Hematologic tumors and many solid tumors are propagated by a subset of cells called cancer stem cells. These cells appear to be resistant to the standard cancer treatments of chemotherapy and radiation therapy, and therefore new therapeutic approaches are needed to eliminate them. We have developed a monoclonal antibody (anti-CD47 antibody) that recognizes and causes elimination of these cancer stem cells and other cells in the cancer, but not normal blood-forming stem cells or blood cells. Cancer stem cells regularly produce a cell surface ‘invisibility cloak’ called CD47, a ‘don’t eat me signal’ for cells of the native immune system. Anti-CD47 antibody counters the ‘cloak, allowing the patient’s natural immune system eating cells, called macrophages, to eliminate the cancer stem cells.
As discussed in our two-year report, we optimized our anti-CD47 antibody so that it looks like a normal human protein that the patient’s immune system will not eliminate because it appears ‘foreign’. In this third year of the grant, we initiated the pre-clinical development of this humanized antibody, and assigned the antibody the development name of Hu5F9. Our major accomplishments in the third year of our grant are as follows:
(i) In addition to the hematological malignancies we have studied in previous years, we have now demonstrated the Hu5F9 is effective at inhibiting the growth and spread throughout the body [metastasis] of a large panel of human solid tumors, including breast, bladder, colon, ovarian, glioblastoma [a very aggressive brain cancer], leiomyosarcoma, head & neck squamous cell carcinoma, and multiple myeloma.
(ii) We have performed extensive studies optimizing the production and purification of Hu5F9 to standards compatible with use in humans, including that it is sterile, free of contaminating viruses, microorganisms, and bacterial products. We will commence manufacturing of Hu5F under highly regulated sterile conditions to produce what is known as GMP material, suitable for use in humans.
(iii) Another step to show Hu5F9 is safe to administer to humans is to administer it to experimental animals and observe its effects. We have demonstrated that Hu5F9 is safe and well tolerated when administered to experimental animals. Notably, no major abnormalities are detected when blood levels of the drug are maintained in the potentially therapeutic range for an extended duration of time.
(iv) We have initiated discussions with the FDA regarding the readiness of our program for initiating clinical trials, which we anticipate to start in the first quarter of 2014. To prepare for these trials we have established a collaboration between the Stanford Cancer Institute and the University of Oxford in the United Kingdom, currently our partners in this CIRM-funded program.
To our knowledge, CD47 is the first common target in all human cancers, one which has a known function that enables cancers to grow and spread, and one which we have successfully targeted for cancer therapy. Our studies show that Hu5F9 is a first-in-class therapeutic candidate that offers cancer treatment a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and their metastases.