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

Lu, Yun-Chi and Chuang, Chih-Hung and Chuang, Kuo-Hsiang and Chen, I-Ju and Huang, Bo-Cheng and Lee, Wen-Han and Wang, Hsin-Ell and Li, Jia-Je and Cheng, Yi-An and Cheng, Kai-Wen and Wang, Jaw-Yuan and Hsieh, Yuan-Chin and Lin, Wen-Wei and Cheng, Tian-Lu and Cadwell, Ken (2019) Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. PLOS Biology, 17 (6). e3000286. ISSN 1545-7885

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Abstract

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.

Item Type: Article
Subjects: AP Academic Press > Biological Science
Depositing User: Unnamed user with email support@apacademicpress.com
Date Deposited: 24 Jan 2023 06:38
Last Modified: 29 Jul 2024 10:19
URI: http://info.openarchivespress.com/id/eprint/215

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