Blocking the CD40-CD154 co-stimulation pathway has been shown to effectively prolong renal allograft survival in non-human primates. OM11-62MF (OM11) is a novel, fully human anti-CD40 monoclonal antibody devoid of antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity activities (i.e., Fc-silent) being developed for use in transplantation. To assess the human safety, tolerability, PK and PD activity of OM11, single doses were administered to healthy male and female volunteers in a Phase 1 trial. METHODS: A double-blind, placebo controlled, time-lagged, ascending, single-dose study using intravenous infusions of 0.03, 0.1, 0.3, 1.0 and 3.0 mg/kg OM11 or 3.0 mg/kg OM11 subcutaneously was conducted. PK and CD40 receptor occupancy (RO) samples were collected during all treatment periods up to 180 days post dose. RESULTS: A total of 48 subjects were enrolled. All doses were well tolerated. There were no serious adverse events (SAEs) or discontinuations due to AEs. A total of 50 adverse events were reported by 64% (23/36) of OM11 treated subjects. The most frequent adverse events on OM11 were headache (12%) and injection site pain (8%). There were no clinically significant changes in laboratory results including coagulation parameters, thromboelastography or multiplex cytokine analysis. There was no effect on leukocyte subsets via FACS or B-cell depletion. OM11 PK concentrations were quantifiable at all dose levels tested. OM11 demonstrates classical target mediated elimination with accelerated clearance below 100% CD40 RO. The concentration-PD response results shown below, demonstrate sustained CD40 target suppression on peripheral B-cells through 28 days with the highest dose tested.Figure: No Caption available.CONCLUSION: The favorable safety and tolerability profile of both intravenous and subcutaneous OM11-62MF coupled with a predictable concentration-CD40 receptor occupancy relationship support future clinical trials of OM11 in transplantation. DISCLOSURE:Slade, A.: Employee, Novartis Pharmaceuticals Corp. Koo, P.: Employee, Novartis Pharmaceuticals Corp. Espie, P.: Employee, Novartis Pharma AG. Rush, J.: Employee, Novartis Pharma AG. Klupp, J.: Employee, Novartis Pharma AG. Lee, D.: Employee, Novartis Pharma AG.