BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics
Autor: | Graham Paul, Stuart W. Naylor, Nicholas P. Macri, Scott Manetz, Richard Haworth, A. Peter Hall, David Jones, Thierry Flandre, Jeffrey S. Tepper, Michela Gregori, Annick Cauvin, Molly H. Boyle, Sydney Mukaratirwa, Alison Wolfreys, Renaud Fleurance, Inge Tarnow, Kristen J. Nikula, Alessandro Piaia, Mark Price, Ian Robinson, Andrew Allen, Tom Gelzleichter, Mark C Freke, Karyn Colman, Andreas M Hohlbaum, Maurice G Cary |
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Rok vydání: | 2021 |
Předmět: |
Pathology
medicine.medical_specialty 040301 veterinary sciences medicine.drug_class Inflammation Toxicology Monoclonal antibody Pathology and Forensic Medicine 0403 veterinary science 03 medical and health sciences Administration Inhalation Macrophages Alveolar Hypersensitivity medicine Animals Type III hypersensitivity Lung Molecular Biology 030304 developmental biology Biological Products 0303 health sciences biology business.industry Immunogenicity 04 agricultural and veterinary sciences Cell Biology Eosinophil medicine.disease medicine.anatomical_structure Toxicity biology.protein Rabbits medicine.symptom Antibody business Bronchoalveolar Lavage Fluid Immune complex disease |
Zdroj: | Toxicologic Pathology. 49:235-260 |
ISSN: | 1533-1601 0192-6233 |
Popis: | The inhalation route is a relatively novel drug delivery route for biotherapeutics and, as a result, there is a paucity of published data and experience within the toxicology/pathology community. In recent years, findings arising in toxicology studies with inhaled biologics have provoked concern and regulatory challenges due, in part, to the lack of understanding of the expected pathology, mechanisms, and adversity induced by this mode of delivery. In this manuscript, the authors describe 12 case studies, comprising 18 toxicology studies, using a range of inhaled biotherapeutics (monoclonal antibodies, fragment antigen-binding antibodies, domain antibodies, therapeutic proteins/peptides, and an oligonucleotide) in rodents, nonhuman primates (NHPs), and the rabbit in subacute (1 week) to chronic (26 weeks) toxicology studies. Analysis of the data revealed that many of these molecules were associated with a characteristic pattern of toxicity with high levels of immunogenicity. Microscopic changes in the airways consisted of a predominantly lymphoid perivascular/peribronchiolar (PV/PB) mononuclear inflammatory cell (MIC) infiltrate, whereas changes in the terminal airways/alveoli were characterized by simple (“uncomplicated”) increases in macrophages or inflammatory cell infiltrates ranging from mixed inflammatory cell infiltration to inflammation. The PV/PB MIC changes were considered most likely secondary to immunogenicity, whereas simple increases in alveolar macrophages were most likely secondary to clearance mechanisms. Alveolar inflammatory cell infiltrates and inflammation were likely induced by immune modulation or stimulation through pharmacologic effects on target biology or type III hypersensitivity (immune complex disease). Finally, a group of experts provide introductory thoughts regarding the adversity of inhaled biotherapeutics and the basis for reasonable differences of opinion that might arise between toxicologists, pathologists, and regulators. |
Databáze: | OpenAIRE |
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