Department of Clinical Research and Regulatory Affairs, ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, USA.
Curr Drug Targets. 2011 Dec;12(14):2016-33. doi: 10.2174/138945011798829401.
Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.
胰岛素样生长因子 1 型受体（IGF-1R）在细胞增殖和存活中发挥核心作用，在许多肿瘤类型中过度表达。值得注意的是，IGF-1R 介导的信号转导赋予了对多种细胞毒性、激素和生物制剂的耐药性，这表明针对 IGF-1R 的治疗可能对广泛的人类恶性肿瘤有效。西妥昔单抗（IMC-A12；ImClone Systems）是一种完全人源化 IgG1 单克隆抗体，可特异性抑制 IGF-1R 信号转导。西妥昔单抗与 IGF-1R 的结合导致受体内化和降解。由于西妥昔单抗是一种 IgG1 单克隆抗体，它可能通过免疫效应机制（如抗体依赖性细胞毒性）诱导额外的细胞毒性。在临床前研究中，西妥昔单抗单药治疗导致多种实验性癌症的生长抑制。此外，西妥昔单抗安全地增强了广泛的化疗药物的肿瘤生长抑制和细胞毒性作用，并调节了针对激素受体和信号转导的药物的作用，这可能对癌症治疗具有重要意义。在此，我们综述了西妥昔单抗的已发表临床前和临床数据，并对选定的临床研究进行了全面概述。
