Targeting glycosylated PD-L1 by antibody-drug conjugate

Identification: Lim, Seung-Oe


Targeting glycosylated PD-L1 by antibody-drug conjugate
Seung-Oe Lim1,2,#, Chia-Wei Li1,#,  Mien-Chie Hung1*
1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 2Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA
#These authors contributed equally to this work.
*Corresponding Author
EGF signaling inhibits GSK3β-β-TrCP-mediated degradation of N-linked glycosylated programmed death ligand-1 (PD-L1), resulting in PD-L1 protein destabilization and enhanced immune checkpoint blockade efficacy. Here we show that EGF also mediates PD-L1 and receptor programmed cell death protein-1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer cells. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces potent cell-killing effect as well as bystander-killing effect on adjacent cancer cells without PD-L1 expression with virtually no detectable toxicities. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.


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