Temporal pharmacokinetic/pharmacodynamic interaction between human CD3ε antigen-targeted monoclonal antibody otelixizumab and CD3ε binding and expression in human peripheral blood mononuclear cell static culture.
Otelixizumab is a monoclonal antibody (mAb) directed to human CD3ε, a protein forming part of the CD3/T-cell receptor (TCR) complex on T lymphocytes. This study investigated the temporal interaction between varying concentrations of otelixizumab, binding to human CD3 antigen, and expression of CD3/TCR complexes on lymphocytes in vitro, free from the confounding influence of changing lymphocyte frequencies observed in vivo. A static in vitro culture system was established in which primary human peripheral blood mononuclear cells (PBMCs) were incubated over an extended time course with titrated concentrations of otelixizumab. At each time point, free, bound, and total CD3/TCR expression on both CD4+ and CD8+ T cells and the amount of free otelixizumab antibody in the supernatant were measured. The pharmacokinetics of free otelixizumab in the culture supernatants was saturable, with a shorter apparent half-life at low concentration. Correspondingly, a rapid, otelixizumab concentration-, and time-dependent reduction in CD3/TCR expression was observed. These combined observations were consistent with the phenomenon known as target-mediated drug disposition (TMDD). A mechanistic, mathematical pharmacokinetic/pharmacodynamic (PK/PD) model was then used to characterize the free otelixizumab-CD3 expression-time relationship. CD3/TCR modulation induced by otelixizumab was found to be relatively fast compared with the re-expression rate of CD3/TCR complexes following otelixizumab removal from supernatants. In summary, the CD3/TCR receptor has been shown to have a major role in determining otelixizumab disposition. A mechanistic PK/PD model successfully captured the PK and PD in vitro data, confirming TMDD by otelixizumab.
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.) kevin.r.page@gsk.com.
Kevin R
KR
Page
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.).
Enrica
E
Mezzalana
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.).
Alexander J
AJ
MacDonald
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.).
Stefano
S
Zamuner
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.).
Giuseppe
G
De Nicolao
GlaxoSmithKline, Stevenage, United Kingdom (K.R.P., A.J.M., S.Z., A.vM.); University of Pavia, Pavia PV, Italy (E.M., G.D.N.).
Andre
A
van Maurik
D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics / Q000494:pharmacology*; D017252:CD3 Complex / Q000097:blood*; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013997:Time Factors
D061067:Antibodies, Monoclonal, Humanized; D017252:CD3 Complex; C115335:CD3E protein, human; D011948:Receptors, Antigen, T-Cell; C550701:otelixizumab