Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule,RSC Chemical Biology

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Finding and characterizing a catalytic antibody light chain, H34, capable of degrading the PD-1 molecule
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-12-10 , DOI: 10.1039/d0cb00155d
Emi Hifumi ₁ , Hiroaki Taguchi ₂ , Tamami Nonaka ₁ , Takunori Harada ₃ , Taizo Uda ₄

Affiliation

Programmed cell death 1 (PD-1) is an immune checkpoint molecule regulating T-cell function. Preventing PD-1 binding to its ligand PD-L1 has emerged as an important tool in immunotherapy. Here, we describe a unique human catalytic antibody light chain, H34, which mediates enzymatic degradation of human PD-1 peptides and recombinant human PD-1 protein and thus functions to prevent the binding of PD-1 with PD-L1. H34 degraded one half of the PD-1 molecules within about 6 h under the experimental conditions. Investigating the acquisition of the catalytic function by H34, which belongs to subgroup I and lacks a Pro⁹⁵ residue in CDR-3, revealed the importance of this sequence, as a Pro⁹⁵-reconstituted mutant (H34-Pro⁹⁵(+)) exhibited very little catalytic activity to cleave PD-1. Interestingly, EDTA inhibited the catalytic activity of H34, which could work as a metallo-protease. Zn²⁺ or Co²⁺ ions may work as a cofactor. It is meaningfull that H34 was obtained from the human antibody gene taken from a healthy volunteer, suggesting that we potentially have such unique molecules in our body.

中文翻译：

寻找并表征能够降解 PD-1 分子的催化抗体轻链 H34

程序性细胞死亡 1 (PD-1) 是一种调节 T 细胞功能的免疫检查点分子。阻止 PD-1 与其配体 PD-L1 结合已成为免疫治疗的重要工具。在这里，我们描述了一种独特的人催化抗体轻链 H34，它介导人 PD-1 肽和重组人 PD-1 蛋白的酶促降解，从而起到阻止 PD-1 与 PD-L1 结合的作用。在实验条件下，H34在约6小时内降解了一半的PD-1分子。H34 属于亚组 I，在 CDR-3 中缺少 Pro ⁹⁵残基，对 H34 获得催化功能的研究揭示了该序列的重要性，因为 Pro ⁹⁵重构突变体 (H34-Pro ⁹⁵ (+)) 表现出裂解 PD-1 的催化活性非常小。有趣的是，EDTA 抑制了 H34 的催化活性，而 H34 可以作为金属蛋白酶。Zn ²⁺或Co ²⁺离子可以作为辅助因子。有意义的是，H34是从健康志愿者的人体抗体基因中获得的，这表明我们体内可能存在这种独特的分子。

更新日期：2020-12-10

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