Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions

Abstract

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.

The Critical Choice of Animal Models in Nanomedicine Safety Assessment: A Lesson Learned From Hemoglobin-Based Oxygen Carriers

“…A body of preclinical data and expert opinions, free from financial conflict of interests or intellectual biases, is critical to help informed, more nuanced judgments. Nevertheless, beside addressing and clarifying the claims that we found incorrect in the reviews by Moghimi et al (6,33), we acknowledged the benefits of professional disputes, as they extend understanding and may resolve unclear issues in the field (34).…”

“…Thus, it does not seem reasonable to replace the pig model with a rat or mouse model to mimic human HSRs, and the idea to use a cirrhotic rat model seems even more far-fetched (6). On the other hand, arguing against a model which can sensitively show these adverse effects (6,33) diminishes the possibility of early identification of potential SAEs on grounds that can be fundamentally questioned (34).…”

“…The porcine CARPA test (7,(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24) overcomes the problem of rare manifestation of NP-induced hypersensitivity in man inasmuch as pigs "outwardly reproduce" (6) the life-threatening symptoms of human HSRs to certain reactogenic NPs (e.g., liposomes) in essentially all pigs, without substantial individual variation. Because of this feature, the model is increasingly used both in academic and industrial R&D (34). However, as mentioned in the introduction, the model was vociferously opposed on the basis of a claim that the cardiopulmonary reaction of pigs represents a cloven-hoof-specific "global" phagocytic response by PIM cells to NPs, i.e., a uniform, non-specific and non-quantitative response (6,33).…”

“…However, as mentioned in the introduction, the model was vociferously opposed on the basis of a claim that the cardiopulmonary reaction of pigs represents a cloven-hoof-specific "global" phagocytic response by PIM cells to NPs, i.e., a uniform, non-specific and non-quantitative response (6,33). These and other claims in (6,33) were closely scrutinized and rejected in many aspects (34), however, an important role of PIM cell stimulation leading to HSRs in pigs has not been questioned (34).…”

“…C activation to PIM cell release reaction (Figure 6) (21), and C activation can induce pulmonary hypertension independent of PIMs [e.g., pulmonary leuko-thromboembolism (34)], just as PIM cells can release vasoactive mediators independent of C activation (C-independent pseudoallergy, CIPA). All these variations taken together, it cannot be generalized which step or event in the HSR cascade is rate limiting in man or different animals under different conditions.…”