CD47 antibody blockade as novel therapy for ovarian and breast cancer

• Main Authors: Volkmer, AK, Willingham, SB, Volkmer, JP, Tseng, SR, Ho, PD, Sikic, BI, Majeti, R, Weissman, IL
• Format: Conference Proceeding
• Language: English
• ISSN: 0016-5751; 1438-8804
• DOI: 10.1055/s-0034-1388418

Introduction: We have identified CD47 as a “don't eat me” signal expressed by cancer cells to escape elimination by the innate immune system. Upon binding to its receptor SIRPalpha on macrophages, CD47 initiates an inhibitory signal that blocks phagocytosis. We have developed a humanized anti-CD47 antibody, Hu5F9-G4 and tested its therapeutic efficacy on ovarian cancer (OC) and breast cancer (BC) in preclinical models. Methods: The efficacy of Hu5F9-G4 on OC was tested first in an in vitro phagocytosis-assay. Next, GFP-luciferase positive OC cells were transplanted into immunodeficient mice and treated with Hu5F9-G4, Bevacizumab, Carboplatin or combinations of the former compared to PBS control. Tumor growth was monitored by bioluminescent imaging. Therapeutic efficacy of HU5F9-G4 on BC was assessed in a neoadjuvant setting of an orthotopic, metastatic patient BC xenotransplantation model. After transplantation of GFP-luciferase positive BC cells and tumor and lung metastasis formation, primary site tumors were resected and treatment of the remaining residual tumors and metastases with Hu5F9-G4 or control was initiated. Results: CD47-blockade with Hu5F9-G4 enabled phagocytosis in vitro, inhibited tumor growth and metastases in vivo and prolonged survival for OC and BC. Therapeutic serum levels determined in these studies have been shown to be safely administrable in toxicokinetic non-human primate studies. Conclusion: Blockade of CD47 is a novel immunotherapeutic approach for OC and BC. Hu5F9-G4 shows the desired therapeutic and safety profile in preclinical studies. Stanford has initiated a development program of Hu5F9-G4 with the start of the all-comers phase-I trial anticipated for Q3 of 2014.