Systemic lupus erythematosus (SLE)remains a disease of high unmet need, evidenced by a relatively low efficacy ceiling and highly variable patient response across current therapies. Strategic development of novel therapeutics coupled with innovative combination treatment paradigms offers promisetodeliver improved efficacy and outcomes in SLE patients. A data-driven QSP model was developed to predict the effects of combined targeting of BAFF and CD40 and mechanistically recapitulate clinically measurable impacts (anti-dsDNA titers) in SLE patients. This model will quantitatively inform clinical design rationale, guide combination strategies in SLE, and support decision-making.