학술논문
Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors
Document Type
Academic Journal
Author
Gholamin, Sharareh; Mitra, Siddhartha S.; Feroze, Abdullah H.; Liu, Jie; Kahn, Suzana A.; Zhang, Michael; Esparza, Rogelio; Richard, Chase; Ramaswamy, Vijay; Remke, Marc; Volkmer, Anne K.; Willingham, Stephen; Ponnuswami, Anitha; McCarty, Aaron; Lovelace, Patricia; Storm, Theresa A.; Schubert, Simone; Hutter, Gregor; Narayanan, Cyndhavi; Chu, Pauline; Raabe, Eric H.; Harsh, Griffith, IV; Taylor, Michael D.; Monje, Michelle; Cho, Yoon-Jae; Majeti, Ravi; Volkmer, Jens P.; Fisher, Paul G.; Grant, Gerald; Steinberg, Gary K.; Vogel, Hannes; Edwards, Michael; Weissman, Irving L.; Cheshier, Samuel H.
Source
Science Translational Medicine. Mar 15, 2017 9(381)
Subject
Language
English
ISSN
1946-6234
Abstract
Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.