ArticleJournal for immunotherapy of cancer2024
Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations.
Article in Journal for immunotherapy of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Realizing the potential of agonistic antibody immunotherapy.Nature reviews. Drug discovery · 2026Review
- Tumor evolution: signaling pathways, molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- Immunogenic tumor cell death and T-cell-derived IFN-γ elicit tumoricidal macrophages to potentiate OX40 immunotherapy.Cell reports. Medicine · 2026Article
- HFB301001, an OX40-based immunotherapy, drives Treg clearance and CTL activation through optimized OX40 receptor clustering.Journal for immunotherapy of cancer · 2026Article
- Magnesium ion hydrogel enhances resistance to radiation-induced bone injury by modulating the bone immune microenvironment and promoting microvascularization.Regenerative biomaterials · 2025Article
- Microwave ablation triggers OX40L-mediated disruption of TNFRSF4+ Treg immunosuppressive activity.Frontiers in immunology · 2025Article
- Regulatory T cells in cancer: from immunosuppression to therapeutic targeting.Frontiers in immunology · 2025Review
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Authors and funding
32 authors.
Funding
Abstract
backgroundOX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.
methodsAnti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.
resultsIsotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.
conclusionsThese findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.
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