Article date: April 2019
By: Georgios Vlasakakis, Antonella Napolitano, Ruth Barnard, Kim Brown, Jonathan Bullman, David Inman, Bart Keymeulen, David Lanham, Quentin Leirens, Alexander MacDonald, Enrica Mezzalana, Kevin Page, Minesh Patel, Caroline O. Savage, Stefano Zamuner, Andre Maurik in Volume 85, Issue 4, pages 704-714
Aims
This paper describes the pharmacological findings from a study where otelixizumab, an anti‐CD3ɛ 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‐CD3ɛ 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, CD3ɛ 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, CD3ɛ 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. CD3ɛ 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 CD3ɛ/TCR downmodulation by Day 6.
Conclusions
Data from this study revealed maximum target engagement and CD3ɛ/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‐CD3ɛ mAbs.
DOI: 10.1111/bcp.13842
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