Introduction: CD40L blockade is a validated strategy to prevent transplant rejection, but prior anti-CD40L antibodies such as Ruplizumab were discontinued due to Fc-mediated thromboembolic complications. Emerging IgG-degrading enzyme therapies further highlight the need for compatible and safer CD40L antibodies.
Methods: We developed KJ047, a novel anti-CD40L antibody incorporating the clinically proven Fab of Ruplizumab and engineered Fc regions to eliminate Fc gamma receptor binding and resist proteolysis by IgG-degrading enzymes. Its pharmacokinetics, immune function, and biophysical properties were evaluated in preclinical studies.
Results: KJ047 maintained potent CD40L binding and functional immunosuppression while demonstrating complete loss of thromboinflammatory Fc activity. KJ047 remained intact and functional when co-administered with IgG-degrading enzymes, preventing degradation and ensuring sustained immunosuppressive activity. KJ047 also showed extended half-life, good physicochemical stability, and suitability for subcutaneous injection.
Conclusion: KJ047 offers a next-generation solution to overcome safety and compatibility limitations of earlier CD40L antibodies. Its design allows safe, durable, and enzyme-combination–compatible immunosuppression, with significant potential in xenotransplantation and other rejection-prone clinical settings.