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

Publication ,  Journal Article
Keir, ST; Chandramohan, V; Hemphill, CD; Grandal, MM; Melander, MC; Pedersen, MW; Horak, ID; Kragh, M; Desjardins, A; Friedman, HS; Bigner, DD
Published in: J Neurooncol
July 2018

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.

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Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

July 2018

Volume

138

Issue

3

Start / End Page

489 / 498

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Subcutaneous Tissue
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Male
  • Humans
  • Glioblastoma
  • Female
  • ErbB Receptors
 

Citation

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Keir, S. T., Chandramohan, V., Hemphill, C. D., Grandal, M. M., Melander, M. C., Pedersen, M. W., … Bigner, D. D. (2018). Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models. J Neurooncol, 138(3), 489–498. https://doi.org/10.1007/s11060-018-2832-6
Keir, Stephen T., Vidyalakshmi Chandramohan, Carlee D. Hemphill, Michael M. Grandal, Maria Carlsen Melander, Mikkel W. Pedersen, Ivan D. Horak, et al. “Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.J Neurooncol 138, no. 3 (July 2018): 489–98. https://doi.org/10.1007/s11060-018-2832-6.
Keir ST, Chandramohan V, Hemphill CD, Grandal MM, Melander MC, Pedersen MW, et al. Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models. J Neurooncol. 2018 Jul;138(3):489–98.
Keir, Stephen T., et al. “Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.J Neurooncol, vol. 138, no. 3, July 2018, pp. 489–98. Pubmed, doi:10.1007/s11060-018-2832-6.
Keir ST, Chandramohan V, Hemphill CD, Grandal MM, Melander MC, Pedersen MW, Horak ID, Kragh M, Desjardins A, Friedman HS, Bigner DD. Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models. J Neurooncol. 2018 Jul;138(3):489–498.
Journal cover image

Published In

J Neurooncol

DOI

EISSN

1573-7373

Publication Date

July 2018

Volume

138

Issue

3

Start / End Page

489 / 498

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Subcutaneous Tissue
  • Oncology & Carcinogenesis
  • Mice, Nude
  • Mice, Inbred BALB C
  • Male
  • Humans
  • Glioblastoma
  • Female
  • ErbB Receptors