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.
The anti-cancer efficacy and specificity of magrolimab (formerly known as 5F9), our antibody versus CD47, involves tipping the balance between the “eat me” and “don’t eat me” signals received by macrophages when they encounter a potential target cell.
Magrolimab Mechanism of Action Explained
Macrophages and Healthy Cells
Macrophages use a signaling pathway to detect abnormal cells for elimination. When macrophages encounter healthy cells, its receptor SIRP-alpha binds to CD47, a "don't eat me" signal, preventing phagocytosis.
Macrophages, Cancer Cells and CD47
When the "eat me" signals found on abnormal cells, including cancer, outweigh the "don't eat me" signals, macrophages will digest them. Some cancers overexpress CD47, allowing them to evade phagocytosis.
Using Magrolimab Against Cancer Cells
Forty Seven's immunotherapy, magrolimab, is an antibody that blocks the CD47 "don't eat me" signal, restoring the macrophages ability to detect and destroy cancer cells. In addition, the Fc region of magrolimab can bind the Fc receptor on macrophages providing an additional phagocytic "eat me" signal.
Combining Magrolimab with Tumor Targeting Antibodies
Combining magrolimab with other immunotherapies such as the anti-CD20 antibody rituximab, can produce an additional "eat me" signal on cancer cells, further stimulating macrophage response.
Healthy cells express CD47 which protects them from macrophages by sending a “don’t eat me” signal though the SIRP-alpha receptor. Cancer cells express signals of abnormality on their surface which send an “eat me” signal to the macrophage but this is neutralized by the “don’t eat me” signal provided by CD47 over-expressed on cancer cells.
When our antibody, magrolimab, binds CD47 on cancer cells it blocks the interaction with SIRP-alpha on the macrophage eliminating the “don’t eat me” signal, unmasking the “eat me” signals, and also provides an additional “eat me” signal by engaging with the Fc receptors on the macrophage tipping the balance towards phagocytosis.
Combining magrolimab with a second cancer-targeting antibody, such as rituximab which binds CD20 on Non-Hodgkin's lymphoma cells, tips the balance even further towards phagocytosis by engaging with additional Fc receptors on the macrophage. In contrast, healthy cells are unaffected by magrolimab since they do not express “eat me” signals or targets for cancer-targeting antibodies.
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, demonstrated that CD47 blocking antibodies could cause the clearance of tumors in animals as monotherapy and provided the rationale for three strategic approaches to combination therapy with CD47 antibodies.
Our Immunotherapy
Our immunotherapy, magrolimab (formerly known as 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 magrolimab is among the first in a new class of innate immune checkpoint inhibitors. We are investigating magrolimab 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 magrolimab 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 magrolimab 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 magrolimab 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 magrolimab 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 magrolimab immunotherapy will work in concert with existing therapies to enhance the potency of both innate and adaptive immune responses against cancer.
Pipeline
*Expansion arm of ongoing NHL: magrolimab + Rituximab trial
Preclinical Programs
We are working to develop additional products aimed at enhancing anti-cancer phagocytosis. This includes, but is not limited to the addition or enhancement of pro-phagocytic signals and further inhibition of anti-phagocytic signals. This development pipeline is balanced with preclinical agents at various stages of development, including a mix of both clinically validated and novel targets.
SIRPa Antibody FSI-189
There are multiple types of pharmaceutical interventions that have been used to inhibit receptor-target interactions such as CD47-SIRPa. These have included antibodies that block the interaction by binding to either of the partners. In addition to magrolimab, which is an antibody that binds to CD47 blocking it’s binding to SIRPa, we have also explored the potential of interfering with CD47 activity through other modalities. Our product candidate, FSI-189, is an antibody that binds to SIRPa. We plan to initiate Phase 1 solid tumor trials for FSI-189 in 2020. Each of the different modalities has advantages and disadvantages and we believe that the central role of the CD47-SIRPa in regulating self-recognition in the innate immune system provides opportunities for multiple products to have therapeutic benefit in specific indications.
CKIT Antibody FSI-174 Program
cKIT, also known as CD117, or stem cell growth factor receptor is expressed on the surface of hematopoietic stem cells, or HSCs, as well as other cell types. Alterations of this receptor have been found in certain cancers including leukemia, melanoma and gastrointestinal stroma tumors. Anti-cKIT antibodies can bind to cancer cells and provide an “eat me” signal to macrophages and have been shown to exhibit anti-cancer efficacy in both in vitro and in vivo mouse models. In addition, preclinical studies with anti-cKIT antibodies in combination with anti-CD47 antibodies have been shown to deplete endogenous HSCs. This depletion allows for space in the bone marrow to facilitate transplantation of donor HSCs. The removal or depletion of endogenous HSCs is the goal of a pre-transplant procedure known as “conditioning.”
Transplantation of HSCs is a well-established procedure that may be a potential cure for numerous severe and life-threatening diseases such as genetic blood disorders, blood cancers and autoimmune diseases. While significant advances have been made on stem cell preparation, the “conditioning” itself is still dependent on decades-old chemotherapeutic and radiation-based procedures. “Conditioning” has both acute and long-term toxicities and therefore limits the current use of HSC transplantation to a tiny fraction of patients that could benefit.
Forty Seven aims to overcome this challenge with the development of its cKIT antibody, FSI-174. We believe that FSI-174 when combined with magrolimab or with FSI-189 would be an antibody-based conditioning regimen for HSC transplantation that is free of toxic chemotherapy and radiation. FSI-174 is in pre-clinical development and the first clinical trial is expected to start in early 2020.
Publications
Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies.
Chao et al. Frontiers in Oncology.
January 22, 2020
CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma.
Advani et al. The New England Journal of Medicine.
November 01, 2018
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
Posters and Presentations
A Phase 1b study of the anti-CD47 antibody magrolimab with the PD-L1 inhibitor avelumab in solid tumor and ovarian cancer patients
Clinical Immuno-Oncology Symposium (ASCO-SITC) | February 2020
A Phase 1b/2 study of the anti-CD47 antibody magrolimab with cetuximab in solid tumor and colorectal cancer patients
Gastrointestinal Cancers Symposium (ASCO GI) | January 2020
An All Antibody Approach for Conditioning for Hematopoietic Stem Cell Transplantation with Anti-cKIT and Anti-CD47 in Non-Human Primates
The American Society of Hematology Annual Meeting (ASH) | December 2019
The First-in-Class Anti-CD47 Antibody Magrolimab in Combination with Azacitidine is Effective in MDS and AML Patients: Updated Ongoing 1b Results
The American Society of Hematology Annual Meeting (ASH) | December 2019
The First-in-Class Anti-CD47 Antibody Hu5F9-G4 is Well Tolerated and Active Alone or with Azacitidine in AML and MDS Patients: Initial Phase 1b Results
Congress of The European Hematology Association (EHA) | June 2019
Activity of the first-in-class anti-CD47 antibody Hu5F9-G4 with rituximab in relapsed/refractory Non-Hodgkin’s lymphoma: interim Phase 1b/2 results
Congress of The European Hematology Association (EHA) | June 2019
The First-in-Class Anti-CD47 Antibody Hu5F9-G4 is Well Tolerated and Active Alone or with Azacitidine in AML and MDS Patients: Initial Phase 1b Results
American Society of Clinical Oncology Annual Meeting (ASCO) | June 2019
RBC-Specific CD47 Pruning Confers Protection and Underlies the Transient Anemia in 5F9 Anti-CD47 Treatment
The American Society of Hematology Annual Meeting (ASH) | December 2018
Combination Treatment with 5F9 and Azacitidine Enhances Phagocytic Elimination of Acute Myeloid Leukemia
The American Society of Hematology Annual Meeting (ASH) | December 2018
Initial Phase 1 Results of the First-in-Class Anti-CD47 Antibody Hu5F9-G4 in Relapsed/Refractory Acute Myeloid Leukemia Patients
Congress of The European Hematology Association (EHA) | June 2018