Target Validation Information | |||||
---|---|---|---|---|---|
TTD ID | T87075 | ||||
Target Name | T-cell surface glycoprotein CD3 epsilon (CD3E) | ||||
Type of Target |
Successful |
||||
Action against Disease Model | Otelixizumab | Drug Info | Otelixiz uMab is an aglycosylated chimeric/h uManized monoclonal antibody (mAb) directed to h uMan CD3epsilon. This report describes population pharmacokinetics/pharmacodynamic (PK/PD) modeling of ser uM otelixiz uMab concentrations, changes in CD4+ and CD8+ T-cell counts, and modulation and saturation of CD3/T-cell receptors (TCR) (determined by flow cytometry) after IV administration of otelixiz uMab in subjects with either type 1 diabetes or psoriasis. Otelixiz uMab PK were monoexponential with Michaelis-Menten elimination. Nonlinearity was manifested at high concentrations (K(m) = 0.968 microg/mL). Lymphocyte dynamics were captured by an indirect response model simplified to direct inhibition. In diabetic subjects, the otelixiz uMab ser uM concentration producinga 50% decrease in peripheral blood counts was 0.0187 microg/mL for CD4+ T cells and 0.0120 microg/mL for CD8+ T cells. Corresponding values for psoriatic subjects were much lower: 0.000533 for CD4+ Tcells and 0.000269 microg/mL for CD8+ T cells. Total (s uM of unbound and otelixiz uMab-bound) CD3/TCR was approximately equal to unbound CD3/TCR, suggesting that there were few otelixiz uMab-(CD3/TCR) complexes at the T-cell surface. Down-modulation of CD3/TCR was described by direct inhibition. Otelixiz uMab concentrations producing 50% reduction in free CD3/TCR sites was similar for diabetes and psoriasis, 0.0144 and 0.0162 microg/mL. Integrated PK/PD models were successfully applied to assess otelixiz uMab PK and diverse PD responses. | [1] | |
References | |||||
REF 1 | Pharmacokinetics and pharmacodynamics of a chimeric/humanized anti-CD3 monoclonal antibody, otelixizumab (TRX4), in subjects with psoriasis and with type 1 diabetes mellitus. J Clin Pharmacol. 2010 May;50(5):494-506. | ||||
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