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Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models
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 indivi...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer US
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999169/ https://www.ncbi.nlm.nih.gov/pubmed/29564747 http://dx.doi.org/10.1007/s11060-018-2832-6 |
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author | Keir, Stephen T. Chandramohan, Vidyalakshmi Hemphill, Carlee D. Grandal, Michael M. Melander, Maria Carlsen Pedersen, Mikkel W. Horak, Ivan D. Kragh, Michael Desjardins, Annick Friedman, Henry S. Bigner, Darell D. |
author_facet | Keir, Stephen T. Chandramohan, Vidyalakshmi Hemphill, Carlee D. Grandal, Michael M. Melander, Maria Carlsen Pedersen, Mikkel W. Horak, Ivan D. Kragh, Michael Desjardins, Annick Friedman, Henry S. Bigner, Darell D. |
author_sort | Keir, Stephen T. |
collection | PubMed |
description | 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11060-018-2832-6) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5999169 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Springer US |
record_format | MEDLINE/PubMed |
spelling | pubmed-59991692018-06-28 Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models Keir, Stephen T. Chandramohan, Vidyalakshmi Hemphill, Carlee D. Grandal, Michael M. Melander, Maria Carlsen Pedersen, Mikkel W. Horak, Ivan D. Kragh, Michael Desjardins, Annick Friedman, Henry S. Bigner, Darell D. J Neurooncol Laboratory Investigation 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11060-018-2832-6) contains supplementary material, which is available to authorized users. Springer US 2018-03-21 2018 /pmc/articles/PMC5999169/ /pubmed/29564747 http://dx.doi.org/10.1007/s11060-018-2832-6 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Laboratory Investigation Keir, Stephen T. Chandramohan, Vidyalakshmi Hemphill, Carlee D. Grandal, Michael M. Melander, Maria Carlsen Pedersen, Mikkel W. Horak, Ivan D. Kragh, Michael Desjardins, Annick Friedman, Henry S. Bigner, Darell D. Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title | Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title_full | Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title_fullStr | Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title_full_unstemmed | Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title_short | Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models |
title_sort | sym004-induced egfr elimination is associated with profound anti-tumor activity in egfrviii patient-derived glioblastoma models |
topic | Laboratory Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999169/ https://www.ncbi.nlm.nih.gov/pubmed/29564747 http://dx.doi.org/10.1007/s11060-018-2832-6 |
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