Targeting Glycosylated PD-1 Induces Potent Anti-Tumor Immunity

Authors

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

Organizations

1. Tianjin Medical University General Hospital
2. The University of Texas MD Anderson Cancer Center
3. R&D, STCube Pharmaceuticals
4. Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center
5. StCube Pharmaceuticals
6. Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center
7. Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center
8. Institute of Biological Chemistry, Academia Sinica
9. China Medical University
10. President, China Medical University

Abstract

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

Epitope Mapping
MALDI-ToF
HM4

Discussion

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.

Source