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

dc.contributor.author

Keir, Stephen T

dc.contributor.author

Chandramohan, Vidyalakshmi

dc.contributor.author

Hemphill, Carlee D

dc.contributor.author

Grandal, Michael M

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Melander, Maria Carlsen

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Pedersen, Mikkel W

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Horak, Ivan D

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Kragh, Michael

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Desjardins, Annick

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Friedman, Henry S

dc.contributor.author

Bigner, Darell D

dc.date.accessioned

2022-09-01T13:32:11Z

dc.date.available

2022-09-01T13:32:11Z

dc.date.issued

2018-07

dc.date.updated

2022-09-01T13:32:08Z

dc.description.abstract

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.
dc.identifier

10.1007/s11060-018-2832-6

dc.identifier.issn

0167-594X

dc.identifier.issn

1573-7373

dc.identifier.uri

https://hdl.handle.net/10161/25630

dc.language

eng

dc.publisher

Springer Science and Business Media LLC

dc.relation.ispartof

Journal of neuro-oncology

dc.relation.isversionof

10.1007/s11060-018-2832-6

dc.subject

Subcutaneous Tissue

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Animals

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Mice, Inbred BALB C

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Humans

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Mice, Nude

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Glioblastoma

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Brain Neoplasms

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Antineoplastic Agents

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Antibodies, Monoclonal

dc.subject

Xenograft Model Antitumor Assays

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Female

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Male

dc.subject

ErbB Receptors

dc.title

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

dc.type

Journal article

duke.contributor.orcid

Chandramohan, Vidyalakshmi|0000-0002-0653-3014

duke.contributor.orcid

Friedman, Henry S|0000-0001-7588-032X

duke.contributor.orcid

Bigner, Darell D|0000-0001-5548-4899

pubs.begin-page

489

pubs.end-page

498

pubs.issue

3

pubs.organisational-group

Duke

pubs.organisational-group

School of Medicine

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Institutes and Centers

pubs.organisational-group

Medicine

pubs.organisational-group

Pathology

pubs.organisational-group

Pediatrics

pubs.organisational-group

Surgery

pubs.organisational-group

Medicine, Medical Oncology

pubs.organisational-group

Duke Cancer Institute

pubs.organisational-group

Neurology

pubs.organisational-group

Neurology, General & Community Neurology

pubs.organisational-group

Neurosurgery

pubs.organisational-group

Neurosurgery, Neuro-Oncology

pubs.publication-status

Published

pubs.volume

138

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