Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response.
Drozitumab, a human antibody to death receptor 5, has potent antitumor activity against rhabdomyosarcoma with the expression of caspase-8 predictive of response.
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DOI：
10.1158/1078-0432.ccr-10-2874
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发表时间：
2011-05-15
期刊：
影响因子：
--
通讯作者：
Cao L
中科院分区：
文献类型：
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作者：
Kang Z;Chen JJ;Yu Y;Li B;Sun SY;Zhang B;Cao L
横纹肌肉瘤（RMS）是一种常见的小儿软组织肿瘤。在这项研究中，我们在RMS临床前模型中评估了drozitumab（一种针对死亡受体dr5的治疗性抗体）的疗效和选择性。一组11个RMS细胞系用于体外研究。对drozitumab反应预测的分子标记进行了研究。将选择的RMS细胞系注射到小鼠腓肠肌中，在体内评估drozitumab的效力和选择性。我们报告了DR5，而不是DR4，在所有RMS细胞系的表面持续存在高水平。DR5抗体drozitumab在体外对大多数RMS细胞系有效。caspase-8的表达与对drozitumab的敏感性之间存在很强的相关性，仅在敏感细胞中诱导死亡诱导信号复合体（DISC）的快速组装和caspase-8的裂解。更重要的是，caspase-8的催化活性是介导对drozitumab敏感性的必要和充分条件。此外，drozitumab对已建立的RMS异种移植物具有强大的抗肿瘤活性，具有从体外分析预测的特异性，并且在一半的治疗小鼠中具有无肿瘤状态。我们的研究首次提供了横纹肌肉瘤中死亡受体抗体效力和选择性的临床前评估。在体外，Drozitumab对大多数表达caspase-8的RMS细胞系有效，在体内，可以提供RMS的长期控制。
Rhabdomyosarcoma (RMS) is a common pediatric soft-tissue tumor. In this study, we evaluated the efficacy and selectivity of drozitumab, a death receptor DR5-targeted therapeutic antibody, in RMS preclinical models. A panel of 11 RMS cell lines was used for in vitro studies. The molecular marker predictive of response to drozitumab was interrogated. Selected RMS cell lines were injected into the gastrocnemius muscle of mice for in vivo assessment of the potency and selectivity of drozitumab. We report that DR5, but not DR4, persisted at high levels and on the surface of all RMS cell lines. DR5 antibody drozitumab was effective in vitro against the majority of RMS cell lines. There was a strong correlation between caspase-8 expression and the sensitivity to drozitumab, which induced the rapid assembly of the death-induced signaling complex (DISC) and the cleavage of caspase-8 only in sensitive cells. More importantly, caspase-8 catalytic activity was both necessary and sufficient for mediating the sensitivity to drozitumab. Furthermore, drozitumab had potent anti-tumor activity against established RMS xenografts with a specificity predicted from the in vitro analysis and with tumor-free status in half of the treated mice. Our study provides the first preclinical evaluation of the potency and selectivity of a death receptor antibody in rhabdomyosarcoma. Drozitumab is effective, in vitro, against the majority of RMS cell lines that express caspase-8 and, in vivo, may provide long-term control of RMS.