Issafras, Hassan and Fan, Shilong and Tseng, Chi-Ling and Cheng, Yunchih and Lin, Peihua and Xiao, Lisa and Huang, Yun-Ju and Tu, Chih-Hsiang and Hsiao, Ya-Chin and Li, Min and Chen, Yen-Hsiao and Ho, Chien-Hsin and Li, Ou and Wang, Yanling and Chen, Sandra and Ji, Zhenyu and Zhang, Eric and Mao, Yi-Ting and Liu, Eugene and Yang, Shumin and Jiang, Weidong and Balalaeva, Irina V. (2021) Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy. PLOS ONE, 16 (12). e0257972. ISSN 1932-6203
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Abstract
Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10’s mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10’s epitope was closer to Pembrolizumab’s epitope than Nivolumab’s epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.
Item Type: | Article |
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Subjects: | Science Repository > Medical Science |
Depositing User: | Managing Editor |
Date Deposited: | 24 Jan 2023 05:00 |
Last Modified: | 25 May 2024 07:30 |
URI: | http://research.manuscritpub.com/id/eprint/1081 |