A modeling analysis of monoclonal antibody percolation through tumors: a binding-site barrier.
For successful use of radiolabeled monoclonal antibodies (MAbs) for diagnosis and therapy, it is helpful to understand both global and microscopic aspects of antibody biodistribution. In this study, antibody distribution in a tumor is simulated by splicing together information on global pharmacokinetics: transport across the capillary wall, diffusive penetration through the tumor interstitial space, and antigen-antibody interaction. The geometry simulated corresponds to spherical nodules of densely packed tumor cells. This modeling analysis demonstrates that: 1) antigen-antibody binding in tumors can retard antibody percolation; 2) high antibody affinity at a given dose tends to decrease antibody percolation because there are fewer free antibody molecules. The result is a more heterogeneous distribution; 3) the average antibody concentration in the tumor does not increase linearly with affinity; and 4) increasing antibody dose leads to better percolation and more uniform distribution. This mathematical model and the general principles developed here can be applied as well to other biologic ligands.
Fujimori
K
K
Laboratory of Mathematical Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Covell
D G
DG
Fletcher
J E
JE
Weinstein
J N
JN
D000911:Antibodies, Monoclonal / Q000097:blood / Q000276:immunology / Q000493:pharmacokinetics*; D000915:Antibody Affinity; D001666:Binding Sites, Antibody; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal