An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors
An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors
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DOI：
10.1126/scitranslmed.aal4291
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发表时间：
2017-10-04
影响因子：
17.1
通讯作者：
Nezu, Junichi
中科院分区：
文献类型：
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作者：
Ishiguro, Takahiro;Sano, Yuji;Nezu, Junichi
免疫检查点抑制剂、工程T细胞转移和细胞疫苗等免疫疗法正在为癌症治疗带来革命性的变化。双特异性T细胞重定向抗体(TRAb)是一种很有前途的免疫治疗方法，它通过结合T细胞表面的CD3和肿瘤细胞上的抗原，将T细胞重定向至肿瘤细胞。由于无论T细胞受体的特异性如何，T细胞都可以被重定向到肿瘤细胞，因此TRAb被认为对缺乏足够新抗原的免疫原性较低的肿瘤是有效的。它的临床疗效以blinatumomab为例，blinatumomab是一种针对CD19和CD3的双特异性T细胞结合分子，已显示出对血液系统恶性肿瘤的显著临床反应。然而，TRAb在实体瘤中的成功一直受到缺乏具有足够肿瘤选择性的靶分子以避免“靶标上肿瘤外”毒性的阻碍。Glypical3(GPC3)是一种高度肿瘤特异性抗原，在胎儿发育过程中表达，但在正常成人组织中严格抑制。我们开发了ERY974，一种完整的人源化免疫球蛋白G结构的TRAb，含有共同的轻链，与GPC3和CD3双特异性结合。利用重组人免疫细胞的小鼠模型，我们发现ERY974对GPC3表达与临床肿瘤相当的各种类型的肿瘤具有高效的杀伤作用。ERY974甚至对具有非免疫原性特征的肿瘤也具有强大的抗肿瘤效果，这些肿瘤很难通过抑制免疫检查点来治疗，如PD-1(程序性细胞死亡蛋白-1)和CTLA-4(细胞毒性T淋巴细胞相关蛋白-4)。免疫监测显示，ERY974将炎症程度较低的肿瘤微环境转变为高度炎症的微环境。对食蟹猴的毒理学研究显示，细胞因子有一过性升高，但这是可控和可逆的。没有明显的器官毒性。这些数据为ERY974治疗GPC3阳性实体瘤患者的临床测试提供了理论基础。
Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell-redirecting antibody (TRAB) is one such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens. Its clinical efficacy has been exemplified by blinatumomab, a bispecific T cell engager targeting CD19 and CD3, which has shown marked clinical responses against hematological malignancies. However, the success of TRAB in solid tumors has been hampered by the lack of a target molecule with sufficient tumor selectivity to avoid "on-target off-tumor" toxicity. Glypican 3 (GPC3) is a highly tumor-specific antigen that is expressed during fetal development but is strictly suppressed in normal adult tissues. We developed ERY974, a whole humanized immunoglobulin G-structured TRAB harboring a common light chain, which bispecifically binds to GPC3 and CD3. Using a mouse model with reconstituted human immune cells, we revealed that ERY974 is highly effective in killing various types of tumors that have GPC3 expression comparable to that in clinical tumors. ERY974 also induced a robust antitumor efficacy even against tumors with nonimmunogenic features, which are difficult to treat by inhibiting immune checkpoints such as PD-1 (programmed cell death protein-1) and CTLA-4 (cytotoxic T lymphocyte-associated protein-4). Immune monitoring revealed that ERY974 converted the poorly inflamed tumor microenvironment to a highly inflamed microenvironment. Toxicology studies in cynomolgus monkeys showed transient cytokine elevation, but this was manageable and reversible. No organ toxicity was evident. These data provide a rationale for clinical testing of ERY974 for the treatment of patients with GPC3-positive solid tumors.