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Biophysical characterization of PVR family interactions and therapeutic antibody recognition to TIGIT
Sj J Diong1, Aarti Jashnani1, Andrew W Drake1
1Discovery Biologics, Bristol Myers Squibb, Redwood City, CA, USA.
Abstract:
The clinical successes of immune checkpoint blockade have invigorated efforts to activate T cell-mediated responses against cancer. Targeting members of the PVR family, consisting of inhibitory receptors TIGIT, CD96, and CD112R, has been an active area of clinical investigation. In this study, the binding interactions and molecular assemblies of the PVR family receptors and ligands have been assessed in vitro. Furthermore, the anti-TIGIT monoclonal antibody BMS-986207 crystal structure in complex with TIGIT was determined and shows that the antibody binds an epitope that is commonly targeted by the CD155 ligand as well as other clinical anti-TIGIT antibodies. In contrast to previously proposed models, where TIGIT outcompetes costimulatory receptor CD226 for binding to CD155 due to much higher affinity (nanomolar range), our data rather suggest that PVR family members all engage in interactions with relatively weak affinity (micromolar range), including TIGIT and CD155 interactions. Thus, TIGIT and other PVR inhibitory receptors likely elicit immune suppression via increased surface expression rather than inherent differences in affinity. This work provides an improved foundational understanding of the PVR family network and mechanistic insight into therapeutic antibody intervention.
Insights
Immune checkpoint blockade research is advancing cancer therapies. This study reveals that TIGIT and similar immune receptors suppress T cells through surface expression, not just binding affinity, offering new therapeutic insights.
Area of Science:
- Immunology
- Molecular Biology
- Structural Biology
Background:
- Immune checkpoint blockade has shown clinical success in cancer treatment.
- The PVR family of receptors, including TIGIT, CD96, and CD112R, are key targets for cancer immunotherapy.
- Understanding the interactions within the PVR family is crucial for developing effective therapies.
Purpose of the Study:
- To investigate the binding interactions and molecular assemblies of PVR family receptors and ligands.
- To determine the crystal structure of an anti-TIGIT antibody in complex with TIGIT.
- To elucidate the mechanism by which TIGIT and related receptors mediate immune suppression.
Main Methods:
- In vitro assessment of PVR family receptor-ligand interactions.
- X-ray crystallography to determine the structure of BMS-986207 bound to TIGIT.
- Affinity measurements using nanomolar and micromolar ranges.
Main Results:
- The anti-TIGIT antibody BMS-986207 binds to an epitope shared by the CD155 ligand and other clinical antibodies.
- Contrary to prior models, TIGIT and CD155 interactions occur at weak affinities (micromolar range).
- PVR family members likely suppress immune responses through increased surface expression rather than high-affinity binding.
Conclusions:
- This study provides a refined understanding of the PVR receptor-ligand network.
- The findings suggest that immune suppression by TIGIT and related receptors is primarily mediated by surface expression levels.
- Mechanistic insights into therapeutic antibody intervention against the PVR family are established.
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