Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types
Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types
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DOI：
10.4161/cbt.9.8.11264
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发表时间：
2010-04-15
影响因子：
3.6
通讯作者：
Gliniak, Brian C.
中科院分区：
文献类型：
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作者：
Kaplan-Lefko, Paula J.;Graves, Jonathan D.;Gliniak, Brian C.
肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 与死亡受体 4 和 5 (DR4、DR5) 结合以转导凋亡信号。 Conatumumab (AMG 655) 是一种针对人 DR5 的研究性全人单克隆激动剂抗体 (IgG(1))，可通过 caspase 激活诱导细胞凋亡。在这项研究中，我们证明 conatumumab 与 DR5 结合，在交联剂存在的情况下体外激活细胞内半胱天冬酶。我们还表明，conatumumab 具有体内活性，可抑制结肠（Colo205 和 HCT-15）、肺（H2122）和胰腺（MiaPaCa2/T2）异种移植模型中的肿瘤生长。 Conatumumab 还增强化疗药物的体内抗肿瘤活性。 Colo205 肿瘤中的 Caspase 激活呈剂量依赖性，并与 conatumumab 的血清浓度相关。我们首次证明，在临床前模型中使用 conatumumab 时，血清 caspase-3/7 活性和 M30（caspase 裂解的细胞角蛋白-18 的新表位）水平的增加与外源性凋亡途径的激活有关。这些数据表明 conatumumab 有潜力作为治疗多种肿瘤类型患者的治疗剂，并且血清 caspase-3/7 和 M30 水平可以作为 conatumumab 活性的生物标志物。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors 4 and 5 (DR4, DR5) to transduce apoptotic signals. Conatumumab (AMG 655) is an investigational, fully human monoclonal agonist antibody (IgG(1)) to human DR5, which induces apoptosis via caspase activation. In this study, we demonstrate that conatumumab binds to DR5, activating intracellular caspases in vitro in the presence of a cross-linker. We also show that conatumumab has activity in vivo and inhibits tumor growth in colon (Colo205 and HCT-15), lung (H2122) and pancreatic (MiaPaCa2/T2) xenograft models. Conatumumab also enhances the antitumor activity of chemotherapeutics in vivo. Caspase activation in Colo205 tumors is dose-dependent and correlated with serum concentrations of conatumumab. We demonstrate for the first time that increases in serum caspase-3/7 activity and levels of M30 (neoepitope of caspase-cleaved cytokeratin-18) are linked to activation of the extrinsic apoptotic pathway using conatumumab in a preclinical model. These data suggest that conatumumab has potential as a therapeutic agent for treating patients with multiple tumor types, and that serum caspase-3/7 and M30 levels may serve as biomarkers of conatumumab activity.