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Genetic Encoding of a Non-Canonical Amino Acid for the Generation of Antibody-Drug Conjugates Through a Fast Bioorthogonal Reaction
Published on: September 14, 2018
Antibody-directed enzyme prodrug therapy (ADEPT) for cancer
Kenneth D Bagshawe1, Surinder K Sharma, Richard H J Begent
1Department of Oncology, Royal Free & University College Medical School, University College London, UK.
Abstract:
Antibody-directed enzyme prodrug therapy (ADEPT) aims to restrict the cytotoxic action to tumour sites. The obstacles to achieve this were recognised at the outset, but time and experience have given these better definition. The development of fusion proteins has provided the means of making consistent antibody-enzyme constructs on an adequate scale, and glycosylation has provided the means to control the clearance of enzyme from non-tumour sites. Human enzymes have yet to be tested in a clinical setting, and there are pointers indicating that the immunological response to foreign enzymes can be overcome. The relatively small number of purpose-designed prodrugs tested so far leaves this an area ripe for further development. The ongoing iterative process between preclinical and clinical studies is critical to achieving the objective.
Insights
Antibody-directed enzyme prodrug therapy (ADEPT) enhances cancer treatment by targeting cytotoxic drugs to tumors. Advances in fusion proteins and glycosylation improve enzyme delivery and reduce side effects, optimizing ADEPT efficacy.
Area of Science:
- Oncology
- Biotechnology
- Pharmacology
Background:
- Antibody-directed enzyme prodrug therapy (ADEPT) aims to localize cytotoxic effects at tumor sites.
- Historical challenges in ADEPT efficacy and specificity have been identified and refined over time.
Purpose of the Study:
- To review the progress and challenges in Antibody-directed enzyme prodrug therapy (ADEPT).
- To highlight advancements in antibody-enzyme construct development and enzyme clearance control.
- To identify areas for future development in ADEPT, particularly prodrug design.
Main Methods:
- Development of consistent antibody-enzyme fusion proteins for ADEPT.
- Utilizing glycosylation to modulate enzyme clearance rates from circulation.
- Iterative preclinical and clinical studies to refine ADEPT strategies.
Main Results:
- Fusion proteins enable consistent and scalable antibody-enzyme construct production.
- Glycosylation effectively controls enzyme clearance, minimizing off-target effects.
- Evidence suggests overcoming immunological responses to foreign enzymes is feasible.
Conclusions:
- ADEPT shows promise for targeted cancer therapy with ongoing advancements.
- Further development of purpose-designed prodrugs is crucial for maximizing ADEPT's potential.
- Continuous integration of preclinical and clinical findings is essential for successful ADEPT implementation.
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