The other studies (Abuqayyas and Balthasar, 2013 and Garg and Balthasar, 2009) involved administration of IgG into the circulation of wild-type and FcRn knock-out mice and relied

on the ability of IgG to cross into the brain to measure AUC differences between brain content and serum levels. There was no direct evidence that the IgG crossed the BBB into the brain parenchyma as the group did not measure IgG levels in the brain directly, but instead measured levels in residual blood. It is also unclear what the affinity of their IgG antibody was to murine FcRn. Therefore, there is limited evidence that FcRn had the ability Antidiabetic Compound Library ic50 to play a role in the efflux within that previously published study. Another disadvantage of this protocol was their use of FcRn knock-out mice. With no FcRn, the recycling and salvation of IgGs would not be present in these mice so IgG half-life would be substantially decreased. Although the study involving these mice was shortened to 4 d to compensate for this, there would be significantly less IgG in the circulation after 4 d (95% less). This adds differences in AUC of mAb in WT and knock-out

LDK378 order mice confounding brain exposure. Indeed, clearance was eight-fold faster in FcRn knock-out mice compared to the other strains, as would be expected (Abuqayyas and Balthasar, 2013). In addition, the observed brain to plasma AUC ratio was greater in mice in the second study and the data was adjusted for differences in hematocrit (Abuqayyas and Balthasar, 2013 and Garg and Balthasar, 2009). The emphasis on mathematical modeling may account for the differences in their conclusions compared to the observations in FcRn knock-out mice where brain clearance

of a systemically administered mAb was lower than wild type controls (Deane et al., 2005 and Deane et al., 2009). In summary, this study demonstrates that FcRn plays ASK1 an important role in the efflux of IgGs. These results need to be taken into account in future studies evaluating therapeutic IgGs containing an Fc portion when targets in the brain are investigated. As the variants in the present study did not have a neuronal target, future studies should consider the impact of target receptor occupancy for the therapeutic target to determine the maintenance of IgG brain levels or when investigating the relevance of FcRn-dependent efflux. Male Sprague Dawley rats, 7–10 weeks old (200–300 g) (Charles River, Wilmington, MA, USA) were kept in plastic filter-topped cages and allowed free access to food and water. All animal studies were performed in accordance with the Federal Animal Welfare Act and methods approved by the Institutional Animal Care and Use Committee at Janssen R&D.