A mutant
epidermal growth factor receptor (variously called DeltaEGFR, de2-7 EGFR, or
EGFRvIII) containing a deletion of 267
amino acids of the extracellular domain is frequently highly expressed in human
malignant gliomas and has been reported for
cancers of the lung, breast, and prostate. We tested the efficacy of a novel monoclonal anti-DeltaEGFR antibody,
mAb 806, on the growth of intracranial xenografted
gliomas in nude mice. Systemic treatment with
mAb 806 significantly reduced the volume of
tumors and increased the survival of mice bearing xenografts of U87 MG.DeltaEGFR, LN-Z308.DeltaEGFR, or A1207.DeltaEGFR
gliomas, each of which expresses high levels of DeltaEGFR. In contrast,
mAb 806 treatment was ineffective with mice bearing the parental U87 MG
tumors, which expressed low levels of endogenous wild-type EGFR, or U87 MG.DK
tumors, which expressed high levels of
kinase-deficient DeltaEGFR. A slight increase of survival of mice xenografted with a wild-type EGFR-overexpressing U87 MG
glioma (U87 MG.wtEGFR) was effected by
mAb 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.DeltaEGFR
tumors in mice with
mAb 806 caused decreases in both
tumor growth and angiogenesis, as well as increased apoptosis. Mechanistically, in vivo
mAb 806 treatment resulted in reduced phosphorylation of the constitutively active DeltaEGFR and caused down-regulated expression of the apoptotic protector, Bcl-XL. These data provide preclinical evidence that
mAb 806 treatment may be a useful biotherapeutic agent for those aggressive
gliomas that express DeltaEGFR.