OX40 (CD134), a member of the tumor necrosis factor receptor (TNFR) superfamily, is primarily expressed on activated T cells, particularly CD4+ and CD8+ effector T cells. Its ligand, OX40L (CD252), is found on antigen-presenting cells. The OX40/OX40L signaling pathway plays a critical role in promoting T cell survival, proliferation, and memory formation, serving as a co-stimulatory immune checkpoint. Therapeutic targeting of OX40 has emerged as a promising strategy in immuno-oncology and autoimmune diseases.
Agonistic OX40 antibodies enhance T cell activation and effector functions, potentially overcoming tumor-induced immunosuppression. Preclinical studies show that OX40 agonists synergize with checkpoint inhibitors (e.g., anti-PD-1) to boost antitumor immunity. Conversely, antagonistic OX40 antibodies block OX40/OX40L interactions, dampening excessive T cell responses in autoimmune disorders like rheumatoid arthritis or psoriasis.
Clinical trials of OX40-targeting antibodies have yielded mixed results, with efficacy influenced by factors such as antibody epitope, binding affinity, and dosing schedules. Safety profiles generally show manageable toxicity, though cytokine release syndrome remains a concern. Ongoing research focuses on optimizing antibody design (e.g., bispecific antibodies) and combination therapies to improve clinical outcomes. Biomarker development is also critical to identify patient populations most likely to benefit from OX40-targeted therapies.