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

Abstract

Aims

This paper describes the pharmacological findings from a study where otelixizumab, an anti‐CD3_ɛ 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_ɛ 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_ɛ target engagement and down‐modulation.

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/cohort) at doses of 9, 18 or 27mg respectively. The study allowed quantification of otelixizumab PK, CD3_ɛ 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 (Geom.mean, %CV) at the 9, 18 and 27 mg dose respectively. CD3_ɛ target engagement was found to be rapid (within the first 30 minutes), leading to a receptor occupancy of ~60% within 6 hours 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_ɛ/TCR downmodulation by day 6.

Conclusions

Data from this study revealed maximum target engagement and CD3_ɛ/TCR modulation is achieved at doses of 18, 27mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti‐CD3_ɛ mAbs.

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