| Autor: |
Jeong, Tae-Jun, Lee, Hyun-Tae, Gu, Nahyeon, Jang, Yu-Jeong, Choi, Seung-Beom, Park, Ui-Beom, Lee, Sang-Hyung, Heo, Yong-Seok |
| Předmět: |
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| Zdroj: |
Biomedicines; Dec2022, Vol. 10 Issue 12, p3154, 13p |
| Abstrakt: |
Multiple tumors have responded well to immunotherapies, which use monoclonal antibodies to block the immune checkpoint proteins and reactivate the T-cell immune response to cancer cells. Significantly, the anti-PD-1 antibodies pembrolizumab and nivolumab, which were approved in 2014, have revolutionized cancer therapy, demonstrating dramatic improvement and longer duration. The US FDA authorized the third anti-PD-1 medication, cemiplimab, in 2018 for use in patients with cutaneous squamous cell carcinoma. To further understand the molecular mechanism of the antibody drug, we now reveal the intricate structure of PD-1 in complex with the cemiplimab Fab at a resolution of 1.98 Å. The cemiplimab–PD-1 interaction preoccupies the space for PD-L1 binding with a greater binding affinity than the PD-1/PD-L1 interaction, which is the basis for the PD-1 blocking mechanism. The structure reveals that cemiplimab and dostarlimab are significantly similar in PD-1 binding, although the precise interactions differ. A comparative investigation of PD-1 interactions with the four FDA-approved antibodies reveals that the BC, C'D, and FG loops of PD-1 adopt distinct conformations for optimal interaction with the antibodies. The structural characteristics in this work could be helpful information for developing more potent anti-PD-1 biologics against cancer. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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