Exploring strategies to enhance DNAM1 signaling and inhibit the TIGIT/PVRIG axis
Oleg Demin Jr (1), Galina Kolesova (1), Oleg Demin (2), Dmitry Shchelokov (1)
(1) InSysBio CY, Cyprus; (2) InSysBio UK, UK
Objectives: PVR (CD155) and CD112 are two ligands from the Nectin/Nectin-like family which are frequently expressed on different types of tumor cells. PVR binds to inhibitory receptors TIGIT and CD96 triggering a direct inhibitory signal in T and NK-cells and binds to co-stimulatory receptor DNAM1 (CD226) causing its downregulation. CD112 binds to inhibitory receptor PVRIG expressed on T and NK-cells and to DNAM1 stimulating T and NK-cells. Late-stage clinical trials of anti-TIGIT monoclonal antibodies (mAbs) showed controversial results regarding efficacy [1-3]. A lot of anti-PVR, anti-CD96 and anti-PVRIG mAbs and their combinations with anti-TIGIT mAbs and other therapies are currently in early clinical development. The objective of this study was to compare how the complete inhibition of TIGIT, PVRIG, PVR or their combinations affects the engagement of TIGIT, CD96, PVRIG and DNAM1.
Methods: We developed a mechanistic model describing surface PVR, CD112 on cancer cells and TIGIT, CD96, DNAM1, PVRIG on CD8 T-cells and the interaction of these ligands and receptors in immunological synapse (IS) between CD8 T-cell and cancer cell in the tumor. These interactions in IS occur in the 2D dimension. Soluble PVR and its binding with CD96, TIGIT and DNAM1 in 3D dimension are also described in the model. In vitro data and data on the expression of described ligands and receptors in blood and tumor were used to identify parameters. Validation of the model was done against the data on downmodulation of DNAM1 and TIGIT on CD8 T-cells in the tumor in comparison to the blood. Total DNAM1 on the surface of CD8 T-cell in the tumor and engagement of TIGIT, CD96, PVRIG and DNAM1 in IS (i.e., numbers of PVR:TIGIT, PVR:CD96, CD112:PVRIG, PVR:DNAM1 and CD112:DNAM1 complexes) were simulated under 100% inhibition of TIGIT, PVR, PVRIG, TIGIT and PVRIG, or PVR and PVRIG.
Results: TIGIT blockade didn’t increase total DNAM1 and bound DNAM1 in IS. Moreover, there was an enhancement of CD96 engagement upon the TIGIT blockade. The reason is an increase of available free PVR which binds to DNAM1 causing its downmodulation and to CD96. Inhibition of PVRIG resulted in an increase of bound DNAM1 (in ~1.3 times), but not total DNAM1. The combination of TIGIT and PVRIG blockade didn’t increase engaged DNAM1 above the level observed for anti-PVRIG monotherapy. Inhibition of PVR resulted in a strong increase of total DNAM1 (in ~2.5 times) and a moderate increase of bound DNAM1 (in ~1.3 times) in addition to the disruption of TIGIT and CD96 engagements. The combination of PVR and PVRIG blockade resulted in the strongest increase of bound DNAM1 (in ~ 2 times) in addition to the disruption of TIGIT, CD96 and PVRIG engagements.
Conclusions: The model captures complex interactions of receptors and ligands of TIGIT/PVRIG axis, resulting in complex dynamics of DNAM1. The failure to enhance DNAM1 engagement during TIGIT inhibition could explain the observed lack of efficacy in the phase 3 trials of tiragolumab (anti-TIGIT mAb) used in combination with atezolizumab (anti-PDL1 mAb) in lung cancer [3]. Targeting PVR alone or in combination with PVRIG is predicted to be a better strategy than targeting TIGIT or TIGIT in combination with PVRIG.
References:
[1] Cho et al. Lancet Oncol . 2022 Jun;23(6):781-792.
[2] https://www.gene.com/media/press-releases/14998/2023-08-22/genentech-provides-update-on-phase-iii-s
[3] Rudin et al. J Clin Oncol . 2024 Jan 20;42(3):324-335.