Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody
Retargeting T Cells to GD2 Pentasaccharide on Human Tumors Using Bispecific Humanized Antibody
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DOI：
10.1158/2326-6066.cir-14-0230-t
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发表时间：
2015-03-01
影响因子：
10.1
通讯作者：
Cheung, Nai-Kong V.
中科院分区：
文献类型：
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作者：
Xu, Hong;Cheng, Ming;Cheung, Nai-Kong V.
抗二唾液酸神经节苷脂 GD2 IgG 抗体依靠 Fc 依赖性细胞毒性，在缺乏人类白细胞抗原的实体瘤（例如神经母细胞瘤）中显示出临床疗效。然而，补体激活会继发疼痛副作用。 T 细胞重定向双特异性抗体 (BsAb) 也具有临床潜力，但迄今为止仅对液体肿瘤有效。本研究开发了一种完全人源化的hu3F8-BsAb，其中抗CD3 huOKT3单链Fv片段（ScFv）连接至抗GD2 hu3F8 IgG1轻链的羧基端，并在Fc的N297处进行非糖基化，以防止补体激活和细胞因子风暴。在体外，hu3F8-BsAb通过经典的免疫突触激活T细胞，以飞摩尔EC50诱导GD2特异性肿瘤细胞毒性，其选择性比正常组织高10（5）倍，当GD2（+）肿瘤存在时，释放Th1细胞因子（TNF α，IFN γ和IL2）。在单独的小鼠神经母细胞瘤和黑色素瘤异种移植模型中，静脉内 hu3F8-BsAb 原位激活 T 细胞并招募静脉内 T 细胞进行肿瘤消融，显着延长局部复发或转移性疾病的生存期。 Hu3F8-BsAb（而非对照 BsAb）驱动 T 细胞和单核细胞浸润肿瘤基质。这些单核细胞是 T 细胞持续增殖和/或存活所必需的，并且对抗肿瘤作用有显着贡献。 hu3F8-BsAb 的体外和体内抗肿瘤特性及其安全性支持其作为癌症治疗药物的进一步临床开发，并为探索非糖基化 IgG-scFv 作为重新靶向人类 T 细胞的结构平台提供了理论基础。 (C) 2014 年 AACR。
Anti-disialoganglioside GD2 IgG antibodies have shown clinical efficacy in solid tumors that lack human leukocyte antigens (e.g., neuroblastoma) by relying on Fc-dependent cytotoxicity. However, there are pain side effects secondary to complement activation. T-cell retargeting bispecific antibodies (BsAb) also have clinical potential, but it is thus far only effective against liquid tumors. In this study, a fully humanized hu3F8-BsAb was developed, in which the anti-CD3 huOKT3 single-chain Fv fragment (ScFv) was linked to the carboxyl end of the anti-GD2 hu3F8 IgG1 light chain, and was aglycosylated at N297 of Fc to prevent complement activation and cytokine storm. In vitro, hu3F8-BsAb activated T cells through classic immunologic synapses, inducing GD2-specific tumor cytotoxicity at femtomolar EC50 with >10(5)-fold selectivity over normal tissues, releasing Th1 cytokines (TNF alpha, IFN gamma, and IL2) when GD2(+) tumors were present. In separate murine neuroblastoma and melanoma xenograft models, intravenous hu3F8-BsAb activated T cells in situ and recruited intravenous T cells for tumor ablation, significantly prolonging survival from local recurrence or from metastatic disease. Hu3F8-BsAb, but not control BsAb, drove T cells and monocytes to infiltrate tumor stroma. These monocytes were necessary for sustained T-cell proliferation and/or survival and contributed significantly to the antitumor effect. The in vitro and in vivo antitumor properties of hu3F8-BsAb and its safety profile support its further clinical development as a cancer therapeutic, and provide the rationale for exploring aglycosylated IgG-scFv as a structural platform for retargeting human T cells. (C) 2014 AACR.