Translating antibody directed enzyme prodrug therapy (ADEPT) and prospects for combination

Introduction: The generation of cytotoxic drugs, selectively within tumours, from non-toxic prodrugs by targeted enzymes provides a powerful system for cancer therapy. In the form of Antibody directed enzyme prodrug therapy (ADEPT), this approach has shown feasibility in the clinic. Areas covered: Although numerous enzyme prodrug combinations have been reported over the last two decades, only the CPG2 ADEPT system has progressed to clinical trials. Using readily available components such as chemical antibody enzyme conjugate or recombinant multifunctional fusion protein, delivery of a specific enzyme to tumours, its elimination from non-tumour sites and prodrug activation has been achieved with therapeutic benefit in the clinic. The challenge here is to overcome immunogenicity of CPG2. Technology exists to overcome this limitation together with prospects for rational design of combined therapy. Expert opinion: ADEPT has the potential to be an effective treatment for solid cancer. However, the system necessitates a multi-disciplinary and iterative approach. Although xenograft studies provide a consistent guide it is only through clinical studies that the real challenges can be identified. The emerging preclinical data with other enzyme prodrug systems may provide the opportunity to develop the next generation ADEPT comprising non-immunogenic enzymes to generate potent cytotoxic drugs within tumours.