Abstract P102: NTX-1088, A potent first-in-class, anti-PVR mAb, restores expression and function of DNAM1 for optimal DNAM1-mediated antitumor immunity

The poliovirus receptor (PVR, CD155) represents a resistance mechanism to approved immune checkpoint inhibitors (ICIs). It is a key regulator of immune activation, that modifies immune function through multiple mechanisms. Increased levels of PVR expression on tumor cells have been associated with resistance to anti-PD-(L)1 therapy in clinical settings, while loss of PVR led to reduced tumor growth in multiple pre-clinical models. Targeting PVR using blocking mAbs offers an attractive therapeutic approach for patients with advanced cancer. NTX-1088 is a first-in-class, potent, anti-PVR mAb being developed for the treatment of solid tumors. The antibody binds to PVR with high affinity, blocks its interactions with TIGIT and CD96, and thus interrupt their immunosuppressive signaling. However, NTX-1088 forte is manifested through its ability to block the critical interaction between PVR and the costimulatory receptor DNAM1 (CD226). This blockade prevents internalization of DNAM1, restores its expression on the surface of immune cells and results in a robust antitumor activation. NTX-1088 was tested using several tumor and immune cell co-culture systems. Various cancer cell lines were co-incubated with relevant immune effector cells from healthy human donors, in the presence of NTX-1088, as a single agent and in combination with anti-PD-1 mAb (pembrolizumab). NTX-1088 significantly increased immune cell activation, as measured by IFNg release from activated polyclonal CD8+ T cells, induction of CD137 and killing of tumor cells. When tested in combination with pembrolizumab, NTX-1088 further increased all measured activation parameters, suggesting a potential synergistic effect. When compared to anti-TIGIT mAb (tiragolumab), NTX-1088 demonstrated clear superiority in its ability to activate T and NK cells. Furthermore, NTX-1088 in combination with pembrolizumab was significantly superior to the combination of pembrolizumab with anti-TIGIT mAb. Interestingly, NTX-1088 as a single agent showed a comparable effect to that of the combined blockade of TIGIT and CD112R, and further synergized with anti-CD112R for maximal activity. NTX-1088 was the only intervention that significantly restored DNAM1 levels, whereas blockade of DNAM1 reduced the activity of NTX-1088 to levels comparable to that of anti-TIGIT mAb. Humanized murine models confirmed the above observations; NTX-1088 exhibited strong efficacy, inducing a robust tumor growth inhibition, accompanied by significantly higher prevalence of CD137+, DNAM1+, CD8+ tumor infiltrating cells, compared to control treated mice. This is the first report of drug-induced DNAM1 restoration and immune activation. NTX-1088 shows, for the first time, exclusive triple mechanism of action, whereby simultaneous and effective blockade of TIGIT and CD96 is complemented by the efficient restoration of DNAM1. This is a step change in antitumor immune activation, which will soon be tested in the clinic. Citation Format: Pini Tsukerman, Anas Atieh, Akram Obeidat, Keren Paz, Guy Cinamon, Tihana Lenac Roviš, Lea Hirsl, Paola Kucan Brilc, Stipan Jonjic, Ofer Mandelboim. NTX-1088, A potent first-in-class, anti-PVR mAb, restores expression and function of DNAM1 for optimal DNAM1-mediated antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P102.