# Antibody-based therapeutic strategy for New World mammarenavirus hemorrhagic fever

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $753,610

## Abstract

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)...

## Key facts

- **NIH application ID:** 10740875
- **Project number:** 5R01AI173769-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Brian B. Gowen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $753,610
- **Award type:** 5
- **Project period:** 2022-11-15 → 2027-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10740875

## Citation

> US National Institutes of Health, RePORTER application 10740875, Antibody-based therapeutic strategy for New World mammarenavirus hemorrhagic fever (5R01AI173769-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10740875. Licensed CC0.

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