Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.

Autor: Keir ST; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA. Keir0001@mc.duke.edu., Chandramohan V; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA., Hemphill CD; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA., Grandal MM; Symphogen A/S, Pederstrupvej 93, 27500, Ballerup, Denmark., Melander MC; Symphogen A/S, Pederstrupvej 93, 27500, Ballerup, Denmark., Pedersen MW; Symphogen A/S, Pederstrupvej 93, 27500, Ballerup, Denmark., Horak ID; Symphogen A/S, Pederstrupvej 93, 27500, Ballerup, Denmark., Kragh M; Symphogen A/S, Pederstrupvej 93, 27500, Ballerup, Denmark., Desjardins A; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA., Friedman HS; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA., Bigner DD; Preston Robert Tisch Brain Tumor Center at Duke, Department of Neurosurgery, Duke University Medical Center, 3624 DUMC, Baker House, Durham, NC, 27710, USA.
Jazyk: angličtina
Zdroj: Journal of neuro-oncology [J Neurooncol] 2018 Jul; Vol. 138 (3), pp. 489-498. Date of Electronic Publication: 2018 Mar 21.
DOI: 10.1007/s11060-018-2832-6
Abstrakt: Background: Sym004 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).
Methods: To 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.
Results: In 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.
Conclusion: These 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.
Databáze: MEDLINE
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