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

by 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 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 i n 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 againstListeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). Th...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research