Year 2

Our program is focused on producing new therapeutic candidates to prolong remission and potentially cure highly lethal cancers where patients have few alternative treatment options. Our strategy is to develop an antibody that will eliminate the cancer stem cells which are the source of the disease, and responsible for the disease recurrence that can occur months-to-years following the remission achieved with initial clinical treatment. The cancer stem cells are a small proportion of the total cancer cell burden, and they appear to be resistant to the standard treatments of chemotherapy and radiation therapy. Therefore new therapeutic approaches are needed to eliminate them.

In year 2 of the CIRM award, we have continued to develop a clinical-grade antibody that will eliminate the cancer stem cells in Acute Myelogenous Leukemia (AML). We have identified several antibodies that cause human leukemia cells to be eaten and destroyed by healthy human white blood cells when tested in cell culture experiments. These antibodies bind to a protein called CD47 that is present on the outer surface of human leukemia cells. The anti-CD47 antibodies can eliminate leukemia growing in mice injected with AML cells obtained from patients. We have now extensively characterized the properties of our panel of anti-CD47 antibodies, and have identified the lead candidate to progress though the process of drug development. There are several steps in this process, which takes 18-24 months to fully execute. In the last 12 months, we have focused on the following steps:

(i) ‘Humanization’ of the antibody: The antibody needs to be optimized so that it looks like a normal human protein that the patient’s immune system will not eliminate because it appears ‘foreign’ to them.
(ii) Large scale production of the antibody: To make sufficient quantities of the antibody to complete the culture and animal model experiments required to progress to clinical safety trials with patients, we have contracted with a highly experienced manufacturing facility capable of such large-scale production. We have successfully transferred our antibody to them, and they have inserted it into a proprietary expression cell that will produce large amounts of the protein. This process is managed through weekly interactions with this contract lab. They send us small amounts of the material from each step of their manufacturing process and we test it in our models to ensure the antibody they are preparing retains its anti-cancer properties throughout production.
(iii) Pre-clinical safety studies: The antibody must be tested extensively in animals to ensure it does not cause serious limiting damage to any of the normal healthy tissues in the recipient. We have spent much of the last 12 months performing these types of safety experiments. The antibody has been administered to both mice and non-human primates and we have evaluated their overall health status, as well as analyzing their blood cells, blood enzyme levels, and urine, for up to 28 days. We have also collected samples of their organs and tissues to evaluate for abnormalities. Thus far, these assessments have appeared normal except for the development of a mild anemia a few days after the initial antibody injection. Subsequent experiments indicate that this anemia can be managed with existing approved clinical strategies
(iv) Determination of optimal dose: We have used mice injected with human cancer cells from AML patients, and determined how much antibody must be injected into these mice to produce a blood level that destroys the leukemia cells. This relationship between antibody dose and anti-cancer activity in the mouse cancer model enables us to estimate the dose to administer to patients.