PDF(Pubmed)
Abstract：
Transferrin receptor 1 (TfR1), also known as CD71, is a transmembrane protein involved in the cellular uptake of iron and the regulation of cell growth. This receptor is expressed at low levels on a variety of normal cells, but is upregulated on cells with a high rate of proliferation, including malignant cells and activated immune cells. Infection with the human immunodeficiency virus (HIV) leads to the chronic activation of B cells, resulting in high expression of TfR1, B-cell dysfunction, and ultimately the development of acquired immunodeficiency syndrome-related B-cell non-Hodgkin lymphoma (AIDS-NHL). Importantly, TfR1 expression is correlated with the stage and prognosis of NHL. Thus, it is a meaningful target for antibody-based NHL therapy. We previously developed a mouse/human chimeric IgG3 specific for TfR1 (ch128.1/IgG3) and showed that this antibody exhibits antitumor activity in an in vivo model of AIDS-NHL using NOD-SCID mice challenged intraperitoneally with 2F7 human Burkitt lymphoma (BL) cells that harbor the Epstein-Barr virus (EBV). We have also developed an IgG1 version of ch128.1 that shows significant antitumor activity in SCID-Beige mouse models of disseminated multiple myeloma, another B-cell malignancy. Here, we aim to explore the utility of ch128.1/IgG1 and its humanized version (hu128.1) in mouse models of AIDS-NHL. To accomplish this goal, we used the 2F7 cell line variant 2F7-BR44, which is more aggressive than the parental cell line and forms metastases in the brain of mice after systemic (intravenous) administration. We also used the human BL cell line JB, which in contrast to 2F7, is EBV-negative, allowing us to study both EBV-infected and non-infected NHL tumors. Treatment with ch128.1/IgG1 or hu128.1 of SCID-Beige mice challenged locally (subcutaneously) with 2F7-BR44 or JB cells results in significant antitumor activity against different stages of disease. Treatment of mice challenged systemically (intravenously) with either 2F7-BR44 or JB cells also showed significant antitumor activity, including long-term survival. Taken together, our results suggest that targeting TfR1 with antibodies, such as ch128.1/IgG1 or hu128.1, has potential as an effective therapy for AIDS-NHL.
摘要：
转铁蛋白受体1（TfR1），也称为CD71,是参与细胞摄取铁和调节细胞生长的跨膜蛋白。这种受体在多种正常细胞上低水平表达，但在高增殖率的细胞上上调，包括恶性细胞和活化的免疫细胞。感染人类免疫缺陷病毒（HIV）导致B细胞的慢性激活，导致TfR1高表达，B细胞功能障碍，并最终发展为获得性免疫缺陷综合征相关的B细胞非霍奇金淋巴瘤（AIDS-NHL）。重要的是,TfR1的表达与NHL的分期和预后相关。因此，它是基于抗体的NHL治疗的有意义的靶点。我们先前开发了对TfR1具有特异性的小鼠/人嵌合IgG3（ch128.1/IgG3），并显示该抗体在AIDS-NHL的体内模型中显示出抗肿瘤活性，该模型使用NOD-SCID小鼠腹膜内攻击2F7人伯基特淋巴瘤（BL）携带爱泼斯坦-巴尔病毒（EBV）的细胞。我们还开发了ch128.1的IgG1版本，在播散性多发性骨髓瘤的SCID-Beige小鼠模型中显示出显着的抗肿瘤活性，另一个B细胞恶性肿瘤.这里,我们旨在探索ch128.1/IgG1及其人源化版本（hu128.1）在AIDS-NHL小鼠模型中的实用性。为了实现这个目标,我们使用2F7细胞系变体2F7-BR44,该细胞系比亲本细胞系更具侵袭性,在全身(静脉内)给药后在小鼠脑中形成转移.我们还使用了人类BL细胞系JB，与2F7相反，它是EBV阴性的，允许我们研究EBV感染和未感染的NHL肿瘤。用2F7-BR44或JB细胞局部(皮下)攻击的SCID-米色小鼠的ch128.1/IgG1或hu128.1处理导致针对疾病的不同阶段的显著抗肿瘤活性。用2F7-BR44或JB细胞全身（静脉内）攻击的小鼠的治疗也显示出显着的抗肿瘤活性，包括长期生存。一起来看,我们的结果表明，用抗体靶向TfR1，例如ch128.1/IgG1或hu128.1，有可能作为AIDS-NHL的有效疗法。
