First-in-Human Phase 1 Randomized Trial with the Anti-CD40 Monoclonal Antibody KPL-404: Safety, Tolerability, Receptor Occupancy, and Suppression of T-Cell-Dependent Antibody Response

Blockade of the cluster of differentiation 40 (CD40)-CD40L inter-action has potential for treating autoimmune diseases and pre-venting graft rejection. This first-in-human, randomized, double-blind, placebo-controlled study (NCT04497662) evaluated safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the humanized anti-CD40 monoclonal antibody KPL-404. Healthy volunteers were randomized to one of two single-ascending -dose groups: single intravenous KPL-404 dose 0.03, 0.3, 1, 3, or 10 mg/kg or single subcutaneous KPL-404 dose 1 or 5 mg/kg. There were no dose-limiting or dose-related safety findings. Non-linear dose-dependent changes in various pharmacokinetic pa-rameters were identified following the range of intravenous doses. At the 10 mg/kg intravenous dose level, the t1/2 was approximately 7 days, and full receptor occupancy was observed through Day 71, with complete suppression of T-cell-dependent antibody re-sponse (TDAR) to keyhole limpet hemocyanin (KLH) challenge on Day 1 and rechallenge on Day 29 through Day 57. With KPL-404 5 mg/kg subcutaneously, full receptor occupancy was observed through Day 43, with complete suppression of TDAR through at least Day 29. Antidrug antibodies to KPL-404 were suppressed for 57 days with 10 mg/kg intravenously and for 50 days with 5 mg/kg subcutaneously, further confirming prolonged target engagement and pharmacodynamics. These findings support continued investi-gation of KPL-404 intravenous and subcutaneous administration in a broad range of indications.SIGNIFICANCE STATEMENTThis first-in-human clinical trial of KPL-404, a fully humanized IgG4 monoclonal antibody, was designed with two independent (by route of administration) placebo-controlled single-ascending -dose-level groups, one with four intravenous single-dose cohorts and another with two subcutaneous single-dose cohorts. The pharmacokinetic profile, duration of full CD40 receptor occu-pancy, and magnitude and duration of memory immune response suppression observed confirm pharmacodynamic activity regard-less of administration route. These data provide evidence that chronic KPL-404 dosing regimens (intravenous or subcutaneous) could be practical.

Automated summary

This study investigated the safety, pharmacokinetics, receptor occupancy, and pharmacodynamics of the anti-CD40 monoclonal antibody KPL-404. The results showed that KPL-404 exhibited dose-dependent changes in pharmacokinetic parameters and long duration of receptor occupancy, leading to suppression of immune response. These findings support further investigation of KPL-404 in various indications.