| First Author | Lu YC | Year | 2019 |
| Journal | PLoS Biol | Volume | 17 |
| Issue | 6 | Pages | e3000286 |
| PubMed ID | 31194726 | Mgi Jnum | J:276479 |
| Mgi Id | MGI:6314961 | Doi | 10.1371/journal.pbio.3000286 |
| Citation | Lu YC, et al. (2019) Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. PLoS Biol 17(6):e3000286 |
| abstractText | During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor alpha antibodies (anti-TNFalpha 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 TNFalpha-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 TNFalpha 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 TNFalpha neutralizing ability of pro-Infliximab to block TNFalpha 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. |
