A pioneering study recently published in the Cell Reports Medicine, has demonstrated a groundbreaking approach to fighting bacterial infections. The research, titled "An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions," exploited a Lipid Nanoparticle (LNP) - mRNA platform to design pathogen-specific Immunoglobulin A (IgA) monoclonal antibodies. These antibodies were effectively delivered to mucosal secretions, yielding structurally and functionally intact human IgA, which successfully defends against Salmonella Typhimurium and Pseudomonas aeruginosa infections.
The Hurdles in Developing IgA and the Clinical Implementations of mRNA
The concept of passive immunization by using IgA is not a novelty; however, developing recombinant IgA (rIgA) and providing a sufficient quantity for consistent functioning pose significant challenges. Further complexities arise from the high glycosylation of human IgA proteins, which affects their conformation, thermal stability, folding efficiency, solubility, and susceptibility to proteolysis, making the production process difficult. The use of IgAR for most clinical applications is also problematic due to a shorter serum half-life compared to IgG, causing it to be removed from circulation more swiftly than endogenous human IgA. Therefore, the focus of numerous researchers has been to create an IgG/IgA chimera with desired Fc receptor interactions, extended serum half-life, and mucus delivery. Nevertheless, this has yet to reach the clinical stage. In contrast, the novel research introduced a new method that employs synthetic mRNA to produce structurally complete, functional human IgA in the body.
Fig 1. An mRNA-based platform delivers pathogen-specific IgA into mucosal secretions.1
The Future of mRNA-Encoded Antibodies in Disease Prevention and Treatment
Sal4 is an IgA monoclonal antibody recognizing the O5- antigen of Salmonella Typhimurium's lipopolysaccharide, which effectively reduces the bacteria's intestinal invasion. CAM003 is an IgG1 binding to a component of the biofilm of Pseudomonas aeruginosa, and its protective effects have been demonstrated in various animal models. The researchers encoded the heavy chain, light chain, and J chain of Sal4 and CAM003 into human IgA2 (IgA2 mRNA) or IgA1 (IgA1 mRNA), respectively. They then compared these with rIgA, both in vivo and in vitro, to evaluate the potential of mRNA platforms to produce potent and protective monoclonal antibodies in mucosal secretions. The study revealed that, compared to rIgA, the mRNA-produced IgA showed a significantly prolonged serum half-life and a more natural glycosylation spectrum. Importantly, mRNA encoding IgA specific for Salmonella Typhimurium significantly inhibited intestinal invasion by bacteria. Similarly, mRNA encoding IgA targeted for Pseudomonas aeruginosa provided successful protection against lung infections.
These findings imply that mRNA encoded antibody technology could prove a powerful tool in intercepting bacterial pathogens on the mucosal surface, providing a new pathway for prevention and treatment interventions. The study marks a significant step in the application of RNA technology and opens up new horizons for further research and development in immunology and pathology.
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Reference
- Deal, Cailin E et al. "An mRNA-based platform for the delivery of pathogen-specific IgA into mucosal secretions." Cell reports. Medicine vol. 4,11 (2023).
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