Quantitative immuno-positron emission tomography imaging of HER2-positlve tumor xenografts with an iodine-124 labeled anti-HER2 diabody

Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Cancer Research (Impact Factor: 9.33). 03/2005; 65(4):1471-8. DOI: 10.1158/0008-5472.CAN-04-2008
Source: PubMed


Positron emission tomography (PET) provides an effective means of both diagnosing/staging several types of cancer and evaluating efficacy of treatment. To date, the only U.S. Food and Drug Administration-approved radiotracer for oncologic PET is (18)F-fluoro-deoxyglucose, which measures glucose accumulation as a surrogate for malignant activity. Engineered antibody fragments have been developed with the appropriate targeting specificity and systemic elimination properties predicted to allow for effective imaging of cancer based on expression of tumor associated antigens. We evaluated a small engineered antibody fragment specific for the HER2 receptor tyrosine kinase (C6.5 diabody) for its ability to function as a PET radiotracer when labeled with iodine-124. Our studies revealed HER2-dependent imaging of mouse tumor xenografts with a time-dependent increase in tumor-to-background signal over the course of the experiments. Radioiodination via an indirect method attenuated uptake of radioiodine in tissues that express the Na/I symporter without affecting the ability to image the tumor xenografts. In addition, we validated a method for using a clinical PET/computed tomography scanner to quantify tumor uptake in small-animal model systems; quantitation of the tumor targeting by PET correlated with traditional necropsy-based analysis at all time points analyzed. Thus, diabodies may represent an effective molecular structure for development of novel PET radiotracers.

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Available from: Calvin Shaller, Jan 27, 2014
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    • "One drawback of the in vivo use of scFvs is represented by their rapid off rates, with consequent low retention in the target tissue, due to their monovalency. For instance, it has been argued that an optimal tumor-targeting fragment should be a diabody characterized by high tissue penetrating ability, target retention, and rapid blood clearance (Robinson et al. 2005; Wu et al. 2015). "
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    • "Genetic manipulation has led to the design of diabodies, triabodies and tetrabodies that have higher avidity and increased maintenance of circulation, thus promoting tumor uptake for a long time without compromising tissue penetration properties (Hudson 1998). It has been demonstrated that the optimal structure which has both high tissue penetration and enough retention with rapid clearance would be a diabody (55 kDa), which is constructed by noncovalently linking two scFv fragments (Robinson et al. 2005, Sundaresan et al. 2003). "
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    • "This enhanced penetration could increase overall efficacy. The diabodies in particular have been shown to provide rapid tissue penetration, high target retention, and rapid blood clearance presumably as a result of their multi-valent nature and intermediate size (55 kDa) (161). The use of alternative antibody formats also opens up the possibility of delivering multiple therapies from one oncolytic virus. "
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