Tislelizumab uniquely binds to the CC' loop of PD-1 with slow-dissociated rate and complete PD-L1 blockage
Yuan Hong1, Yingcai Feng1, Hanzi Sun1
1BeiGene Global Research, BeiGene (Beijing) Co., Ltd., China.
Abstract:
Programmed cell death protein 1 (PD-1), an immune checkpoint receptor expressed by activated T, B, and NK cells, is a well-known target for cancer immunotherapy. Tislelizumab (BGB-A317) is an anti-PD-1 antibody that has recently been approved for treatment of Hodgkin's lymphoma and urothelial carcinoma. Here, we show that tislelizumab displayed remarkable antitumor efficacy in a B16F10/GM-CSF mouse model. Structural biology and Surface plasmon resonance (SPR) analyses revealed unique epitopes of tislelizumab, and demonstrated that the CC' loop of PD-1, a region considered to be essential for binding to PD-1 ligand 1 (PD-L1) but not reported as targeted by other therapeutic antibodies, significantly contributes to the binding of tislelizumab. The binding surface of tislelizumab on PD-1 overlaps largely with that of the PD-L1. SPR analysis revealed the extremely slow dissociation rate of tislelizumab from PD-1. Both structural and functional analyses align with the observed ability of tislelizumab to completely block PD-1/PD-L1 interaction, broadening our understanding of the mechanism of action of anti-PD-1 antibodies.
Insights
Tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, shows strong antitumor effects by uniquely targeting the PD-1 CC
Area of Science:
- Immunology and Cancer Research
- Structural Biology
- Pharmacology
Background:
- Programmed cell death protein 1 (PD-1) is a critical immune checkpoint receptor targeted in cancer immunotherapy.
- Tislelizumab is an approved anti-PD-1 antibody used for treating Hodgkin's lymphoma and urothelial carcinoma.
Purpose of the Study:
- To elucidate the mechanism of action and binding characteristics of tislelizumab.
- To investigate the antitumor efficacy of tislelizumab in a preclinical cancer model.
Main Methods:
- Utilized a B16F10/GM-CSF mouse model to assess antitumor efficacy.
- Employed structural biology techniques and Surface Plasmon Resonance (SPR) for epitope mapping and binding kinetics.
- Analyzed the interaction interface between tislelizumab, PD-1, and PD-1 ligand 1 (PD-L1).
Main Results:
- Tislelizumab demonstrated significant antitumor efficacy in the tested mouse model.
- Structural and SPR analyses revealed unique binding epitopes, including the PD-1 CC' loop, crucial for tislelizumab binding.
- Tislelizumab binding largely overlaps with PD-L1 binding on PD-1, with an extremely slow dissociation rate, indicating potent blockade of PD-1/PD-L1 interaction.
Conclusions:
- Tislelizumab exhibits potent antitumor activity through a unique binding mechanism targeting the PD-1 CC' loop.
- The antibody effectively blocks PD-1/PD-L1 interaction, expanding the understanding of anti-PD-1 antibody mechanisms.
- These findings support tislelizumab's therapeutic potential in various cancers.
