Abstract
FcRn protects immune gamma globulin (IgG) from intracellular catabolism, and thereby contributes to the long plasma half-life associated with this class of antibody. The present study tested the hypothesis that 4C9, an anti-FcRn antibody, would increase the in vivo systemic clearance of a model antibody, anti-methotrexate IgG (AMI), in rats. Hybridomas secreting 4C9 and AMI were grown in serum free medium, and monoclonal 4C9 and AMI were purified via protein-G chromatography. Rats were instrumented with jugular vein cannulas 2-3 days prior to investigation, and 4C9 was administered intravenously at doses of 3, 15, and 60 mg/kg. AMI was then administered 4, 24, and 48 h after administration of 4C9. Blood samples were collected and assayed to determine AMI concentrations. The anti-FcRn antibody, 4C9, increased AMI systemic clearance in a dose-dependent manner (from 0.99+/-0.14 mg/h/kg in control animals to 1.27+/-0.05, 1.73+/-0.50, and 1.97+/-0.49 mL/h/kg in animals treated with 3, 15, and 60 mg/kg 4C9; p<0.05). These data were well-captured with an indirect-effect pharmacokinetic-pharmacodynamic model. The effect of 4C9 was found to be transient; no significant effects on AMI systemic clearance were observed when pre-treatment time was increased to 24 or 48 h. As such, the data demonstrate that 4C9, a monoclonal anti-FcRn antibody, induces a transient, dose-dependent increase in the elimination of IgG. The results suggest that FcRn inhibitors may have utility in the treatment of antibody-mediated autoimmune and alloimmune conditions.
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