Researchers Discover Way to Modify Rheumatoid Arthritis Drugs to Reduce Immune Suppression

“A new way to improve the efficacy of a drug taken by millions of patients throughout the world.”

Background

Adalimumab (also known as Humira) and infliximab (also known as Remicade) are novel therapies developed to treat rheumatoid arthritis (RA). They work by blocking TNF-alpha activity, which is the key molecule that causes the autoimmune response in the disease. However, there are two huge issues with both of these therapies.

  1. When the drugs block TNF-alpha in non-arthritic tissues, immune suppression can occur.
  2. Many RA patients develop antibodies to these drugs after just a short time using them. This suppresses the activity of the therapy.

New Study

This study was led by Wen-Wei Lin and published in PLOS BiologyThe idea was that by adding a protein “lock” to the typical Remicade treatment, they may be able to narrow the target of the treatment only to arthritic tissues. Additionally, they believed the addition of this lock could prevent anti-Remicade antibodies from developing.

If both of these reactions were proven to be true, the two primary issues with the Remicade treatment would be mitigated.

This team of researchers attached the lock by using a protein tag. This tag is removable with an enzyme called MMP. High concentrations of this enzyme are present in arthritic tissues, and work to breakdown tissue as a response to the RA. When the Remicade with the lock moved to these arthritic tissues, researchers believed the MMP enzyme would remove the lock, effectively releasing Remicade at the disease site. Since high concentrations of MMP are only located in the arthritic tissues, the hope was that the lock would remain inactive as it traveled to non-arthritic tissues.

If the lock acted the way the researchers planned, the risk of systemic immune suppression would be significantly reduced.

Results

The modified antibody worked just as researchers hoped. In mice models with RA, the modified form of Remicade produced the same response as the typical Remicade treatment. Additionally, there were fewer infections documented in the mice treated with the modified form (with the lock), indicating that immune suppression was reduced with the therapy. Antibody response was also extremely positive. The anti-Remicade antibodies bound to the modified form of the therapy with <1% of the strength they bound to the non-modified therapy.

While this study only examined Remicade, this is a hopeful finding for many as the same “lock” idea may be able to be applied to other monoclonal antibody therapies.

Researchers make it clear there is a lot more work to be done before this model can move into human clinical trials. But, if preclinical results continue to show its promise, this new modified therapy could significantly improve the patient’s risk/benefit ratio. It would make the treatment both safer and more effective, truly enhancing this therapy’s benefit on RA patient lives. 

You can read more about this new development here.

Citation: Lu Y-C, Chuang C-H, Chuang K-H, Chen I-J, Huang B-C, Lee W-H, et al. (2019) Specific activation of pro-Infliximab enhances selectivity and safety of rheumatoid arthritis therapy. PLoS Biol 17(6): e3000286. https://doi.org/10.1371/journal.pbio.3000286


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