Pro-Infliximab provided equivalent therapeutic efficacy to Infliximab while maintaining mouse immunity against Listeria infection, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%).

Published in PLoS Biology 2019 Jun 13;17(6):e3000286. doi: 10.1371/journal.pbio.3000286.

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

Lu YC, Chuang CH, Chuang KH, Chen IJ, Huang BC, Lee WH, Wang HE, Li JJ, Cheng YA, Cheng KW, Wang JY, Hsieh YC, Lin WW, Cheng TL.

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 specif- ically 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 down- stream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Fur- thermore, 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 therapeu- tic efficiency, providing a novel strategy for RA therapy.

 

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