Switzerland's Serono has initiated Phase I clinical testing of TACI-Ig, a therapeutic that may have a role to play in the management of autoimmune diseases. The company is developing the drug in tandem with ZymoGenetics of the USA.
The launch in 2001 of the first drug based on a soluble receptor - Amgen's Enbrel (etanercept) for rheumatoid arthritis - provided a validation of the use of this type of drug as a therapeutic agent. Enbrel remains the only soluble receptor-based drug on the market, but the versatility of the approach, in which the soluble receptor binds to its target and blocks its activity, has led to a number of other candidates starting clinical development.
TACI-Ig is a soluble form of the TACI receptor, found on antibody-producing B lymphocytes and thought to have a regulatory function. Serono entered into a $52.5 million agreement with ZymoGenetics in 2001 for the development of drugs targeting TACI and another B lymphocyte receptor called BCMA.
TACI has been shown to bind to BLyS and APRIL, two cytokines that stimulate B-cell growth and the production of autoantibodies. Studies have shown that in mice where production of BlyS is shut down (by deletion of the gene coding for the cytokine), the animals develop with no mature B cells present and produce fewer antibodies in response to immunisation.
ZymoGenetics scientists also showed that mice genetically engineered to overexpress the gene for BLyS develop symptoms of the autoimmune disease systemic lupus erythematosus (SLE), including the generation of autoantibodies.
By using the receptor portion of TACI responsible for binding the growth factors, ZymoGenetics researchers have produced TACI-Ig, an antagonist protein that can 'mop up' increased BLyS and APRIL cytokines in the blood. The drug thus prevents binding of the growth factors to the B cells, regulating the development of mature B cells and antibody production.
"Through the ability of soluble receptors to bind to and eliminate the BLyS and APRIL growth factors and consequently avert production of destructive autoantibodies, it may be possible to limit the extent of tissue damage observed in patients with autoimmune disease," said the company in a statement.
The double-blind placebo controlled Phase I trial will be conducted in the UK in healthy volunteers randomised to receive either TACI-Ig or placebo. In addition to monitoring safety and pharmacokinetics of TACI-Ig, the effects on B-lymphocytes will also be measured.
"TACI-Ig has the potential to be an important treatment for a variety of immunological diseases, such as lupus and rheumatoid arthritis, as well as other indications such as non-Hodgkin's lymphoma," commented Bruce A. Carter, ZymoGenetics' CEO.