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Engineering of a Cell-Penetrating Degrading Antibody to Degrade Cytosolic β-catenin by Recruiting E3 Ubiquitin Ligase
- Author(s)
- 서지수
- Alternative Author(s)
- Ji-Su Seo
- Advisor
- 김용성
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2022-02
- Language
- eng
- Alternative Abstract
- Abnormal activation of Wnt signaling is oncogenic and caused by mutations in the destruction complex components. β-catenin is mutated in ~80% of human Colorectal Cancers (CRC) and is one of the undruggable proteins due to its flat surfaces that lack deep binding pockets. Despite the discovery of small molecules that target the Wnt pathway, β-catenin is rarely inhibited. As same as the Targeted Protein Degradation (TPD) approach, I designed a cytosol-penetrating/degrading IgG antibody, Degrobody, which is directly bound to cytosolic β-catenin and selectively removed it, thereby suppressing its CRC cell/tumor growth. Degrobody bound to the C-terminal domain of β-catenin and recruited the CUL5 E3 ligase to induce degradation. Degrobody showed potent anti-cancer effects on a CRC xenograft model. This study offers a promising β-catenin degrading antibody that could be an effective mAb-based strategy in overcoming the limitations of existing TPD approaches.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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