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Amgen expounds IL-17 potential as arthritis target

By Mike Nagle , 23-Aug-2007

Amgen is rushing to discover how interleukin-17 causes inflammation and bone destruction in rheumatoid arthritis, as it could provide a valuable new therapeutic target.

Amgen's director of inflammation research, Joel Tocker, outlined the biotech's progress in early-stage research at the Drug Discovery and Development of Innovative Therapeutics (DDT) conference in Boston, US.


In rheumatoid arthritis patients, levels of interleukin-17 (IL-17) are present in much higher levels in synovial fluid, compared with osteoarthritis patients, suggesting this protein may become a significant target for new rheumatoid arthritis drugs.


In a market valued at over $4bn (€2.95bn) in 2004, according to Datamonitor, new therapeutic targets are widely sought. Current treatment often relies on older classes of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying anti-rheumatic drugs (DMARDs) and corticosteroids.


Newer drugs do focus immune system targets such as tumour necrosis factor-alpha (TNF-alpha), IL-1, IL-6, IL-15 and p38-MAP-kinase. However, IL-17 provides a possible new strategy to tackle this debilitating condition.


Amgen already have two marketed arthritis products - Enbrel (etanercept) and Kineret (anakinra), which are a tumour necrosis factor (TNF) blocker and a recombinant, nonglycosylated synthetic form of the human interleukin-1 receptor antagonist (IL-1Ra) respectively.


The company has another two in development: AMG 108, a monoclonal antibody (mAb) that targets IL-1 and denosumab, another mAb that specifically targets the receptor activator of nuclear factor kappa B ligand (RANKL).


Tocker said that IL-17 has now been shown to be involved in bone destruction through a number of mechanisms. For example, interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of IL-17.


There are several members of the IL-17 family, from IL-17A to IL-17F (IL-17E is also called IL-25). They all have very similar structures, with four cysteine residues that are highly conserved. However, they bear no resemblance to other cytokines.


Amgen have conducted extensive research on this family. IL-17A and IL-17F have been shown to induce pulmonary neutrophilia in mice, which was confirmed using antibodies to block the effect of these proteins and then measuring the number of neutrophils. A monoclonal antibody (mAb) against the IL-17 receptor also reduced CIA in animals.


For the next step in their research, Amgen decided to focus on the nature of the IL-17R signalling complex - an area Tocker said has often been overlooked in the past. The team showed that formation of the receptor complex was independent of IL-17 and so proposed that the receptor forms prior to ligand binding.


Another group at Zymogenetics showed that IL-17RC can bind to IL-17 and IL-17F, thus discovering that the C receptor is a functional component of the full IL-17R complex.


Based on this research, and their own studies, Tocker said that Amgen developed the theory that IL17A and IL-17F signalling is mediated by a receptor complex composed of both IL-17RA and IL-17RC subunits. Amgen then went on to use immnoprecipitation techniques to show that the two chains do indeed physically associate in cells.


Wyeth is also looking into IL-17 and has reported the formation of a heterodimer. Amgen are investigating the research but, as yet, have been unable to replicate Wyeth's results.


Tocker said at the very least receptor A should provide a druggable target but scientists need to know more about receptor F before that protein becomes viable for drug discovery.

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