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Open AccessReview

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

by János Szebeni 1,2,3,4,* and Raj Bawa 5,6,7
1
Nanomedicine Research and Education Center, Institute of Translational Medicine, Semmelweis University, 1089 Budapest, Hungary
2
SeroScience Ltd., 1089 Budapest, Hungary
3
SeroScience International LLC., Cambridge, MA 02138, USA
4
Department of Nanobiotechnology and Regenerative Medicine, Faculty of Health, Miskolc University, 3515 Miskolc, Hungary
5
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12144, USA
6
Patent Law Department, Bawa Biotech LLC, Ashburn, VA 20147, USA
7
Guanine Inc., Rensselaer, NY 12144, USA
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(4), 82; https://doi.org/10.3390/biomedicines8040082
Received: 24 January 2020 / Revised: 1 April 2020 / Accepted: 1 April 2020 / Published: 8 April 2020
Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the “global response” of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the “global response” claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model’s demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine “complement activation-related pseudoallergy” (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs. View Full-Text
Keywords: adverse drug reactions; anaphylaxis; anaphylactoid reactions; shock; nanomedicine; nanoparticle; pigs; complement; pulmonary intravascular macrophages adverse drug reactions; anaphylaxis; anaphylactoid reactions; shock; nanomedicine; nanoparticle; pigs; complement; pulmonary intravascular macrophages
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Szebeni, J.; Bawa, R. Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions. Biomedicines 2020, 8, 82.

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