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

Sci Transl Med. 2017 Mar 15;9(381):eaaf2968. doi: 10.1126/scitranslmed.aaf2968.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

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

Substances

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