What do a cancerous tumor and fatty buildup in an artery have in common? Their harmful cells may have the same way of hiding themselves from the immune system, a study out today suggests. In the new work, researchers studying atherosclerosis—the progressive buildup of fat-laden cells into arterial plaque—found a signaling molecule that may prevent dead cells in the arteries from being eaten and disposed of. Blocking that signal, they found, reduces arterial plaque in mice. And because their signal blocker is an antibody already in phase I clinical trials for cancer treatment, they’re hoping to make a quick jump into human testing for cardiovascular disease.
“It’s going to be a new platform of therapy, not just another cholesterol-lowering drug,” says Nicholas Leeper, a vascular biologist at Stanford University in Palo Alto, California, and senior author on the new study.
Although cholesterol contributes to atherosclerosis, the story of the disease’s progression is much more complex. When these fatty deposits damage an artery wall, immune cells flock to the scene—notably macrophages, which gobble up dying and damaged cells all over the body. But when they arrive at the inflamed artery, they fail to perform that cleanup. Soon, dying muscle cells and dying macrophages join a growing plaque on the artery wall. Nestled inside is a “necrotic core,” a graveyard of cells that destabilizes the rest of the plaque and makes it prone to rupture, which can block the artery and cause a heart attack or stroke.
Leeper and his colleagues have been studying the signaling between dying cells and the macrophages that are supposed to put them out of their misery. The team previously found that many of these dying cells are missing a surface molecule that labels them for destruction—called calreticulin—in people at risk for cardiovascular disease. But other common surface molecules in the body send a different signal: “I’m healthy—leave me alone!” And that may give scientists an opening. It might be easier to block that message than to force cells to express more “eat me” signals. In fact, researchers at Stanford are already collaborating on initial clinical trials of an antibody that blocks cancer cells from displaying one such death-evading signal—a molecule called CD47.
Atherosclerosis researchers have had their eye on “don’t eat me” signaling molecules like CD47 for some time, says Matthias Nahrendorf, a cell biologist at Harvard Medical School in Boston who was not involved in the new study. But no one had measured this common molecule in arterial plaques. “I don’t have a good reason why people haven’t looked at this particular molecule in atherosclerosis before,” he says. “Retrospectively, it’s an obvious choice.”
Leeper’s team analyzed samples of arterial plaque from people undergoing surgery for a clogged carotid artery and from organ donors without cardiovascular disease. They found that arterial plaque contained significantly higher levels of CD47 than healthy arterial tissue. To see whether blocking CD47 could reverse plaque buildup, the group tested the experimental anticancer antibody drug in several different mouse models of cardiovascular disease. On a high-fat diet, these animals quickly develop plaques in their arteries because they lack a gene that regulates cholesterol metabolism. But intravenous treatment with the anti-CD47 treatment reduced by roughly half the buildup of plaque in these mice, Leeper and colleagues report online today in Nature.
“These findings are groundbreaking for the field of atherosclerosis research,” says MacRae Linton, an endocrinologist at Vanderbilt University in Nashville, who was not involved in the study. The results make anti-CD47 antibodies a promising drug candidate for cardiovascular disease, he notes, though there may be other “don’t eat me” signaling molecules in plaques that it can’t address. If the drug progresses to human trials, researchers will also have to watch for anemia, a side effect hinted at in the mouse results. CD47 is key to protecting red blood cells from macrophages, and red blood cells are particularly sensitive to the blocking effects of the antibody as they get older, Leeper says. Treated mice in the study did show drops in red blood cell count, though they showed no clinical sign of illness.
The researchers have patented their treatment approach and licensed it to Forty Seven Inc., the Stanford spinout already developing anti-CD47 antibodies for cancer. Stanford stem cell biologist and Forty Seven Inc. founder Irving Weissman, whose group pioneered research on CD47 in cancer, is a co-author on the new paper. Although no new therapy faces a smooth or certain path to the clinic, this one may have a head start. The drug has already demonstrated safety in nonhuman primate trials, and the cardiovascular research might even be able to skip ahead to a larger phase II trial based on safety data from the ongoing phase I studies, Leeper suggests. “This may be a very unusual circumstance where we can piggyback.”