A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients
A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients
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DOI：
10.1182/blood-2003-07-2440
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发表时间：
2004-03-01
期刊：
影响因子：
20.3
通讯作者：
Hermine, O
中科院分区：
文献类型：
--
作者：
Moura, IC;Lepelletier, Y;Hermine, O
成人T细胞白血病/淋巴瘤(ATL)是一种侵袭性淋巴增生性疾病，临床表现多样，从慢性到急性不等。虽然ATL患者的白血病细胞对化疗表现出内在的耐药性，但针对CD25(白细胞介素2受体α[IL-2Rpha]抗体)的单抗已被用作特异性治疗药物。然而，这些抗体的显著临床结果仅在慢性ATL中被证明。与静止的T细胞相比，人类T细胞嗜淋巴病毒1型(HTLV-1)感染的细胞结构性地表达高水平的表面转铁蛋白受体(TFR)。在此，我们报道了一种新的针对人TFR的单抗(MAbA24)的特性，并评价了其体外阻断ATL细胞增殖的能力。我们确定A24与TFR结合的平衡常数(K‘(D))为2.7 nM，并与转铁蛋白竞争结合TFR。A24还抑制活化的T细胞摄取[Fe-55]-转铁蛋白，并阻断T细胞的增殖。此外，A24分别减少和损害了TFR的表达和循环。最重要的是，我们发现A24通过诱导程序性细胞死亡，阻断了急性和慢性ATL恶性T细胞的体外增殖。因此，A24可能是治疗急性ATL的有效治疗工具。(C)2004年，由美国血液病学会提供。
Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoid proliferative disease that exists under diverse clinical forms ranging from chronic to acute. Although leukemic cells from patients with ATL exhibit an intrinsic resistance to chemotherapy, monoclonal antibodies directed against CD25 (interleukin 2 receptor alpha [IL-2Ralpha] antibody) have been used as specific therapeutic agents. However, significant clinical results with these antibodies have been demonstrated only in chronic forms of ATL. In contrast to resting T cells, human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells constitutively express high levels of surface transferrin receptor (TfR). Herein, we report the characterization of a new monoclonal antibody (mAb A24) directed against the human TfR and the evaluation of its capacity to block the proliferation of ATL cells ex vivo. We determined that A24 binds TfR with an equilibrium constant (K'(d)) of 2.7 nM and competes with transferrin for binding to TfR. A24 also inhibited [Fe-55]-transferrin uptake in activated T cells and blocked T-cell proliferation. Moreover, A24 reduced and impaired TfR expression and recycling, respectively. Most important, we showed that A24 blocked the ex vivo proliferation of malignant T cells from both acute and chronic forms of ATL, through induction of programmed cell death. Therefore efficient therapeutic tools to treat acute forms of ATL might be derived from A24. (C) 2004 by The American Society of Hematology.