The role of airway mucus and diseased pulmonary epithelium on the absorption of inhaled antibodies.

Inhaled antibody therapy for the treatment of respiratory diseases is a promising strategy to maximize pulmonary exposure and reduce side effects associated with parenteral administration. However, the development of inhaled antibodies is often challenging due to a poor understanding of key mechanisms governing antibody absorption and clearance in healthy and diseased pulmonary epithelium. Here, we utilize well established Human Bronchial Epithelial Cell (HBEC) models grown at air-liquid interface to study the absorption process of antibodies and antibody fragments. With these cellular models, we recapitulate the morphology and function of healthy and diseased pulmonary epithelium, and incorporate the mucosal barrier to enable the investigation of both cellular permeability as well as mucodiffusion. We studied the saturation of antibody transport across the HBEC barriers and estimated the impact of disease-like epithelial barriers on antibody paracellular transport. Additionally, we identified a potential role of neonatal Fc receptor (FcRn)-independent and target-mediated transcytosis in the transport of Fragment antigen-binding (Fab) and F(ab)2 antibody fragments. Lastly, our models were able to pinpoint an impaired antibody diffusion across mucus gels. These mechanistic cellular models are promising in vitro tools to inform Physiologically-based Pharmacokinetic (PBPK) computational models for dose prediction toward de-risking the development of inhaled biologics.

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Déclaration de conflit d'intérêts

Declaration of Competing Interest A. M. L., E. G., D. R., T. D. and W. R. T. declare to work at Novartis AG. A. M. L., E. G., D. R. and W. R. T. declare to hold stock in Novartis AG. The authors declare no other potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The Novartis Discovery Postdoctoral Fellowships provided financial support for the conduct of the research but had no role in study design, data collection, analysis and interpretation of data, writing of the report or the decision to submit the article for publication.