NCE Year 5

Hematologic tumors and many solid tumors are driven by a subset of cells called cancer stem cells. These cancer stem cells must be eliminated for cures, however, they have been found to be resistant to the standard cancer treatments of chemotherapy and radiation therapy. Therefore, new therapeutic approaches are needed to target these abnormal stem cells. Previously, we found that cancer stem cells have developed a clever way to hide from the patient’s immune system. They display a protein called CD47 on their surface that signals to the immune system “don’t eat me”, thereby preventing their elimination. We have developed a monoclonal antibody (anti-CD47 antibody) that blocks this signal leading to elimination of these cancer stem cells, but not normal most normal cells, by the natural immune system. In our pre-clinical studies, we showed that anti-CD47 antibodies eliminates cancer cells and cancer stem cells from many different types of human cancer including: leukemia, breast cancer, colon cancer, prostate cancer, ovarian cancer, and others. In addition, anti-CD47 antibodies are effective at preventing and even eliminating metastases in animal models. These results indicate that anti-CD47 antibodies have great potential for the treatment of human cancer.

In order to develop this approach into a clinical therapeutic, we first optimized our anti-CD47 antibody so that it looks like a normal human protein that the patient’s immune system will not reject. Over the course of this grant project, we have conducted the pre-clinical development of this humanized antibody, termed Hu5F9-G4.
(1) Hu5F9-G4 has been manufactured according to Good Manufacturing Practices (GMP) as required by the United States Food and Drug Administration (FDA) for administration to humans. The drug product was manufactured and tested to be free of contaminants and is now ready for clinical use.
(2) Hu5F9-G4 has undergone extensive testing to investigate potential toxic effects in humans. According to FDA regulatory guidelines, Hu5F9-G4 was tested in experimental animals where it was given in various increasing doses. In all studies, Hu5F9-G4 was well-tolerated and caused no serious side effects.
(3) Our stability studies have shown that refrigerated Hu5F9-G4 has a shelf life of at least 24 months and probably longer. This is an excellent storage life for any therapeutic.
(4) We have developed a phase 1 first-in-human clinical trial protocol for the investigation of Hu5F9-G4 in patients with solid tumors. In addition, we have prepared all the necessary documentation and clinical operations plans necessary to execute this clinical trial.
(5) We have submitted the necessary information on anti-cancer activity, manufacturing, safety, and clinical trial plans to the FDA in an Investigational New Drug (IND) application. This application was approved by FDA for the clinical trial in patients with solid tumors.
(6) We continue to develop parallel clinical trial plans for a phase 1 study in patients with acute myeloid leukemia (AML), and anticipate submitting our regulatory filing in 2015.

In summary, our studies show that Hu5F9-G4 is a first-in-class therapeutic candidate that approaches cancer treatment through a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and prevent their metastases. CIRM Grant DR1-01485 has provided us the resources to develop our new antibody to the point that it can be safely administered to human patients. Indeed we have started administering this drug to patients with advanced solid tumors that have failed all other treatments.