A Novel <scp>d</scp>‐Peptide Identified by Mirror‐Image Phage Display Blocks TIGIT/PVR for Cancer Immunotherapy
Xiuman Zhou, Chao Zuo, Wanqiong Li, Weiwei Shi, Xiaowen Zhou, Hongfei Wang, Shaomeng Chen, Jiangfeng Du, Guanyu Chen, Wenjie Zhai, Wenshan Zhao, Yahong Wu, Yuanming Qi, Lei Liu, Yanfeng Gao
Abstract
Abstract The low response rate and adaptive resistance of PD‐1/PD‐L1 blockade demands the studies on novel therapeutic targets for cancer immunotherapy. We discovered that a novel immune checkpoint TIGIT expressed higher than PD‐1 in many tumors especially anti‐PD‐1 resistant tumors. Here, mirror‐image phage display bio‐panning was performed using the d ‐enantiomer of TIGIT synthesized by hydrazide‐based native chemical ligation. d ‐peptide D TBP‐3 was identified, which could occupy the binding interface and effectively block the interaction of TIGIT with its ligand PVR. D TBP‐3 showed proteolytic resistance, tumor tissue penetrating ability, and significant tumor suppressing effects in a CD8 + T cell dependent manner. More importantly, D TBP‐3 could inhibit tumor growth and metastasis in anti‐PD‐1 resistant tumor model. This is the first d ‐peptide targeting TIGIT, which could serve as a potential candidate for cancer immunotherapy.