Details

Autor(en) / Beteiligte

• Lu, Yun-Chi
• Chuang, Chih-Hung
• Chuang, Kuo-Hsiang
• Chen, I-Ju
• Huang, Bo-Cheng
• Lee, Wen-Han
• Wang, Hsin-Ell
• Li, Jia-Je
• Cheng, Yi-An
• Cheng, Kai-Wen
• Wang, Jaw-Yuan
• Hsieh, Yuan-Chin
• Lin, Wen-Wei
• Cheng, Tian-Lu
• Cadwell, Ken

Titel

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

Ist Teil von

• PLoS biology, 2019-06, Vol.17 (6), p.e3000286

Ort / Verlag

United States: Public Library of Science

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.