4.6 Article

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

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PLOS BIOLOGY
卷 17, 期 6, 页码 -

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PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3000286

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资金

  1. Ministry of Science and Technology, Taiwan [MOST 106-2632-B-037-003, MOST106-2311-B-037-001-MY2, MOST107-2320-B-037-024-MY3]
  2. National Health Research Institutes, Taiwan [NHRI-EX107-10729EI]
  3. Academia Sinica, Taiwan [AS-107-TP-B11]
  4. Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis
  5. Grant of Biosignature in Colorectal Cancers
  6. Kaohsiung Medical University [KMU-DK108002]
  7. Center for Biomarkers and Biotech Drugs, Kaohsiung Medical University, Taiwan

向作者/读者索取更多资源

During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor alpha antibodies (anti-TNF alpha 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 TNF alpha-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 TNF alpha 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 TNF alpha neutralizing ability of pro-Infliximab to block TNF alpha 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.

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