Abstract

BackgroundSym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII).MethodsTo address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models.ResultsIn vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture.ConclusionThese results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.

Highlights

  • Glioblastoma (GBM) is the most common, aggressive and subsequently lethal tumor of the central nervous system in adults [1, 2]

  • All patient-derived xenograft models used in this study were obtained from the Duke Brain Tumor Biorespository after receiving appropriate written consent by the Duke University Institutional Review Board

  • All xenograft lines have been profiled with short tandem repeat using ABI Profiler and COfiler commercial reagent kits made by Applied Biosystems

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Summary

Introduction

Glioblastoma (GBM) is the most common, aggressive and subsequently lethal tumor of the central nervous system in adults [1, 2]. We investigated whether Sym induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII). Results In vitro studies demonstrated that Sym internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. The anti-tumor activity of Sym in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture. Conclusion These results demonstrate the broad activity of Sym in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym in EGFRvIII-positive adult GBM patients

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