Bispecific MASP-2/3 Antibody Provides Superior Renoprotection Over Monotherapy in Pristane-Induced Lupus Nephritis

Abstract Introduction Lupus nephritis (LN) is a major cause of organ damage in systemic lupus erythematosus (SLE) and is driven in part by overactivation of the lectin pathway (LP) and alternative pathway (AP) of complement. Mannan-binding lectin–associated serine protease-2 (MASP-2) initiates LP through C4/C2 cleavage, whereas MASP-3 enables AP amplification by activating pro-factor D. Methods We hypothesized that concurrent inhibition of both proteases would provide superior renoprotection compared with single-pathway blockade in established disease. Female BALB/c mice with pristane-induced LN received anti-MASP-2, anti--MASP-3, bispecific antibodies, or vehicle for 4 weeks. Results Bispecific MASP-2/3 inhibition produced greater improvements in albuminuria, renal activity index, and glomerular C3d and C5b-9 deposition than either monotherapy. Functional assays confirmed selective LP suppression with MASP-2 blockade and AP suppression with MASP-3 blockade, whereas dual inhibition maximally reduced both pathways and their downstream complement effectors. Kidney transcriptomics demonstrated broad down-regulation of complement, coagulation, and inflammatory gene networks. Conclusion Together, these findings indicate that bispecific MASP-2/3 blockade provides robust complement-directed protection in established LN and may represent an effective therapeutic strategy for complement-mediated kidney disease.