November 10-15

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Home // IL-6 shows promise in treating RA, other inflammatory diseases

IL-6 shows promise in treating RA, other inflammatory diseases


4 minutes

Stefan Rose-John, PhD
Stefan Rose-John, PhD

IL-6 is emerging as a key therapeutic target in chronic inflammatory diseases, including rheumatoid arthritis (RA), cancer, coronary heart disease, and Crohn’s disease. In RA, inhibiting IL-6 by blocking the IL-6 receptor can be even more effective than inhibiting TNFα.

“IL-6 is part of a larger gp130 family, named for the glycoprotein l130 expressed on the surface,” said Stefan Rose-John, PhD, Professor and Director of the Institute of Biochemistry at the University of Kiel, Germany. “There is some promiscuity between the different members of this family, so when you block the IL-6 receptor, you may see enhanced activity from blocking multiple cytokines.”

Dr. Rose-John explored the potential impact of IL-6 receptor blockade during the session Immunology Update: IL-6 Signaling from Bench to Bedside on Monday. What began as basic research to understand the role of IL-6 has generated multiple therapeutic agents, with more in the pipeline.

IL-6 is involved in most, if not all, inflammatory diseases, Dr. Rose-John said. And its biology is more complex than many cytokines. IL-6 does not bind directly to its receptor, but requires a co-receptor, gp130. IL-6 signaling begins only when the three-way complex with IL-6, IL-6 receptor, and gp130 is formed.

Another complication is that IL-6 receptors are typically expressed only on hepatocytes and some leukocytes. They are seldom expressed on endothelial cells, smooth muscle cells, and other cell types. The question is how IL-6 is able to affect these and other cell types that do not express the IL-6 receptor.

The key is a metalloprotien, ADAM17, which cleaves the surface-bound IL-6 receptor and transforms it into a soluble form. This soluble receptor then migrates to other cells that express gp130, where it binds with gp130 and IL-6 to begin the signaling cascade.

Dr. Rose-John called the familiar binding between IL-6, its surface-bound receptor, and gp130 classical signaling. The second, more widespread binding between IL-6, soluble IL-6 receptor, and gp130, termed trans-signaling, binds IL-6 more tightly than classical signaling and is an important factor in cellular differentiation, apoptosis, and a variety of other processes.

His lab has also found a third type of IL-6 binding, trans-presentation, in which dendritic cells, which produce IL-6, present the protein to T cells, which bind IL-6 and initiate signaling.

Each of the three types of signaling is involved in different processes, he said.

Classic signaling, involving membrane-bound IL-6 receptor, is associated with anti-inflammatory processes.

Trans-signaling, involving soluble IL-6 receptors, is associated with pro-inflammatory processes as well as processes involving endothelial and smooth muscle cells.

Trans-presentation, involving dendritic cells, is still an open question, Dr. Rose-John said. It appears to be involved in immune response to viral infection.

“The complexity of IL-6 increases the more experiments you do with it,” he said.

Early work in IL-6 focused on the protein itself as a potential therapeutic target. Many researchers believed there was little clinical difference between targeting a protein versus targeting its receptor. But targeting IL-6 receptor, particularly the soluble form, can be far more effective than targeting IL-6 itself.

IL-6 has a relatively low affinity to its membrane-bound receptor and a very high affinity to the soluble receptor, Dr. Rose-John said.

His lab worked with a nucleotide polymorphism that substitutes a single amino acid and leads to significantly increased levels of soluble IL-6 receptor and greatly reduced risk for RA, cancer, congestive heart disease, type 1 diabetes, and other inflammatory conditions. The protective effect stems from the high affinity of the soluble receptor for IL-6, which protects against IL-6-mediated inflammation.

Current anti-IL-6 agents tocilizumab and sarilumab are IL-6 receptor antibodies that overwhelm soluble IL-6 receptors and then membrane-bound receptors, Dr. Rose-John said.

His lab is developing another strategy that targets IL-6 trans-signaling. Researchers developed a fusion protein of soluble gp130 and the crystalizable fragment of immunoglobulin G1, sgp130Fc. The protein showed very strong activity against murine sepsis, with dose-dependent survival up to 100 percent. Survival was just 45 percent using standard anti-IL-6 therapy.

Sgp130Fc also showed significant activity against RA, Crohn’s disease, and inflammatory bowel cancer.

“We now have sgp130Fc in phase 2 trials for inflammatory bowel disease,” Dr. Rose-John said. “We have good evidence that blocking trans-signaling can be very effective.”