(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL
Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.
Contributed by Morgan Janes
(1) Holay N (2) Yadav R (3) Ahn SJ (4) Kasiewicz MJ (5) Polovina A (6) Rolig AS (7) Staebler T (8) Becklund B (9) Simons ND (10) Koguchi Y (11) Eckelman BP (12) de Durana YD (13) Redmond WL
Holay et al. engineered INBRX-106, an OX40 agonist composed of six binding domains fused to a human IgG1 Fc. INBRX-106 promoted distinct OX40 surface clustering and internalization in T cells, improving NFκB signaling and CD8+ T cell-dependent tumor control compared to lower-valency agonists. The therapy enhanced CD8+ T cell proliferation in tdLNs and frequency in tumors, and upregulated cytokine–receptor interaction and cytotoxicity genes. Interestingly, INBRX-106 only modestly reduced Tregs compared to other agonists. In a phase 1/2 trial, INBRX-106 synergized with ICB to enhance peripheral T cell proliferation and activation.
Contributed by Morgan Janes
BACKGROUND: Immunotherapies 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. METHODS: We assessed INBRX-106's effects on receptor clustering, signal transduction, and T-cell activation using NF-k§ 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. RESULTS: INBRX-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. CONCLUSIONS: Our 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.
Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA
Author Info: (1) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (2) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (3) Inhibrx Biosciences Inc, La Jolla, California, USA. (4) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (5) Inhibrx Biosciences Inc, La Jolla, California, USA. (6) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. Oregon Health and Science University, Portland, Oregon, USA. (7) Inhibrx Biosciences Inc, La Jolla, California, USA. (8) Inhibrx Biosciences Inc, La Jolla, California, USA. (9) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. (10) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA. The Ohio State University, Columbus, Ohio, USA. (11) Inhibrx Biosciences Inc, La Jolla, California, USA. (12) Inhibrx Biosciences Inc, La Jolla, California, USA william.redmond@providence.org yaiza@inhibrx.com. (13) Earle A Chiles Research Institute, Providence Cancer Institute, Portland, Oregon, USA william.redmond@providence.org yaiza@inhibrx.com.
Citation: J Immunother Cancer 2025 May 21 13: Epub05/21/2025
