Anti-tumor antibodies could counter atherosclerosis

CD47 in atherosclerotic tissue

In the new study, Leeper, Kojima and their colleagues performed genetic analyses of hundreds of human coronary and carotid artery tissue samples collected at Stanford and at Sweden’s Karolinska Institute. They found that CD47 is extremely abundant in atherosclerotic tissue compared with normal vascular tissue, and correlated with risk for adverse clinical outcomes such as stroke.

Much of what’s now known about CD47’s function stems from pioneering work by Irving Weissman, MD, professor of pathology and of developmental biology and director of Stanford’s Institute of Stem Cell Biology and Regenerative Medicine and the Ludwig Cancer Stem Cell Institute. In the late 1990s and early 2000s, Weissman and his colleagues first identified CD47 as being overexpressed on tumor cells, which helps them evade destruction by macrophages. Weissman’s group went on to show that blocking CD47 with monoclonal antibodies that bind to and obstruct the protein on tumor cells restores macrophages’ ability to devour those cells. Phase-1 clinical safety trials of CD47-blocking antibodies in patients with solid tumors and blood cancers are now underway.

Alerted to the Leeper lab’s discovery, Weissman, a co-author of the new study, provided anti-CD47 antibodies so Leeper’s group could test their efficacy in battling atherosclerosis.

In a laboratory dish, anti-CD47 antibodies induced the clearance of diseased, dying and dead smooth muscle cells and macrophages incubated in conditions designed to simulate the atherosclerotic environment. And in several different mouse models of atherosclerosis, blocking CD47 with anti-CD47 antibodies dramatically countered the buildup of arterial plaque and made it less vulnerable to rupture. Many mice even experienced regression of their plaques — a phenomenon rarely observed in mouse models of cardiovascular disease.

Looking at data from other genetic research, the scientists learned that surplus CD47 in atherosclerotic plaques strongly correlates with elevated levels, in these plaques, of a well-known inflammation-promoting substance called TNF-alpha. Further experiments showed that TNF-alpha activity prevents what would otherwise be a progressive decrease of CD47 on dying cells. Hence, those cells are less susceptible to being eaten by macrophages, especially in an atherosclerosis-promoting environment.

A vicious circle?

“The problem could be an endless loop,” said Leeper, “in which TNF-alpha-driven CD47 overexpression prevents macrophages from clearing dying cells in the lesion. Those cells release substances that promote the production of even more TNF-alpha in nearby cells.”

Leeper and Weissman said they hope to find out, in clinical trials of human patients, whether CD47-blocking antibodies will prove effective in breaking that vicious circle.

It seems that heart disease may be driven by our immune system’s inability to ‘take out the trash.’

“This opens up the door for these antibodies’ use in noncancerous pathological states where cell proliferation is a primary attribute of the diseased cells,” said Weissman, who is the Virginia and D.K. Ludwig Professor for Clinical Investigation in Cancer Research.

One side effect of anti-CD47 antibodies in the mouse experiments, Leeper said, was transitory anemia. “Young red blood cells have high surface levels of CD47, which tells macrophages to leave them alone. Older red blood cells lose this protection, allowing macrophages to cull them from the herd,” he said. Anti-CD47 antibodies render these older cells more prone to macrophage attack. But the anemia appeared to clear up fairly quickly in the mice as their bodies adapted by producing numerous fresh red blood cells with high surface CD47 levels.

The work is an example of Stanford Medicine’s focus on precision health, the goal of which is to anticipate and prevent disease in the healthy and precisely diagnose and treat disease in the ill.

Leeper and Weissman have filed a patent describing inhibition of CD47 as a method to prevent atherosclerosis. Both researchers hold equity in Palo Alto-based Forty Seven Inc., a company they cofounded that has licensed related intellectual property from Stanford’s Office of Licensing Technology for cancer applications.

The study was carried out in collaboration with investigators at the David Geffen School of Medicine at UCLA and the Icahn School of Medicine in New York City. Other Stanford study co-authors are instructors Jens-Peter Volkmer, MD, and Clint Miller, PhD; postdoctoral scholars Paola Betancur, PhD, Daniel Direnzo, PhD, and Vivek Nanda, PhD; life science research assistant Kelly McKenna; laboratory manager Jianqin Ye, MD, PhD; associate professor of pathology Andrew Connolly, MD, PhD; and professor of cardiovascular medicine Thomas Quertermous, MD.

The study was funded by National Institutes of Health grants (R01HL12522401, R01HL12337001 and U01HL099999).

Stanford’s departments of Medicine, of Surgery, of Developmental Biology and of Pathology also supported this work.

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Anti-tumor antibodies could counter atherosclerosis