INBRX-106, a novel Hexavalent OX40 agonist, potentiates T-cell receptor clustering, leading to improved activation and potent anti-tumor responses 3058

Abstract Description OX40 agonists have shown underwhelming clinical efficacy. One explanation is the suboptimal agonism of prior bivalent OX40 Abs, which lack the ability to effectively cluster the OX40 receptor and trigger optimal downstream signaling. To address this limitation, we developed a hexavalent OX40 agonist (INBRX-106) that mediates higher-order clustering, boosting downstream signaling and enhancing anti-tumor immunity. We assessed peripheral changes by flow cytometry after INBRX-106 +/- aPD-1 treatment in patients from a phase I/II clinical trial (NCT04198766). Consistent with stronger OX40 signaling, we observed robust increases in effector and memory T cell proliferation (Ki-67) following INBRX-106 mono- and combination therapy. These effects correlated with increases in activation (CD38+HLA-DR+) and were sustained in subsequent cycles of both treatment regimens, though more prominently in the combination treated cohort. We also observed increases in effector and memory CD8 T cells and Th1 CD4+ T cells, while Tregs remained unchanged. Single-cell RNA-seq confirmed these findings, with post-treatment samples showing increased expression of Ki-67, granzyme B, perforin, CD38, and HLA-DR. Thus, these data indicates that INBRX-106 induces potent agonistic OX40 activity in CD8 and CD4 T cells. Overall, our results demonstrate that INBRX-106 is a potent OX40 agonist that is biologically active in patients supporting further efficacy evaluation in clinical trials (NCT04198766/NCT06295731). Funding Sources Funding was provided by an Inhibrx research grant, the M. J. Murdock Charitable Trust, and the Providence Portland Medical Foundation (WLR). Confocal microscopy ZEISS LSM980 was funded by S10 OD030417. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)