A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART^®.

ABSTRACT: CD3 bispecific antibody constructs recruit cytolytic T cells to kill tumor cells, offering a potent approach to treat cancer. T cell activation is driven by the formation of a trimolecular complex (trimer) between drugs, T cells, and tumor cells, mimicking an immune synapse. A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimer concentration and linking it to tumor cell killing. The model was used to quantify the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes the disposition of PF-06671008 in the central compartment and tumor in mouse xenograft models, including binding to target and T cells in the tumor to form the trimer. The model inc

SUBMITTER: Betts A 

PROVIDER: S-EPMC6531394 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature