Computational systems biology of the B cell, its neoplastic transformation and clinical treatment.

摘要

Here we take a multiscale approach to the problem of cancer treatment, from gene expression patterns in cancer cells to whole-body kinetics of anti-tumor drugs.;Bruton's tyrosine kinase (Btk) acts downstream of phosphoinositide 3-kinase (PI3K) in a pathway required for B cell receptor (BCR)-dependent proliferation of B lymphocytes. We use oligonucleotide microarrays to determine what fraction of genes are influenced by this pathway, and to investigate whether PI3K and Btk mediate both shared and distinct gene regulation events. Clustering and statistical analysis indicated that PI3K and Btk share target genes, and that PI3K influences additional genes independently of Btk. Fewer genes were identified as targets of Btk only.;We also describe the construction and implementation of a novel physiologically-based pharmacokinetic (PBPK) model for predicting interactions between the neonatal Fc receptor (FcRn) and anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs) with varying affinity for FcRn. Our model includes mechanistic structure that details internalization of class G immunoglobulins by endothelial cells, subsequent FcRn binding, recycling into plasma of FcRn-bound IgG and degradation of free endosomal IgG. We fitted the new multiscale model to published anti-CEA mAb biodistribution data, providing new estimates of mAb-FcRn related kinetic parameters. The model was further validated by successful prediction of F(ab')2 mAb fragment biodistribution, providing additional evidence of its potential value in optimizing intact mAb and mAb fragment dosing for clinical imaging and immunotherapy applications.;We recently developed the scFv-Fc mAb, which consists of an intact IgG 1 Fc region coupled to two variable domain dimers. Point mutations which attenuate its binding affinity to FcRn were introduced into the Fc region of the wild type scFv-Fc mAb, resulting in several new antibodies, each with a different half-life. We constructed a two-tiered physiologically-based pharmacokinetic (PBPK) model capable of describing the apparent biodistribution of both 111In and 125I labeled scFv-Fc mAbs. The difference between the apparent concentration-time profiles of 111In and 125I mAbs allows us to estimate the degradation capacity of each organ and gives insight into the dependence of liver, muscle and skin degradation rates on FcRn affinity.