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

• Published in: British Journal of Cancer Vol. 80; no. 11; pp. 1747 - 1753
• Main Authors: JACKSON, T. L, LUBKIN, S. R, SIEMERS, N. O, KERR, D. E, SENTER, P. D, MURRAY, J. D
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 01.08.1999
• Subjects: Animals; Antibodies, Monoclonal - pharmacokinetics; Antineoplastic agents; beta-Lactamases - metabolism; beta-Lactamases - therapeutic use; Biological and medical sciences; Chemotherapy; Female; Humans; Immunoglobulin G - metabolism; Immunoglobulin G - therapeutic use; Kinetics; Medical sciences; Melanoma - drug therapy; Melanoma - immunology; Melanoma - metabolism; Mice; Mice, Nude; Models, Biological; Models, Statistical; Neoplasms - drug therapy; Neoplasms - immunology; Neoplasms - metabolism; Pharmacology. Drug treatments; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - therapeutic use; Regular; Tissue Distribution; Transplantation, Heterologous; Tumor Cells, Cultured; Antineoplastic agent; Human; Animal model; Enzyme; Rodentia; Melanoma; Antibody directed enzyme prodrug therapy; Activation; Malignant tumor; Monoclonal antibody; Immunoconjugate; Prodrug; Vertebrata; Mammalia; Mouse; Animal; Distribution; Established cell line; Localization; Mathematical model; Pharmacokinetics
• ISSN: 0007-0920; 1476-5381; 1532-1827
• DOI: 10.1038/sj.bjc.6690592

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 tumours employs monoclonal antibody (mAb)-enzyme conjugates for the activation of anticancer prodrugs. We present, analyse and numerically simulate a mathematical model based on the biology of the system to study the biodistribution, pharmacokinetics and localization properties of mAb-enzyme conjugates in tumour tissue. The model predictions were compared with experimental observations and an excellent correlation was found to exist. In addition, the critical parameters affecting conjugate half-life were determined to be the 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 examine various dosing strategies in an attempt to determine which regimen would provide the best biodistribution results. We compared the results of administering a uniform dose of fusion protein via bolus injection, multiple injections and continuous infusion. The model predicts that dosing strategy has little effect on the amount of conjugate that localizes in the tumour.