Unlocking Cancer Immunotherapy: The Impact of GSK3174998, a Robust Anti-OX40 Agonist

GSK3174998 is an IgG1 humanized monoclonal antibody targeting OX40, a receptor on activated T cells, and is being developed for cancer immunotherapy. It is currently undergoing Phase I clinical trials. The drug is designed to enhance the activity of effector T cells while reducing the suppressive action of regulatory T cells within tumors. Studies have shown that OX40 agonists can boost immune responses and are synergistic with PD1 inhibitors.

In preclinical trials, GSK3174998 exhibited cross-reactivity with cynomolgus monkey OX40, facilitating toxicology and pharmacological studies. To assess its antitumor effects, a surrogate antibody was used in mouse models of lymphoma and colon cancer. The study evaluated the impact of the drug on T cell proliferation, cytokine secretion, and gene expression both within tumors and systemically.

Results indicated that GSK3174998 was well-tolerated and stimulated the proliferation of CD4+ and CD8+ T cells in vitro. It also suppressed the differentiation of Tregs and induced the production of Th1 cytokines, which was further increased by the addition of pembrolizumab. In vivo studies with the surrogate OX40 antibody showed a significant, durable anti-tumor effect, particularly when combined with a PD1 inhibitor. The efficacy was associated with changes in various immunological markers.

Computational and immunohistochemical analyses were used to identify human tumors with high OX40 and PDL1 expression, indicating potential responsiveness to the therapy. The findings support the ongoing Phase I clinical trial of GSK3174998 as a monotherapy and in combination with pembrolizumab for patients with advanced solid tumors.