonnei mAb B17 and the anti-Klebsiella pneumoniae mAb F18, previously isolated and characterized by the Monoclonal Antibody Discovery (MAD) Laboratory as IgG, were selected to explore the anti-bacterial properties of their IgA counterparts. Monomeric and dimeric IgA1, IgA2 and IgA3.0, an engineered IgA2 format ready for clinical development, were recombinantly produced in mammalian cells and analysed by size exclusion affinity chromatography. Functional validation was performed to confirm biological functionalities of IgA molecules using in vitro assays based on confocal microscopy and cytofluorimetry. Delivery of mRNA-encoded mAbs in lipid nanoparticles (LNP) was optimized to improve translation efficiency in vivo. Additionally, the in vivo functionality and mRNA delivery of anti-S. sonnei dimeric IgAs were evaluated in a preclinical animal model. Lastly, the biodistribution profile was evaluated in various organs to compare expression mediated by mRNA-LNPs to the administration of the corresponding recombinant protein. Data obtained in this study confirmed the functionality of IgAs, highlighting the potential of IgA antibodies and mRNA technology to develop novel therapeutic approaches to combat AMR pathogens. This, in line with other recent reports, supports the growing interest in expanding the scope of antibody-based therapies beyond traditional formats and delivery systems.