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A look at the science behind a new class of rheumatoid arthritis drugs that act by suppressing an early stage of inflammation, the activation of T cells.
The FDA Arthritis Advisory Committee recommended Bristol-Myers Squibb’s Orencia (abatacept), one of a new class of drugs designed to treat rheumatoid arthritis by inhibiting the activation of immune cells known as T cells.
How T Cells Work:
Rheumatoid arthritis is a complex disease and many cell types are involved,” explained Gary Firestein, professor and chief of rheumatology, allergy, and immunology at University of California San Diego. “Every investigator has a favorite cell but most agree that T cells play a role very early and can help orchestrate an immune response that ultimately becomes rheumatoid arthritis.”
T cell activation is the first step in an “inflammatory cascade” that leads to an immune response, said Jeff Macdonald, a spokesman for BMS. This response is overactive in people with rheumatoid arthritis, an autoimmune disease that causes chronic inflammation of joint tissue and pain, Firestein said.
T cells are activated by multiple interactions with an antigen-presenting cell, which has already bound an invading molecule on its surface, Macdonald said. The T cell recognizes the combination of antigen-presenting cell and bound foreign particle. Or in the case of an autoimmune disease, it mistakes a bound indigenous molecule for a dangerous invader. This is the first step of activation, Macdonald said.
The second step occurs when a protein on the antigen-presenting cell called CD80/86 binds with a protein on the T cell called CD28. This interaction further activates the T cell, which then goes on to activate other cells involved in inflammation and in the production of the immune response, according to Firestein, who is also a former member and chair of the Arthritis Advisory Committee.
The Drug’s Mechanism:
The CD80/86 cell binds to abatacept more selectively than to the CD28 protein, which suppresses T cell activation, Firestein said. This, in turn, derails the chain of activation that some scientists believe is propagated by T cells, according to Macdonald.
Abatacept is more attractive to the CD80/86 receptor because it contains a modified protein called CTLA4, Macdonald said. This naturally occurs on the surface of T cells and is used to inhibit T cell activation in the body, according to BMS data presented to the advisory committee. This synthetic CTLA4 is attached to a modified fragment of another protein, IgG1, which Macdonald described as a part of an antibody molecule that does not bind the antigen.
But any time the immune response is suppressed, Firestein explained, people can become more susceptible to infections. According to BMS data the frequency of infection and cancer for trial participants on abatacept was higher than placebo. But the advisory committee found that the risks were not significant enough to prevent them from recommending approval.
Firestein said rheumatoid arthritis therapies “walk a fine line” between an over active immune system and a susceptible immune system.
“It’s naïve to try and seek only a 100 percent safe therapy for rheumatoid arthritis,” he said. “At least in the sight of current science, it’s impossible.”
The Larger Picture:
According to Firestein, previous attempts to treat rheumatoid arthritis by modifying the T cell response had mixed responses. The role of T cells in the disease was studied frequently in the 1990s but, abatacept is the first drug that is definitely “doing something,’ he said.
But he added that the drug is not a “magic bullet” that will treat all cases of rheumatoid arthritis. Firestein predicted that if abatacept is approved, most patients would use it in combination with other drugs.
“Targeting a single molecule, thus far, has not been truly effective it the majority of patients,” Firestein said. “That means combination therapy.”