Humanized Mouse as a Tool to Predict Immunotoxicity of Human Biologics

Abstract

Advancements in science enable researchers to constantly innovate and create novel biologics. However, the use of non-human animal models during the development of biologics impedes identification of precise in vivo interactions between the human immune system and treatments. Due to lack of this understanding, adverse effects are frequently observed in healthy volunteers and patients exposed to potential biologics during clinical trials. In this study, we evaluated and compared the effects of known immunotoxic biologics, Proleukin ® /IL-2 and OKT3 in humanized mice (reconstituted with human fetal cells) to published clinical outcomes. We demonstrated that humanized mice were able to recapitulate in vivo pathological changes and human-specific immune responses, such as elevated cytokine levels and modulated lymphocytes and myeloid subsets. Given the high similarities of immunological side effects observed between humanized mice and clinical studies, this model could be used to assess immunotoxicity of biologics at a pre-clinical stage, without placing research participants and/or patients at risk.

Interleukin‐2‐induced skin inflammation

“…Therefore, upregulation of CD25 on γδ T cells might be crucial to induce IL-17 production observed in our study, suggesting a central role of CD25 expression in inducing the shift toward type 17 immune reac- tions in response to IL-2 injections. Besides direct IL-2-induced effects, a variety of cytokines are secreted during IL-2 therapy in mice and humans [18,35,38], which might further impact cutaneous cells indirectly. For instance, cell plasticity in the skin of IL-2-treated mice could be affected by the complex inflammatory milieu induced by IL-2 injections.…”

Applications of Intravital Imaging in Cancer Immunotherapy

“…Therefore, window chamber models should be considered in conjunction with humanized mouse models. Humanized mouse models, as described above, offer an important alternative to overcome the problem of the differences between mice and humans, and recipient mice can even be genetically engineered to study specific immune system attributes [ 60 , 61 ]. When tumor tissues from patients are transplanted in situ or ectopically, dynamic and longitudinal information can be obtained in relation to the immune response to human antigens.…”

Emerging Preclinical Applications of Humanized Mouse Models in the Discovery and Validation of Novel Immunotherapeutics and Their Mechanisms of Action for Improved Cancer Treatment

“…Repurposing existing de-risked compounds and drugs also requires a profound understanding of the mechanisms underlying disease progression and drug resistance before novel sequences can be designed. Insight into the unknown mechanisms of action of new drugs or biologics also allows for accurate safety assessment and designing optimal dose-administration protocols for patients [ 105 ].…”

“…A humanized mouse model, which was generated by researchers who sought to compare the effects of known immunotoxic biologics like IL-2 and OKT-3 between a humanized mouse model’s predictions and clinical outcomes [ 105 ], proved able to replicate in vivo pathological changes and human immune responses more accurately than other models and detailed a competitive dynamic process between inflammation and immunosuppression as was seen in the clinical data. Studying the adverse effects of these biologics led to a deeper understanding of the immunological landscape, thus confidently enabling the use of this technology in order to determine human-specific biologic mechanisms of action [ 105 ].…”

“…A humanized mouse model, which was generated by researchers who sought to compare the effects of known immunotoxic biologics like IL-2 and OKT-3 between a humanized mouse model’s predictions and clinical outcomes [ 105 ], proved able to replicate in vivo pathological changes and human immune responses more accurately than other models and detailed a competitive dynamic process between inflammation and immunosuppression as was seen in the clinical data. Studying the adverse effects of these biologics led to a deeper understanding of the immunological landscape, thus confidently enabling the use of this technology in order to determine human-specific biologic mechanisms of action [ 105 ]. Further, using our humanized mouse model, an in vivo model for a human-specific circadian rhythm of leukocyte trafficking was generated, and the researchers successfully discovered key mechanisms of circadian rhythms by identifying a unique pathway involving p38MAPK/MK, ROS, HIF1α, ARNTL1, and CXCR4 in the regulation of leukocyte trafficking, thus proving the usefulness of this model in uncovering novel disease and regulatory mechanisms [ 106 ].…”