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Aug 25, 2016
 |  BC Innovations  |  Targets & Mechanisms

Forty Seven and counting

Stanford and Forty Seven Inc. count up new indications for CD47 blockade

With companies lining up to block CD47 for cancer, the cell surface protein is emerging as one of the top new targets in oncology. But the list of suitors could be about to get a lot longer as the target could have uses in a much broader range of indications, according to two studies from Stanford University that extend its prospects to cardiovascular disease and transplant biology, and hint at roles in several more diseases.

The discoveries have been licensed by Forty Seven Inc. as part of the 100-plus patent portfolio licensed from the university when the company was spun out by Stanford professor Irving Weissman to develop inhibitors of CD47 for cancer. The company raised $75 million in series A financing in February, and has its lead compound, the CD47-blocking mAb Hu5F9-G4, in Phase I for acute myelogenous leukemia (AML) and solid tumors.

Weissman, a professor of pathology and developmental biology, is also director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford.

Last week's announcement by Tioma Therapeutics Inc. of an $86 million series A round brings to six the number of companies with disclosed programs targeting CD47 (see Table: Chasing CD47). Since April of last year, companies targeting CD47 have raised more than $247 million.

Commonly known as a "don't eat me" signal, CD47 is expressed on the surface of red blood cells (RBCs), and many other cell types, where it interacts with the receptor protein SIRPA on macrophages to prevent phagocytosis.

Cancers can co-opt this biology, up-regulating CD47 to avoid getting eaten by macrophages. Blocking CD47 via mAbs or SIRPA-derived antagonists allows macrophages to both clean up tumors and recruit other immune cells to help.

Forty Seven CBO Craig Gibbs told BioCentury that Weissman - a pioneer in the field - and his colleagues have established the target's extensive role in cancer. "Just in oncology, they've demonstrated efficacy against 23 different human tumors in preclinical animal models," said Gibbs.

Now two other Stanford groups, in collaboration with Weissman's lab, have published studies in Nature and Science Translational Medicine, respectively, showing that blocking CD47 to promote macrophage activity could also help treat atherosclerosis or precondition patients for bone marrow transplant (BMTs) (see Figure: Cleanup crew). Nicholas Leeper, an associate professor of vascular surgery at Stanford and principal investigator on the atherosclerosis study, said the results reveal a surprising overlap between the biology of cancer and heart disease. "It's pretty amazing that you can have a single common pathway responsible for the top two leading causes of death in the U.S."

Likewise, the transplantation study showed CD47 blockade could have unanticipated benefits in BMTs by eliminating the need for irradiation or chemotherapy and minimizing toxicity. The team combined CD47 inhibitors with hematopoietic cell-targeting antibodies to make room for donor cells in recipient bone marrow, without relying on DNA-damaging agents.

"We create this window when the cells in the bone marrow are depleted enough that if you infuse donor cells, then they're able to occupy those niches and reconstitute the blood system," said Akanksha Chhabra, a postdoctoral fellow in blood and marrow transplantation at Stanford's School of Medicine, who was first author on the paper.

But Gibbs thinks the potential of the...

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