{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T02:52:06Z","timestamp":1792291926743,"version":"4.4.0"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,2,5]],"date-time":"2019-02-05T00:00:00Z","timestamp":1549324800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>This paper describes the pharmacological findings from a study where otelixizumab, an anti\u2010CD3\u025b mAb, was dosed in new onset Type 1 diabetes mellitus (NOT1DM) patients. This is the first time that the full dose\u2013response of an anti\u2010CD3\u025b 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\u025b target engagement and downmodulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients were randomized to control or active treatment with otelixizumab (1:4), administered via infusion over 6 days, in a dose\u2010ascending study consisted of three cohorts (<jats:italic>n<\/jats:italic>\u00a0=\u00a010 per cohort) at doses of 9, 18 or 27\u00a0mg respectively. The study allowed quantification of otelixizumab PK, CD3\u025b target engagement and its pharmacodynamic effect (CD3\u03b5\/TCR modulation on circulating T lymphocytes).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Otelixizumab concentrations increased and averaged to 364.09 (54.3), 1625.55 (72.5) and 2781.35 (28.0) ng\u00a0ml<jats:sup>\u22121<\/jats:sup> (Geom.mean, %CV) at the 9, 18 and 27\u00a0mg dose respectively. CD3\u025b target engagement was found to be rapid (within the first 30\u00a0min), leading to a receptor occupancy of ~60% within 6\u00a0h of dosing in all three doses. A dose\u2013response relationship was observed with the two highest doses achieving a ~90% target engagement and consequential CD3\u025b\/TCR downmodulation by Day 6.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Data from this study revealed maximum target engagement and CD3\u025b\/TCR modulation is achieved at doses of 18, 27\u00a0mg of otelixizumab. These findings can be useful in guiding dose selection in clinical trials with anti\u2010CD3\u025b mAbs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.13842","type":"journal-article","created":{"date-parts":[[2018,12,19]],"date-time":"2018-12-19T21:24:36Z","timestamp":1545254676000},"page":"704-714","source":"Crossref","is-referenced-by-count":12,"title":["Target engagement and cellular fate of otelixizumab: a repeat dose escalation study of an anti\u2010CD3\u03b5 mAb in new\u2010onset type 1 diabetes mellitus patients"],"prefix":"10.1111","volume":"85","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7390-9712","authenticated-orcid":false,"given":"Georgios","family":"Vlasakakis","sequence":"first","affiliation":[{"name":"Research and Development GlaxoSmithKline  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Research and Development GlaxoSmithKline  London 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