Abstract 2398: Dual agonist bispecific antibody targeting OX40 and CD137 mediates anti-tumor immunity and synergizes with PD-1/PD-L1 blockade to improve survival in a syngeneic mouse model

Despite recent advances in cancer patient treatment with checkpoint inhibitors (CPI), clinical benefit is limited to a sub-population of patients. This may be explained by inadequate co-stimulation provided to tumor-specific T-cells to elicit and sustain an effective anti-tumor immune response. CD137 (4-1BB) and OX40, members of the TNF receptor superfamily, are key mediators of costimulatory signals and they play important roles in driving anti-tumor immunity. Combination of CPI with costimulatory agonists represents a promising approach with multiple clinical trials currently underway. However, to date, limited clinical activity has been observed with OX40 or CD137 agonists. We hypothesize that the activity of monospecific Fcγ receptor-dependent agonists may be limited by (1) suboptimal co-stimulation of CD8+ T-cells by OX40 agonists, or (2) insufficient ‘help’ from CD4+ T-cells for optimal CD137 agonist activity, and (3) inadequate level of clustering via Fcγ receptors at the relevant tissue compartments. To overcome these limitations, we have developed FS120, a dual agonist bispecific antibody (mAb2) with minimized FcγR binding, that drives potent activation of CD4+ and CD8+ T-cells in vitro dependent on co-engagement of CD137 and OX40. To evaluate the pharmacology and mechanism of action (MOA) of anti-OX40/CD137 mAb2 in the CT26 mouse tumor model, as monotherapy or in combination with PD-1 blockade, a murine surrogate was generated. This surrogate has comparable properties in mouse assay systems compared to FS120 in human systems in relation to binding affinities, potency in primary T-cell-based assays in vitro, and the requirement for OX40/CD137 co-engagement for activity. Here we report the relationship between dose, anti-tumor activity, pharmacodynamic (PD) response and the FcγR-binding independent MOA of an anti-mouse OX40/CD137 mAb2 in vivo. Anti-tumor activity was dose-dependent from 0.1 to 1 mg/kg. Surrogate mAb2 induced substantial increases in proliferating CD4+ and CD8+ T-cells in the blood, the magnitude of effect was inversely correlated with dose between 1 to 30 mg/kg. In a depletion study, anti-mouse OX40/CD137 mAb2 driven increases in peripheral proliferating CD8+ T-cells was partially inhibited by CD4+ T-cell depletion. Combination with anti-PD-1 antibody showed significant improvement in long-term survival resulting in complete tumor regression in 47% of animals compared to 7% and 0%, following single agent therapy with surrogate mAb2