Tocilizumab but not Siltuximab prevents systemic inflammation in a humanized mouse model.

Objectives: The present study aimed to assess the therapeutic efficacy of neutralizing monoclonal antibodies targeting a prominent proinflammatory cytokine in a PBMC transfer-induced humanized mouse model of systemic inflammation. Methods: Inflammatory cytokines were measured in human and murine sera using the LEGENDplex™ cytokine panel. Humanized mice were treated with neutralizing antibodies against human IL-6 (Siltuximab) or the human IL-6 receptor (Tocilizumab), along with matched IgG isotype controls. Results: Cytokine responses in the humanized mouse model were predominantly of human, not murine, origin. Elevated levels of human IL-6 were observed in both SSc patients and their corresponding mouse models. Preventive administration of Tocilizumab reduced anti-nuclear antibody production and mitigated disease severity in the PBMCs-transfer-induced humanized mouse model. In contrast, treatment with Siltuximab, an antibody targeting human IL-6, did not prevent disease development in the humanized mouse model. The lack of efficacy of Siltuximab was associated with the accumulation of human IL-6/anti-human IL-6 monoclonal antibody immune complexes. Conclusion: These findings highlight the pivotal role of IL-6 signaling in the SSc related systemic inflammation within the humanized mouse model and underscore the therapeutic potential of IL-6 receptor blockade. Furthermore, the PBMCs-based humanized mouse model offers a valuable preclinical platform for evaluating human-specific therapeutic interventions in systemic inflammation.