Linlin Sun1, Chia-Wei Li2, Ezra M. Chung3, Riyao Yang4, Yong-Soo Kim5, Andrew H. Park5, Yun-Ju Lai6, Yi Yang4, Yu-Han Wang4, Jielin Liu7 , Yufan Qiu4 , Kay-Hooi Khoo8, Jun Yao2 4, Jennifer L. Hsu4, Jong-Ho Cha4, Li-Chuan Chan4, Jung-Mao Hsu9, Heng-Huan Lee4, Stephen S. Yoo5, and Mien-Chie Hung10
- Tianjin Medical University General Hospital
- The University of Texas MD Anderson Cancer Center
- R&D, STCube Pharmaceuticals
- Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center
- StCube Pharmaceuticals
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center
- Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center
- Institute of Biological Chemistry, Academia Sinica
- China Medical University
- President, China Medical University
Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T-cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using monoclonal antibodies, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The monoclonal antibody STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing anti-tumor immunity. Together these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy.
CovalX Technology Used
Breakthrough research in cancer treatment by targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints using immunotherapies is discussed in this research. The higher binding affinity to PD-1 than FDA-approved PD-1 antibodies was exhibited by the monoclonal antibody STM418 to specifically target glycosylated PD-1, and potently inhibiting PD-L1/PD-1 binding to enhance anti-tumor immunity. A high-mass MALDI ToF MS analysis using CovalX’s HM4 is used to analyze the antigen-antibody complex samples to detect different mass ranges from 0 to 2,000 kDa. The findings from this research provide insights into the significance of PD-1 glycosylation functionality and reasoning behind the potential immunotherapy strategy of targeting glycosylated PD-1.