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Quantifying Monoclonal Antibody Disposition Following Aerosol Administration: Systemic and Airway Exposure in Non-human Primates

Sakagami M, Nicholson KL, Byron PR.

RDD Europe 2015. Volume 1, 2015: 27-36.

Abstract:

The discovery of immunoglobulin G (IgG)-binding transcytotic receptor FcRn (the neonatal constant region fragment receptor) expression in the lung may offer the potential for “needle-free” systemic aerosol delivery of monoclonal antibodies (mAbs). This study was designed to quantify the lung dose and region-dependent disposition of mAbs necessary to reach therapeutically effective systemic blood levels. Adalimumab (Humira) was used as a model mAb, and pharmacokinetic profiles were determined in non-human primates following inhaled administration targeting central or peripheral lung deposition. Lung absorption of adalimumab produced therapeutically effective peak serum concentrations (Cmax = 2.3-4.2 mg/l) at two or four days. However, a considerably high target lung dose of 10 mg/kg was required, presumably due to high affinity and low capacity kinetics of FcRn-mediated transcytotic lung absorption. As a result, while this lung absorption was kinetically not rate-limiting, the bioavailability (F%) remained low at 1.0-4.2 %, which was irrespective of 60% central or peripheral regional lung deposition, verified with a marker solute, fluorescein isothiocyanate-labeled dextran (FD-150). This high dose requirement for systemic delivery is a significant formulation challenge, yet perhaps mitigated by engineering Fc-portion to enhance FcRn binding and minimizing binding to phagocytotic Fcϒ receptors. Alternatively, slow and minimal lung absorption may be advantageous for local lung delivery due to sustained mAb residence and local pharmacological action in the lung, while reducing the risk of systemic adverse effects.