Antibody directed enzyme prodrug therapy : a mechanistic approach
Antibody directed enzyme prodrug therapy (ADEPT) is a two-step targeting system, which utilises pretargeting of antibody-enzyme to tumour followed by administration of a prodrug, which is converted to an active cytotoxic by the enzyme at tumour sites. This system aims to overcome cancer resistance mechanisms by the tumour specific generation of large quantities of a cytotoxic agent. ADEPT is a complex therapeutic strategy as it involves multiple components, each of which has their own unique requirements for the system as a whole to be successful. It is hypothesised that by measuring mechanism in a clinical trial setting, a greater understanding of ADEPT can be achieved. Additionally, rational modifications can be determined and implemented, thereby accelerating the development process. This thesis demonstrates how mechanistic data attained from one phase I/II ADEPT clinical trial lead to the development of a novel genetically engineered antibody-enzyme fusion protein for ADEPT, which was shown in a second clinical trial to have enhanced features for tumour targeting in ADEPT. The metabolic assessment of tumours using F-18 FDG PET was assessed during both ADEPT trials and shown to provide additional information when compared with conventional response assessment, particularly in the assessment of patients with radiological stable disease. As the data generated on ADEPT from both preclinical and clinical development is large, and the possibilities for modification to the system are numerous, an Ontology and Conceptual Model have been developed to organise the data attained on ADEPT. This thesis demonstrates that although ADEPT is a complex therapeutic strategy it can be successfully studied in a clinical setting using mechanistic clinical trial design, rational modifications can be made and data can be organised to facilitate development for the future.