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엔도좀 탈출능이 향상된 종양 특이적 세포질 침투항체의 개발
- Alternative Title
- Generation of tumor-specific cytosol-penetrating antibody with improved endosomal escape activity
- Author(s)
- 박재영
- Alternative Author(s)
- Jae-Yeong Park
- Advisor
- 김용성
- Department
- 일반대학원 분자과학기술학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Alternative Abstract
- In general, Intact form of IgG antibodies cannot reach the cytosol by escaping from the endosome after receptor-mediated endocytosis because they have no endosomal escape activity. Our group recently reported the cytosol-penetrating antibody TMab4 cytotransmab. Also, we generated TMab4-3 which is an engineered version of TMab4 to improve the endosomal escape efficiency and its expression yield. However, TMab4-3 is not yet suitable for targeted therapy because TMab4-3 has a binding activity against HSPG expressed on the surface of normal cells. In addition, it is necessary to improve the endosomal escape efficiency to increase the therapeutic efficacy of cytotransmab. Here, I generated a tumor-specific cytotransmab with improved endosomal escape efficiency. First, I have created a new cytotransmab called as CT-41 with the elimination of HSPG binding activity. Second, a cyclic peptide for targeting EpCAM which is well known for over-expressed on surface of tumor cell was fused with N-terminus of CT-41 to confer tumor tissue specificity. Third, an additional endosomal escape motif for cytotransmab have been introduced into the EpCAM specific cytotransmab called as CT-ep41. Lastly, charged residue mutations are inserted near the hydrophobic endosomal escape motif to increase its developability and solubility. As a result, CT12-ep61 as a final clone is showed a specificity to EpCAM-positive tumor cells and increased endosome escape efficiency about 34% compared to CT-ep41 and its expression level is higher about 8-fold compared to CT-ep41. These results suggest that tumor-tissue specific cytotransmab can be applied as a tool for targeted cancer therapy.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Molecular Science and Technology > 3. Theses(Master)
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