The biological characteristics, activating ligands, and functioning of the different members of the transmembrane epidermal growth factor receptor (EGFR) family are described elsewhere (1-3). These receptors are known to regulate the growth, survival, differentiation, and migration of cells through the activation of an associated intracellular tyrosine kinase (TK) signaling pathway, and they are overexpressed in many malignant epithelial tumors (1, 2). In addition, overexpression of the EGFR usually indicates a poor clinical prognosis for the patient (4). Overexpression of the EGFR in the tumors has been attributed to gene amplification, and this phenomenon is believed to introduce mutations in the receptor (2, 4). The most common mutation observed in the EGFR receptor is the deletion of a segment of the EGFR extracellular domain, including the ligand-binding region, which results in the generation of an EGFR variant known as the de2-7 EGFR or EGFRvIII (2, 4). The generation, structure, functions, and role of EGFRvIII in tumor malignancy have been reviewed by Gan et al. (5). Although EGFRvIII is nonresponsive to the ligand, it is constitutively active with a constantly operating downstream TK signal transduction pathway that appears to promote the development of a neoplastic phenotype, particularly for glioblastoma and to some extent for other cancers such as those of the prostate and the breast (2, 6).

Because the EGFR promotes and helps maintain the cancerous state of cells, several antibodies that inhibit the receptor activity and small molecules that block the downstream TK signaling pathway have been developed and have been approved by the United States Food and Drug Administration (FDA) for the treatment of certain cancers (2). The antibodies are directed toward the extracellular domain of the receptor, block ligand binding, and inhibit activation of the TK signal transduction pathway, which ultimately results in downregulation of the EGFR on the cell surface. However, because the EGFRvIII lacks the ligand-binding region on the extracellular domain, these antibodies cannot obstruct the constitutive mutant receptor activity (2). As a consequence, the monoclonal antibody (mAb) 806, which specifically targets the EGFRvIII, was generated and characterized in preclinical studies (7, 8). Subsequently, a chimeric form of the mAb (chAb), designated as ch806, was developed and evaluated in a phase I clinical trial with patients having cancerous tumors overexpressing the EGFRvIII (4). Results obtained from this trial indicated that ch806 could be a good biotherapeutic agent for the treatment of cancers expressing the ch806 antigen (4). In addition, several other clinical trials approved by the FDA are in progress to evaluate the targeting of EGFRvIII as a treatment against various cancers.

The internalization, intracellular trafficking, and biodistribution (in nude mice bearing xenograft human epidermoid carcinoma cell tumors) of mAb806 labeled with ¹¹¹In ([¹¹¹In]-mAb806) and ¹²⁵I ([¹²⁵I]-mAb806) have been investigated by Perera et al. (8). The characterization and biodistribution (in nude mice bearing xenograft human glioblastoma cell tumors) of ch806 labeled with ¹²⁵I and ¹¹¹In, respectively, are described in separate chapters in MICAD (www.micad.nih.gov) (9, 10). Another chapter describes the use of ¹²⁴I-labeled ch806 for the detection of EGFRvIII-expressing xenograft human glioblastoma tumors in nude mice with an immuno–positron emission tomography (PET) technique (11). This chapter describes the studies performed with [¹¹¹In]-mAb806. Studies performed with [¹²⁵I]-mAb806 are described in a separate chapter in MICAD (12).