SCIENTIFIC ABSTRACT Five New World mammarenaviruses (NWMs) cause life-threatening viral hemorrhagic fever. NWM transmission to humans most commonly occurs through inhalation of aerosolized viral particles or direct contact with virus-containing rodent excreta or secreta. Pathogenic NWMs are considered priority pathogens by federal and international public health agencies because they pose a significant public health risk and threat to national security. Thus, there is an urgent need to develop new strategies to treat NWM infection. A distinguishing feature of the pathogenic NWMs is the ability to enter cells through human transferrin receptor 1 (TfR1), also known as CD71. Binding of NWMs to TfR1 occurs through the interaction of their envelope glycoprotein GP1 subunit to the apical domain of TfR1, outside of the transferrin (Tf) binding site, which presents a target for the development of broadly active therapeutics that disrupt viral GP1 attachment to TfR1 without interfering with cellular uptake of iron. We have developed a mouse/human chimeric antibody (Ab), ch128.1/IgG1, targeting the apical domain of human TfR1 that effectively competes with pathogenic NWM cellular entry in vitro and provides protection in a model of lethal JUNV disease that we developed using transgenic mice expressing human TfR1 (huTfR1 Tg mice). Consistent with the competitive nature of the Ab mechanism of action, protection was superior using a ch128.1/IgG1 mutant with impaired FcgR and C1q binding, resulting in lack of Ab Fc receptor effector functions (Fc silent; Fc/s). Consistent with human data, we also found that increased interferon-a (IFN-a) blood levels are important in the pathogenesis of severe NWM infection. We have also recently developed a humanized version of ch128.1/IgG1 (hu128.1), which not only increases the human content of the Ab variable regions for human use but also retains the chimeric Ab properties and exhibits superior thermal stability, making it a better therapeutic candidate. We hypothesize that TfR1 can be used as an effective target to neutralize NWM infection, not only using the anti-TfR1 Ab ch128.1/IgG1 Fc/s but also using a new hu128.1 Fc/s as monomeric IgG1 and also as polymeric IgM-like IgG1 Ab. We also hypothesize that the use of an antagonistic Ab specific for IFN-a/b receptor IFNAR-1 (MAR1-5A3 Ab) would be effective in preventing severe NWM disease, used as a monotherapy or combined with anti-TfR1 Abs. To test our hypotheses, we have four Specific Aims. Aim 1: Define the ability of ch128.1 Fc/s and MAR1- 5A3 as monotherapy or combination therapy to inhibit/eliminate NWM infection in huTfR1 Tg mice; Aim 2: Develop a hu128.1 Fc/s and an IgM-like hu128.1 IgG1 Fc/s as novel therapeutic Abs against NWM infection; Aim 3: Define the antiviral activity of hu128.1 Fc/s and IgM-like hu128.1 IgG1 Fc/s in cell culture and huTfR1 Tg mice NWM infection models; and Aim 4: Define the properties of a selected anti-TfR1 Ab in non-human primates (NHPs)...