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-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.

• Authors: 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 van Maurik
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 85 Issue 4 Pg. 704-714 (04 2019) ISSN: 1365-2125 [Electronic] England
• PMID: 30566758 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The British Pharmacological Society.

Chemical References

• Antibodies, Monoclonal, Humanized
• CD3 Complex
• CD3E protein, human
• Receptors, Antigen, T-Cell
• otelixizumab

Topics

• Adolescent
• Adult
• Antibodies, Monoclonal, Humanized (administration & dosage, pharmacokinetics)
• CD3 Complex (antagonists & inhibitors, immunology, metabolism)
• Diabetes Mellitus, Type 1 (drug therapy, immunology)
• Dose-Response Relationship, Drug
• Female
• Humans
• Infusions, Intravenous
• Male
• Molecular Targeted Therapy (methods)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Treatment Outcome
• Young Adult