Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors.

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.

• Authors: Sharareh Gholamin, Siddhartha S Mitra, Abdullah H Feroze, Jie Liu, Suzana A Kahn, Michael Zhang, Rogelio Esparza, Chase Richard, Vijay Ramaswamy, Marc Remke, Anne K Volkmer, Stephen Willingham, Anitha Ponnuswami, Aaron McCarty, Patricia Lovelace, Theresa A Storm, Simone Schubert, Gregor Hutter, Cyndhavi Narayanan, Pauline Chu, Eric H Raabe, Griffith Harsh 4th, Michael D Taylor, Michelle Monje, Yoon-Jae Cho, Ravi Majeti, Jens P Volkmer, Paul G Fisher, Gerald Grant, Gary K Steinberg, Hannes Vogel, Michael Edwards, Irving L Weissman, Samuel H Cheshier
• Journal: Science translational medicine (Sci Transl Med) Vol. 9 Issue 381 (03 15 2017) ISSN: 1946-6242 [Electronic] United States
• PMID: 28298418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017, American Association for the Advancement of Science.

Chemical References

• Antibodies
• Antigens, Differentiation
• CD47 Antigen
• CD47 protein, human
• Receptors, Immunologic
• SIRPA protein, human

Topics

• Animals
• Antibodies (pharmacology, therapeutic use)
• Antigens, Differentiation (metabolism)
• Brain Neoplasms (drug therapy, pathology)
• CD47 Antigen (immunology)
• Cell Proliferation (drug effects)
• Child
• Disease Models, Animal
• Humans
• Immunocompetence
• Injections, Intraventricular
• Medulloblastoma (drug therapy, pathology)
• Meningeal Neoplasms (pathology, secondary)
• Mice, Inbred C57BL
• Models, Biological
• Neoplasm Metastasis
• Phagocytosis (drug effects)
• Receptors, Immunologic (metabolism)
• Survival Analysis
• Xenograft Model Antitumor Assays