The seasons are changing. The days are getting shorter. The air is getting cool and crisp. Soon, the outdoors will be covered by a lovely blanket of fresh snow. As serene as this image may be, the fact is that the changing seasons maybe painful for those who suffer from rheumatoid arthritis (RA) (Savage et al., 2015).
There are several treatments for RA available today (briefly reviewed in Hirota et al., 2016), including non-steroidal anti-inflammatory drugs, small molecule disease-modifying anti-rheumatic drugs, and a growing number of biologics that specifically target inflammatory pathway components. None of these therapeutics can cure the disease, but they can make life a bit more comfortable for RA sufferers (though not without some significant side-effects).
One protein target of particular interest for new RA treatments is interleukin-6 (IL-6) (briefly reviewed in Hirota et al., 2016). As a cytokine (a protein involved in the communication between cells), IL-6 is involved in the immune response, inflammation, hematopoiesis (making of new blood cells) and bone metabolism. During an RA response, IL-6 and the IL-6 receptor-α together bind to signal transducing protein gp130 (CD130), which activates the cell signaling pathway known as “JAK-STAT3” and phosphorylation (the addition of phosphates) of STAT3.
A research team led by Dr. Masao Hirota recently developed a new approach to inhibit the IL-6 signaling pathway (Hirota et al., 2016). They developed SL1026, a SOMAmer reagent that has a strong binding affinity for both human and monkey IL-6.
Dr. Hirota and his team determined that SL1026 inhibits IL-6-induced STAT3 phosphorylation in human peripheral blood lymphocytes (a type of white blood cell). First, they incubated whole blood with IL-6 alone, or with IL-6 in combination with either SL1026 or tocilizumab (a current drug that specifically inhibits IL-6 signaling in RA). The researchers then isolated and analyzed the cells and, as expected, IL-6 treatment increased STAT3 phosphorylation. Treatment of the cells with either SL1026 or tocilizumab inhibited STAT3 phosphorylation.
The researchers tested whether or not SL1026 could delay the actual progression of RA in a primate collagen-induced arthritis model (an established model system for evaluating the therapeutic and preventative effects of existing RA drugs). Similar to human RA, the monkeys experienced an autoimmune-mediated polyarthritis, joint inflammation and erosion of bone and cartilage. While one group of monkeys went untreated, a subset of the monkeys received intravenous doses of SL1026. The animals were monitored and scored for behavior and movement. The researchers also scored the degree of swelling and rigidity in numerous joints.
SL1026 not only reduced arthritis symptoms in the monkey model, but also delayed arthritis onset in treated monkeys for 20 days compared to 13 days for the untreated monkeys. The monkeys treated with higher doses of SL1026 also had a reduced arthritis score at day 34 that was significantly different than the untreated monkeys’ score.
One concern with any potential new therapeutic is an allergic reaction on the part of the recipient. To see if this might happen, the team measured levels of anti-SL1026 antibodies. None were identified in the plasma of treated monkeys, indicating that the SL1026 did not trigger an immune/allergic response. In addition, the researchers noted that the SL1026 was well tolerated by the monkeys, and no adverse events occurred.
The efforts put forth by Dr. Hirota and his team established that SOMAmer reagents can be effective therapeutics as a result of their exquisite binding affinities for their target proteins. This particular work demonstrates that the SL1026 is a potent antagonist of the IL-6 signaling pathway. SL1026 may be a promising drug candidate for RA and potentially in other IL-6 mediated diseases. If it makes it to market, SL1026 may prove to be a better treatment option for RA suffers during these cooler and darker days.
Hirota, M., Murakami, I., Ishikawa, Y., Suzuki, T., Sumida, S., Ibaragi, S., . . . Schneider, D. J. (2016). Chemically Modified Interleukin-6 Aptamer Inhibits Development of Collagen-Induced Arthritis in Cynomolgus Monkeys. Nucleic Acid Ther, 26(1), 10-19. doi:10.1089/nat.2015.0567
Savage, E. M., McCormick, D., McDonald, S., Moore, O., Stevenson, M., & Cairns, A. P. (2015). Does rheumatoid arthritis disease activity correlate with weather conditions? Rheumatol Int, 35(5), 887-890. doi:10.1007/s00296-014-3161-5