An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA
An engineered antibody binds a distinct epitope and is a potent inhibitor of murine and human VISTA
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DOI：
10.1038/s41598-020-71519-4
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发表时间：
2020-09-16
影响因子：
4.6
通讯作者：
Cochran, Jennifer R.
中科院分区：
文献类型：
--
作者：
Mehta, Nishant;Maddineni, Sainiteesh;Cochran, Jennifer R.
V区免疫球蛋白(Ig)是T细胞活化的抑制因子(VistA)，是维持外周T细胞静止和抑制抗肿瘤免疫反应的免疫检查点。Vista通过抑制髓系细胞和T细胞之间的相互作用发挥作用，与PD-1和肿瘤-T细胞信号轴的其他检查点垂直。在这里，我们报告了利用酵母表面展示技术来设计一种与小鼠、人和食蟹猴Vista具有高亲和力的抗Vista抗体。我们的抗Vista抗体(SG7)抑制Vista功能，并阻断据称与PSGL-1和VSIG3蛋白的相互作用。SG7在Vista表面结合了一个独特的表位，该表位与其他临床相关抗体部分重叠。作为单一疗法，SG7在更大程度上作为抗PD1抗体的组合，可以减缓多种同基因小鼠模型中的肿瘤生长。SG7是一种很有前途的临床候选药物，可以在完全免疫活性的小鼠模型中进行测试，其结合表位可以用于未来开发Vista的物种交叉反应抑制剂的活动。
V-domain immunoglobulin (Ig) suppressor of T cell activation (VISTA) is an immune checkpoint that maintains peripheral T cell quiescence and inhibits anti-tumor immune responses. VISTA functions by dampening the interaction between myeloid cells and T cells, orthogonal to PD-1 and other checkpoints of the tumor-T cell signaling axis. Here, we report the use of yeast surface display to engineer an anti-VISTA antibody that binds with high affinity to mouse, human, and cynomolgus monkey VISTA. Our anti-VISTA antibody (SG7) inhibits VISTA function and blocks purported interactions with both PSGL-1 and VSIG3 proteins. SG7 binds a unique epitope on the surface of VISTA, which partially overlaps with other clinically relevant antibodies. As a monotherapy, and to a greater extent as a combination with anti-PD1, SG7 slows tumor growth in multiple syngeneic mouse models. SG7 is a promising clinical candidate that can be tested in fully immunocompetent mouse models and its binding epitope can be used for future campaigns to develop species cross-reactive inhibitors of VISTA.