Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
FEBS Lett. 2014 Jan 21;588(2):288-97. doi: 10.1016/j.febslet.2013.11.030. Epub 2013 Dec 1.
Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy.
神经节苷脂 GD2 在神经外胚层来源的肿瘤和肉瘤中高度表达，包括神经母细胞瘤、视网膜母细胞瘤、黑色素瘤、小细胞肺癌、脑肿瘤、骨肉瘤、横纹肌肉瘤、青少年尤文肉瘤，以及脂肪肉瘤、纤维肉瘤、平滑肌肉瘤和其他成人软组织肉瘤。由于 GD2 在正常组织中的表达仅限于大脑，而大脑中不存在循环抗体，并且在选定的周围神经和黑色素细胞中表达，因此它被认为是全身肿瘤免疫治疗的合适靶点。过去二十年来，抗 GD2 抗体一直在神经母细胞瘤的临床试验中得到积极测试，已被证明具有安全性和疗效。主要限制因素是与外周神经纤维上 GD2 表达相关的急性疼痛毒性，以及抗体无法治疗大体积肿瘤。已经开发了几种策略来降低疼痛毒性，包括绕过补体激活、使用阻断抗体或针对不在外周神经上表达的 O-乙酰化 GD2 衍生物。为了增强抗肿瘤疗效，抗 GD2 单克隆抗体和片段已被设计成免疫细胞因子、免疫毒素、抗体药物偶联物、放射性标记抗体、靶向纳米颗粒、T 细胞结合双特异性抗体和嵌合抗原受体。将回顾这些方法的挑战，为癌症治疗中下一代抗 GD2 治疗药物建立一个视角。
