A monoclonal antibody recognizing human cancers with amplification/overexpression of the human epidermal growth factor receptor

Abstract

CorrectionsArai, and Glenn D. Prestwich, which appeared in number 1, January 7, 2003, of Proc. Natl. Acad. Sci. USA (100, 131-136; First Published December 26, 2002; 10.1073͞pnas.0135855100), Fig. 4 should have appeared in color. The correct figure and its legend appear below. Fig. 4.LPA stimulates lipid accumulation, CD36 expression, and oxidized LDL uptake through a PPAR-responsive element. (a) LPA stimulates monocyte uptake of oxidized LDL. Freshly elutriated human monocytes were allowed to interact with an anti-ICAM3-coated well, which leads to rapid PPAR␥ expression (13), and then stimulated, or not (negative, oxLDL), with oleoyl LPA. Some cells were then briefly exposed to oxidized LDL before intracellular lipid stores were visualized with oil red O stain. (b) LPA increases the expression of CD36 on the surface of primary human monocytes. Monocytes engaging anti-ICAM3 were treated or not with LPA, and then recovered by gentle scraping and washing by centrifugation before their surface CD36 was assessed by flow cytometry. (c) LPA and the LPA analogs XY4 and XY8 stimulate CD36 promoter function only when the PPRE is present. RAW264.7 cells were transfected with the human CD36 promoter containing the PPRE (CD36 Ϫ273 ) or a reporter that lacks only this element (CD36 Ϫ261 ) and then stimulated with oleoyl LPA, azPC, XY4, or XY8. Expression of luciferase normalized to ␤-galactosidase was determined as above. (d) Anti-CD36 blocks LPA-stimulated accumulation of cholesterol from oxidized LDL. Freshly isolated human monocytes were treated as in a, but after being preincubated with a blocking anti-CD36 antibody before exposure to oxidized LDL. G rowth factor receptors are promising targets for antibodybased cancer therapies. Because of their cell-surface location, they are readily accessible, and therapeutic antibodies can exert their inhibitory effects by either interfering with cellular signaling or targeting toxic molecules or biological effectors to the tumor site (1).The epidermal growth factor receptor (EGFR) is expressed in normal tissues and neoplastic lesions of most organs, and its expression level has been associated with biological characteristics of tumors (2). Elevated levels of EGFR have been demonstrated in many different types of cancer including glioblastoma, and EGFR overexpression seems to be associated with poor prognosis in several neoplasms (3). EGFR overexpression is often associated with gene amplification (4-8). In glioblastoma, EGFR amplification has been shown to be accompanied by gene rearrangement (9-11), frequently with deletions in the coding region. Several mutant forms have been found (12, 13), and among these the most common mutation is the ⌬2-7 deletion (⌬EGFR), which lacks exons 2-7 of the external EGFR domain, resulting in the loss of an 801-bp fragment of the wild-type (wt) gene (14). Several studies have indicated that the presence of ⌬EGFR enhances the tumorigenic behavior of cancer cells (15-17). ⌬EGFR has only been found in neoplastic lesions and not in any normal tissue. ...

Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

“…ABT-806-binding properties and published results with mAb 806 and ch806 suggested that ABT-806 may also be effective against tumor cells overexpressing wild-type EGFR (6,13,16). Because EGFR is frequently overexpressed in squamous tumors, the antitumor efficacy of ABT-806 was compared with cetuximab in the A431 squamous xenograft model that expresses amplified EGFR (22).…”

“…MAb 806 is a novel anti-EGFR antibody that selectively targets a unique epitope of the EGFR which is largely inaccessible when EGFR is expressed at normal physiologic levels (6,7). The targeted epitope is accessible in tumors with wild-type EGFR amplification or in tumors that express EGFRvIII, the most common deletion mutant of EGFR that lacks the ligand-binding domain of exons 2-7 and retains constitutive kinase activity (8)(9)(10).…”

Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer

“…The parental m806 antibody was originally raised against the EGFRvIII mutant receptor (16,17), most commonly observed in glioblastomas, which often also display EGFR overexpression. This suggests that 806-PE38 may be effective as a glioblastoma therapeutic.…”

“…The m806 antibody binds cells expressing misfolded, amplified, or overexpressed EGFR but not to cells expressing wildtype EGFR ( [16][17][18] ). The m806 epitope is not accessible when the receptor is in an inactive monomer or activated dimer but is exposed in the locally misfolded (transitional), or "untethered," conformation, which preferentially occurs under oncogenic conditions (19,20).…”

Aberration of epidermal growth factor receptor expression in bone and soft-tissue tumors: protein overexpression, gene amplification and activation of downstream molecules

“…10 Another group described EGFR amplification in one of malignant fibrous histiocytoma out of 20 cases of sarcomas. 34 However, this latter study was based on immunohistochemical analysis utilizing an amplification/overexpression-specific antibody generated by the authors, and was not accompanied by a genetic analysis. Pathologists sometimes have a hard time to differentiate malignant fibrous histiocytoma from undifferentiated carcinoma when the tumor occurs in the organ with epithelial tissue.…”