In Early Study, Researchers Modify Infliximab to Make It Safer, More Effective

The rheumatoid arthritis (RA) drugs infliximab and adalimumab have revolutionized autoimmune disease treatment because of their ability to block the activity of tumor necrosis factor alpha (TNFα), but they run the risk of patients developing dangerous immune resistance, thus becoming susceptible to infections or becoming nonresponsive to the drugs themselves.

In a new paper published in PLoS Biology, researchers say they were able to create an “antibody lock” (Ab lock) that makes infliximab more selective in its activity, making it safer and more effective. They say they used an immunoglobulin G1 hinge as an Ab lock to cover the TNFα-binding site of infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate; the MMP enzyme is abundant at the site of RA, where it contributes to the tissue breakdown that is a major consequence of the disease. That generated pro-infliximab, which was specifically activated in the RA region to enhance the selectivity and safety of treatment.

In this mouse study, a high concentration of MMP removed the lock and released pro-infliximab primarily at the site of disease; in nonarthritic tissues where MMP levels were lower, this lock remained closed. In a bacterial challenge, the mice treated with the pro-infliximab had fewer infections.

In addition, anti-infliximab antibodies bound to the locked form of infliximab with less than 1% of the strength with which they bound to infliximab itself, suggesting it may be less immunogenic and so less likely to lead to a lack of response to infliximab.

The researchers say the discovery, if confirmed in human trials, could revolutionize RA treatment and improve quality of life. They say the pro-infliximab has 5 advantages:

• It can be selectively activated in the RA region after cleaving by overexpressed protease.
• It does not dysregulate the systemic immunity of TNFα.
• It does not change the productive yield, biodistribution, or pharmacokinetics of the original antibody.
• It may have the lowest immunogenicity because the hinge normally exists in human serum.
• It can prevent the neutralizing effects of anti-infliximab idiotypic Ab and allow for the full potential of infliximab.

Reference

Lu YC, Chuang CH, Chuang KH, et al. Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy [published online June 13, 2019]. PLoS Biol. doi: 10.1371/journal.pbio.3000286.