Science
Why CD47 Matters
Cancer cells commandeer a “don’t eat me” signal, called CD47, to escape elimination by our innate immune system’s first responders.
These innate immune cells, called macrophages, respond to “eat me” signals, non-specific signs of danger, from pathogens or abnormal cells, including cancer cells. When a macrophage recognizes a cancer cell through its “eat me” signals, it swallows and digests the cancer cell as a first line of defense. The macrophage then alerts specialized cells in the adaptive branch of our immune system, which include T cells, to specific foreign features, antigens, of that cancer cell. This mobilizes targeted, long-term defenses against the cancer cells.
Macrophages respond to threats when “don’t eat me” signals, often found on normal cells to prevent unwanted auto-immune attacks, are outweighed by “eat me” signals commonly found on pathogens or abnormal cells but not on normal cells.
Blocking CD47 “don’t eat me” signals while releasing and boosting “eat me” signals is the core focus of our research to enable the patient’s own immune system to attack and destroy their cancer.
Nearly all types of tumors overexpress CD47. When CD47 binds to its receptor SIRP-alpha on macrophages, it sends a “don’t eat me" signal and thus inhibits destruction by macrophages. Overexpression of CD47 is correlated with poor prognosis in multiple cancers, including acute myeloid leukemia, Non-Hodgkin's lymphoma, ovarian cancer, gastric cancer, and lung cancer.
Our Scientific Foundation
Our company was founded by leading scientists at Stanford University who uncovered the fundamental role of CD47 in cancer evasion. Preclinical work performed in the laboratory of our co-founder, Irv Weissman, at Stanford University established the three pillars of our CD47 targeted therapy:
- Blocking the CD47 “don’t eat me” signaling pathway leads to elimination of many types of tumors and increased survival
- Boosting “eat me” signals on cancer cells using therapeutic anti-cancer antibodies results in a synergistic effect with blocking CD47
- Macrophages digest cancer cells in a process called phagocytosis and present tumor-specific antigens that can activate T cells against the cancer and can result in long-term anti-tumor immunity, when combined with T cell checkpoint inhibitors.
Our Immunotherapy
Our immunotherapy, 5F9, is an antibody that is designed to block the CD47 “don’t eat me” signal, restoring the ability of macrophages to attack and destroy cancer.
Preventing cancer from suppressing the innate immune system is an emerging field in oncology, and 5F9 is among the first in a new class of innate immune checkpoint inhibitors. We are investigating 5F9 in multiple Phase 1 and Phase 2 trials in various cancers, including non-Hodgkin’s lymphoma, colorectal cancer, ovarian cancer and acute myeloid leukemia as both monotherapy and in combination with approved therapies.
Combination with Our Immunotherapy
We believe combining our 5F9 immunotherapy with existing cancer therapies can further enhance macrophages' ability to recognize cancer cells and can mobilize potent adaptive immune responses to eliminate cancer.
Targeted Antibodies. Therapeutic antibodies that target specific cancers can produce strong “eat me” signals on cancer cells, stimulating macrophage recognition and response. For example, many B cell lymphomas, including follicular lymphoma and diffuse large B-cell lymphoma, express CD20 on the cell surface and some solid tumors, including colorectal cancer, express EGFR. We are conducting clinical trials in collaboration with Genentech and Eli Lilly to test 5F9 in combination with the anti-CD20 antibody rituximab and the anti-EGFR antibody cetuximab.
T Cell Checkpoint Inhibitors. In a similar way that CD47 on cancer cells suppresses macrophages, some cancer cells can suppress T cell attacks by expressing immune checkpoint proteins such as PD-L1. This can reduce the potency of the specific anti-cancer T cell responses that macrophages mobilize after ingesting cancer cells. Combining our 5F9 immunotherapy with T cell checkpoint inhibitors may help maximize the T cell response induced by macrophages.
We are collaborating with Merck KGaA and Genentech to test 5F9 in combination with the PD-L1 checkpoint inhibitors avelumab and atezolizumab in clinical trials for ovarian cancer, acute myeloid leukemia, and urothelial (bladder) cancer. Additionally, preclinical studies suggest the binding of a PD-L1 checkpoint inhibitor to cancer cells provides an “eat me” signal on cancer cells that can further stimulate macrophage responses and can combine multiple mechanisms of action in one combination.
We believe our 5F9 immunotherapy will work in concert with existing therapies to enhance the potency of both innate and adaptive immune responses against cancer.
Pipeline
Preventing Innate Immune Suppression
T Cell Checkpoint Inhibitors
Publications
Anti-SIRPα antibody immunotherapy enhances neutrophil and macrophage antitumor activity.
Ring et al. Proceedings of the National Academy of Sciences.
December 05, 2017
Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.
Gholamin et al. Science Translational Medicine.
March 17, 2017
The CD47‐SIRPα signaling axis as an innate immune checkpoint in cancer.
Matlung et al. Immunological Reviews
March 04, 2017
CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.
Kojima et al. Nature.
August 04, 2016
CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer.
Weiskopf et al. Journal of Clinical Investigation.
July 01, 2016