Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
AIDS Institute, University of California Los Angeles, Los Angeles, California.
Mol Cancer Ther. 2021 Sep;20(9):1592-1602. doi: 10.1158/1535-7163.MCT-21-0074. Epub 2021 Jun 22.
Epstein-Barr virus (EBV) is a human gammaherpesvirus associated with the development of hematopoietic cancers of B-lymphocyte origin, including AIDS-related non-Hodgkin lymphoma (AIDS-NHL). 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. TfR1 is highly expressed in proliferating cells, including activated lymphocytes and malignant cells. We developed a mouse/human chimeric antibody targeting TfR1 (ch128.1/IgG1) that has previously shown significant antitumor activity in immunosuppressed mouse models bearing human malignant B-cells, including multiple myeloma and AIDS-NHL cells. In this article, we examined the effect of targeting TfR1 to inhibit EBV-driven activation and growth of human B-cells using an immunodeficient NOD.Cg- /SzJ [NOD/SCID gamma (NSG)] mouse model. Mice were implanted with T-cell-depleted, human peripheral blood mononuclear cells (PBMCs), either without EBV (EBV), or exposed to EBV (EBV), intravenously via the tail vein. Mice implanted with EBV cells and treated with an IgG1 control antibody (400 μg/mouse) developed lymphoma-like growths of human B-cell origin that were EBV, whereas mice implanted with EBV cells and treated with ch128.1/IgG1 (400 μg/mouse) showed increased survival and significantly reduced inflammation and B-cell activation. These results indicate that ch128.1/IgG1 is effective at preventing the growth of EBV human B-cell tumors , thus, indicating that there is significant potential for agents targeting TfR1 as therapeutic strategies to prevent the development of EBV-associated B-cell malignancies. SIGNIFICANCE: An anti-TfR1 antibody, ch128.1/IgG1, effectively inhibits the activation, growth, and immortalization of EBV human B-cells , as well as the development of these cells into lymphoma-like tumors in immunodeficient mice.
爱泼斯坦-巴尔病毒（EBV）是一种人类γ疱疹病毒，与 B 淋巴细胞来源的造血系统癌症的发展有关，包括艾滋病相关非霍奇金淋巴瘤（AIDS-NHL）。B 细胞的 EBV 原发性感染导致其多克隆激活和永生化。转铁蛋白受体 1（TfR1），也称为 CD71，对于铁摄取和细胞增殖的调节很重要。TfR1 在增殖细胞中高度表达，包括活化的淋巴细胞和恶性细胞。我们开发了一种针对 TfR1 的小鼠/人嵌合抗体（ch128.1/IgG1），该抗体先前在携带人恶性 B 细胞的免疫抑制小鼠模型中显示出显著的抗肿瘤活性，包括多发性骨髓瘤和 AIDS-NHL 细胞。在本文中，我们使用免疫缺陷型 NOD.Cg- /SzJ [NOD/SCID 伽马（NSG）]小鼠模型研究了靶向 TfR1 抑制 EBV 驱动的人 B 细胞激活和生长的效果。通过尾静脉静脉内将 T 细胞耗尽的人外周血单核细胞（PBMC）植入小鼠体内，要么不暴露于 EBV（EBV），要么暴露于 EBV（EBV）。植入 EBV 细胞并用 IgG1 对照抗体（400μg/只）治疗的小鼠会发展出 EBV 阳性的人 B 细胞来源的淋巴瘤样生长，而植入 EBV 细胞并用 ch128.1/IgG1（400μg/只）治疗的小鼠则显示出存活率增加，炎症和 B 细胞激活明显减少。这些结果表明，ch128.1/IgG1 能有效阻止 EBV 人 B 细胞瘤的生长，因此，表明靶向 TfR1 的药物具有作为预防 EBV 相关 B 细胞恶性肿瘤发展的治疗策略的巨大潜力。意义：一种抗 TfR1 抗体 ch128.1/IgG1 可有效抑制 EBV 人 B 细胞的激活、生长和永生化，以及这些细胞在免疫缺陷小鼠中发展为淋巴瘤样肿瘤。
