Growth suppression of intracranial xenografted glioblastomas overexpressing mutant epidermal growth factor receptors by systemic administration of monoclonal antibody (mAb) 806, a novel monoclonal antibody directed to the receptor

A mutant epidermal growth factor receptor (variously called Delta EGFR, de2 -7 EGFR, or EGFRvIII) containing a deletion of 267 amino acids of the extra cellular domain is frequently highly expressed in human malignant gliomas a nd has been reported for cancers of the lung, breast, and prostate. We test ed the efficacy of a novel monoclonal anti-Delta EGFR antibody, mAb 806, on the growth of intracranial xenografted gliomas in nude mice. Systemic trea tment with mAb 806 significantly reduced the volume of tumors and increased the survival of mice bearing xenografts of U87 MG.Delta EGFR, LN-Z308.Delt a EGFR, or A1207.Delta EGFR gliomas, each of which expresses high levels of Delta EGFR. In contrast, mAb 806 treatment was ineffective with mice beari ng the parental U87 MG tumors, which expressed low levels of endogenous wil d-type EGFR, or U87 MG tumors, which expressed high levels of kinase-defici ent Delta EGFR. A slight increase of survival of mice xenografted with a wi ld-type EGFR-overexpressing U87 MG glioma (U87 MG.wtEGFR) was effected by m Ab 806 concordant with its weak cross-reactivity with such cells. Treatment of U87 MG.Delta EGFR tumors in mice with mAb 806 caused decreases in both tumor growth and angiogenesis, as well as increased apoptosis, Mechanistica lly, in vivo mAb 806 treatment resulted in reduced phosphorylation of the c onstitutively active Delta EGFR and caused down-regulated expression of the apoptotic protector, Bcl-X-L. These data provide preclinical evidence that mAb 806 treatment may be a useful biotherapeutic agent for those aggressiv e gliomas that express Delta EGFR.