Amgen Inc., Thousand Oaks, CA, USA.
Cancer Biol Ther. 2010 Apr 15;9(8):618-31. doi: 10.4161/cbt.9.8.11264. Epub 2010 Apr 20.
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.
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，传递凋亡信号。康奈妥单抗（AMG 655）是一种研究中的、完全人源化的单克隆激动剂抗体（IgG(1)），可与人类 DR5 结合，通过半胱天冬酶激活诱导细胞凋亡。在这项研究中，我们证明康奈妥单抗在存在交联剂的情况下与 DR5 结合，在体外激活细胞内半胱天冬酶。我们还表明，康奈妥单抗在体内具有活性，并抑制结直肠癌（Colo205 和 HCT-15）、肺癌（H2122）和胰腺癌（MiaPaCa2/T2）异种移植模型中的肿瘤生长。康奈妥单抗还增强了体内化疗药物的抗肿瘤活性。Colo205 肿瘤中的半胱天冬酶激活与剂量有关，并与康奈妥单抗的血清浓度相关。我们首次证明，在临床前模型中使用康奈妥单抗可增加血清 caspase-3/7 活性和 M30（半胱天冬酶切割细胞角蛋白-18 的新表位）水平，与外源性凋亡途径的激活有关。这些数据表明，康奈妥单抗具有作为治疗多种肿瘤类型患者的治疗剂的潜力，并且血清 caspase-3/7 和 M30 水平可能作为康奈妥单抗活性的生物标志物。
