Lipid Nanoparticle-Encapsulated mRNA-Targeting CD19 for B and Plasma Cell Depletion in Autoimmune Diseases 2308376

Abstract Introduction Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases driven by autoreactive B cells and plasma cells, leading to chronic inflammation and organ damage. Current therapies targeting B cells, such as anti-CD20 monoclonal antibodies, are ineffective in depleting long-lived plasma cells. This limitation highlights the need for novel therapeutic strategies to reset the immune system in these diseases. Methods We developed lipid nanoparticle-encapsulated mRNA (mRNab-LNPs) encoding anti-CD19 antibodies to deplete autoreactive B cells and plasma cells. mRNab-LNPs were administered intramuscularly to lupus and RA mouse models. We evaluated the therapeutic efficacy by assessing the depletion of CD19+ B cells and plasma cells, and the subsequent reduction in disease-related histopathological damage. Results Intramuscular injection of mRNab-LNPs in both lupus and RA mice led to high and sustained production of anti-CD19 antibodies. This resulted in significant depletion of circulating CD19+ B cells and tissue-resident plasma cells. Histopathological analysis showed reduced damage in the skin, kidneys, and joints of treated mice. Additionally, mRNab-LNPs exhibited favorable pharmacokinetics with prolonged antibody production and minimal systemic inflammatory response. Conclusion mRNab-LNPs effectively target and deplete both B cells and plasma cells in lupus and RA mouse models. These findings suggest that mRNab-LNPs offer a promising alternative to current therapies, providing a safer, more efficient approach to treating autoimmune diseases by resetting the humoral immune system. Funding Source This work was supported by the following grants: National Natural Foundation of China Grant (Nos. 81970632 and 52473328), Guangdong Science and Technology Department Grant (Nos. 2020B1212060018 and 2020B1212030004), Sun Yat-sen Pilot Scientific Research F Topic Categories Therapeutic Approaches to Autoimmunity (THER)