Effect of FcRn Binding on Monoclonal Antibody Disposition in the Brain.

This study investigates the role of FcRn in brain disposition of monoclonal antibodies. Human FcRn (hFcRn) expressing mice and different FcRn binding variants of a non-target binding antibody trastuzumab (WT) were used for the investigation. The FcRn binding mutations were: YTE, YPY, YQAY, and IHH. YQAY and YPY mutants have enhanced FcRn binding at both neutral and acidic pH (7+/6+). YTE mutant has enhanced FcRn binding at only acidic pH (7-/6+), and IHH mutant has no FcRn binding (7-/6-). The pharmacokinetics (PK) of these mutants in plasma, brain interstitial fluid (ISF), and brain homogenate were measured following intravenous administration. The area under the concentration-time curve (AUC) for all PK profiles and ratios of brain and plasma AUCs were calculated for comparison. Results showed that WT antibody had brain:plasma AUC ratio of 0.70% and ISF:plasma AUC ratio of 0.59%. Among all mutants, YPY exhibited the highest AUC ratio for brain (3.86%) and ISF (3.49%). YQAY had relatively high AUC ratios of 1.49% in the brain and 0.81% in ISF. YTE showed a similar AUC ratio in the brain (0.60%) and ISF (0.62%) compared to WT, while IHH exhibited similar AUC ratio in the brain (0.52%) but higher AUC ratio in ISF (2.48%). The results suggest that binding to FcRn at neutral and acidic pH facilitates transcytosis of antibody into the brain. Just increasing the binding to FcRn at acidic pH does not impact the disposition of antibody in the brain. Complete removal of FcRn binding might lead to prolonged retention of antibody in ISF. Together, these data demonstrate that FcRn significantly affects brain disposition of antibody, and engineering of Fc domain to alter the binding of antibody to FcRn may be exploited to achieve better exposure of antibodies in the brain.