Vascular Imaging of Solid Tumors in Rats with a Radioactive Arsenic-Labeled Antibody that Binds Exposed Phosphatidylserine

Institute of Nuclear Chemistry, Johannes Gutenberg-University of Mainz, Mainz, Germany.
Clinical Cancer Research (Impact Factor: 8.72). 04/2008; 14(5):1377-85. DOI: 10.1158/1078-0432.CCR-07-1516
Source: PubMed


We recently reported that anionic phospholipids, principally phosphatidylserine, become exposed on the external surface of vascular endothelial cells in tumors, probably in response to oxidative stresses present in the tumor microenvironment. In the present study, we tested the hypothesis that a chimeric monoclonal antibody that binds phosphatidylserine could be labeled with radioactive arsenic isotopes and used for molecular imaging of solid tumors in rats.
Bavituximab was labeled with (74)As (beta(+), T(1/2) 17.8 days) or (77)As (beta(-), T(1/2) 1.6 days) using a novel procedure. The radionuclides of arsenic were selected because their long half-lives are consistent with the long biological half lives of antibodies in vivo and because their chemistry permits stable attachment to antibodies. The radiolabeled antibodies were tested for the ability to image subcutaneous Dunning prostate R3227-AT1 tumors in rats.
Clear images of the tumors were obtained using planar gamma-scintigraphy and positron emission tomography. Biodistribution studies confirmed the specific localization of bavituximab to the tumors. The tumor-to-liver ratio 72 h after injection was 22 for bavituximab compared with 1.5 for an isotype-matched control chimeric antibody of irrelevant specificity. Immunohistochemical studies showed that the bavituximab was labeling the tumor vascular endothelium.
These results show that radioarsenic-labeled bavituximab has potential as a new tool for imaging the vasculature of solid tumors.

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    • "These characteristics suggest that bavituximab and similar PS-targeting antibodies may not only be useful for cancer therapy, but that they may also be useful for cancer imaging. We have previously shown that bavituximab labeled with the 74As (t1/2 = 17.8 days) gave clear PET images of subcutaneous prostate tumors in rats [22]. Optimal images were obtained 72 h after injection, when concentrations of the probe in the blood had fallen to levels that did not obscure signal from the tumor [22]. "
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    ABSTRACT: Phosphatidylserine (PS) is an attractive target for imaging agents that identify tumors and assess their response to therapy. PS is absent from the surface of most cell types, but becomes exposed on tumor cells and tumor vasculature in response to oxidative stresses in the tumor microenvironment and increases in response to therapy. To image exposed PS, we used a fully human PS-targeting antibody fragment, PGN635 F(ab')2, that binds to complexes of PS and β2-glycoprotein I. PGN635 F(ab')2 was labeled with the positron-emitting isotope iodine-124 ((124)I) and the resulting probe was injected into nude mice bearing subcutaneous or orthotopic human PC3 prostate tumors. Biodistribution studies showed that (124)I-PGN635 F(ab')2 localized with remarkable specificity to the tumors with little uptake in other organs, including the liver and kidneys. Clear delineation of the tumors was achieved by PET 48 hours after injection. Radiation of the tumors with 15 Gy or systemic treatment of the mice with 10 mg/kg docetaxel increased localization in the tumors. Tumor-to-normal (T/N) ratios were inversely correlated with tumor growth measured over 28 days. These data indicate that (124)I-PGN635 F(ab')2 is a promising new imaging agent for predicting tumor response to therapy.
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    • "Furthermore, endothelial cells in a normal cerebral vascular system show an absence of Weibel Palade bodies [11]; however, in GBM vessel walls, Weibel Palade bodies can be identified in endothelial cells. Most importantly, the prothrombotic lipid phosphatidylserine (PS) is exposed on the vascular endothelium of all solid tumors, including GBM, but not on endothelium in normal tissues [12] [13] [14] [15] [16] [17]. All of these features are also seen in cerebral arteriovenous malformations [11, 18–24], and may represent the key to translating our effective radiosurgery enhanced vascular targeting for cerebral arteriovenous malformations into GBM therapy. "
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    • "For example, 111 In has been widely used for SPECT imaging and arsenic isotopes (e.g. 72 As and 74 As) have been reported for PET imaging [47]. It is likely that we will see reports on r-QDs that contain clinically relevant radionuclides in the near future, such as 111 In-containing r-QDs. "
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