In-Labeled DTPA conjugated monoclonal antibody 12A8 that targets the c-kit receptor

The c-kit (CD 117 antigen or stem cell factor ligand receptor) is a 145-kDa type III glycoprotein receptor tyrosine kinase (TK; encoded by the proto-oncogene) that has a TK at the juxtamembrane position, which is activated when a ligand binds to the extracellular ligand-binding domain of the receptor (1). Almost 70% of gastrointestinal stromal tumors (GISTs) are known to overexpress a c-kit that has a mutation in exon 11 and produces a constitutively activated TK that promotes the survival and proliferation of cells and leads to the development of a malignant phenotype in the cells of the GISTs (1, 2). The biology and mutations of the c-kit gene and the detection, diagnosis, and chemotherapy of the cancerous GISTs are discussed in detail elsewhere (3, 4). An immunohistochemical method is commonly used to detect the overexpression of c-kit in GIST cancers, but this invasive technique is known to generate variable results (3, 5). In addition, investigators often use positron emission tomography (PET) with F-fluoro-deoxyglucose to detect, monitor, and assess the response of GISTs to chemotherapy, but this radiolabeled probe does not distinguish between GISTs and other cancerous tumors that have an epithelial or lymphatic origin (6). In an effort to develop a reliable method for the detection of GISTs, the In-labeled anti–c-kit monoclonal antibody (mAb) 12A8 ([In]12A8) was developed and evaluated for the detection of xenograft GISTs in nude mice with the use of single-photon emission computed tomography (SPECT) (6). Recently, the Fab fragment of mAb 12A8 was labeled with In or with Cu to obtain [In]12A8 Fab or [Cu]12A8 Fab, and the two probes were evaluated for the detection of tumors that express c-kit in nude mice (2). This chapter describes the and studies performed with [In]12A8. Investigations conducted with [In]12A8 Fab and [Cu]12A8 Fab are discussed in separate chapters of MICAD (www.micad.nih.gov) (7, 8).