CD74-Targeting Antibody–Drug Conjugate Enhances Immunosuppression of Glucocorticoid in Systemic Lupus Erythematosus

Glucocorticoid drugs (GCs), while effective in systemic lupus erythematosus (SLE), cause severe systemic side effects due to lack of tissue-specificity. To overcome this bottleneck, we developed a CD74-directed antibody-drug conjugate (Bud-ADC) to deliver budesonide, a potent GC drug, selectively to target CD74-expressing immune cells (e.g., B cells, dendritic cells), which play an important role in SLE pathogenesis. Bud-ADC combines a cross-species anti-CD74 antibody with budesonide via a cleavable linker, enabling immunosuppression on targeted cells. In vitro, Bud-ADC selectively inhibited CD74-high immune cell activation and cytokine production. In two SLE mouse models, Bud-ADC significantly alleviated disease hallmarks-reducing autoantibodies, splenomegaly, and kidney damage-while showing superior efficacy to free budesonide at equivalent doses. The therapeutic effects involved both direct targeting of CD74-high immune cells and indirect modulation of T cell responses despite low CD74 expression. This study establishes CD74-targeted ADC as a novel strategy to enhance GC efficacy in SLE, aiming at minimizing off-target toxicity while maintaining broad immunosuppressive activity. The translatable design supports further preclinical and clinical development for autoimmune diseases.