Year 1

We have previously developed a new therapeutic candidate, the anti-CD47 humanized antibody, Hu5F9-G4, which demonstrates potent anti-cancer activity in animal models of malignancy. The goal of CIRM DTIII Grant DR3-06965 is to conduct initial phase I clinical trials of this antibody in advanced cancer patients. We originally proposed to conduct two separate Phase I clinical trials: one in solid tumor patients with advanced malignancy (commenced in August 2014), the other in relapsed, refractory AML patients (anticipated to start in September 2015). The primary endpoints for these trials will be to assess safety and tolerability, and additional endpoints include obtaining information about the dosing regimen for subsequent clinical investigations, and initial efficacy assessments.

CD47 is a dominant anti-phagocytosis signal that is expressed on all types of human cancers assessed thus far. It binds to SIRPα, an inhibitory receptor on macrophages, and in so doing, blocks the ability of macrophages to engulf and eliminate cancer cells. Hu5F9-G4 blocks binding of CD47 to SIRPα, and restores the ability of macrophages to engulf or phagocytose cancer cells. In pre-clinical cancer models, treatment with Hu5F9-G4 shrunk tumors, eliminated metastases, and in some cases resulted in long-term protection from cancer recurrence. These results suggest that Hu5F9-G4 leads to elimination of cancer stem cells in addition to differentiated cancer cells.

We have developed Hu5F9-G4 for human clinical trials by demonstrating safety and tolerability in pre-clinical toxicology studies. These studies also indicated that we can achieve serum levels associated with potent efficacy in pre-clinical models. The regulatory agencies (FDA in the U.S., and MHRA in the U.K.) reviewed the large package of pre-clinical data describing Hu5F9-G4, and approved our requests to commence separate Phase I clinical trials in solid tumor and AML patients. The solid tumor trial commenced at Stanford in August 2014 and has been designed to assess patients in separate groups, or cohorts, treated with increasing doses of Hu5F9-G4. The trial is ongoing as primary endpoints have not been met. The acute myeloid leukemia trial has been given regulatory approval in the U.K., and will start enrolling patients in September 2015. In summary, during the last year, the Hu5F9-G4 clinical trials have made substantial progress and all milestones have been met.