BSTP Review of 12 Case Studies Discussing the Challenges, Pathology, Immunogenicity, and Mechanisms of Inhaled Biologics

Abstract

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.

The Influence of Geographical Origin, Age, Sex, and Animal Husbandry on the Spontaneous Histopathology of Laboratory Cynomolgus Macaques (Macaca Fascicularis): A Contemporary Global and Multisite Review of Historical Control Data

“…This is of particular importance in studies with inhaled biologics. In these studies, the characteristic pattern of perivascular/peribronchiolar mononuclear inflammatory cell infiltrates, which is considered to occur secondary to immunogenicity and increased alveolar macrophages secondary to clearance mechanisms, 41 may be difficult to differentiate from spontaneous histopathology findings.…”

Recovery Animals in Toxicology Studies: An Innovation and Quality Consortium Perspective on Best Practices With Case Study Examples

“…[18][19][20][21][22] Multiple additional publications offer a deeper review of findings for a specific tissue/organ system (i.e., Keenan and Vidal 2006 for heart findings of dogs and NHP), vehicle, and/or study type. 23,24 Omitting control recovery of non-rodent animals may be a reasonable approach particularly when biomarker(s), HCD, or literature are available to identify and track reversibility of a change documented during the dosing phase. Use of literature and/or HCD is also accepted by HA to characterize and support reversibility.…”

Protein Aggregates in Inhaled Biologics: Challenges and Considerations

“…A recent study by Secher et al reported immune-toxic events in the lungs of C57BL/6 mice after the pulmonary administration of IgG aggregates generated during nebulization of the antibody 42 . Lastly, a review article by Hall P et al, 43 which summarized the toxicology results of 12 different inhaled biologics, proposed adaptive immunity as the putative mechanism behind the most commonly observed lung pathology finding; perivascular/peribronchiolar mononuclear cell infiltrates and increased eosinophils in the bronchioalveolar lavage, although the potential for these findings to be exacerbated by protein aggregates is not known. Thus, it is rational to evaluate the potential for protein aggregation in the lungs as a precautionary approach based on the established correlation between protein aggregation and immunogenicity from parenteral products 20 .…”