| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T87075 | ||||
| Target Name | T-cell surface glycoprotein CD3 epsilon chain | ||||
| Target Type | Successful |
||||
| Action against Disease Model | Otelixizumab | 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. | [553002] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | In this study, we examined the role of CD3straightepsilon ITAM-mediated signals in T cell development by genetically reconstituting CD3 epsilon-deficient mice with transgenes encoding either wild-type or ITAM-mutant (signaling defective) forms of the protein. The results demonstrate that signals transduced by CD3 epsilon are not specifically required for T cell maturation but instead contribute quantitatively to TCR signaling in a manner similar to that previously observed for zeta chain. Unexpectedly, analysis of TCR-transgenic/CD3 epsilon-mutant mice reveals a potential role for CD3 epsilon signals in T cell survival. | [553002] | |||
| References | |||||
| Ref 553002 | 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. doi: 10.1177/0091270009349376. Epub 2009 Nov 23. | ||||
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