Theoretical analysis of conjugate localization in two-step cancer chemotherapy

Considerable research has been aimed at improving the efficacy of chemother apeutic agents for cancer therapy. A promising two-step approach that is de signed to minimize systemic drug toxicity while maximizing activity in tumo rs employs monoclonal antibody-enzyme conjugates for the activation of anti -cancer prodrugs. A mathematical model based on the biology of human 3677 m elanoma xenografts in nude mice is presented, analyzed, and numerically sim ulated to study the biodistribution, pharmacokinetics, and intratumoral loc alization properties of L49-beta-lactamase fusion proteins in solid tumor m asses. 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 halflife of conjug ate in the tissue were derived. From these results, key parameters were iso lated; and the effects of the tumor vasculature, binding kinetics, and admi nistration schedule were investigated. The antibody-antigen dissociation ra tio, the conjugate permeability, and the intercapillary half distance withi n the tumor mass were found to strongly influence localization and retentio n in the tumor. The model was used to examine various dosing strategies in an attempt to determine which regimen would provide the best biodistributio n results. The results of administering a uniform dose of conjugate via bol us injection, multiple injections, and continuous infusion were compared. T he model predicts that when saturation of binding sites does not occur, dos ing strategy has little effect on the amount of conjugate that localizes in the tumor.