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Going Along for the Ride Gastroenterology Research Yields a New Way to Deliver Protein Drugs
Research on how cholera toxin gets into the body is yielding an unexpected dividend: a technology that may allow drugs that now must be injected to instead be inhaled. The research is a boon for patients with chronic conditions who now endure repeated shots or intravenous hookups, and it could become a big business success for Children's Hospital Boston and its collaborators. According to Syntonix Pharmaceuticals, which has licensed the technology, some of the first people expected to benefit are patients receiving erythropoietin for anemia due to kidney dialysis or cancer chemotherapy, patients taking alpha interferon for hepatitis C and patients taking interferon beta for multiple sclerosis. Like many products of the biotech revolution, these drugs consist of large proteins that currently must be injected directly into the bloodstream because they're too large to be absorbed through the intestine or lungs. Back in the early 1990s, Children's gastroenterology researcher Wayne Lencer, MD, was at Brigham and Women's Hospital (BWH) studying how cholera toxin manages to be absorbed through the intestine and cause disease. Normally, the mucosal epithelium - which lines the intestine, genital tract, nose, mouth and lungs - prevents large molecules like toxins and germs from reaching the bloodstream. But Lencer, a cell biologist, found that cholera toxin does an end-run around this barrier by exploiting a natural cell transport system known as transcytosis. Meanwhile, Rick Blumberg, a mucosal immunologist from BWH, had become interested in a cellular receptor molecule called FcRn. It enables newborn mice to absorb immunoglobulins (IgGs), which are proteins that function as antibodies, from the mother¡s breast milk. Like cholera toxin, these protective proteins are normally too large to pass through the mucosal epithelium. But when they bind to the FcRn receptor, they easily hitch a ride across. FcRn was thought to occur only in baby rodents, but Blumberg unexpectedly found it in the cells of adult mice as well. Knowing of Lencer's work on cholera and transcytosis, Blumberg told him about the finding. "We started to collaborate on the idea that FcRn is in adult animals, and maybe in humans, and that it functions to move IgG - the body's main antibody - from the blood into the intestines and back into the blood,” says Lencer. The scientists further speculated that the FcRn receptor could be used as a natural "escort” to get other big things into the body - useful things like vaccines or drugs. "FcRn takes up the IgG protein, so anything linked to IgG would be transported across the cell into the bloodstream,” Lencer says. "This was the beginning of the idea that IgG could be used to deliver medications.” Transcytosis begins on the "outer” side of the mucosal epithelial cell - the side bordering the intestinal cavity or airways of the lung, for example. The IgG protein binds to the FcRn receptor, and the cell then pinches off a little bubble, or vesicle, which travels across the cell and empties its contents on the other side, next to the bloodstream. There, the FcRn receptor "lets go” of IgG, which then enters the blood. In theory at least, any drug attached to IgG could go along for the ride. The work shifted to Children's, where Lencer had relocated his lab. Over the next few years, he and Blumberg showed that the FcRn receptor does exist in adult human cells, both in the intestine and the lung, functioning as a transport system for the IgG protein. Along with Neil Simister of Brandeis University, they won a patent, today held jointly by Children's, BWH and Brandeis. They formed a start-up company called Syntonix with former executives of biotech company Genetics Institute signing on as investors, executive management and scientific advisors. Early financing enabled Lencer, Blumberg and Simister to do the experiments that proved the transcytosis approach would actually work. They first demonstrated, in mice, that absorption of the IgG protein from the lung is dependent on the FcRn receptor. Next, they piggybacked a test drug onto IgG, which is a Y-shaped molecule; one end of the Y binds to the FcRn receptor, and the other ends are responsible for IgG's antibody function. These latter portions were stripped out and replaced with two copies of erythropoietin (EPO), a drug based on a natural hormone that increases production of red blood cells. Tests showed that this EPO "fusion molecule” is efficiently absorbed into the body and that red blood cell counts increase as a result. Syntonix confirmed these findings in human volunteers given the molecule by inhalation. Further tests revealed that drugs last longer in the body when joined to the IgG protein, allowing them to be taken less often or in smaller doses. EPO alone lasts for 5-6 hours, whereas EPO fused to IgG persists for 20-25 hours, says Garen Bohlin, Syntonix¡s CEO. Syntonix is courting pharmaceutical and biotech partners to conduct further clinical trials and develop inhalable products. (Oral versions are also possible, but need more work since the drugs tend to get digested upon reaching the intestine.) Fusion drugs based on EPO, interferon alpha, and interferon beta are furthest along in the pipeline, but others are in development. One is an inhaled version of follicle-stimulating hormone, a fertility drug that is now given by painful daily injections. Another is factor IX, a hemophilia drug. Most patients now inject it once they begin to bleed, but a more user-friendly inhaled version could be used preventively. An inhaled version of the AIDS drug Fuzeon, now injected twice daily, is also under consideration; its longer half-life could reduce dosing frequency. According to Bohlin, EPO and the interferons alone represent a potential multi-billion-dollar market. The three academic institutions recently reworked their licensing arrangement with Syntonix so the company could better attract partners. Don Lombardi, chief intellectual property officer at Children's, says that money isn't the hospital's only goal. "A big moneymaker? Who knows?” he says. "What we're really focused on is gestating technology for the public benefit. In structuring deals, we ask, 'What can we get out of the way to let the science go forward?'” To support
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