Selective activation of pro-anti-IL-1β antibody enhances specificity for autoinflammatory disorder therapy View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2021-07-21

AUTHORS

Wen-Wei Lin, Yun-Chi Lu, Bo-Cheng Huang, Chih-Hung Chuang, Yi-An Cheng, I.-Ju Chen, Hui-Ju Liu, Kai-Wen Ho, Tzu-Yi Liao, En-Shuo Liu, Ting-Yi Wu, Long-Sen Chang, Shih-Ting Hong, Tian-Lu Cheng

ABSTRACT

Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1β 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-1β 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-1β-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-1β-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1β neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1β-downstream signaling and IL-1β-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. More... »

PAGES

14846

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-021-94298-y

DOI

http://dx.doi.org/10.1038/s41598-021-94298-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1139829599

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34290297


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20 schema:description Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1β 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-1β 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-1β-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-1β-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1β neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1β-downstream signaling and IL-1β-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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27 Drug Administration
28 IL-1β
29 IL-1β antibody
30 IgG1 hinge
31 MMP-9
32 US Food
33 ability
34 activation
35 administration
36 adverse events
37 antibodies
38 arthritis
39 autoinflammatory diseases
40 autoinflammatory disorders
41 canakinumab
42 circulation
43 cryopyrin
44 development
45 different types
46 disease
47 disease sites
48 disorder therapy
49 disorders
50 downstream signaling
51 events
52 food
53 future
54 genes
55 hinges
56 human interleukin
57 human monoclonal antibody
58 idiopathic arthritis
59 infection
60 inflamed regions
61 inflammation
62 interleukin
63 juvenile idiopathic arthritis
64 life
65 lock
66 min
67 monoclonal antibodies
68 necrosis factor receptor-associated periodic syndrome
69 neutralization
70 patients
71 periodic syndrome
72 potential
73 quality
74 quality of life
75 reaction
76 region
77 respiratory tract infections
78 safety
79 safety of treatment
80 selective activation
81 selective reaction
82 selectivity
83 severe adverse events
84 signaling
85 sites
86 specificity
87 substrate
88 syndrome
89 systemic circulation
90 systemic juvenile idiopathic arthritis
91 systemic neutralization
92 target toxicity
93 therapy
94 toxicity
95 tract infections
96 treatment
97 tumor necrosis factor receptor-associated periodic syndrome
98 types
99 upper respiratory tract infection
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