An Integrative Approach to Inform Optimal Administration of OX40 Agonist Antibodies in Patients with Advanced Solid Tumors.
Level 4 - case-series / case-control
Early-phase non-randomized clinical trial combined with preclinical and in vitro PK/PD modeling
PubMed 31573956 · doi:10.1158/1078-0432.CCR-19-0526
What was done
Preclinical and clinical biomarker datasets (dose, exposure, receptor occupancy, receptor engagement, and downstream pharmacodynamic markers) were integrated to model the optimal dosing schedule for the OX40 agonist antibody BMS-986178, administered alone or combined with checkpoint blockade. Evaluations included in vitro assays, mouse models using the surrogate antibody OX40.23, and clinical evaluation in patients with advanced solid tumors.
What was found
Anti-OX40 monotherapy and combination therapy increased peripheral CD4+ and CD8+ T-cell activation in both tumor-bearing mice and patients with solid tumors. Maximal enhancement of T-cell effector function occurred at 20% to 50% OX40 receptor occupancy in vitro and in vivo. Receptor occupancy above 40% led to profound loss of OX40 surface receptor expression.
Why it matters
Unlike checkpoint inhibitors that often require near-complete receptor saturation, T-cell costimulatory agonists exhibit non-linear biological responses where excessive occupancy downregulates target expression. This translational framework provides a rational basis for dosing agonist antibodies at intermediate receptor occupancy.
Limits
The abstract does not report clinical sample size, patient characteristics, specific tumor types, or clinical efficacy outcomes (such as response rate or survival). Quantitative dosing amounts and safety data are omitted.