研究新型单克隆抗体mAb059c与hPD-1受体的相互作用。,Scientific Reports

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研究新型单克隆抗体mAb059c与hPD-1受体的相互作用。
Scientific Reports ( IF 3.8 ) Pub Date : 2019-11-28 , DOI: 10.1038/s41598-019-54231-w
Jingxian Liu ₁ , Guiqun Wang ₁ , Liu Liu ₁ , Runjie Wu ₁ , Yi Wu ₁ , Cheng Fang ₁ , Xinhong Zhou ₁ , Jing Jiao ₁ , Ying Gu ₁ , He Zhou ₁ , Zhenhui Xie ₁ , Zhiwu Sun ₁ , Dakai Chen ₁ , Ken Dai ₂ , Dongxu Wang ₂ , Wei Tang ₁ , Teddy Tat Chi Yang ₁

Affiliation

程序性细胞死亡1（PD-1）单克隆抗体已获得监管机构的批准，可用于治疗各种类型的癌症，其机制涉及T细胞功能的恢复。我们在本文中以1.70Å的分辨率报道了与PD-1细胞外域（ECD）结合的完全人源单克隆抗体mAb059c片段抗原结合（Fab）的X射线晶体结构。结构分析表明：1）包含PD-1 C'D，BC和FG环片段的表位有助于mAb059c相互作用，2）C'D环的独特构型和R86的不同方向可以捕获抗体互补决定区（CDR）形成PD-1，并形成一个盐桥接触-ASP101（HCDR3）：ARG86（PD-1），3）通过第二个盐桥和两个主链氢键维持FG与轻链（LC）CDR3的接触。界面分析表明，PD-1上的N-糖基化位点49、74和116不接触mAb059c。而BC环中的N58被mAb059c重链CDR1和CDR2识别。N58的突变减弱了mAb059c与PD-1的结合。这些发现和新颖的抗PD-1抗体将有助于更好地理解抗PD-1 mAb对PD-1受体的分子识别机制，从而能够开发出具有更大疗效范围的新疗法满足未满足的医疗需求。而BC环中的N58被mAb059c重链CDR1和CDR2识别。N58的突变减弱了mAb059c与PD-1的结合。这些发现和新颖的抗PD-1抗体将有助于更好地理解抗PD-1 mAb对PD-1受体的分子识别机制，从而能够开发出具有更大疗效范围的新疗法满足未满足的医疗需求。而BC环中的N58被mAb059c重链CDR1和CDR2识别。N58的突变减弱了mAb059c与PD-1的结合。这些发现和新颖的抗PD-1抗体将有助于更好地理解抗PD-1 mAb对PD-1受体的分子识别机制，从而能够开发出具有更大疗效范围的新疗法满足未满足的医疗需求。

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Study of the interactions of a novel monoclonal antibody, mAb059c, with the hPD-1 receptor.

Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C'D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C'D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact - ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs.

更新日期：2019-11-29

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