An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions
Cailin E. Deal, Angelene F. Richards, Tracy Yeung, Max J. Maron, Ziqiu Wang, Yen‐Ting Lai, Brian R. Fritz, Sunny Himansu, Elisabeth Narayanan, Ding Liu, Rositsa Koleva, Stuart Licht, Chiaowen Joyce Hsiao, Ivana L. Rajlic, Hillary Koch, Michael Kleyman, Mark Pulse, Jason Weiss, Jennifer Doering, Samantha K. Lindberg, Nicholas J. Mantis, Andrea Carfı́, Obadiah J. Plante
Abstract
Colonization of the gut and airways by pathogenic bacteria can lead to local tissue destruction and life-threatening systemic infections, especially in immunologically compromised individuals. Here, we describe an mRNA-based platform enabling delivery of pathogen-specific immunoglobulin A (IgA) monoclonal antibodies into mucosal secretions. The platform consists of synthetic mRNA encoding IgA heavy, light, and joining (J) chains, packaged in lipid nanoparticles (LNPs) that express glycosylated, dimeric IgA with functional activity in vitro and in vivo. Importantly, mRNA-derived IgA had a significantly greater serum half-life and a more native glycosylation profile in mice than did a recombinantly produced IgA. Expression of an mRNA encoded Salmonella-specific IgA in mice resulted in intestinal localization and limited Peyer's patch invasion. The same mRNA-LNP technology was used to express a Pseudomonas-specific IgA that protected from a lung challenge. Leveraging the mRNA antibody technology as a means to intercept bacterial pathogens at mucosal surfaces opens up avenues for prophylactic and therapeutic interventions.