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[Cancer Research 61, 5349-5354, July 15, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

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 Receptor1

Kazuhiko Mishima, Terrance G. Johns, Rodney B. Luwor, Andrew M. Scott, Elisabeth Stockert, Achim A. Jungbluth, Xiang-Dong Ji, Padma Suvarna, Joseph R. Voland, Lloyd J. Old, H-J. Su Huang and Webster K. Cavenee2

Ludwig Institute for Cancer Research, San Diego Branch [K. M., H-J. S. H., W. K. C.], Center for Molecular Genetics [W. K. C.], Department of Medicine [H-J. S. H., W. K. C.], and Cancer Center [W. K. C.], University of California at San Diego, La Jolla, California 92093-0660; Ludwig Institute for Cancer Research, Melbourne Branch, Austin Hospital, Heidelberg, Victoria 3084 Australia [T. G. J., R. B. L., A. M. S.]; Ludwig Institute for Cancer Research, New York Branch, New York, New York 10021-6007 [E. S., A. A. J., L. J. O.]; and Becton-Dickinson PharMingen, San Diego, California 92121 [X-D. J., P. S., J. R. V.]

A mutant epidermal growth factor receptor (variously called {Delta}EGFR, 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-{Delta}EGFR 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.{Delta}EGFR, LN-Z308.{Delta}EGFR, or A1207.{Delta}EGFR gliomas, each of which expresses high levels of {Delta}EGFR. 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 {Delta}EGFR. 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.{Delta}EGFR 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 {Delta}EGFR 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 {Delta}EGFR.




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