Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti‐CD3ε mAb in new‐onset type 1 diabetes mellitus patients

摘要

Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti‐CD3? mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose–response of an anti‐CD3? mAb has been investigated in the clinic. The data have been validated using a previously developed pharmacokinetic/pharmacodynamic (PK/PD) model of otelixizumab to simulate the interplay between drug administration, CD3? target engagement and downmodulation. Methods Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose‐ascending study consisted of three cohorts ( n ?=?10 per cohort) at doses of 9, 18 or 27?mg respectively. The study allowed quantification of otelixizumab PK, CD3? target engagement and its pharmacodynamic effect (CD3ε/TCR modulation on circulating T lymphocytes). Results Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng?ml ?1 (Geom.mean, %CV) at the 9, 18 and 27?mg dose respectively. CD3? target engagement was found to be rapid (within the first 30?min), leading to a receptor occupancy of ~60% within 6?h of dosing in all three doses. A dose–response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3?/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3?/TCR modulation is achieved at doses of 18, 27?mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti‐CD3? mAbs.