Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy.

Autor: Yun-Chi Lu, Chih-Hung Chuang, Kuo-Hsiang Chuang, I-Ju Chen, Bo-Cheng Huang, Wen-Han Lee, Hsin-Ell Wang, Jia-Je Li, Yi-An Cheng, Kai-Wen Cheng, Jaw-Yuan Wang, Yuan-Chin Hsieh, Wen-Wei Lin, Tian-Lu Cheng
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: PLoS Biology, Vol 17, Iss 6, p e3000286 (2019)
Druh dokumentu: article
ISSN: 1544-9173
1545-7885
DOI: 10.1371/journal.pbio.3000286
Popis: During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specifically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα downstream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Furthermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeutic efficiency, providing a novel strategy for RA therapy.
Databáze: Directory of Open Access Journals
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