Drug Developers Identify Novel Target for Treatment of Autoimmune Disease

A recent study identified the target molecule for quinoline-3-carboxamides (Q compounds), a class that developers of drugs for treatment of autoimmune and inflammatory diseases have been working with for more than 25 years.

Q compounds have proven effective in clinical trials for the treatment of multiple sclerosis (MS) and type I diabetes. Furthermore, they are currently in phase III clinical development for the treatment of MS and are about to enter phase II for the treatment of systemic lupus erythematosus (SLE). However, despite intensive research efforts, the target molecule and the mode of action of this class of compounds have remained unknown for over 25 years.

Q compounds are unique in that they have a potent effect on disease development in several animal models of autoimmune or inflammatory disease without inducing suppression of adaptive immunity. In the current study, investigators from Lund University (Sweden), the University of Muenster (Germany), and the company Active Biotech AB (Lund, Sweden) successfully identified a molecular target for quinoline compounds.

The investigators reported in the April 28, 2009, online edition of the journal PLoS Biology that the target was a protein called S100A9. This protein belongs to the family of calcium-binding S100 proteins and has been extensively studied. It is expressed in granulocytes and at early stages of monocyte differentiation. S100A9 has also been detected on the cell surface of mouse macrophages at sites of inflammation, but the role of surface-bound S100A9 in immunity and inflammation is still unclear.

In the current study, the investigators revealed that S100A9 interacted with two known proinflammatory receptors (Toll-like receptor 4 [TLR4] and receptor of advanced glycation end products [RAGE]), and that this interaction was inhibited by quinoline compounds.

These findings allowed the authors to conclude that, " S100A9 appears to be a focal molecule in the control of autoimmune disease via its interactions with proinflammatory mediators. The specific binding of quinoline-3-carboxamides to S100A9 explains the immunomodulatory activity of this class of compounds and defines S100A9 as a novel target for treatment of human autoimmune diseases."

Active Biotech AB currently has three experimental quinoline drugs (laquinimod, 57-57, and TASQ) under active investigation.

Related Links:
Lund University
University of Muenster
Active Biotech