Several New World mammarenaviruses (NWMs), including Junín virus (JUNV), can cause a severe, potentially fatal hemorrhagic fever (HF) syndrome. In the absence of FDA-approved vaccines or antivirals, there is an urgent need to develop broadly active countermeasures against these viral infections. Cellular entry by all pathogenic NWMs is mediated by transferrin receptor 1 (TfR1). Here, we report on the pharmacokinetics (PK) and antiviral activity of a mouse/human chimeric antibody, targeting the apical domain of human TfR1 and lacking effector functions (ch128.1/IgG1 Fc-silent) in two transgenic mouse models of JUNV infection. Assessment of tolerability and PK in human TfR1 knock-in/mouse TfR1 knock-out mice (huTfR1 Tg mice) demonstrated that ch128.1/IgG1 Fc-silent (FcS) was well-tolerated at doses up to 800 μg, and that once-daily dosing may be the most effective regimen for achieving optimal therapeutic benefit. Prophylactic and post-infection intervention efficacy studies employing once-daily antibody treatments in huTfR1 Tg mice challenged with JUNV revealed significant protection against mortality, even when treatment was delayed until 5 days post-infection. In mice with TfR1 containing only the apical domain of the human receptor (huApTfR1 Tg mice), the ch128.1/IgG1 FcS treatment trended toward increased survival and significantly reduced weight loss following JUNV challenge. The antibody treatments also significantly decreased infectious JUNV titers in target organs (liver and spleen) in the more physiologically relevant huApTfR1 Tg mouse model. Taken together, effective treatment of advanced JUNV infection in two transgenic mouse models with ch128.1/IgG1 FcS antibody supports the development of a humanized version of this antibody for clinical application.
Li et al. (Tue,) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: