Host receptor-targeted therapeutic approach to counter pathogenic New World mammarenavirus infections

Abstract

Five New World mammarenaviruses (NWMs) cause life-threatening hemorrhagic fever (HF). Cellular entry by these viruses is mediated by human transferrin receptor 1 (hTfR1). Here, we demonstrate that an antibody (ch128.1/IgG1) which binds the apical domain of hTfR1, potently inhibits infection of attenuated and pathogenic NWMs in vitro. Computational docking of the antibody Fab crystal structure onto the known structure of hTfR1 shows an overlapping receptor-binding region shared by the Fab and the viral envelope glycoprotein GP1 subunit that binds hTfR1, and we demonstrate competitive inhibition of NWM GP1 binding by ch128.1/IgG1 as the principal mechanism of action. Importantly, ch128.1/IgG1 protects hTfR1-expressing transgenic mice against lethal NWM challenge. Additionally, the antibody is well-tolerated and only partially reduces ferritin uptake. Our findings provide the basis for the development of a novel, host receptor-targeted antibody therapeutic broadly applicable to the treatment of HF of NWM etiology.

Combination Therapy of an Antibody Specific for Transferrin Receptor 1 (ch128.1/IgG1) With Bortezomib or Lenalidomide Results in Increased Survival in an In Vivo Model of Human Multiple Myeloma: A Brief Communication

“…26 In the same study, we also showed that ch128.1/IgG1 has minimal toxicity to human committed hematopoietic progenitor cells (including erythroid progenitors) in vitro. 26 Therefore, the combination of bortezomib and ch128.1/IgG1 or lenalidomide and ch128.1/IgG1 would likely present side effects that can be controlled and the risks they convey in humans mitigated. A limitation of using mice in our studies is that this species does not properly address the issue of toxicity of ch128.1/IgG1 since this antibody does not crossreact with the murine TfR1.…”

“…Furthermore, we have recently shown that ch128.1/IgG1 does not inhibit transferrin binding and only partially inhibits the binding of ferritin (important for iron uptake in erythroid progenitor cells) to TfR1 26. In the same study, we also showed that ch128.1/IgG1 has minimal toxicity to human committed hematopoietic progenitor cells (including erythroid progenitors) in vitro 26. Therefore, the combination of bortezomib and ch128.1/IgG1 or lenalidomide and ch128.1/IgG1 would likely present side effects that can be controlled and the risks they convey in humans mitigated.…”

Serum biomarkers for nutritional status as predictors in COVID-19 patients before and after vaccination

“…Moreover, ferritin presents higher levels in response to infection ( Sandalinas et al, 2022: ), and hemoglobin participates in iron metabolism, response to oxidative stress and inflammation and low levels are associated with a decrease in cellular immunity ( Yang et al, 2022 ). Lastly, TfR is involved in the iron metabolism and virus infection ( Hickerson et al, 2022 ), having a potential role in entry of SARS-CoV-2 ( Dai et al, 2021 ).…”

Efficacy of Antibodies Targeting TfR1 in Xenograft Mouse Models of AIDS-Related Non-Hodgkin Lymphoma

“…With the use of anti-TfR1 antibodies, toxicity to these normal cells expressing high levels of TfR1 is a concern. Previous studies show that antibodies containing the 128.1 variable regions bind the apical domain of TfR1 and do not inhibit the binding of transferrin to the receptor or block TfR1 internalization [ 21 , 22 , 34 , 43 ]. However, ch128.1/IgG1 partially blocks the binding of the heavy chain of ferritin (H-Ft) [ 43 ], known to bind the apical domain of TfR1 and play a role in the uptake of iron in erythroid progenitor cells [ 44 , 45 , 46 ].…”