Gamma delta T (γδ T) cells are among the most potent cytotoxic lymphocytes. Activating anti–butyrophilin 3A (BTN3A) antibodies prime diverse tumor cell types to be killed by Vγ9Vδ2 T cells, the predominant γδ T cell subset in peripheral circulation, by mechanisms independent of tumor antigen–major histocompatibility complex (MHC) complexes. In this report, we describe the development of a humanized monoclonal antibody, ICT01, with subnanomolar affinity for the three isoforms of BTN3A. We demonstrate that ICT01-activated Vγ9Vδ2 T cells kill multiple tumor cell lines and primary tumor cells, but not normal healthy cells, in an efficient process requiring approximately 20% target occupancy. We show that ICT01 activity is dependent on BTN3A and BTN2A but independent of the phosphoantigen (pAg)–binding B30.2 domain. ICT01 delays the growth of hematologic and solid tumor xenografts and prolongs survival of NOD/SCID/IL2rγ^null (NSG) mice adoptively transferred with human Vγ9Vδ2 T cells. In single- and multiple-dose safety studies in cynomolgus macaques that received up to 100 mg/kg once weekly, ICT01 was well tolerated. With respect to pharmacodynamic endpoints, ICT01 selectively activated Vγ9Vδ2 T cells without affecting other BTN3A-expressing lymphocytes such as αβ T or B cells. A first-in-human, phase 1/2a, open-label, clinical study of ICT01 was thus initiated in patients with advanced-stage solid tumors (EVICTION: NCT04243499; EudraCT: 2019-003847-31). Preliminary results show that ICT01 was well tolerated and pharmacodynamically active in the first patients. Digital pathology analysis of tumor biopsies of a patient with melanoma suggests that ICT01 may promote immune cell infiltration within the tumor microenvironment.

中文翻译：

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开发 ICT01，一种一流的抗 BTN3A 抗体，用于激活 Vγ9Vδ2 T 细胞介导的抗肿瘤免疫反应

Gamma delta T (γδ T) 细胞是最有效的细胞毒性淋巴细胞之一。激活抗嗜丁酸 3A (BTN3A) 抗体引发多种肿瘤细胞类型被 Vγ9Vδ2 T 细胞杀死，Vγ9Vδ2 T 细胞是外周循环中主要的 γδ T 细胞亚群，其机制独立于肿瘤抗原-主要组织相容性复合物 (MHC) 复合物。在本报告中，我们描述了人源化单克隆抗体 ICT01 的开发，该抗体对 BTN3A 的三种亚型具有亚纳摩尔亲和力。我们证明 ICT01 激活的 Vγ9Vδ2 T 细胞杀死多个肿瘤细胞系和原发性肿瘤细胞，但不是正常的健康细胞，在一个需要大约 20% 的目标占有率的有效过程中。我们表明 ICT01 活性依赖于 BTN3A 和 BTN2A，但不依赖于磷酸抗原 (pAg) 结合 B30.2 结构域。用人Vγ9Vδ2 T细胞过继转移的^{无效（NSG）小鼠。}在每周一次接受高达 100 mg/kg 的食蟹猴的单剂量和多剂量安全性研究中，ICT01 具有良好的耐受性。关于药效学终点，ICT01 选择性激活 Vγ9Vδ2 T 细胞，而不影响其他表达 BTN3A 的淋巴细胞，如 αβ T 或 B 细胞。因此，在晚期实体瘤患者中启动了 ICT01 的首次人体 1/2a 期开放标签临床研究（EVICTION：NCT04243499；EudraCT：2019-003847-31）。初步结果表明，ICT01 在第一批患者中具有良好的耐受性和药效学活性。对黑色素瘤患者肿瘤活检的数字病理学分析表明，ICT01 可能促进肿瘤微环境内的免疫细胞浸润。