title: Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system.
abstract: Monoclonal antibodies (mAbs) are usually delivered systemically, but only a small proportion of the drug reaches the lung after intravenous injection. The inhalation route is an attractive alternative for the local delivery of mAbs to treat lung diseases, potentially improving tissue concentration and exposure to the drug while limiting passage into the bloodstream and adverse effects. Several studies have shown that the delivery of mAbs or mAb-derived biopharmaceuticals via the airways is feasible and efficient, but little is known about the fate of inhaled mAbs after the deposition of aerosolized particles in the respiratory system. We used cetuximab, an anti-EGFR antibody, as our study model and showed that, after its delivery via the airways, this mAb accumulated rapidly in normal and cancerous tissues in the lung, at concentrations twice those achieved after intravenous delivery, for early time points. The spatial distribution of cetuximab within the tumor was heterogeneous, as reported after i.v. injection. Pharmacokinetic (PK) analyses were carried out in both mice and macaques and showed aerosolized cetuximab bioavailability to be lower and elimination times shorter in macaques than in mice. Using transgenic mice, we showed that FcRn, a key receptor involved in mAb distribution and PK, was likely to make a greater contribution to cetuximab recycling than to the transcytosis of this mAb in the airways. Our results indicate that the inhalation route is potentially useful for the treatment of both acute and chronic lung diseases, to boost and ensure the sustained accumulation of mAbs within the lungs, while limiting their passage into the bloodstream.
authors.affiliation: Université François Rabelais, EA6305, F-37032 Tours, France; Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; CHRU de Tours, Service de Pneumologie et d'Explorations Fonctionnelles, Tours, France.
authors.forename: L
authors.initials: L
authors.lastname: Guilleminault
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.
authors.forename: N
authors.initials: N
authors.lastname: Azzopardi
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Arnoult
authors.affiliation: TAAM-UPS44, CIPA, CNRS Orléans, Orléans, France.
authors.forename: J
authors.initials: J
authors.lastname: Sobilo
authors.affiliation: Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, UMR 1100, F-37032 Tours, France.
authors.forename: V
authors.initials: V
authors.lastname: Hervé
authors.affiliation: Université François Rabelais de Tours, Faculté de Médecine, PPF Animalerie, Tours, France.
authors.forename: J
authors.initials: J
authors.lastname: Montharu
authors.affiliation: Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, UMR 1100, F-37032 Tours, France; CHRU de Tours, Service de Réanimation Polyvalente, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Guillon
authors.affiliation: CHRU de Tours, Service de Biochimie, Tours, France.
authors.forename: C
authors.initials: C
authors.lastname: Andres
authors.affiliation: CHRU de Tours, Service d'Hématologie Biologique, Tours, France.
authors.forename: O
authors.initials: O
authors.lastname: Herault
authors.affiliation: TAAM-UPS44, CIPA, CNRS Orléans, Orléans, France.
authors.forename: A
authors.initials: A
authors.lastname: Le Pape
authors.affiliation: Université François Rabelais, EA6305, F-37032 Tours, France; Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; CHRU de Tours, Service de Pneumologie et d'Explorations Fonctionnelles, Tours, France.
authors.forename: P
authors.initials: P
authors.lastname: Diot
authors.affiliation: Université François Rabelais, EA6305, F-37032 Tours, France; Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France; CHRU de Tours, Service de Pneumologie et d'Explorations Fonctionnelles, Tours, France.
authors.forename: E
authors.initials: E
authors.lastname: Lemarié
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France; CHRU de Tours, Laboratory of Pharmacology-Toxicology, Tours, France.
authors.forename: G
authors.initials: G
authors.lastname: Paintaud
authors.affiliation: Université François-Rabelais de Tours, CNRS, GICC UMR 7292, Tours, France; CHRU de Tours, Laboratory of Immunology-Toxicology, Tours, France.
authors.forename: V
authors.initials: V
authors.lastname: Gouilleux-Gruart
authors.affiliation: Université François Rabelais, EA6305, F-37032 Tours, France; Centre d'Etude des Pathologies Respiratoires, UMR 1100/EA6305, F-37032 Tours, France. Electronic address: nathalie.vourch@med.univ-tours.fr.
authors.forename: N
authors.initials: N
authors.lastname: Heuzé-Vourc'h
mesh_terms: D000280:Administration, Inhalation; D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000068818:Cetuximab; D016503:Drug Delivery Systems; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D011961:Receptors, Fc / Q000235:genetics; D012137:Respiratory System / Q000378:metabolism*
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D000068818:Cetuximab; C100688:Fc receptor, neonatal
keywords: FcRn; Monoclonal antibodies; Pharmacokinetics; Pulmonary delivery