期刊
SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41598-021-94298-y
关键词
-
资金
- Ministry of Science and Technology, Taipei, Taiwan [MOST 107-2320-B-037-024 -MY3, MOST107-2320-B-037-028-MY2, MOST106-2311-B-037-001-MY2, 109-2320-B-037 -010 -MY3, 109-2627-M-037 -001, 110-2628-B-037-010]
- National Health Research Institutes, Taiwan [NHRI-EX107-10729EI, NHRI-EX108-10729EI]
- Academia Sinica, Taiwan [AS-107-TP-B11, AS-TP-107-L11]
- Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Academia Sinica, Taiwan [AS-KPQ-106-TSPA]
- Ministry of Education, Taiwan [108RSB0029]
- KMU-KMUH Co-Project of Key Research [KMU-DK108002, KMU-DK109001]
- Research Foundation from Kaohsiung Medical University, Taiwan [KMU-Q108001, KMU-Q109002, KMU-DK109004, KMU-KI110004]
- CCH-KMU joint research project [108-CCH-KMU-010]
- NSYSU-KMU joint research project [NK-108I08]
- Medical Research Fund of Kaohsiung Armed Forces General Hospital [802KB109388]
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Taiwan [KMU-TC108A03]
Canakinumab is a fully human monoclonal antibody used to treat autoinflammatory disorders, but long-term use can cause severe adverse events. Researchers successfully enhanced the selectivity and safety of treatment by designing an Ab lock.
Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1 beta and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome and systemic juvenile idiopathic arthritis. However, long-term systemic neutralization of IL-1 beta by Canakinumab may cause severe adverse events such as serious upper respiratory tract infections and inflammation, thereby decreasing the quality of life of patients. Here, we used an IgG1 hinge as an Ab lock to cover the IL-1 beta-binding site of Canakinumab by linking with matrix metalloprotease 9 (MMP-9) substrate to generate pro-Canakinumab that can be specifically activated in the inflamed regions in autoinflammatory diseases to enhance the selectivity and safety of treatment. The Ab lock significantly inhibited the IL-1 beta-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1 beta neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1 beta-downstream signaling and IL-1 beta-regulated genes (i.e., IL-6). It is expected that MMP-9 cleavable and efficient Ab lock will be able to significantly enhance the selective reaction of Canakinumab at the disease site and reduce the on-target toxicities of Canakinumab during systemic circulation, thereby showing potential for development to improve the safety and quality of life of patients with autoinflammatory disorders in the future.
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