Quantitative Immuno-Positron Emission Tomography Imaging of HER2-Positive Tumor Xenografts with an Iodine-124 Labeled Anti-HER2 Diabody

Abstract

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. (Cancer Res 2005; 65(4): 1471-8)

Development of radioimmunotherapeutic and diagnostic antibodies: an inside-out view

“…The commercial availability of radionuclides such as 131 67 Cu, and 177 Lu require chelation chemistry for radiolabeling to an Ab. Radiometal complexation must occur under practical conditions.…”

“…Methods for attaching metal chelating groups have facilitated study of metallic radionuclides (e.g., 90 Y, 177 Lu, and 67 Cu) that are potentially far better suited for RIT. Yttrium-90 lacks interfering γ-emissions altogether, and, while 177 Lu and 67 Cu emit γ-rays, they are of much lower energy with respect to 131 I. Yttrium-90 provides advantages over 131 I because it delivers on average a more energetic tumor-killing β − (935 keV versus 182 keV for 131 I) and concomitantly, a longer mean range (3.78 mm versus 0.36 mm for 131 I) ( Table 1).…”

“…Yttrium-90 lacks interfering γ-emissions altogether, and, while 177 Lu and 67 Cu emit γ-rays, they are of much lower energy with respect to 131 I. Yttrium-90 provides advantages over 131 I because it delivers on average a more energetic tumor-killing β − (935 keV versus 182 keV for 131 I) and concomitantly, a longer mean range (3.78 mm versus 0.36 mm for 131 I) ( Table 1). These characteristics improve the ability of a radiolabeled Ab to kill both targeted and neighboring cells and offer a particular advantage in treating bulky or poorly vascularized disease.…”

“…Lutetium-177 is not optimal for treatment of a large-diameter solid tumor as low energy β particles lack sufficient tumor penetration while conversely, 90 Y is not suited for treating disseminated microscopic tumor burden. Use of 131 I, 177 Lu, or 67 Cu is more appropriate in an adjuvant or small tumor setting. In contrast, 90 Y seems suited for use in patients with clearly detectable lesions due to its higher energy and consequent better penetration.…”

Radioprotection associée aux nouvelles évolutions, diagnostiques et thérapeutiques, en médecine nucléaire

“…Par contre, il ne convient pas au marquage de gros vecteurs qui mettent plusieurs jours à se distribuer dans leurs cibles (anticorps). Certaines études précliniques d'immuno-TEP ont déjà montré l'intérêt d'utiliser des émetteurs de positons avec des périodes physiques de quelques heures à quelques jours pour le radiomarquage d'anticorps ou de « diabody » (Robinson et al, 2005). Les radionucléides les plus prometteurs sont le cuivre-64 (période de 12 heures), l'iode-124 (période de 4,1 jours) et l'yttrium-86 (période de 15 heures).…”