Brentuximab Vedotin (SGN-35)
Brentuximab Vedotin (SGN-35)
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DOI：
10.1158/1078-0432.ccr-11-0488
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发表时间：
2011-10-15
影响因子：
11.5
通讯作者：
Younes, Anas
中科院分区：
文献类型：
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作者：
Katz, Jessica;Janik, John E.;Younes, Anas
本妥昔单抗维汀（SGN - 35）是一种抗体 - 药物偶联物（ADC），针对霍奇金淋巴瘤和间变性大细胞淋巴瘤上表达的CD30抗原。SGN - 35由cAC10嵌合IgG1单克隆抗体SGN30组成，通过添加一个缬氨酸 - 瓜氨酸二肽连接子进行修饰，以便连接微管聚合的强效抑制剂单甲基奥瑞他汀E（MMAE）。在II期试验中，SGN - 35在霍奇金淋巴瘤患者（n = 102）中产生了75%的缓解率，在间变性大细胞淋巴瘤患者（n = 30）中产生了87%的缓解率。对SGN - 35的反应可能不仅与MMAE在恶性细胞内释放所产生的细胞毒性作用有关，还与其他作用有关。首先，SGN - 35可能通过CD30连接向恶性细胞发出信号，传递凋亡或增殖反应。前者会增强MMAE的细胞毒性。在MMAE中毒的情况下传递的增殖信号可能会增强细胞死亡。其次，SGN - 35的疗效，特别是在霍奇金淋巴瘤中的疗效，可能归因于其对肿瘤微环境的影响。游离MMAE从靶向肿瘤细胞扩散可能会产生旁观者效应，杀死紧邻恶性细胞的正常支持细胞。消除抑制细胞毒性效应细胞的调节性T细胞以及消除为霍奇金/里德 - 施特恩伯格细胞提供生长因子支持的细胞，可以进一步增强SGN - 35的细胞毒活性。在此我们综述SGN - 35的生物学特性以及使用SGN - 35的临床效果。《临床癌症研究》；17(20)；6428 - 6436。（C）2011美国癌症研究协会。
Brentuximab vedotin (SGN-35) is an antibody-drug conjugate (ADC) directed against the CD30 antigen expressed on Hodgkin lymphoma and anaplastic large cell lymphoma. SGN-35 consists of the cAC10 chimerized IgG1 monoclonal antibody SGN30, modified by the addition of a valine-citrulline dipeptide linker to permit attachment of the potent inhibitor of microtubule polymerization monomethylauristatin E (MMAE). In phase II trials, SGN-35 produced response rates of 75% in patients with Hodgkin lymphoma (n = 102) and 87% in patients with anaplastic large cell lymphoma (n = 30). Responses to SGN-35 might be related not only to the cytotoxic effect due to release of MMAE within the malignant cell but also to other effects. First, SGN-35 may signal malignant cells through CD30 ligation to deliver an apoptotic or proliferative response. The former would amplify the cytotoxicity of MMAE. A proliferative signal delivered in the context of MMAE intoxication could enhance cell death. Second, the efficacy of SGN-35, particularly in Hodgkin lymphoma, might be attributed to its effect on the tumor microenvironment. Diffusion of free MMAE from the targeted tumor cells could result in a bystander effect that kills the normal supporting cells in close proximity to the malignant cells. The elimination of T regulatory cells that inhibit cytotoxic effector cells and elimination of cells that provide growth factor support for Hodgkin/Reed-Sternberg cells could further enhance the cytotoxic activity of SGN-35. Here we review the biology of SGN-35 and the clinical effects of SGN-35 administration. Clin Cancer Res; 17(20); 6428-36. (C) 2011 AACR.