Pharmacology and Medical Oncology Section, Department of Neuroscience, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy.
Pharmacol Res. 2012 Jan;65(1):9-22. doi: 10.1016/j.phrs.2011.09.002. Epub 2011 Sep 10.
Ipilimumab (Yervoy, developed by Medarex and Bristol-Myers Squibb) is a fully human monoclonal IgG1κ antibody against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), an immune-inhibitory molecule expressed in activated T cells and in suppressor T regulatory cells. Interaction of the monoclonal antibody with CTLA-4 blocks inhibitory signals generated through this receptor and enhances T cell activation, leading to increased antitumor responses. Ipilimumab has been approved by FDA in March 2011 as monotherapy (3mg/kg every 3 weeks for 4 doses) for the treatment of advanced (unresectable or metastatic) melanoma both in pre-treated or chemotherapy naïve patients. Four months later, ipilimumab has received a rapid approval by the European Commission, after a positive opinion from the Committee for Medicinal Products for Human Use. However, the indication in the EU is limited to previously-treated patients with advanced melanoma. Ipilimumab is the first agent that has demonstrated to improve overall survival in patients with metastatic melanoma, which has a very poor prognosis, in randomized phase III clinical trials. The patterns of tumour response to ipilimumab differ from those observed with cytotoxic chemotherapeutic agents, since patients may have a delayed yet durable response and obtain long-term survival benefit despite an initial tumour growth. The major draw-back of ipilimumab is the induction of immune-related adverse effects; the latter can be life-threatening, unless promptly managed with immunosuppressive agents (most frequently corticosteroids) according to specific guidelines. Further development of ipilimumab includes its use in the neoadjuvant or adjuvant high-risk melanoma setting and for the treatment of other refractory and advanced solid tumours, either as single agent or in combination with additional immunostimulating agents or molecularly targeted therapies.
依匹单抗（Yervoy，由 Medarex 和 Bristol-Myers Squibb 开发）是一种针对细胞毒性 T 淋巴细胞相关抗原 4（CTLA-4）的完全人源化单克隆 IgG1κ 抗体，CTLA-4 是一种在活化的 T 细胞和抑制性 T 调节细胞中表达的免疫抑制分子。单克隆抗体与 CTLA-4 的相互作用阻断了通过该受体产生的抑制信号，并增强了 T 细胞的激活，从而导致抗肿瘤反应增加。依匹单抗于 2011 年 3 月被 FDA 批准作为单药治疗（3mg/kg，每 3 周一次，共 4 剂），用于治疗预处理或化疗初治的晚期（不可切除或转移性）黑色素瘤。四个月后，依匹单抗在人用药品委员会的积极意见后，获得了欧洲委员会的快速批准。然而，在欧盟的适应症仅限于晚期黑色素瘤的既往治疗患者。依匹单抗是在随机 III 期临床试验中证明可改善转移性黑色素瘤患者总生存期的第一种药物，转移性黑色素瘤患者的预后非常差。与细胞毒性化学治疗药物相比，肿瘤对依匹单抗的反应模式不同，因为患者可能有延迟但持久的反应，并获得长期生存获益，尽管最初有肿瘤生长。依匹单抗的主要缺点是诱导免疫相关的不良反应；这些不良反应可能危及生命，除非根据特定指南用免疫抑制药物（最常为皮质类固醇）及时处理。依匹单抗的进一步开发包括将其用于新辅助或辅助高危黑色素瘤环境以及治疗其他难治性和晚期实体瘤，无论是作为单一药物还是与其他免疫刺激剂或分子靶向治疗联合使用。
