Tuning Unsymmetrical Tetrazines Accelerates Bioorthogonal Click-to-Release Chemistry for Immune Stimulating Antibody Drug Conjugate
- 주제(키워드) Tetrazine , click to release , bio-orthogonal chemistry
- 주제(DDC) 547
- 발행기관 아주대학교 일반대학원
- 지도교수 김은하
- 발행년도 2026
- 학위수여년월 2026. 8
- 학위명 석사
- 학과 및 전공 일반대학원 분자과학기술학과
- 실제URI http://www.dcollection.net/handler/ajou/000000036676
- 본문언어 영어
- 저작권 아주대학교 논문은 저작권에 의해 보호받습니다.
초록/요약
Immune checkpoint inhibitors have transformed cancer therapy, but their efficacy remains limited in many solid tumors with poor immune cell infiltration. Although activation of the stimulator of interferon genes （STING） pathway is a promising strategy to convert immunologically “cold” tumors into “hot” tumors, systemic administration of free STING agonists is often associated with peripheral toxicity. Conventional antibody–drug conjugates （ADCs） provide targeted delivery but rely on receptor-mediated internalization and lysosomal degradation, which may restrict efficient payload delivery to intratumoral immune cells. Here, we report a bioorthogonal activation-based non-internalizing ADC platform for controlled extracellular release of immune-activating payloads. This strategy employs the ultrafast inverse electron-demand Diels–Alder reaction between trans-cyclooctene （TCO） and tetrazine to trigger selective payload release within the tumor microenvironment. By bypassing intracellular processing, this approach expands the targetable space beyond internalizing antigens and enables released payloads to access intratumoral immune cells. Further optimization of tetrazine structures enhanced click-to-release performance, enabling translation of this chemistry into an ADC system that induces potent STING-mediated immune activation. This work establishes a modular platform for spatially and temporally controlled immune activation and provides a promising strategy for the development of next-generation immune-activating ADCs. [Keywords: Click-to-release, Tetrazine, Antibody drug conjugate, STING agonist, bioorthogonal chemistry, IEDDA]
more목차
1 Introduction 1
1.1 Unmet need of immune checkpoint inhibitors 1
1.2 Immune stimulating antibody drug conjugate 2
1.3 On demand cleavage platform using click-to-release chemistry 2
1.4 Aim of thesis 4
2 Results and Discussion. 5
2.1 Structure property relationship of tetrazines 5
2.2 Computational evaluation of unsymmetrical tetrazines. 9
2.3 Synthesis of ADC linker 10
2.4 TCO based antibody drug conjugate. 11
2.5 In vitro cleavage of Ave-STINGa ADC 13
2.6 Tetrazine responsive activation of Ave-STINGa in THP-1 cells 14
3 Conclusion 15
4 Experimental Section 16
4.1 General information 16
4.2 General Synthetic procedure of tetrazines 17
4.3 Synthesis of TCO conjugates 29
5 References 34
6 Analytical results 36
6.1 Computational methods and results 36
6.2 Absorption spectra of tetrazines 36
6.3 Click kinetics measurement 37
6.4 1H NMR and 13C NMR spectra 39
