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.
RCT Entities:
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: Br J Clin Pharmacol Date: 2019-02-05 Impact factor: 4.335
Authors: K J Parlevliet; M E Chamuleau; S L Yong; M H Raasveld; I J ten Berge; P T Schellekens Journal: Clin Exp Immunol Date: 1995-02 Impact factor: 4.330
Authors: C R Stiller; J Dupré; M Gent; M R Jenner; P A Keown; A Laupacis; R Martell; N W Rodger; B von Graffenried; B M Wolfe Journal: Science Date: 1984-03-30 Impact factor: 47.728
Authors: Ronnie Aronson; Peter A Gottlieb; Jens S Christiansen; Thomas W Donner; Emanuele Bosi; Bruce W Bode; Paolo Pozzilli Journal: Diabetes Care Date: 2014-07-10 Impact factor: 19.112
Authors: William Hagopian; Robert J Ferry; Nicole Sherry; David Carlin; Ezio Bonvini; Syd Johnson; Kathryn E Stein; Scott Koenig; Anastasia G Daifotis; Kevan C Herold; Johnny Ludvigsson Journal: Diabetes Date: 2013-06-25 Impact factor: 9.461
Authors: Simon D Harding; Joanna L Sharman; Elena Faccenda; Chris Southan; Adam J Pawson; Sam Ireland; Alasdair J G Gray; Liam Bruce; Stephen P H Alexander; Stephen Anderton; Clare Bryant; Anthony P Davenport; Christian Doerig; Doriano Fabbro; Francesca Levi-Schaffer; Michael Spedding; Jamie A Davies Journal: Nucleic Acids Res Date: 2018-01-04 Impact factor: 16.971
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: Br J Clin Pharmacol Date: 2019-02-05 Impact factor: 4.335
Authors: Bart Keymeulen; André van Maurik; Dave Inman; João Oliveira; Rene McLaughlin; Rachel M Gittelman; Bart O Roep; Pieter Gillard; Robert Hilbrands; Frans Gorus; Chantal Mathieu; Ursule Van de Velde; Nicolas Wisniacki; Antonella Napolitano Journal: Diabetologia Date: 2020-11-04 Impact factor: 10.122