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

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

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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.

Original languageEnglish
Pages (from-to)e3000286
JournalPLoS Biology
Volume17
Issue number6
DOIs
Publication statusPublished - Jun 1 2019

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Agricultural and Biological Sciences(all)

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  • Cite this

    Lu, Y. C., Chuang, C. H., Chuang, K. H., Chen, I. J., Huang, B. C., Lee, W. H., Wang, H. E., Li, J. J., Cheng, Y. A., Cheng, K. W., Wang, J. Y., Hsieh, Y. C., Lin, W. W., & Cheng, T. L. (2019). Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. PLoS Biology, 17(6), e3000286. https://doi.org/10.1371/journal.pbio.3000286