Anti-CD24 antibody-nitric oxide donor conjugates bearing a self-bioorthogonal cleavable linker.
10.1016/j.apsb.2025.07.037
- Author:
Jianbing WU
1
;
Tianyue CHENG
2
;
Jiajun XIE
2
;
Ziyu QIAN
1
;
Linhua HUANG
2
;
Xun YUAN
1
;
Libang ZHANG
1
;
Shan YANG
3
;
Yihua ZHANG
1
;
Tonglin XU
4
;
Juan ZHANG
2
;
Zhangjian HUANG
1
Author Information
1. State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, Nanjing 211198, China.
2. Antibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing 211198, China.
3. School of Pharmacy, Key Laboratory of Active Components of Xinjiang Natural Medicine and Drug Release Technology, Engineering Research Center of Xinjiang and Central Asian Medicine Resources, Xinjiang Medical University, Urumqi 830054, China.
4. Nantong Third People's Hospital, Affiliated Nantong Hospital 3 of Nantong University, Nantong 226006, China.
- Publication Type:Journal Article
- Keywords:
Antibody-nitric oxide donor conjugate;
Bioorthogonal chemistry;
CD24;
Cisplatin;
Self-cleavable linker;
Site-specific conjugation;
Triple-negative breast cancer;
Tumor microenvironment
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5366-5386
- CountryChina
- Language:English
-
Abstract:
Triple-negative breast cancer (TNBC) is a highly aggressive malignancy predominantly managed via chemotherapy. Our clinical sample analysis revealed a significant correlation between elevated CD24 expression in TNBC tumor cells and patient survival rates. We developed a novel antibody-drug conjugate (ADC), named HN03, consisting of an antibody with engineered cysteines for site-specific conjugation with a low toxic nitric oxide (NO) precursor as its payload through a novel Pt(IV)-mediated bioorthogonal self-cleavable linker. HN03 specifically targets tumor cells expressing high levels of CD24, concurrently generating cisplatin and releasing NO upon activation. HN03 also exhibited potent in vitro and in vivo antitumor activity. It significantly reduced tumor growth at various doses, prevented tumor metastasis, with markedly lower toxicity than traditional chemotherapy agents. We found that a key mechanism of its action involved inducing apoptosis and endoplasmic reticulum stress, substantially decreasing the number of M2-type macrophages. Overall, HN03 stands out as a promising therapeutic option for TNBC, offering a targeted treatment with reduced side effects and the potential for improved outcomes. Furthermore, using Pt(IV) in the linker and an NO precursor as the payload enhances the versatility of the Antibody-NO donor Conjugate (ANC), offering new avenues for the design of the next generation of ADCs.
