Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death
Activity of selective fully human agonistic antibodies to the TRAIL death receptors TRAIL-R1 and TRAIL-R2 in primary and cultured lymphoma cells: induction of apoptosis and enhancement of doxorubicin- and bortezomib-induced cell death
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DOI：
10.1111/j.1365-2141.2005.05656.x
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发表时间：
2005-08-01
影响因子：
6.5
通讯作者：
Younes, A
中科院分区：
文献类型：
--
作者：
Georgakis, GV;Li, Y;Younes, A
肿瘤坏死因子相关凋亡诱导配体（TRAIL/Apo 2L）是一种死亡蛋白，优先杀死肿瘤细胞，同时保留正常细胞。TRAIL有四种排他性受体，其中两种（TRAIL-R1，TRAIL-R2）是死亡受体。目前正在探索TRAIL/Apo 2L和TRAIL死亡受体的激动性抗体用于癌症治疗。虽然TRAIL/Apo 2L在多种血液恶性肿瘤中的活性已被检测，但抗TRAIL受体激动性抗体在原代和培养的淋巴瘤细胞中的活性尚未被检测。使用两种针对TRAIL死亡受体TRAIL-R1的全人选择性激动性单克隆抗体（HGS-ETR 1）和TRAIL-R2（HGS-ETR 2）该研究表明，两种单克隆抗体在9种人淋巴瘤细胞系中的5种中激活半胱天冬酶-8并诱导细胞死亡，并且分别在27种原发性淋巴瘤细胞中的67%和70%中诱导> 10%的细胞死亡，并且在至少三分之一的样品中> 20%的细胞死亡。HGS-ETR 1和HGS-ETR 2在新鲜肿瘤样本中表现出相当的活性，这与TRAIL受体表面表达、Bax、cFLIP或半胱氨酸天冬氨酸蛋白酶原-8表达或暴露于既往治疗无关。此外，这两种抗体增强了阿霉素和硼替佐米的杀伤作用。我们的数据表明，HGS-ETR 1和HGS-ETR 2单克隆抗体可以诱导多种培养的和原代淋巴瘤细胞的细胞死亡，并可能在淋巴瘤中具有治疗价值。
Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) is a death protein that preferentially kills tumour cells while sparing normal cells. TRAIL has four exclusive receptors, two of which (TRAIL-R1, TRAIL-R2) are death receptors. Both TRAIL/Apo2L and agonistic antibodies to the TRAIL death receptors are currently being explored for cancer therapy. Although the activity of TRAIL/Apo2L in a variety of haematological malignancies has been examined, the activity of anti-TRAIL receptor agonistic antibodies in primary and cultured lymphoma cells has not. Using two fully human selective agonistic monoclonal antibodies to the TRAIL death receptors TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) this study demonstrated that both monoclonal antibodies activated caspase-8 and induced cell death in five of nine human lymphoma cell lines, and induced > 10% cell death in 67% and 70%, respectively, of 27 primary lymphoma cells, and > 20% cell death in at least one-thirds of the samples. HGS-ETR1 and HGS-ETR2 demonstrated comparable activity in the fresh tumour samples, which was independent of TRAIL receptor surface expression, Bax, cFLIP, or procaspase-8 expression, or exposure to prior therapy. Furthermore, both antibodies enhanced the killing effect of doxorubicin and bortezomib. Our data demonstrate that HGS-ETR1 and HGS-ETR2 monoclonal antibodies can induce cell death in a variety of cultured and primary lymphoma cells, and may have therapeutic value in lymphoma.