Journal Article

INBRX-106: a hexavalent OX40 agonist that drives superior antitumor responses via optimized receptor clustering

Holay, Nisha, Staebler, Thi, Simons, Noah D, Kasiewicz, Melissa J, Polovina, Anya, Rolig, Annah S, Koguchi, Yoshinobu, Redmond, William L, Eckelman, Brendan P, Yadav, Rashi, Becklund, Bryan, Ahn, Sae Jeong, de Durana, Yaiza Diaz

2025

Overview

BackgroundImmunotherapies targeting immune checkpoint inhibitors have revolutionized cancer treatment but are limited by incomplete patient responses. Costimulatory agonists like OX40 (CD134), a tumor necrosis factor receptor family member critical for T-cell survival and differentiation, have shown preclinical promise but limited clinical success due to suboptimal receptor activation. Conventional bivalent OX40 agonists fail to induce the trimeric engagement required for optimal downstream signaling. To address this, we developed INBRX-106, a hexavalent OX40 agonist designed to enhance receptor clustering independently of Fc-mediated crosslinking and boost antitumor T-cell responses.MethodsWe assessed INBRX-106’s effects on receptor clustering, signal transduction, and T-cell activation using NF-kß reporter assays, confocal microscopy, flow cytometry, and single-cell RNA sequencing. Therapeutic efficacy was evaluated in murine tumor models and ex vivo human samples. Clinical samples from a phase I/II trial (NCT04198766) were also analyzed for immune activation.ResultsINBRX-106 demonstrated superior receptor clustering and downstream signaling compared with bivalent agonists, leading to robust T-cell activation and proliferation. In murine models, hexavalent OX40 agonism resulted in significant tumor regression, enhanced survival, and increased CD8+ T-cell effector function. Clinical pharmacodynamic analysis in blood samples from patients treated with INBRX-106 showed heightened T-cell activation and proliferation, particularly in central and effector memory subsets, validating our preclinical findings.ConclusionsOur data establish hexavalent INBRX-106 as a differentiated and more potent OX40 agonist, showcasing its ability to overcome the limitations of conventional bivalent therapies by inducing superior receptor clustering and multimeric engagement. This unique clustering mechanism amplifies OX40 signaling, driving robust T-cell activation, proliferation, and effector function in preclinical and clinical settings. These findings highlight the therapeutic potential of INBRX-106 and its capacity to redefine OX40-targeted immunotherapy, providing a compelling rationale for its further clinical development in combination with checkpoint inhibitors.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Agonists / Animals / Antibodies / Basic and Translational Cancer Immunology / Cell growth / Cell Line, Tumor / Clinical Trials, Phase I as Topic / Clinical Trials, Phase II as Topic / Cytotoxicity / Female / Humans / Immunity (Disease) / Immunotherapy / Immunotherapy - methods / Ligands / Lymphocyte Activation - drug effects / Lymphocytes / Mice / Microscopy / Oncology / Original Research / Proteins / Receptors, OX40 - agonists / Receptors, OX40 - metabolism / Signal transduction / Solid tumor / T cell / Tumor infiltrating lymphocyte - TIL