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

ABSTRACT

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.

KEYWORDS:

• ADEPT
• cancer
• combination therapy
• enzyme
• prodrug

Article highlights

• This review highlights that ADEPT can be designed to achieve high concentration of drug selectively within solid tumours by enzymatic catalysis of a low toxicity prodrug into a highly toxic form.

• Many reported preclinical studies of ADEPT with a variety of enzyme and prodrug systems suggest flexibility of components utilized in this approach.

• ADEPT has been successfully translated into clinical application with the CPG2 system where delivery of enzyme to tumour, elimination of enzyme from normal tissues and prodrug activation has been achieved. In addition, prolongation of life of patients with advanced terminal solid cancers has been demonstrated with limited normal tissue toxicity.

• ADEPT can be augmented with combination therapy.

• The development of non-immunogenic enzymes that generate potent cytotoxic drugs is now required to make this a useful strategy for the treatment of solid cancers

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

S Sharma is supported by Award No. 158722 from charity “The Post Natal Chorionepithelioma Trust” (Registered UK Charity Number: 227767).