Investigation of the role of FcRn in the absorption, distribution, and elimination of monoclonal antibodies
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There is a substantial interest in developing monoclonal antibodies (mAb) for the treatment of several human diseases. However, there is very limited understanding of the determinants of many aspects of mAb pharmacokinetics. The purpose of this research was to investigate the role played by the neonatal Fc receptor (FcRn) on the distribution of mAb to tissues (including brain), and on the absorption of mAb following subcutaneous dosing. To quantitatively assess the importance of FcRn in tissue distribution of mAb, we developed a physiologically-based pharmacokinetic (PBPK) model of IgG tissue disposition. Our PBPK model incorporated key features related to IgG tissue disposition such as binding to FcRn followed by recycling, degradation of unbound IgG, transport from blood to tissue interstitial fluid via convective transport and FcRn pathway, and return of IgG to blood via lymphatic transport. The PBPK model was able to accurately predict IgG tissue disposition in both C57BL/6J control and FcRn knockout mice. Further, to improve our understanding of the determinants of IgG disposition in tissues, we examined the tissue disposition of IgG in control and FcRn knockout animals, with and without administration of intravenous immunoglobulin (IVIG), an FcRn inhibitor. PBPK model was utilized to characterize all the data and to obtain tissue-specific estimates for vascular reflection coefficients (σ V ) and lymphatic flows (L). The PBPK model characterized all the data very well and provided estimates of lymphatic flow and reflection coefficients which were consistent with the physiology of each tissue. The PBPK model predicted that FcRn-mediated transport of IgG accounts for ∼40% of the distribution of IgG to the muscle; however, in all other tissues, the contribution of FcRn-mediated transport was negligible. The model prediction was further confirmed by tissue sectioning and visualization using fluorescent microscopy, which showed that in the FcRn knockout muscle tissue, more IgG was associated with CD31 (a marker for vascular endothelium) compared to the wild-type muscle tissue, where IgG distribution was uniform. However, in case of liver, there was no difference in the tissue distribution of IgG in wild-type and FcRn knockout mice. Further, we investigated the role of FcRn in the absorption of mAb following subcutaneous (SC) dosing. Interestingly, we found that the mean SC bioavailability in the control animals was 3-fold higher compared to the mean bioavailability in the FcRn knockout group (82.5±15.6% in wild-type vs. 28.3±6.9% in FcRn knockout group). Our studies showed that FcRn is a major determinant of bioavailability of IgG following subcutaneous dosing. Additionally, we investigated the role of FcRn as a determinant of the distribution of IgG to the brain. Few studies have indicated that FcRn might efflux IgG out of the brain and may be responsible for the low IgG brain concentrations. However, there is no direct evidence that implicate FcRn for the low concentrations of IgG in the brain. The study demonstrated that there was no significant difference between the brain-to-plasma AUC ratios in the control and FcRn-knockout mice (0.0022±0.00015 vs. 0.0021±0.00011, p=0.3347). Our study provides direct evidence demonstrating that FcRn does not contribute significantly to the blood-brain barrier for IgG in mice, and that FcRn is not responsible for the low exposure of IgG in the brain relative to plasma. These findings will have an immediate and significant impact on the development of mAb, potentially leading to novel strategies for influencing the tissue-specific distribution of mAb, novel strategies for enhancing mAb bioavailability, and potentially stimulating the investigation of new pathways for enhancing mAb distribution to the brain.