Mathematical and experimental analysis of localization of anti-tumour antibody-enzyme conjugates

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 urs employs monoclonal antibody (mAb)-enzyme conjugates for the activation of anticancer prodrugs. We present, analyse and numerically simulate a math ematical model based on the biology of the system to study the biodistribut ion, pharmacokinetics and localization properties of mAb-enzyme conjugates in tumour tissue. The model predictions were compared with experimental obs ervations and an excellent correlation was found to exist. In addition, the critical parameters affecting conjugate half-life were determined to be th e inter-capillary half-distance and the antibody-antigen binding affinity. An approximation is presented relating the per cent injected dose per gram to inter-capillary half-distance and time. Finally, the model was used to e xamine various dosing strategies in an attempt to determine which regimen w ould provide the best biodistribution results. We compared the results of a dministering a uniform dose of fusion protein via bolus injection, multiple injections and continuous infusion. The model predicts that dosing strateg y has little effect on the amount of conjugate that localizes in the tumour .