Development and Application of FcRn Monoclonal Antibody-IL-2 Fusion Protein Targeting Plasma Cells for Lupus Nephritis Treatment

Background: Interleukin-2 (IL-2) is an immune regulator used in treating certain cancers and immunodeficiencies but has clinical limitations due to its activation of both regulatory T cells (Treg) and effector T cells (Tcon), disrupting immune balance. The neonatal Fc receptor (FcRn) extends immunoglobulin G (IgG) half-life and maintains serum IgG homeostasis. FcRn antagonists reduce pathogenic IgG by blocking FcRn-IgG interaction. In this study, we developed a novel IL-2-FcRn monoclonal antibody fusion protein (ACC) that enhances plasma cell inhibition while preserving Treg function, offering promising therapeutic potential in lupus nephritis models. Methods: We constructed the IL-2-FcRn monoclonal antibody fusion protein (ACC) and evaluated its effects in lupus nephritis using MRL/Lpr lupus model mice. Mice were divided into control, low-dose, medium-dose, and high-dose groups. Flow cytometry assessed changes in T cells, B cells, plasma cells, and subsets. ELISA measured plasma IgG and anti-dsDNA antibody levels. Renal pathology was examined via HE staining, and IgG and C3 deposition were analyzed by immunofluorescence. The pharmacokinetics of ACC were studied in wild-type C57BL/6 mice, monitoring IL-2 levels in plasma after subcutaneous injection. ACC stability was assessed through plasma stability and thermal shift assays. Small animal in vivo imaging was used to assess tissue distribution and kidney targeting. In vitro assays examined ACC’s impact on immune cell subsets in spleen single-cell suspensions. Results: ACC significantly reduced plasma anti-dsDNA antibody levels and IgG/C3 deposition in kidneys. HE staining revealed improved glomerular lesions and reduced tubulointerstitial damage, alleviating lupus nephritis. Immune analysis indicated ACC suppressed plasma cells and effector T cells (Tcon). In vitro, these effects were confirmed. ACC demonstrated superior plasma and thermal stability compared to traditional IL-2. In vivo imaging showed increased renal accumulation, indicating enhanced kidney targeting. Conclusion: The IL-2-FcRn monoclonal antibody fusion protein (ACC) selectively inhibits plasma cells and effector T cells, effectively alleviating lupus nephritis. Its stability and kidney-targeting properties offer a promising approach for targeted immune therapy in lupus nephritis.