Translational Clinical Research Division, Chugai Pharmaceutical Co., Ltd., 1-1 Nihonbashi-Muromachi 2-Chome Chuo-ku, Tokyo 103-8324, Japan.
Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Sci Transl Med. 2017 Oct 4;9(410). doi: 10.1126/scitranslmed.aal4291.
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.
癌症治疗正在发生革命性变化，免疫疗法如免疫检查点抑制剂、工程 T 细胞转移和细胞疫苗正在发挥作用。双特异性 T 细胞重定向抗体（TRAB）是一种很有前途的免疫疗法，它可以通过结合 T 细胞上的 CD3 和肿瘤细胞上的抗原来重定向 T 细胞到肿瘤细胞。由于 T 细胞可以被重定向到肿瘤细胞，而与 T 细胞受体的特异性无关，因此 TRAB 被认为对缺乏足够新抗原的免疫原性较低的肿瘤有效。其临床疗效已被blinatumomab 所证明，blinatumomab 是一种靶向 CD19 和 CD3 的双特异性 T 细胞衔接器，对血液恶性肿瘤显示出显著的临床反应。然而，TRAB 在实体瘤中的成功受到缺乏具有足够肿瘤选择性的靶分子的阻碍，以避免“脱靶毒性”。磷脂酰聚糖 3（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受到抑制。我们开发了 ERY974，这是一种全人源化免疫球蛋白 G 结构的 TRAB，含有常见的轻链，可双特异性结合 GPC3 和 CD3。使用重建了人免疫细胞的小鼠模型，我们揭示了 ERY974 非常有效地杀死各种类型的肿瘤，这些肿瘤的 GPC3 表达与临床肿瘤相当。ERY974 甚至对具有非免疫原性特征的肿瘤也能诱导强大的抗肿瘤疗效，这些肿瘤很难通过抑制免疫检查点（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））来治疗。免疫监测显示，ERY974 将炎症反应不佳的肿瘤微环境转化为高度炎症的微环境。在食蟹猴中的毒理学研究显示细胞因子短暂升高，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依据。
