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Transfer of Manipulated Tumor-associated Neutrophils into Tumor-Bearing Mice to Study their Angiogenic Potential In Vivo
Published on: July 20, 2019
Development of human tumor necrosis factor-alpha muteins with improved therapeutic potential
Seung-Hwan Jang1, Hyojin Kim, Kwang-Hwi Cho
1Department of Bioinformatics and Life Science and Computer Aided Molecular Design Research Center, Soongsil University, Seoul 156-743, Korea.
Abstract:
Tumor necrosis factor-alpha (TNF-alpha) exhibits cytotoxicity towards various tumor cells in vitro and induces apoptotic necrosis in transplanted tumors in vivo. It also shows severe toxicity when used systemically for the treatment of cancer patients, hampering the development of TNF-alpha as a potential anticancer drug. In order to understand the structure-function relation of TNF-alpha with respect to receptor binding, we selected four regions on the bottom of the TNF-alpha trimer that are in close contact with the receptor and carried out mutagenesis studies and computational modeling. From the study, various TNF-alpha muteins with a high therapeutic index were identified. These results will provide a structural basis for the design of highly potent TNF-alpha for therapeutic purposes. By conjugating TNF-alpha muteins with a high therapeutic index to a fusion partner, which targets a marker of angiogenesis, it could be possible to develop TNF-alpha based anticancer drugs.
Insights
Tumor necrosis factor-alpha (TNF-alpha) shows promise against tumors but causes severe toxicity. Researchers engineered TNF-alpha muteins with a high therapeutic index for safer, potent anticancer drug development.
Area of Science:
- Biochemistry and Molecular Biology
- Immunology
- Cancer Research
Background:
- Tumor necrosis factor-alpha (TNF-alpha) demonstrates potent anti-tumor activity in vitro and in vivo.
- Systemic administration of TNF-alpha for cancer treatment is limited by severe toxicity.
- Understanding the structure-function relationship of TNF-alpha is crucial for developing safer therapeutic agents.
Purpose of the Study:
- To investigate the structure-function relationship of TNF-alpha concerning receptor binding.
- To identify TNF-alpha muteins with an improved therapeutic index.
- To provide a structural basis for designing enhanced TNF-alpha-based therapeutics.
Main Methods:
- Site-directed mutagenesis was performed on four key regions of the TNF-alpha trimer.
- Computational modeling was employed to analyze TNF-alpha-receptor interactions.
- Structure-function relationships were evaluated for identified TNF-alpha muteins.
Main Results:
- Several TNF-alpha muteins exhibiting a high therapeutic index were successfully identified.
- Mutagenesis studies revealed critical regions for TNF-alpha receptor binding and activity.
- The identified muteins offer potential for enhanced potency and reduced toxicity.
Conclusions:
- The study provides a structural foundation for engineering more effective TNF-alpha variants.
- Conjugating high-therapeutic-index TNF-alpha muteins with angiogenesis-targeting fusion partners could lead to novel anticancer drugs.
- This research paves the way for developing targeted TNF-alpha-based cancer therapies with improved safety profiles.
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