Targeting Transferrin Receptor 1 (Tfr1) With The Ch128.1/Igg1 Antibody Inhibits Epstein-Barr Virus (Ebv) Driven Lymphoproliferative Growth And Lymphomagenesis In Immunosuppressed Mice Bearing Human B Cells

Epstein-Barr virus (EBV) is a human herpesvirus that is associated with malignancies of both B lymphocyte and epithelial cell origin. EBV is associated with the development of approximately 1.5% of all cancers worldwide, including AIDS-related non-Hodgkin lymphoma (AIDS-NHL), Hodgkin lymphoma (HL), and post-transplant lymphoproliferative disease (PTLD). Primary infection of B cells with EBV results in their polyclonal activation and immortalization. The transferrin receptor 1 (TfR1), also known as CD71, is important for iron uptake and regulation of cellular proliferation. The TfR1 is expressed at high levels in proliferating cells including activated lymphocytes and malignant cells. We have developed a mouse/human chimeric antibody targeting TfR1 (ch128.1/IgG1) that has shown significant anti-tumor activity in immunosuppressed mouse models bearing human malignant B cells, including multiple myeloma and AIDS-NHL cells. In this study, we examined the effect of targeting TfR1 to inhibit EBV driven transformation of human B cells in vivo using an immunodeficient NSG mouse model. T cell-depleted human peripheral blood mononuclear cells were infected by exposure to EBV-containing supernatants from a B-lymphoblastoid cell line (B95-8). Mice were inoculated with these cells immediately following infection with EBV (day 0), or after cells were cultured for 7 days post infection prior to injection (day 7), and treated with ch128.1/IgG1 or an IgG1 isotype control antibody at 2 and 28 days post-inoculation. We monitored survival, serum levels of human cytokines, and characterized tumor-like growths in spleen and liver by assessing expression of human CD19 (marker for human B cells), EBV latent membrane protein 1 (LMP1; a marker for EBV infection), and human immunoglobulin light chain kappa or lambda (markers for monoclonality) by immunohistochemistry. Treatment with ch128.1/IgG1 significantly enhanced survival, compared to mice treated with the isotype control IgG1. Lymphoma-like cells of human B cell origin that were EBV-LMP1-positive, and often monoclonal, developed in most mice injected with EBV-infected cells (day 0 and 7) treated with the IgG1 control antibody, but only rarely in ch128.1/IgG1 treated animals. In addition, serum levels of human IL-6, IL-8, IFN-γ, CXCL13, sCD25, and sCD27, indicators of human B cell activation and proliferation, were lower in animals treated with ch128.1/IgG1. Taken together, these results show that ch128.1/IgG1 inhibited EBV driven lymphomagenesis using the NSG mouse model newly adapted to study EBV infection/transformation, indicating that there is significant potential for agents targeting TfR1 as therapeutic strategies to prevent EBV-associated B cell malignancies, including AIDS-NHL, HL, and PTLD. Citation Format: Laura E. Martinez, Tracy R. Daniels-Wells, Yu Guo, Larry I. Magpantay, Pierre V. Candelaria, Manuel L. Penichet, Otoniel Martinez-Maza, Marta Epeldegui. Targeting transferrin receptor 1 (TfR1) with the ch128.1/IgG1 antibody inhibits Epstein-Barr virus (EBV) driven lymphoproliferative growth and lymphomagenesis in immunosuppressed mice bearing human B cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-089.