Mike May
Contributing Editor
Unraveling the mechanisms behind autoimmune diseases keeps pushing new compounds into development and providing new roles for some approved drugs.
In 1995, Steve Robson tried out a jackhammer just for a minute or two. The next morning, he couldn’t move his left hand. It was rheumatoid arthritis (RA) and turned
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into years of pain. “Imagine pebbles in your shoes that you can’t take out,” Robson says. “Try walking on them all day.” Eventually, he had a hip replaced, got surgery for carpal-tunnel pain, and couldn’t even tie his shoes. Then, he stumbled into a clinical trial for MabThera/Rituxan (rituximab), which targets the B cells involved in RA. “The drug took away the pebbles,” Robson says.
In the 80 or so autoimmune diseases, the immune system mistakenly attacks its maker. In other words, it sees “self” as “non-self,” or an invader. Such mistakes trigger a wide range of diseases, including multiple sclerosis (MS), systemic lupus erythematosus (SLE), and Type 1 diabetes. These diseases also involve many immune players: B cells, T cells, cytokines, and others. Nonetheless, a variety of new or repurposed drugs in development could take advantage of the growing understanding of the science behind autoimmunity.
Taking on T Cells
“T cells play an integral role in autoimmunity,” says Michael Corbo, PhD, RPh, vice president of development for Orencia (abatacept) at Bristol-Myers Squibb, Princeton, N.J. “They coordinate the destructive processes that occur in autoimmune diseases.” He also points out that T cells fight infections, so you can’t just destroy them all.
Some of the compounds being developed by Corbo and his colleagues take on T-cell costimulation. To get activated, T cells first need an antigen-specific signal and then a costimulus, such as binding between CD28—a T-cell surface protein—and CD80/86 on an antigen-presenting cell. “Our molecule competitively binds with CD28,” says Corbo. “That prevents the activation of some T-cells.” In this general class, Orencia is already approved for RA. “We also have recent data for juvenile idiopathic arthritis with Orencia,” says Corbo.
Corbo also points out that T cells play a role in many other autoimmune diseases, including Crohn’s disease and SLE. “The key in treating autoimmunity,” says Corbo, “is to get closer to the pathogenesis of the disease.”
Attacking inflammation
But pathogenesis can be hard to locate. RA, for instance, usually targets joints, but it can affect the entire body. That breadth of attack, though, might indicate an equally broad spectrum of potential therapeutic compounds. In fact, even drugs used for other diseases might fight RA.
For example, William H. Robinson, MD, PhD, assistant professor of medicine at Stanford University School of Medicine, Stanford, Calif., and his colleagues screened already-approved drugs in
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mice with an RA-like condition. “We screened about 20 compounds,” says Robinson. “They had mechanisms of action that might influence inflammation or autoimmune responses.” Robinson’s team assessed drugs on several measures, including the swelling in a mouse’s paws, pathology of tissue sections from joints, and so on.
Surprisingly, Novartis’ cancer drug Gleevec turned down the RA. For mice that didn’t already have RA, Gleevec provided what Robinson calls “dramatic prevention.” For mice with arthritis, Gleevec (imatinib mesylate) prevented progression of the disease. “It makes sense when you think about it,” says Robinson, “because Gleevec inhibits a kinase that plays a role in the pathogenesis of RA.”
Cytokines also play roles in RA. Roche’s Actemra (tocilizumab) inhibits an interleukin-6 (IL-6) receptor. A study by Roche showed that Actemra surpassed methotrexate—a common treatment—in reducing RA symptoms. Anthony Quinn, MD, PhD, head of clinical research and exploratory development for inflammation at Roche, Palo Alto, Calif., says, “By having a portfolio of compounds to test, we have gained new insights into important disease drivers in rheumatoid arthritis and other autoimmune diseases.”
Stopping traffic
Instead of attacking specific components of the immune system, treatments could also block the normal traffic flow. Scientists at Lexicon Pharmaceuticals, The Woodlands, Tex., think that could work.
Lexicon looks for drugs that mimic knockouts for specific genes. For example, LG293 is a gene that impacts the trafficking of lymphocytes. Knockout LG293 and “almost no B or T cells can be found in the periphery,” says Brian Zambrowicz, PhD, Lexicon’s executive vice president and chief scientific officer. “Instead, mature immune cells that should circulate are stuck in the thymus.”
Lexicon scientists developed LX2931, a compound that mimics an LG293 knockout. “In RA,” says Zambrowicz, “lymphocytes migrate to sites of inflammation. Our compound might prevent the egress of lymphocytes from
 click to enlarge B-cells have been shown to be very effective at presenting antigens (1) and activating T-cells in the lining of the joint or synovium (2), which is the main site of disease activity in rheumatoid arthritis. This is important, since B cell–activated T-cells release cytokines (3) that can directly or indirectly promote inflammation and ongoing destruction of the joint, or stimulate other cells to release destructive cytokines (4). (Source: Genentech) |
lymphoid organs.” Nonetheless, LX2931 does not completely shut down the immune system. It leaves 20% to 30% of the B and T cells in the periphery, which might maintain normal immune functions. Later this year, Zambrowicz and his colleagues hope to file an investigational new drug application on this compound.
Science of surface markers
Therapies can also seek cells based on surface proteins. For example, MabThera/Rituxan binds to CD20 on some B cells. As a result, this compound cripples some of the B-cell pathways, such as presentation of self-antigens that contribute to inflammation in RA.
This surface protein, though, can provide other uses. “Compounds that bind CD20,” says Sunil Agarwal, MD, group medical director for immunology at Genentech, South San Francisco, Calif., “can be used as tools to evaluate if B cells play a role in the pathophysiology of a specific autoimmune disease.” So anti-CD20 compounds can be used to slow down B cells and then see if that impacts an autoimmune disease.
Multiple MS compounds
At Bayhill Therapeutics, Palo Alto, Calif., Mark W. Schwartz, PhD, president and chief executive officer, says, “Our goal is to shut down the immune system in an antigen-specific manner.”
Bayhill takes one approach called BHT-DNA, which uses plasmids to deliver a specific autoantigen. For example, BHT-3009 delivers the gene for myelin basic protein, which T cells attack in MS. Schwartz says, “This therapy delivers the autoantigen in a context that the body begins to see as self, resulting in amelioration of the autoimmune disease while leaving the healthy immune cells intact.” The results from a Phase 2 trial for this compound were being analyzed at the time of the interview.
At BioMS Medical, Edmonton, Alberta, Canada, scientists hope that high-dose tolerance can take on MS. “It’s been known for 50 years that giving a high intravenous dose of a soluble foreign substance can make the immune system temporarily unable to respond to that substance,” says Mark Krantz, PhD, vice president scientific affairs. As an example, BioMS’s MBP8298 is a synthetic copy of a myelin region that immune cells commonly attack in MS. Periodic, high intravenous doses of MBP8298 control that MS attack, and a Phase 2 trial suggested clinical benefits. According to Tony Verco, MD, MBA, vice president medical affairs at BioMS Medical, “MBP8298 is in Phase 3 trials around the world, and previous trials provide reasonable confidence that we won’t have a safety issue.”
Scientists hope to get better at targeting the right drug to the right autoimmunity patient. As a long-term goal, researchers envision taking measurements from a patient and using the results to select therapies. Scientists, however, should be able to find ways of identifying responders to therapies at a population level to help target treatments to those patients with the best chance of responding.
About the Author
May is a publishing consultant for science and technology based in Minnesota.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 9, September, 2007, pp. 30-33.
Filed Under: Drug Discovery
