<h3>Objective:</h3> To characterize the mechanism of action, pharmacodynamics and pharmacology of nipocalimab in preclinical models. <h3>Background:</h3> Nipocalimab is a fully human antibody being evaluated in over 10 autoantibody diseases including MG and CIDP. Nipocalimab binds with high affinity to the neonatal Fc receptor (FcRn) inhibiting IgG recycling and inducing autoantibody destruction while permitting key immune functions including IgG production. Here, the molecular, cellular and in vivo pharmacology of nipocalimab are shown to be well aligned with the pharmacodynamic and pharmacological effects observed in MG patients. <h3>Design/Methods:</h3> Nipocalimab in vitro receptor occupancy (RO) was assessed in a fluorescence-activated cell sorting assay in human aortic endothelial cells. In vivo, RO in circulating monocytes and total serum IgG were evaluated in human FcRn transgenic mice (Tg32 strain) or cynomolgus monkeys after i.v. infusions of up to 100 or 300 mg/kg nipocalimab, respectively. <h3>Results:</h3> Nipocalimab exposure at picomolar concentrations results in full RO within 30 minutes and inhibits IgG recycling in endothelial cells. In vivo, full RO was established within 2 hours in mice and 4 hours in monkeys and maintained at picomolar concentrations. The onset of IgG lowering due to inhibition of IgG recycling was detected within 1–2 days and was maintained during the period of full FcRn saturation. Duration of RO in peripheral blood monocytes in both preclinical species was dose-dependent, as was the duration of IgG clearance, suggesting a relationship between RO and maintenance of an increased IgG clearance rate. Nipocalimab in vitro FcRn RO and IgG recycling correlated well with in vivo RO and IgG lowering. <h3>Conclusions:</h3> Nipocalimab is a potent FcRn blocker inducing rapid and sustained lowering of IgG and IgG autoantibodies in preclinical studies. These results are consistent with findings from the phase 1 healthy volunteer (NCT02828046) and phase 2 VIVACITY study in gMG patients (NCT03772587). <b>Disclosure:</b> Dr. Ling has received personal compensation for serving as an employee of Janssen Pharmaceuticals (Johnson&Johnson). Dr. Ling has stock in Janssen Pharmaceuticals (Johnson&Johnson). Dr. Ling has received intellectual property interests from a discovery or technology relating to health care. Dr. Ling has received intellectual property interests from a discovery or technology relating to health care. Dr. Choudhury has stock in Janssen Pharmaceuticals. Mr. Tyler has received personal compensation for serving as an employee of AVROBIO, INC . Mr. Tyler has received personal compensation for serving as an employee of Orna Therapeutics. Mr. Tyler has received personal compensation for serving as an employee of Genevant Sciences. Dr. Avery has received personal compensation for serving as an employee of Lyndra Therapeutics. Dr. Avery has received personal compensation for serving as an employee of Xilio Therapeutics. Dr. Avery has received personal compensation for serving as an employee of Kisbee Therapeutics. Dr. Avery has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Momenta Pharmaceutical. Dr. Avery has received stock or an ownership interest from Life Biosciences.