This study develops a novel aOX40-mIL2-Fc bispecific antibody that effectively enhances antitumor immune responses by simultaneously depleting tumor-infiltrating Treg cells and promoting CD8+ T-cell proliferation, with significantly reduced toxicity. Additionally, the antibody demonstrates further therapeutic improvement when combined with PD-L1 checkpoint inhibitors, providing a potential strategy to overcome resistance to immune checkpoint blockade.
Literature Overview
This paper titled 'Dual Targeting OX40 and IL-2 Receptor Enhances Antitumor Activity Through Tumor-Infiltrating Treg Depletion and CD8+ T-Cell Proliferation' published in the Journal for Immunotherapy of Cancer reviews the application and mechanistic study of a novel bispecific antibody aOX40-mIL2-Fc in cancer immunotherapy. The antibody significantly improves Treg expansion and systemic toxicity associated with traditional IL-2 therapy while enhancing CD8+ T-cell functionality in the tumor microenvironment to improve antitumor efficacy.
Background Knowledge
OX40, a member of the TNF receptor family, is transiently expressed on activated T cells, particularly highly expressed in Treg cells, making it a critical target for modulating tumor immune microenvironment. IL-2 is a pleiotropic cytokine historically used to stimulate cytotoxic T cells and NK cells, but high-dose IL-2 therapy often causes severe toxicity, limiting its clinical application. Previous studies attempted to reduce Treg activation through IL-2 variants but still encountered peripheral NK cell expansion. This study constructs aOX40-mIL2-Fc through structural optimization and receptor-binding modulation, effectively reducing Treg cells while enhancing CD8+ T-cell proliferation and reducing toxicity. This strategy provides a new direction for cancer immunotherapy, particularly demonstrating synergistic therapeutic enhancement with PD-L1 checkpoint inhibitors.
Research Methods and Experiments
The research team developed the aOX40-mIL2-Fc bispecific antibody by physically blocking the Fab domain and introducing an N88D mutation to reduce IL-2 Rβ-binding affinity. Antitumor activity was evaluated in MC38 and CT26 murine tumor models. T-cell subset dynamics were analyzed using flow cytometry and single-cell RNA sequencing. Synergistic effects with PD-L1 checkpoint inhibitors were assessed, along with toxicity evaluation parameters including weight changes, serum IFN-γ levels, and NK cell expansion.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides an innovative design strategy for IL-2 fusion antibodies, resolving Treg expansion and systemic toxicity in traditional therapies. Future research should explore its application in other tumor models and evaluate long-term efficacy/safety in combination immunotherapies. Additionally, this approach may be applicable to optimizing other immunostimulatory cytokines for precise tumor immune regulation.
Conclusion
This study successfully designed a novel dual-targeting OX40 and IL-2 receptor fusion antibody aOX40-mIL2-Fc that effectively depletes Treg cells while promoting CD8+ T-cell expansion and functional enhancement within the tumor microenvironment. The antibody demonstrated robust antitumor activity with reduced peripheral toxicity in murine models, with further therapeutic enhancement observed when combined with PD-L1 checkpoint inhibitors. The research highlights the critical role of IL-2 signaling in OX40 antibody-mediated antitumor immunity and elucidates the synergistic mechanisms between Treg depletion and CD8+ T-cell activation. This strategy provides a promising framework for future cancer immunotherapy, particularly in overcoming resistance to immune checkpoint inhibitors with significant clinical translation potential.
