A Thousand Points of Light or Just Dim Bulbs? Radiolabeled Antibodies and Colorectal Cancer Imaging

Abstract

Radioimmunoscintigraphy (RIS) is coming into its own as an imaging modality in clinical oncology. Early experience with indium-111-labeled intact murine monoclonal antibodies (MoAbs) in colorectal cancer suggested that RIS images hepatic metastases poorly. Moreover, an antimurine immune response was frequently provoked, precluding multiple follow-up RIS studies in individual patients due to reticuloendothelial sequestration of the radioimmunoconjugate before tumor targeting could occur. Recent trials of technetium-99m-labeled antibody fragments and human MoAbs have demonstrated significant improvement in imaging efficacy, and repeated or serial imaging is possible because of the absence of associated immunogenicity. RIS is demonstrably more sensitive than conventional diagnostic modalities (CDM) such as computed tomography (CT) for detection of extrahepatic abdominal and pelvic colorectal carcinoma and is complementary to CDM in imaging liver metastases. In a surgical decision-making analysis comparing CT, RIS (IMMU-4 99mTc-Fab'; CEA-Scan), and CT plus RIS in patients with recurrent or metastatic colorectal cancer, CT plus RIS improved correct prediction of resectability by 40% and correct prediction of unresectability by 100% compared with CT alone. At the present time, RIS used in combination with CDM contributes an incremental improvement in diagnostic accuracy in colorectal cancer patients with known or suspected recurrent disease. Basic and clinical research currently in progress promises to yield agents and methods that provide rapid high-resolution imaging, high tumor-to-background ratios in all organs at risk for tumor recurrence or metastasis, negligible immunogenicity and toxicity, and a significant further improvement in the accuracy of clinical decision making in oncology patients.

High-resolution microPET imaging of carcinoembryonic antigen-positive xenografts by using a copper-64-labeled engineered antibody fragment

“…T he diagnostic potential of radiolabeled antibodies that localize specifically to human malignancies is steadily being realized (1)(2)(3). However, currently available whole antibodies and fragments suffer from shortcomings as radiolabeled pharmaceuticals, including the prolonged biological half life of intact antibodies, leading to high background signal.…”

“…In addition, radiometal-labeled fragments, e.g., Tc-F(abЈ) 2 or FabЈ, demonstrate increased renal activity (5), and targeting by FabЈ fragments may be inherently limited by their monovalent binding to antigen. Nonetheless, radioimmunoscintigraphy is playing an increasingly important role in the clinic (3).…”

“…The increasing availability and lower cost of PET scanners and commercial PET radiopharmaceuticals allow routine imaging with PET in the care of cancer patients as well as provide the impetus to develop molecular imaging probes that are more specific for various cancers, to add to improved clinical management provided with FDG. To facilitate the testing of new positron-labeled agents in small-animal models, microPET technology has been developed that currently provides (Ϸ1.8 mm) 3 volumetric resolution (14). The microPET scanner has an axial field-of-view of 1.8 cm, and an entire mouse can be scanned by using multiple bed positions (14).…”

A limiting factor for the progress of radionuclide-based cancer diagnostics and therapy Availability of suitable radionuclides

“…CEA-scan, an antibody Fab' fragment labelled with 99m Tc, can possibly be used for staging of colorectal carcinoma (18) and imaging of breast cancer (19). Radioimmunoscintigraphy with CEA-scan has been reported to be more sensitive than conventional diagnostic modalities such as CT for detection of extrahepatic abdominal and pelvic colorectal carcinoma and seems to be complementary to conventional diagnostic modalities in imaging of liver metastases (20). Nofetumomab is a fragment of the NR-LU-10 antibody, initially designed for staging of non-small cell lung cancer.…”

Refolding Technology for scFv Using a New Detergent, N-Lauroyl-L-glutamate and Arginine

“…One of the major disadvantages using the whole antibody is its large size, which limits penetration into diseased areas [7][8][9]. Antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) functions mediated by binding of the Fc domain of the whole antibodies to the Fc receptor also limits the circulation and mobility [10]. Smaller version of antibody, lacking Fc-domains, can overcome these problems, provided that the ADCC or CDC function is not required for therapeutic efficacy of the antibodies [11][12][13][14].…”