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Basic Science Investigations |
1 Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California
2 Beckman Research Institute, City of Hope National Medical Center, Duarte, California
3 City of Hope Comprehensive Cancer Center, Duarte, California
4 Radiopharmaceutical Chemistry Service and Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York
5 UCLA Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, California
6 Department of Radiology and Bio-X Program, Stanford University, Stanford, California
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Key Words: radioimmunoimaging • engineered antibody fragments • carcinoembryonic antigen • 124I • PET
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Single-chain Fv fragments (scFv), consisting of the variable regions of the immunoglobulin light and heavy chains tethered via a short peptide linker, have been derived from an array of antitumor antibodies and evaluated for in vivo targeting in tumor xenograft-bearing mice (3). Because scFvs are smaller (25–30 kDa) than intact IgG (150 kDa), they show improved tissue penetration (4) and rapid clearance from circulation, resulting in improved tumor-to-blood ratios. However, because of their monovalent nature and rapid elimination from the circulation, scFvs demonstrate substantially lower tumor uptakes than does the corresponding intact IgG (3).
Antitumor diabodies (noncovalent dimers of scFv fragments, 55 kDa), formed by using short linker peptides to promote cross-pairing, show tumor uptakes superior to those of their scFv counterparts and retain rapid blood clearance (2). This leads to high tumor-to-blood ratios at early times after administration. Larger fragments such as the minibody (scFv-CH3; 80 kDa) (5) and scFv-Fc (110 kDa) (6) fusion proteins can demonstrate even higher tumor uptakes; localization is improved because of the longer serum half-lives of these species, allowing longer exposure of the target tissue to the antibody fragment. The trade-off, however, is that longer intervals are required between administration and image acquisition for optimal contrast.
PET is well established as an imaging modality, offering high sensitivity and resolution; furthermore, tissue uptakes can be quantitated using PET. 18F (half-life, 109 min) has been the favored radionuclide for labeling of small molecule tracers. However, the slower targeting and clearance kinetics of biomolecules, including antibodies and fragments, has prompted the evaluation of intermediate-half-life positron emitters including 64Cu (half-life, 12.7 h) and 124I (half-life, 4.18 d) for PET imaging. In particular, targeting and imaging of 124I-labeled intact antibodies have been evaluated preclinically in animal models of breast or ovarian cancer (7–9) and in humans (10) using clinical PET scanners. However, PET imaging applications using 124I may be hampered by the relatively low positron yield (23%), low inherent resolution due to high energy and longer range of the positron emission, and quantitation issues arising from 
-rays emitted in coincidence with positrons or with other -emissions (11). The high -emissions also raise issues of high radiation doses and additional shielding requirements. Furthermore, the availability of 124I is currently limited to research purposes only. Nonetheless, development of tracers labeled with positron emitters of longer half-life remains an important goal in PET.
In our previous work, diabodies and minibodies were generated from the anticarcinoembryonic antibody (CEA) T84.66. These were radiolabeled with 123I/131I or conjugated with 1,4,7,10-tetraazacyclododecane N,N',N'',N'''-tetraacetic acid (DOTA) for radiolabeling with 111In. The T84.66 diabody (55 kDa) showed rapid tumor localization in athymic mice bearing CEA-positive LS174T human colon carcinoma xenografts, reaching 13.68 ± 1.49 percentage injected dose per gram of tissue (%ID/g) (123I) or 12.5 ± 0.4 %ID/g (111In) 2 h after administration (5,12,13). The larger T84.66/GS18 Flex minibody (80 kDa; above the threshold for renal filtration) reached tumor accumulations of 26.23 ± 4.57 %ID/g (131I) or 24.47 ± 6.1 %ID/g (111In) at 12 h after injection (13). However, in radiometal-labeled forms, these fragments exhibited normal tissue retention as seen for other radiometal-labeled antibody fragments (1,14). In particular, the 111In-minibody showed elevated retention of activity in the liver (25.97 ± 0.99 %ID/g at 24 h), and the 111In-diabody reached very high levels of activity in the kidney (>180 %ID/g at 6 h) (13). PET imaging studies confirmed the hepatic accumulation of 64Cu-DOTA-T84.66 (15). Because neither renal nor hepatic accumulation was significant for radioiodine-conjugated fragments, evaluation using a positron-emitting isotope of iodine was warranted. The combination of 124I-labeled anti-CEA diabody or anti-CEA minibody and PET imaging should take advantage of the favorable biologic properties of these radioiodinated proteins, including rapid reduction of activity in nonspecific tissues and organs.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Cell Lines and Xenografts
The LS174T human colorectal carcinoma cell line (CL 188) and C6 rat glioma cell line (CCL 107) were obtained from the American Type Culture Collection and maintained under standard conditions. Xenografts were established in 8-wk-old CD1 female nude mice (Charles River Laboratories) by subcutaneous inoculation of 1–2 x 106 cells 10–14 d before the imaging studies. All animal handling and studies were performed in accordance with the guidelines of the University of California, Los Angeles (UCLA), Animal Research Committee.
PET Scanning
Mice were imaged using the prototype small-animal PET scanner developed at the Crump Institute for Molecular Imaging, UCLA (20). Thyroid uptake of radioiodine was blocked by pretreatment using 10 drops of saturated KI per 100 mL of drinking water for 24 h before injection of radioiodinated protein. Stomach uptake was blocked by administration of 1.5 mg of potassium perchlorate in 0.2 mL of PBS by gastric lavage 30 min before injection. The mice were injected in the tail vein either with 1.9–3.1 MBq (53–85 µCi) of 124I-minibody or with 3.1 MBq (85 µCi) of 124I-diabody in saline/1% HSA. After the appropriate uptake time had elapsed, the mice were anesthetized by intraperitoneal injection of a mixture of ketamine (80 mg/kg final dose) and xylazine (10 mg/kg final dose), placed prone, and imaged using the PET scanner with the long axis of the mouse parallel to the long axis of the scanner. Acquisition time was 28 min (4 min per bed position; 7 bed positions). Images were reconstructed using a 3-dimensional filtered backprojection reconstruction algorithm (21) for quantitation (see below) or using a maximum a posteriori reconstruction protocol (22) for presentation of images. Some mice were also imaged using 18F-FDG 2 d before the 124I-minibody scan. These were administered 5.6–7.4 MBq (150–200 µCi) of 18F-FDG via the tail vein, and scans were acquired as described above, beginning 1 h after tracer injection. In some experiments, after scanning, the animals were euthanized; the tumors were excised, weighed, and counted in a well counter (Cobra II Auto-Gamma; Packard); and the %ID/g was calculated.
Digital Whole-Body Autoradiography (DWBA)
The mice were sacrificed and frozen in carboxymethyl cellulose (Aldrich) in preparation for sectioning using a Cryostat (PMV). Coronal cross-sections were obtained with a thickness of 45 µm. DWBA was performed using a Fujifilm BAS 5000 PhosphorImager (Fujifilm Medical Systems U.S.A., Inc.) and digital plates with a final resolution of 
100 µm. DWBA data were analyzed using Mac BAS software, version 2.4 (Fujifilm Medical Systems U.S.A., Inc.).
Data Analysis
Preliminary quantitation of the small-animal PET images was performed using the Crump Institute Integrated Imaging Software Package, or CRIIISP (Crump Institute for Molecular Imaging, UCLA). From the 3-dimensional filtered backprojection reconstruction, several planes (of a total of 64) encompassing the tumors were selected in the coronal orientation and averaged. Regions of interest (ROIs) were drawn for both the control and LS174T CEA-positive tumors centered on the peak of the activity profile. A soft-tissue region in the neck, as well as the area of maximum activity in the abdominal region, was also included for ROI analysis. Approximately equal-sized ROIs were drawn. ROI counts per pixel per minute were converted to counts per cubic centimeter per minute using a calibration factor obtained from scanning a cylinder containing a known amount of 124I activity. After decay correction, these data were converted to %ID/g by dividing by the known amount of injected activity. Target-to-background ratios were then determined for individual mice and averaged. The effects of ROI positioning were determined by averaging at least 3 ROIs and assessing the variability across regions. Statistical analysis was performed using the Excel 2000 (Microsoft) software package.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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2 MBq (53 µCi) of 124I-minibody, and whole-body PET scans were obtained beginning 4 and 18 h after administration. The image in Figure 3C clearly demonstrates high uptake into the positive (LS174T) tumor and low activity in the control (C6) tumor. The positive tumor-to-control tumor uptake ratio for the 124I-anti-CEA minibody was 3.46:1 at 4 h and 10.85:1 at 18 h, demonstrating high specificity (n = 8; Table 1).
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Visualization of CEA-Positive Xenografts Using 124I-Anti-CEA Diabody
Experiments were conducted similarly using the 124I-anti-CEA diabody in animals (n = 4) bearing CEA-positive tumors with an average weight of 183 mg (range, 40–420 mg). PET imaging performed 4 h after administration of 124I-anti-CEA diabody revealed rapid and specific uptake in the CEA-positive tumors (Fig. 4 C), with a tumor-to-background uptake ratio of 3.99:1 (Table 1). The contrast between the CEA-positive LS174T and CEA-negative C6 xenografts was even more striking at 18 h (Figs. 4D and 4E); a ratio could not be calculated because the C6 xenografts were not distinguishable.
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Higher tumor-to-background ratios were achieved in animals administered 124I-labeled anti-CEA diabody. In these animals (n = 4), the tumor-to-background (background in abdominal region) ratios improved from 1.8:1 at 4 h after injection (Fig. 4C) to 6.1:1 at 18 h after injection (Figs. 4D and 4E). Background ratios of tumor to soft tissue were even higher, increasing from 4:1 at 4 h to 11:1 by the 18-h scans. This improvement in the tumor-to-background ratios achieved with 124I-labeled anti-CEA diabody, especially regarding the central activity in the abdominal region, provides greater contrast and renders a clear image of the CEA-positive tumor (Fig. 4E).
Tissue Counting
After the 18-h scans, animals not used in DWBA studies were sacrificed, and activity in various tissues was quantitated using a -counter. The results in Table 2 confirm high tumor uptake in the LS174T model, with a mean uptake of 20.55 ± 2.74 %ID/g for the 124I-T84.66 minibody (n = 5), consistent with previous work using 123I/131I-radiolabeled T84.66 minibody (5,13). Uptake of 124I-minibody by the control C6 xenografts and activities in heart, liver, and kidney were significantly lower than uptake in the positive tumors, and the tumor-to-control ratios determined by counting exceeded 13:1 for the indicated tissues and were consistent with ratios determined from the PET scans.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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Development of tracers for radioimmunoimaging requires attention to at least 3 main components: target antigen, antibody (including format), and radionuclide. Carcinoembryonic antigen, a classic tumor-associated antigen in colorectal carcinoma as well as other adenocarcinomas, remains a prime target for antibody-based detection and therapeutic applications (23). The anti-CEA minibody and diabody were derived from T84.66, a high-affinity (KA = 2 x 1011 L/mol), highly specific antibody that recognizes an epitope on the A3 domain of CEA (24). Previous studies demonstrated the favorable tumor-targeting properties of these fragments labeled with radioiodine or 111In in LS174T-xenografted mice (5,12,13). However, radiometal-labeled fragments showed retention of activity in liver (minibody) or kidney (diabody). The T84.66 minibody was radiolabeled with 64Cu, a positron-emitting radiometal with a 12.7-h half-life, to explore its utility as a PET tracer (15). Excellent tumor localization was observed, but as expected, liver activity was elevated, limiting imaging applications to extrahepatic sites.
The present work demonstrated that radiolabeling of the anti-CEA minibody and diabody using 124I for PET imaging preserves the excellent tumor targeting of these fragments while enhancing the overall images because of lower background activity in normal tissues. The question arises as to which of these fragments is preferable as an imaging agent. The T84.66 minibody reaches higher absolute activity levels in tumor, but background activity takes longer to clear and is still apparent at 18 h in the murine model. By contrast, radioactivity delivered to the CEA-positive xenografts by diabody is substantially lower; however, this apparent disadvantage is ameliorated by the much lower background activity seen in the mouse. Further optimization of diabody radioiodination to retain high immunoreactivity should also enhance performance. In this animal imaging model, the diabody appears to have the advantage over the minibody in achieving higher overall contrast; however, performance still needs to be evaluated in the clinic.
Guidance on the selection of an appropriate fragment can be provided by analysis such as calculation of the imaging figure of merit (IFOM) (25), an approach based on determining statistically the required counting time to distinguish tumor from blood background. We calculated IFOM values for 124I-labeled fragments from previously published biodistribution data on radioiodinated minibody and diabody. Results (not shown) suggested that the minibody should be the superior agent, with an optimal imaging time of 20–24 h after administration, and the optimal imaging interval for the diabody would be 8–12 h. However, the current IFOM calculations are dependent on tumor size and do not take into account normal tissue activity. Further PET imaging studies at additional time points will clarify some of these issues, as will human tumor targeting and pharmacokinetic data from ongoing clinical imaging studies of 123I-T84.66 minibody. Either of these fragments labeled with 124I may prove especially useful for imaging hepatic metastases.
Several groups have explored the use of 124I for PET imaging with clinical scanners, including antibody applications. Bakir et al. (8) demonstrated detection of c-erbB2/Her2-overexpressing tumor xenografts in athymic mouse using 124I-ICR12, a rat monoclonal antibody. Tumors as small as 6 mm in diameter were imaged at 24, 48, and 120 h. More recently, Lee and associates (7) imaged human colon carcinoma xenografts using humanized 124I-A33 monoclonal antibody. This intact antibody reached 50 %ID/g 4 d after injection, and clear tumor images (tumor sizes, 0.2–0.7 g) were obtained when mice were imaged at 24, 48, or 240 h after injection. Clinical investigations have included PET imaging of breast cancer patients using 124I-anti-mucin antibodies (10) and evaluation of 124I-3F9 antibody administration for dose estimation in a patient with neuroblastoma (26). Use of a positron-emitting radionuclide with a long physical half-life, such as 124I, has been necessary for applications using intact antibodies because of their extended biologic half-lives. As noted in the above literature, optimal imaging was obtained days after administration. Results presented here indicate that 124I is also well suited for imaging using engineered fragments, with the added advantage of shorter intervals to optimal imaging times (same day or next day).
The use of 124I for radiolabeling the anti-CEA fragments, in particular the minibody, provides advantages over previous work. As expected, the high, persistent liver activity observed in our previous PET studies using 64Cu-anti-CEA minibody was dramatically reduced because of the different metabolism and clearance of activity after administration of radioiodinated protein compared with radiometal-labeled protein. The fact that CEA is not internalized on binding of antibody probably contributes to retention of activity in the LS174T xenografts, enhancing the tumor-to-liver and tumor-to-kidney ratios of the 124I-diabodies and -minibodies. In addition to the favorable biologic properties of these radioiodinated proteins, 124I-minibody and -diabody should also offer the advantage of high avidity compared with 99mTc-labeled Fab' fragment (arcitumomab [CEA-Scan]; Immunomedics, Inc.), as these represent high-affinity bivalent, rather than monovalent, CEA-binding proteins.
The present work suggests that qualitative PET imaging using 124I-engineered fragments may provide a sensitive method for visualization of tumor masses. Relative quantitation (determination of target-to-background ratios) is straightforward. However, absolute quantitation of 124I activity will require correction of the imaging data to compensate for the unfavorable spectrum of emissions generated during the decay of 124I. In particular, 124I decay results in only a 23% yield of positrons, compared with the near 100% positron yield of 18F (27). The average energy of the 124I positrons is higher than that for 18F, and the increased positron range would result in degradation of resolution. 124I also has a complex decay scheme, resulting in a high -component, with many high-energy -emissions occurring in coincidence with each other and with the annihilation photons. Despite these shortcomings, PET imaging studies using phantoms or xenografted mouse models have been conducted under realistic conditions. Results indicate that suitable images could be obtained and that relative quantitation was feasible using a variety of clinical PET scanners (11,27). Recently, a Monte Carlo simulation scheme has been developed for correction of 124I images for scatter, -coincidences, and attenuation and should be applicable to the small-animal PET data generated in the current studies (C. Holdsworth, oral communication, May 2003). Correction of the current datasets is in progress. A final challenge in the current work arises from the small size of some of the tumors used—close to the resolution of the prototype small-animal PET instrument (1.8–2.0 mm). As a result, correction for the partial-volume effect will also be required for accurate quantitation (28).
The present approach can be highly complementary to existing PET oncology imaging, which primarily uses 18F-FDG as a tracer for glucose uptake and use by cancer cells. Direct comparison of quantitative image analysis was not attempted here because of the complexity of the 124I emissions as noted above. However, it is apparent from Figure 3 (which presents raw images of the same tumor-bearing mouse imaged using both tracers on the same color scale) that antibody-fragment imaging resulted in highly specific tumor localization in this xenograft model, when compared with 18F-FDG. Uptake levels for the engineered fragments equal (diabody) or substantially exceed (minibody) the %ID/g levels attained by 18F-FDG (which maximizes at approximately 3–8 %ID/g depending on the tumor model). Imaging modes such as antibody-based imaging would be especially useful as an alternative to 18F-FDG PET in cancers that exhibit low metabolic activity such as low-grade lymphomas, many prostate cancers, and other indolent tumors. There are many well-characterized tumor-associated antigens currently under evaluation for antibody-targeted imaging and therapy in lymphomas and solid tumors, such as CD20, Her2, and TAG-72, that could similarly be targeted using 124I-radiolabeled recombinant fragments.
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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-camera/SPECT imaging in patients is in progress. Results from these studies and 123I-diabody studies will guide selection of appropriate 124I-labeled recombinant fragment for clinical PET studies. Furthermore, current progress in the genomics and proteomics of cancer is rapidly generating new molecular targets that can potentially be accessed using antibody technology. Reformatting of antibodies into diabodies or minibodies for 124I radiolabeling can provide a rapid route for generation of new PET tracers for cancer imaging.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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For correspondence or reprints contact: Anna M. Wu, PhD, Crump Institute for Molecular Imaging, David Geffen School of Medicine at UCLA, 700 Westwood Plaza, Crump A342B, P.O. Box 951770, Los Angeles, CA 90095-1770.
E-mail: awu{at}mednet.ucla.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
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