Blocking the CD40–CD154 interaction is reported to be effective for transplantation management and autoimmune disease models in rodents and nonhuman primates. However, clinical trials with anti-CD154 mAbs were halted because of high incidence of thromboembolic complications. Thus, we generated and characterized a fully human anti-CD40 mAb ASKP1240, as an alternative to anti-CD154 mAb. In vitro ASKP1240 concentration-dependently inhibited human peripheral blood mononuclear cell proliferation induced by soluble CD154. In addition, ASKP1240 did not destabilize platelet thrombi under physiological high shear conditions while mouse anti-human CD154 mAb (mu5C8) did. And ASKP1240 itself did not activate platelet and endothelial cells. In vivo administration of ASKP1240 (1 or 10 mg/kg, intravenously) to cynomolgus monkeys, weekly for 3 weeks, significantly attenuated both delayed-type hypersensitivity and specific antibody formation evoked by tetanus toxoid. The immunosuppressive effect was well correlated with the CD40 receptor saturation. Thus, these results suggest that ASKP1240 is immunosuppressive but not prothromboembolic, and as such appears to be a promising therapeutic candidate for the management of solid organ transplant rejection and autoimmune diseases therapy.

No abstract

Supplemental digital content is available in the text.

BackgroundThe purpose of this study was to evaluate the serum concentration of ASKP1240 (pharmacokinetics [PK]) and the CD40 occupancy of ASKP1240 (pharmacodynamics [PD]) in normal and renal transplanted Cynomolgus monkeys to clarify the PK/PD relationship.MethodsIn a 70-day study, two ASKP1240 doses (2 and 5 mg/kg) were evaluated in normal and transplanted monkeys. Full doses were administered during the induction phase, and half doses were administered during the maintenance phase. The PK and PD were assessed using ELISA and FACS assays.ResultsThe serum concentration and receptor occupancy of ASKP1240 reached their maximum levels rapidly after the first dose and remained at an almost saturated rate during the induction phase. They then decreased gradually during the maintenance phase in all of the groups. The serum concentration and duration of full receptor occupancy were dose dependent in the normal and transplanted monkeys. On day 70 after therapy with 5 mg/kg ASKP1240, the transplanted monkeys presented a significantly lower occupancy of the CD40 receptors compared with the normal animals (5.5%±14.1% vs. 72.8%±3.4%). The serum concentration of ASKP1240 was also strongly correlated with the occupancy of the ASKP1240 receptors.ConclusionThis study showed strong positive PK/PD relationships in renal transplanted and normal monkeys. The results may thus serve as a guide for optimal dosage and timing of ASKP1240 therapy in clinical trials and will propel the translation of ASKP1240 therapeutics from the bench to preclinical and clinical trials.