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An the report by Cai et al. (1) on pages 304-310 of this issue of The Journal of Nuclear Medicine, an important milestone was achieved in the race to develop optimal immuno-PET agents, namely, the demonstration that small antibody fragments, in this case, diabodies, can be labeled with ^sup 18^F and yield high-contrast PET images of tumors with tumor-to-normal tissue ratios as high as 6.2 in 4 h and with sufficient contrast for imaging as early as 1 h. Although these results were achieved with an optimized tumor xenograft animal model, they are the first step in moving the methodology to the clinic. The interest comes from the promise of using the most commonly used PET radionuclide, ^sup 18^F, with engineered antibodies, such as diabodies, which are increasingly easier to produce and which correspond to derivatives of the newest therapeutic agents in the cancer field-humanized antibodies. In this example, the tumor antigen was carcinoembryonic antigen, an excellent target for the imaging of many solid tumors, including colon, breast, and medullary thyroid carcinomas, but for which no cold antibody therapy has yet been demonstrated. Thus, the opportunities to use PET for carcinoembryonic antigenpositive malignancies may be limited to preoperative imaging and radioimmunotherapy. for which therapeutic radionuclides, such as ^sup 90^Y, have shown promise (2). However, the methodology can be easily extended to cold therapeutic antibodies, such as anti-Her2 antibodies, for which humanized diabody fragments have already been developed (3,4). Further extension to anti-vascular endothelial growth factor and anti-epidermal growth factor receptor diabodies cannot be far off.
Several points are worth discussion. The first point is: why diabodies? Diabodies (55 kDa) are the smallest engineered fragments that are bivalent, retaining the chief advantage of whole antibodies, namely, avidity (5). Monovalent antibody fragments, such as single-chain variable fragments (scFvs), have never fared well in the clinic, despite their small size (25 kDa), because of their poor tumor retention. scFvs pay a high price for fast blood clearance, which would otherwise make them attractive as imaging agents because of their high tumor-to-blood ratios. However, high tumor-to-blood ratios alone do not make an optimal imaging agent. There are 2 reasons why scFvs fail the test; the first is that they are cleared too rapidly to accumulate in tumors, and the...