Abstract 6657: Phase I trial of first-in-class anti-PVR mAb NTX1088: Restoration of DNAM1 expression as MOA for enhanced antitumor immunity

Abstract NTX1088, a first-in-class anti-PVR (CD155) monoclonal antibody (mAb), is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425), initiated at MD Anderson Cancer center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 will be investigated as a single agent and combined with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with locally advanced and metastatic solid malignancies. NTX1088 is a humanized, IgG4-S228P mAb that binds PVR with sub-nM affinity and blocks all known interacting receptors with a single nM EC50. PVR, is a membranal protein, highly upregulated on tumor cells, across multiple cancer types. PVR expression has been associated with worse patient outcomes, due to its role in immune suppression. PVR’s impact on immune cells is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. Additionally, PVR is the ligand for the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088, therefore, has a multi-faceted immune-stimulating role, through restoration of DNAM1 expression and its immune activation function, while simultaneously neutralizing TIGIT, CD96 and KIR2DL5A inhibitory signals in immune cells. Importantly, DNAM1 downmodulation was recently identified as a key resistance mechanism to approved immune checkpoint inhibitors (ICIs), and its restoration by NTX1088 is a novel MoA, not demonstrated by other therapies. In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, and was superior to TIGIT, CD112R, and PD1 antibody blockade, leading to greater immune-mediated tumor cell killing, IFNγ secretion, and CD137 induction. Importantly, only NTX1088 was able to restore DNAM1 to the surface of immune cells in all experimental settings. Synergy was observed when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13, in line with the restoration of DNAM1 expression. Numerous humanized murine xenograft models were investigated. NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade. Syngeneic models of PVRK.O resulted in complete immune-mediated tumor regression, including hard to treat colorectal tumors. In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on the ability of simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker data is analyzed to assess clinical impact of the drug and prepare for patient stratification. Citation Format: Anas Atieh, Akram Obiedat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana lenac, Paola Kucan, Marija Mazor, Ofer Mandelboim, Stipan Jonji, Pini Tsukerman. Phase I trial of first-in-class anti-PVR mAb NTX1088: Restoration of DNAM1 expression as MOA for enhanced antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6657.