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.

Aims This paper describes the pharmacological findings from a study where otelixizumab, an anti-CD3e 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-CD3e 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, CD3e 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, CD3e target engagement and its pharmacodynamic effect (CD3 epsilon/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. CD3e target engagement was found to be rapid (within the first 30 min), leading to a receptor occupancy of similar to 60% within 6 h of dosing in all three doses. A dose-response relationship was observed with the two highest doses achieving a similar to 90% target engagement and consequential CD3e/TCR downmodulation by Day 6. Conclusions Data from this study revealed maximum target engagement and CD3e/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-CD3e mAbs.