GSK3174998 is an agonistic IgG1-anti-OX40 (aOX40) monoclonal antibody (mAB) that binds to OX40 receptors expressed on activated T cells. GSK3174998 engages the immune system via several T cell-mediated pathways. The following studies examine 1) OX40 receptor expression and enumeration in T cell populations in patient tumors 2) influence of IgG isotype on GSK3174998-mediated FcγRIIIa engagement 3) dosing regimen effects on efficacy and pharmacodynamic response with the anti-OX40 /anti-PD-1 (aPD-1) combination in preclinical models.
In vitro, an FcγRIIIa reporter assay was used to compare GSK3174998 with other IgG isotype variants and its combination with pembrolizumab. In vivo studies were performed to evaluate tumor growth and survival following concurrent and sequential dosing regimens of aOX40 ± aPD-1 mAbs. Biomarkers of response were monitored by flow cytometry, NanoString, TCRb sequencing and multiplex cytokine analysis.
OX40 receptor density was observed as highest on intra-tumoral Tregs (compared to CD4 effectors and CD8+ T cells) in several primary tumor samples. FcγRIIIa engagement correlated strongly with receptor density and was dependent on an IgG1 wild type Fc isotype. GSK3174998 in combination with pembrolizumab increased inflammatory and Th1 cytokine production in human PBMCs. In vivo studies suggest that concurrent dosing of aOX40 with aPD-1 offers superior anti-tumor efficacy and survival compared to sequential regimens. Furthermore, combination with aPD-1 led to enhanced expression of inflammatory and Th1 cytokines, increased T cell activation, proliferation and cytotoxicity compared to either monotherapy. Concurrent treatment also significantly increased T cell clonal expansion in the periphery, increased clonality both in blood and tumor and induced migration of the expanded clones into the tumors over monotherapy.
Overall, the combination of aOX40 and aPD-1 elicited stronger qualitative and quantitative changes in immune markers both in vitro and in vivo. The potential synergy of concurrent dosing formed the basis for combining GSK3174998 with pembrolizumab in phase I/II clinical studies.
Clinical trial identification
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H. Jackson, D. Kilian, S. Bhattacharya, P. Bojczuk, L. Seestaller Wehr, A. Hahn, H. Shi, M. Bi, M. Adam, J. Jing, P. Morley, C. Hopson, E. Paul, A. Hoos, J. Smothers, R. Srinivasan, N. Yanamandra: Stockholder, Employee: Glaxosmithkline Pharmaceuticals.