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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
Author(s) -
Vlasakakis Georgios,
Napolitano Antonella,
Barnard Ruth,
Brown Kim,
Bullman Jonathan,
Inman David,
Keymeulen Bart,
Lanham David,
Leirens Quentin,
MacDonald Alexander,
Mezzalana Enrica,
Page Kevin,
Patel Minesh,
Savage Caroline O.,
Zamuner Stefano,
Maurik Andre
Publication year - 2019
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13842
Subject(s) - pharmacodynamics , pharmacokinetics , diabetes mellitus , cd3 , medicine , pharmacology , dosing , t cell receptor , endocrinology , immunology , t cell , antigen , cd8 , immune system
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.