Abstract 7539: First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity

Abstract

Abstract NTX1088, a first-in-class anti-PVR (CD155) mAb, is currently evaluated in a Phase 1, open-label, multi-center study (NCT05378425). The trial initiated at MD Anderson Cancer Center, and was expanded into additional sites, including City of Hope, Ochsner Health, Sheba Medical Center and Hadassah Medical Center. Study objectives are safety, dose-finding, and efficacy with focus on pharmacokinetics, pharmacodynamics, and biomarker discovery. NTX1088 is investigated as a single agent and in combination with the anti-PD1 mAb, pembrolizumab (Keytruda) in patients with advanced solid malignancies. Ongoing dose escalation demonstrates a safe profile across ascending dose levels. NTX1088 is a high affinity humanized IgG4-S228P mAb that binds PVR and blocks all known interacting receptors at a single nM EC50. PVR, is a highly upregulated membrane protein on numerous tumor cells. PVR expression has been associated with worse patient outcome, due to its central role in immune suppression. PVR’s impact is mediated through interaction with the key stimulatory receptor, DNAM1 (CD226), on T and NK cells, leading to internalization and degradation of DNAM1. PVR also interacts with the inhibitory immune checkpoint receptors, TIGIT, CD96 and KIR2DL5A. Blocking PVR by NTX1088 has multiple immune-stimulating roles, through restoration of DNAM1 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, and its restoration by NTX1088 is a novel MoA, not demonstrated previously by other therapies.In vitro, as a monotherapy, NTX1088 significantly increased immune cell activation, superior to TIGIT, CD112R, and PD1 antibody blockade, leading to a 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. Synergy was obtained when NTX1088 was combined with PD1 blockers, or with the anti-CD112R mAb, NTX2R13.Syngeneic models of PVRK.O, demonstrated a complete immune-mediated tumor regression. Numerous humanized murine xenograft models were investigated whereby NTX1088 exhibited robust tumor growth inhibition as a standalone and in combination with PD1 blockade.In conclusion, PVR blockade by NTX1088 has a remarkable pre-clinical efficacy, suggesting a potential clinical breakthrough, based on its ability to simultaneously overcome multiple tumor escape mechanisms. First-in-human (FIH) trial is currently ongoing and biomarker analysis is showing initial mechanistic proof of concept for NTX1088 mode of action, including the restoration of DNAM1 surface expression on patients’ immune cells. This is the first case of surface DNAM1 elevation in clinical settings. Citation Format: Anas Atieh, Akram Obeidat, Alon Vitenshtein, Guy Cinamon, Keren Paz, Tihana Roviš, Paola Brilc, Ofer Mandelboim, Stipan Jonjic, Pini Tsukerman. First-in-class anti-PVR mAb NTX1088 advancing through Phase I: Safe and potent in restoring DNAM1 expression to enhance antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7539.