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Poliovirus receptor (PVR, CD155), expressed on the surface of cancer cells, represents a resistance mechanism to approved immune checkpoint inhibitors (ICIs). It is a key regulator of immune activation, that modifies function through multiple mechanisms. Increased PVR expression levels have been associated with resistance to anti-PD-(L)1 therapy, while loss of PVR led to reduced tumor growth. Targeting PVR using mAbs offers an intriguing therapeutic approach for patients with advanced cancers, who are not responding to other ICIs.NTX-1088 is a potent, first-in-class, anti-PVR mAb, developed for the treatment of patients with locally advanced and metastatic solid tumors. The antibody binds PVR with high affinity, blocks its interactions with TIGIT and CD96, and preventing their inhibitory signaling. Moreover, NTX-1088 block the critical interaction between PVR and DNAM1 (CD226). This blockade prevents internalization of DNAM1, restores its expression on the surface of immune cells and results in a robust antitumor activity.NTX-1088 was thoroughly investigated in vitro and in vivo. Various cancer cell lines were co-cultured with immune effector cells from healthy human donors, in the presence of NTX-1088, alone and in combination with anti-PD-1 mAb (pembrolizumab). NTX-1088 significantly increased immune cell activation, as measured by IFN-gamma release from activated polyclonal CD8+ T cells, induction of CD137 and killing of tumor cells. When tested in combination with pembrolizumab, NTX-1088 further improved all measured activation parameters. Synergistic effect was obtained when NTX-1088 was combined with the anti-CD112R mAb, NTX-2R13. The effect surpassed that of TIGIT and CD112R combined inhibition. When compared to anti-TIGIT mAb (tiragolumab), NTX-1088 demonstrated clear superiority in activating T and NK cells as a single agent. Furthermore, NTX-1088 in combination with pembrolizumab, was superior to the combination of pembrolizumab with tiragolumab. Importantly, NTX-1088 was the only intervention that significantly restored DNAM1 levels, leading to an enhanced antitumor immune surveillance. Numerous humanized murine models, including pembrolizumab-insensitive models, confirmed the above observations; NTX-1088 exhibited a robust tumor growth inhibition, accompanied by significantly higher prevalence of CD137+, DNAM1+, CD8+ T cells within the tumor bed, compared to mice treated by other ICIs. 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 that provides a remarkable and differentiated addition to the armamentarium available to patients and their treating oncologists. An IND will be open during 2Q2022. Citation Format: Akram Obiedat, Anas Atieh, Guy Cinamon, Keren Paz, Paola Kucan Brilc, Lea Hirsl, Tihana Lenac Roviš, Ofer Mandelboim, Stipan Jonjic, Pini Tsukerman. NTX-1088, a first-in-class anti-PVR mAb mediates DNAM1-dependent antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5534. |
