The binding epitope of sintilimab on PD-1 revealed by AbMap
| Autor: | Shu-Juan Guo, He-wei Jiang, Chuansheng Hu, Nan Wang, Yani Kang, Yang Li, Zhaowei Xu, Hai-nan Zhang, Dan-yun Lai, Huan Qi, Hua Li, Fan-Lin Wu, Xiaodong Zhao, Qing-Feng Meng, Ming-liang Ma, Sheng-Ce Tao |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Programmed Cell Death 1 Receptor Biophysics Antibodies Monoclonal Humanized Biochemistry Epitope Flow cytometry Epitopes 03 medical and health sciences Antineoplastic Agents Immunological 0302 clinical medicine Western blot Cancer immunotherapy medicine Humans medicine.diagnostic_test biology Chemistry Point mutation General Medicine Immune checkpoint Cell biology 030104 developmental biology Epitope mapping biology.protein Antibody Epitope Mapping 030217 neurology & neurosurgery |
| Zdroj: | Acta Biochimica et Biophysica Sinica. 53:628-635 |
| ISSN: | 1672-9145 |
| Popis: | PD-1 plays an important role as an immune checkpoint. Sintilimab is a newly approved PD-1 antibody for cancer immunotherapy with an unknown binding epitope on PD-1. In this study, to elucidate the molecular mechanism by which sintilimab blocks PD-1 activation, we applied Antibody binding epitope Mapping (AbMap) to identify the binding epitope of sintilimab. An epitope was successfully identified, i.e. SLAPKA, aa 127-132. By constructing a series of point mutations, the dominant residues S127, L128, A129, P130, and A132 of PD-1 were further validated by western blot analysis, biolayer interferometry, and flow cytometry. Structural analysis showed that the epitope is partially within the binding interface of PD-1 and PD-L1, and this epitope also partially overlaps with that of nivolumab and pembrolizumab. These results demonstrate that sintilimab can attenuate PD-1 activation by directly competing with the interaction between PD-1 and PD-L1 through binding with the key residues of the FG loop on PD-1. This study also demonstrates the high efficiency and accuracy of AbMap for determining the binding epitope of therapeutic antibodies. |
| Databáze: | OpenAIRE |
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