Considerable research has been aimed at improving the efficacy of chemotherapeutic agents for cancer therapy. A promising
two-step approach that is designed to minimize systemic drug toxicity while maximizing activity in tumors employs monoclonal
antibody-enzyme conjugates for the activation of anti-cancer prodrugs. A mathematical model based on the biology of human
3677 melanoma xenografts in nude mice is presented, analyzed, and numerically simulated to study the biodistribution, pharmacokinetics,
and intratumoral localization properties of L49-β-lactamase fusion proteins in solid tumor masses. The model predictions were
compared with published experimental data and an excellent correlation was found to exist.
Analytic expressions for the total concentration of conjugate in the tumor, the time at which the concentration is maximal,
and the half life of conjugate in the tissue were derived. From these results, key parameters were isolated; and the effects
of the tumor vasculature, binding kinetics, and administration schedule were investigated. The antibody-antigen dissociation
ratio, the conjugate permeability, and the inter-capillary half distance within the tumor mass were found to strongly influence
localization and retention in the tumor. The model was used to examine various dosing strategies in an attempt to determine
which regimen would provide the best biodistribution results. The results of administering a uniform dose of conjugate via
bolus injection, multiple injections, and continuous infusion were compared. The model predicts that when saturation of binding
sites does not occur, dosing strategy has little effect on the amount of conjugate that localizes in the tumor.
Key words: Mathematical modeling - Cancer chemotherapy - Antibody-enzyme conjugates
Received: 20 April 1998 / Revised version: 12 October 1998