TIGIT is mainly expressed on T cells and is an inhibitory checkpoint receptor that binds to its ligand PVR in the tumor microenvironment. Anti-TIGIT monoclonal antibodies (mAbs) such as Ociperlimab and Tiragolumab block the TIGIT-PVR interaction and are in clinical development. However, the molecular blockade mechanism of these mAbs remains elusive. Here, we report the crystal structures of TIGIT in complex with Ociperlimab_Fab and Tiragolumab_Fab revealing that both mAbs bind TIGIT with a large steric clash with PVR. Furthermore, several critical epitopic residues are identified. Interestingly, the binding affinity of Ociperlimab toward TIGIT increases approximately 17-fold when lowering the pH from 7.4 to 6.0. Our structure shows a strong electrostatic interaction between ASP103 and HIS76 explaining the pH-responsive mechanism of Ociperlimab. In contrast, Tiragolumab does not show an acidic pH-dependent binding enhancement. Our results provide valuable information that could help to improve the efficacy of therapeutic antibodies for cancer treatment.

中文翻译：

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抗 TIGIT 治疗抗体 Ociperlimab 独特 pH 响应特性的结构见解

TIGIT主要在T细胞上表达，是一种抑制性检查点受体，在肿瘤微环境中与其配体PVR结合。 Ociperlimab 和 Tiragolumab 等抗 TIGIT 单克隆抗体 (mAb) 可阻断 TIGIT-PVR 相互作用，目前正处于临床开发阶段。然而，这些单克隆抗体的分子阻断机制仍然难以捉摸。在这里，我们报告了 TIGIT 与 Ociperlimab_Fab 和 Tiragolumab_Fab 复合物的晶体结构，揭示两种 mAb 与 TIGIT 结合，与 PVR 存在较大的空间冲突。此外，还鉴定了几个关键的表位残基。有趣的是，当 pH 从 7.4 降低至 6.0 时，Ociperlimab 对 TIGIT 的结合亲和力增加约 17 倍。我们的结构显示 ASP103 和 HIS76 之间存在强静电相互作用，解释了 Ociperlimab 的 pH 响应机制。相反，Tiragolumab 没有表现出酸性 pH 依赖性结合增强。我们的结果提供了有价值的信息，有助于提高治疗性抗体对癌症治疗的功效。