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Efficient and Site-specific Antibody Labeling by Strain-promoted Azide-alkyne Cycloaddition
Published on: December 23, 2016
Advances in antibody-directed enzyme prodrug therapy
Surinder K Sharma1, Kenneth D Bagshawe, Richard H J Begent
1Department of Oncology, Royal Free & University College Medical School, University College London, Hampstead Campus, Rowland Hill Street, London NW3 2PF. surinder.sharma@ucl.ac.uk
Abstract:
Antibody-directed enzyme prodrug therapy has demonstrated feasibility as a treatment for cancer. Numerous prodrug/drug systems have been developed for activation by a variety of enzymes and although many have shown potential in preclinical studies, so far only one system has progressed to the clinic. Clinical studies have identified issues that were not readily apparent in xenograft models, however, these have not been addressed in the development and testing of new prodrugs. The issue of immunogenicity arising from the use of non-human enzymes has also been a major hurdle. The development of recombinant fusion proteins provides reproducible and effective antibody-enzyme products that retain the necessary specificity for prodrug activation. Advances in molecular, structural and systems biology, in combination with bioinformatics, have allowed these molecules to be readily manipulated to provide the desired characteristics.
Insights
Antibody-directed enzyme prodrug therapy shows promise for cancer treatment. Recombinant fusion proteins offer a solution to immunogenicity issues and improve prodrug activation, addressing challenges seen in clinical studies.
Area of Science:
- Oncology
- Biotechnology
- Pharmacology
Background:
- Antibody-directed enzyme prodrug therapy (ADEPT) is a feasible cancer treatment strategy.
- Existing prodrug systems face challenges in clinical translation, including immunogenicity from non-human enzymes and issues not identified in preclinical models.
Purpose of the Study:
- To address the limitations of current ADEPT approaches.
- To explore the potential of recombinant fusion proteins in improving ADEPT efficacy and safety.
Main Methods:
- Development and characterization of recombinant fusion proteins combining antibody targeting with enzyme activity.
- Utilizing advances in molecular, structural, and systems biology, alongside bioinformatics, for protein engineering.
Main Results:
- Recombinant fusion proteins demonstrate reproducible and effective antibody-enzyme products.
- These engineered molecules retain specificity for prodrug activation and can be manipulated for desired characteristics.
- This approach potentially overcomes the hurdle of immunogenicity associated with non-human enzymes.
Conclusions:
- Recombinant fusion proteins represent a significant advancement in ADEPT.
- This technology offers a more robust and safer platform for developing targeted cancer therapies.
- Addressing clinical challenges through protein engineering is crucial for therapeutic success.
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