title: Development of a drug delivery system for efficient alveolar delivery of a neutralizing monoclonal antibody to treat pulmonary intoxication to ricin.
abstract: The high toxicity of ricin and its ease of production have made it a major bioterrorism threat worldwide. There is however no efficient and approved treatment for poisoning by ricin inhalation, although there have been major improvements in diagnosis and therapeutic strategies. We describe the development of an anti-ricin neutralizing monoclonal antibody (IgG 43RCA-G1) and a device for its rapid and effective delivery into the lungs for an application in humans. The antibody is a full-length IgG and binds to the ricin A-chain subunit with a high affinity (KD=53pM). Local administration of the antibody into the respiratory tract of mice 6h after pulmonary ricin intoxication allowed the rescue of 100% of intoxicated animals. Specific operational constraints and aerosolization stresses, resulting in protein aggregation and loss of activity, were overcome by formulating the drug as a dry-powder that is solubilized extemporaneously in a stabilizing solution to be nebulized. Inhalation studies in mice showed that this formulation of IgG 43RCA-G1 did not induce pulmonary inflammation. A mesh nebulizer was customized to improve IgG 43RCA-G1 deposition into the alveolar region of human lungs, where ricin aerosol particles mostly accumulate. The drug delivery system also comprises a semi-automatic reconstitution system to facilitate its use and a specific holding chamber to maximize aerosol delivery deep into the lung. In vivo studies in monkeys showed that drug delivery with the device resulted in a high concentration of IgG 43RCA-G1 in the airways for at least 6h after local deposition, which is consistent with the therapeutic window and limited passage into the bloodstream.
authors.affiliation: Université François-Rabelais de Tours, UMR 1100, CHRU de Tours, Service de Pharmacie, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Respaud
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France; Aerodrug, F-37032 Tours, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Marchand
authors.affiliation: Institut de Recherche Biomédicale des Armées (IRBA-CRSSA); Département de Microbiologie; Unité de biotechnologie des anticorps et des toxines; Brétigny sur Orge, France; BIOTEM, Parc d'activité Bièvre Dauphine, Apprieu, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Pelat
authors.affiliation: NYU School of Medicine, Department of Environmental Medicine, 57 Old Forge Road, Tuxedo, New York 10987, USA.
authors.forename: Kam-Meng
authors.initials: KM
authors.lastname: Tchou-Wong
authors.affiliation: Department of Microbiology and Immunology, Tulane University School of Medicine, New Orleans, Louisiana, USA; Division of Microbiology, Tulane National Primate Research Center, Covington, Louisiana, USA.
authors.forename: Chad J
authors.initials: CJ
authors.lastname: Roy
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Parent
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France.
authors.forename: Maria
authors.initials: M
authors.lastname: Cabrera
authors.affiliation: SESAME, Expertise en toxicologie, Chambray-les-tours, France.
authors.forename: Joël
authors.initials: J
authors.lastname: Guillemain
authors.affiliation: Aerogen, Galway, Ireland.
authors.forename: Ronan
authors.initials: R
authors.lastname: Mac Loughlin
authors.affiliation: Groupe IMT, Tours, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Levacher
authors.affiliation: LFB Biotechnologies, Lille, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fontayne
authors.affiliation: Université François-Rabelais, EA 6295, « Nanomédicaments et Nanosondes», Tours, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Douziech-Eyrolles
authors.affiliation: CEA Le Ripault, Monts, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Junqua-Moullet
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guilleminault
authors.affiliation: Institut de Recherche Biomédicale des Armées (IRBA-CRSSA); Département de Microbiologie; Unité de biotechnologie des anticorps et des toxines; Brétigny sur Orge, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Thullier
authors.affiliation: DGA, Direction de la Stratégie (DS), Mission pour la recherche et l'Innovation scientifique (MRIS), France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Guillot-Combe
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France; Aerodrug, F-37032 Tours, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vecellio
authors.affiliation: Université François Rabelais, UMR 1100, F-37032 Tours, France; INSERM, Centre d'Etude des Pathologies Respiratoires, UMR 1100, F-37032 Tours, France. Electronic address: nathalie.vourch@med.univ-tours.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heuzé-Vourc'h
mesh_terms: D000336:Aerosols; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D002619:Chemical Warfare Agents / Q000506:poisoning*; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D055370:Lung Injury / Q000139:chemically induced / Q000188:drug therapy*; D008252:Macaca fascicularis; D008297:Male; D008807:Mice, Inbred BALB C; D009330:Nebulizers and Vaporizers; D011650:Pulmonary Alveoli / Q000187:drug effects*; D012276:Ricin / Q000506:poisoning*; D014018:Tissue Distribution
chemical_list: D000336:Aerosols; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D002619:Chemical Warfare Agents; D012276:Ricin
keywords: Aerosol therapy; Bioweapon; Formulation; Mesh nebulizer; Monoclonal antibody; Ricin intoxication