CD47 Inhibition to Slow Atherosclerosis is Entering an Initial Clinical Safety Trial
Atherosclerosis, the growth of fatty plaques in blood vessel walls, is the single largest cause of human mortality. More novel approaches to treatment are welcome, as the present standard of care, involving reduction of circulating LDL-cholesterol in the bloodstream, is nowhere near effective enough. It only modestly reduces plaque growth, and cannot regress existing plaque. Atherosclerotic plaques are fat-laden cell graveyards, regions of disrupted metabolism and inflammation. The innate immune cells called macrophages are drawn there or created locally to attempt to repair the lesion, but are overwhelmed by the toxic environment and become dysfunctional and die, adding their mass to the plaque. Eventually a plaque ruptures, to cause a heart attack or stroke.
Some years back, researchers reported that CD47 is abundant in atherosclerotic plaque, decorating the surface of dying and dead cells. CD47 is a "don't eat me" marker that prevents cells from being destroyed by local immune cells as they interact with tissue. Normally this and other other protective markers are lost when a cell approaches death, but for yet to be fully explored reasons this is not the case in the toxic environment of an atherosclerotic plaque. This unwanted overabundance of CD47 prevents some of the clearance of cell debris in the plaque that would otherwise happen. Using techniques developed in cancer research, where anti-CD47 therapies are now well established to try to prevent cancerous cells from abusing CD47 to protect themselves from immune cells, researchers have shown that delivering CD47 to atherosclerotic plaque can slow its progression in mouse models of atherosclerosis.
This research, starting a decade ago or so, led to the formation of Bitterroot Bio, a company now starting an initial phase 1 safety trial of a CD47 inhibitor targeted to macrophages. Today's open access paper reports on earlier tests of their drug in pigs, one of the many steps along the way to the regulatory approval needed to test in human volunteers. Reading through the various published papers on this approach, it seems the case that this therapy only slows progression of plaque, but it hopefully turns out to be better at doing that than the present approach of lowering LDL cholesterol in the bloodstream.
Among the many emerging translational targets in the field of cardiovascular medicine, a phenomenon known as efferocytosis has recently been prioritized for study. Efferocytosis refers to the engulfment and clearance of pathological cells by professional phagocytes such as macrophages. Within the atherosclerotic plaque, enlargement of the necrotic core is, in part, a consequence of impaired removal of apoptotic vascular cells, which have upregulated the key anti-phagocytic 'don't-eat-me' molecule CD47 on their surface. The growth of a necrotic core contributes to plaque instability and eventual rupture, which serves as a nidus for subsequent acute thrombosis.
Antibodies (Ab) which block the binding of CD47 to its receptor SIRPĪ± potently reduce plaque vulnerability and lesion size by preventing the accumulation of apoptotic debris in murine models of atherosclerosis. These pre-clinical observations were recently extended in a phase I trial of the first humanized anti-CD47 Ab. Subjects receiving 'macrophage checkpoint inhibitors' experienced a dramatic reduction in vascular inflammation of the carotid artery scans. Unfortunately, anti-CD47 Ab treatment in both mouse models and humans has been shown to induce anemia due to the non-specific erythrophagocytosis of aged red blood cells (RBCs) in the spleen.
Studies demonstrating toxicity of anti-CD47 antibody-mediated blockade therefore prompted a search for methods which could reactivate efferocytosis in a precision-targeted manner. To do this, we generated a macrophage-specific nanotherapy loaded with a chemical inhibitor of Src homology 2 domain-containing phosphatase-1 (SHP-1), a small molecule downstream of the CD47-SIRPĪ± signaling axis. This 'Trojan horse' nanoparticle selectively delivered drug to inflammatory monocytes and macrophages within the atherosclerotic plaque, potently augmented phagocytosis, and reduced atherosclerosis as effectively as gold-standard Ab therapies in mouse models. Most notably, this therapy did not cause any hematological toxicity.
Accordingly, the aim of this study was to test our targeted nanoparticles in a large animal model of cardiovascular disease (CVD) to determine if additional translation of our nanotherapy toward human clinical trials is justified.