254 NTX-1088, a potent anti-PVR Mab induces DNAM1-mediated antitumor immunity

• DOI: 10.1136/jitc-2021-sitc2021.254
• Publication Date: 2021-11-09T15:07:43Z
• Authors: Anas Atieh; Akram Obiedat; Guy Cinamon; Tihana Lenac Rovis; Paola Kucan Brlic; Lea Hirsl; Ofer Mandelboim; Stipan Jonjic; Keren Paz; Pini Tsukerman
• Keywords: CD137

<h3>Background</h3> Poliovirus receptor (PVR, CD155) represents a resistance mechanism to approved immune checkpoint inhibitors (ICIs). It is key regulator of activation, that modifies function through multiple mechanisms. Increased PVR expression levels on tumor cells have been associated with anti-PD-(L)1 therapy, while loss led reduced growth. Targeting using mAbs offers an attractive therapeutic approach for patients advanced cancer, who are not responding other ICIs.NTX-1088 first-in-class, anti-PVR mAb developed the treatment solid tumors and will enter clinical trials early 2022. The antibody binds high affinity, blocks its interactions TIGIT CD96, preventing their inhibitory signaling. Moreover, NTX-1088 forte manifested ability block critical interaction between DNAM1 (CD226). This blockade prevents internalization DNAM1, restores surface results in robust antitumor activity. <h3>Methods</h3> was rigorously tested vitro in-vivo. Various cancer cell lines were incubated effector from healthy human donors, presence NTX-1088, alone combination anti-PD-1 (pembrolizumab). <h3>Results</h3> significantly increased as measured by IFNg release activated polyclonal CD8+ T cells, induction CD137 killing cells. When pembrolizumab, further all activation parameters, suggesting potential synergistic effect. A effect obtained when combined anti-CD112R mAb, NTX-2R13, superior TIGIT-CD112R combinations. compared anti-TIGIT (tiragolumab), demonstrated clear superiority activating NK stand-alone agent. Furthermore pembrolizumab anti-TIGIT.Importantly, only intervention restored levels, whereas activity comparable mAb.Humanized murine models confirmed above observations; exhibited growth inhibition, accompanied higher prevalence CD137+, DNAM1+, mice treated ICIs. <h3>Conclusions</h3> first report drug-induced restoration activation. shows, time, exclusive triple action, whereby simultaneous effective CD96 complemented efficient DNAM1. step change which be validated clinic starting