New Drug Targets Emerge to Treat RA

Recent insights into the processes driving the autoimmune attack underlying rheumatoid arthritis are leading to promising new classes of treatments, researchers said here.

At a session at the European League Against Rheumatism (EULAR) meeting, European and Chinese scientists described a variety of novel approaches to the disease that could, within a few years, add to the range of options now available to clinicians and patients.

Moreover, these "new" targets are not really new at all, except in the context of rheumatoid arthritis. They include granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta, both familiar in the cancer world.

Signaling pathways activated by these proteins help drive the proliferation and differentiation of immune cells involved in rheumatoid arthritis.

And a growing body of evidence suggests that a certain type of stem cells may be effective in rheumatoid arthritis and other autoimmune diseases -- not by sparking growth of new tissue, but through recently recognized immunoregulatory powers that these cells seem to have.

A drug candidate for rheumatoid arthritis has already emerged for the GM-CSF pathway, with phase I clinical results reported at EULAR.

Gerd Burmester, M.D., of Humboldt University in Berlin, said a monoclonal antibody called CAM-3001 had shown good enough results in this early study that additional clinical testing would be performed.

The GM-CSF protein is now used in cancer patients to counter the myeloablative effects of many chemotherapies, helping to restore lymphocyte counts.

Because many of these cells -- especially macrophages, Dr. Burmester said -- are involved in rheumatoid arthritis, there has been interest in targeting the GM-CSF receptor in the disease.

The phase I trial tested seven doses of the antibody drug as well as placebo in 32 rheumatoid arthritis patients with low to moderate disease activity (DAS28 scores no more than 4.8, mean 3.6).

As with all phase I trials, efficacy was of secondary interest, and the drug's effects on clinical symptoms weren't assessed.

But Dr. Burmester reported that laboratory measures of disease activity were significantly reduced.

Following a single intravenous infusion, mean C-reactive protein levels declined significantly, and erythrocyte sedimentation rates were normalized in 10 of 27 patients with elevated baseline levels, he said.

No safety concerns were raised in the trial, Dr. Burmester said. Neutrophil counts remained normal in all patients, there were no treatment-emergent adverse events, and the fully human antibody did not appear immunogenic.

He promised that additional trials were planned.

At an earlier stage is an agent targeting a signaling kinase for transforming growth factor-beta called TAK1.

Gabriel Courties, M.S., of the INSERM laboratory in Montpellier, France, reported on tests with a small interfering RNA molecule in a standard mouse model of rheumatoid arthritis.

The molecule blocks expression of TAK1, preventing the receptor for transforming growth factor-beta from transmitting signals when bound by the protein.

Courties explained that TAK1 is a downstream mediator of the response to both interleukin-1 and tumor necrosis factor-alpha.

The RNA molecule was packaged into a liposomal vehicle for the tests, which showed that weekly injections reduced Th1 lymphocytes by 35% and Th17 cells by 75% compared with sham-treated animals, he reported.

Clinical disease symptoms including inflammation and cartilage and bone erosions were reduced as well, along with inflammatory cytokines such as tumor necrosis factor and IL-6, Courties said.
The research on mesenchymal stem cells as rheumatoid arthritis therapy was reported by Yanying Liu, M.D., of Peking University People's Hospital in Beijing, China.

Her study was conducted in vitro on fibroblast-like synoviocytes and T cells taken from rheumatoid arthritis patients.

Mesenchymal stem cells are best known as progenitors of a wide variety of cell types, including many blood cells.

But they also appear to influence behavior of mature immune cells including T cells.

Because of this effect, mesenchymal stem cells have already been tested clinically as possible treatments for other immune-related diseases including multiple sclerosis, graft-versus-host disease, and systemic lupus erythematosus. (See: ASH: Stem Cells Rescue Some Patients With Severe GvHD and Adult Stem Cells May Help Treat Multiple Sclerosis)

Using mesenchymal stem cells derived from human umbilical cord blood, Dr. Liu and colleagues demonstrated that that they inhibit proliferation of synoviocytes when exposed to tumor necrosis factor.

The stem cells also inhibited IL-6 secretion while also upregulating transforming growth factor-beta, Dr. Liu reported.

Also, while overall T cell proliferation was reduced by about 60%, she said, regulatory T cell expression was increased.

Dr. Liu said these effects generally were what one would want to see in a rheumatoid arthritis therapy.

"[Mesenchymal stem cells] could be a potential candidate for rheumatoid arthritis treatment in the future," she said.

Source : www.medpagetoday.com