Amgen expounds IL-17 potential as arthritis target

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Amgen expounds IL-17 potential as arthritis target

http://www.drugresearcher.com/news/ng.asp?n=79206-amgen-wyeth-inflammation-il-ar\

thritis

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, 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 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.