Investigation of the influence of FcRn on the distribution of IgG to the brain

Abstract

It has been suggested that the neonatal Fc receptor (FcRn) is a primary determinant of the distribution of IgG to the brain. In the present report, (125)I-labeled 7E3, a monoclonal IgG1 antibody, was injected intravenously to groups of FcRn-deficient mice and C57BL/6J control mice. Sub-groups of three mice were sacrificed at several time points. Blood and brain tissue were harvested and radioactivity was assessed. Antibody concentrations in brain were corrected for residual blood using (51)Cr-labeled red blood cells. Data were analyzed via WinNonlin, and areas under plasma and tissue concentration vs. time curves (AUCs) were assessed via the Bailer method. The apparent plasma elimination half-life and clearance of 7E3 were 13.61 +/- 0.61 days and 6.5 +/- 0.10 ml/day/kg in control mice and 0.70 +/- 0.05 days and 63.5 +/- 2.7 ml/day/kg in the knockout mice. Plasma and brain AUCs (0-10 days) were found to be 3,338.7 +/- 50.4 and 7.46 +/- 0.5 nM day in control animals and 781.2 +/- 16.6 and 1.65 +/- 0.1 nM day in FcRn-deficient animals. There was no significant difference between brain-to-plasma AUC ratios in control and FcRn-deficient mice (0.0022 +/- 0.00015 vs. 0.0021 +/- 0.00011, p = 0.3347). Two-way analysis of variance showed no significant differences, at any time point, between brain-to-plasma concentration ratios determined from control and knockout animals. The results suggest that FcRn does not contribute significantly to the "blood-brain barrier" for IgG in mice, and the data suggest that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma.

Fig. 1

Plasma and brain disposition of 7E3. Plasma concentration vs. time profiles and brain concentration vs. time profiles 7E3 are shown for control and FcRn-deficient mice. Brain concentrations were corrected for residual blood content, as described in the text. Error bars indicate the standard deviation associated with each mean concentration

Fig. 2

Brain to plasma AUC ratios in control and in FcRn-deficient mice. Areas under the plasma and brain concentration vs. time curves were assessed with the linear trapezoidal method, and variability estimates were determined by the Bailer method. Error bars indicate the standard deviation of the mean AUC ratios