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Radiolabeled antibodies are powerful tools for both imaging and therapy in the field of nuclear medicine. Radiolabeling methods that do not release radionuclides from parent antibodies are essential for radiolabeling antibodies, and practical radiolabeling protocols that provide high in vivo stability have been established for many radionuclides, with a few exceptions. However, several limitations remain, including undesirable side effects on the biodistribution profiles of antibodies. This review summarizes the numerous efforts made to tackle this problem and the recent advances, mainly in preclinical studies. These include pretargeting approaches, engineered antibody fragments and constructs, the secondary injection of clearing agents, and the insertion of metabolizable linkages. Finally, we discuss the potential of these approaches and their prospects for further clinical application. [ABSTRACT FROM AUTHOR]

Titanium-aluminum-vanadium (Ti-6Al-4V) implants were placed in the tibiae of 32 rats (male Sprague-Dawley, 350 g) to examine healing and bone response. Half of the implants were treated with fibroblast growth factor 1 (FGF-1) delivered in an activated fibrinogen matrix. Animals were injected with a radiopharmaceutical imaging agent, technetium-99m-methylene diphosphonate (Tc-99m-MDP), which concentrates in bone, especially in areas of higher osteoblastic activity. Binding of Tc-99m-MDP to the implant was detected in vivo by Anger gamma camera imaging. Fourteen days after implant surgery, specimens were recovered and prepared for histomorphometric analysis. Histologic examination revealed that samples treated with FGF-1 demonstrated significantly greater amounts of bone-to-implant contact (P < .05) compared to controls. Also, FGF-1-treated samples showed significantly greater amounts of bone (percent volume) adjacent to implants (P < .005). These findings were supported by analyses of the non-invasive Tc-99m-MDP images, which demonstrated significantly greater uptake of Tc-99m-MDP adjacent to FGF-1-treated implants (P < .05). Results of the experiments supported the hypothesis that FGF-1 could increase bone production around implants in a rat model. [ABSTRACT FROM AUTHOR]

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The rupture of vulnerable atherosclerotic plaques and subsequent thrombus formation are the major causes of myocardial and cerebral infarction. Accordingly, the detection of vulnerable plaques is important for risk stratification and to provide appropriate treatment. Inflammation imaging using 2-deoxy-2-[F]fluoro-D-glucose (F-FDG) has been most extensively studied for detecting vulnerable atherosclerotic plaques. It is of great importance to develop PET/SPECT probes capable of specifically visualizing the biological molecules involved in atherosclerotic plaque formation and/or progression. In this article, we review recent advances in the development of PET/SPECT probes for visualizing atherosclerotic plaques and their application to therapy monitoring, mainly focusing on experimental studies. [ABSTRACT FROM AUTHOR]

Radiolabeled receptor-binding peptides and proteins have emerged as an important class of radiopharmaceuticals that have changed radionuclide imaging in clinical practice. Many strategies have been developed to radiolabel these peptide and proteins with fluorine-18. The majority of these methods is time-consuming and suffer from low yields. A more straightforward approach was proposed a few years ago, based on the chelation of aluminum fluoride by (1,4,7-triazacyclononane-1,4,7-triacetic acid). This approach has been optimized with regard to labeling yield and specific activity. In addition, crystallography studies have led to the design of optimized chelators. Subsequently, the Al18F technology is finding widespread use in labeling peptides and proteins. Various hapten peptides for pre-targeting studies have been labeled with Al18F, as well as αv β3 integrin-binding peptides have been studied, and also larger peptides, such as exendin-4 and affibody molecules and heat-labile proteins have been labeled with Al18F. Here, we summarize the development, optimization, and applications of the Al18F labeling technology. © 2013 The Authors. J. Label Compd. Radiopharm published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

Bispecific antibody pretargeting is a two-step procedure for selectively delivering radionuclides to tumors. The procedure was developed to solve a number of problems encountered when radionuclides are directly coupled to an IgG, such as slow blood clearance and delayed tumor accretion. While various forms of antibody fragments can reduce blood pool activity and provide faster tumor localization, tumor uptake is reduced considerably. In pretargeting procedures, the radionuclide is attached to a small molecule that quickly traverses the vascular barrier to reach the tumor cells, achieving maximum accretion within 0.5 to 1.0 h. Just as quickly, it is eliminated from the body, thereby minimizing tissue exposure and developing high tumor/tissue ratios very early. In order to capture the radionuclide in the tumor, a bispecific antibody (bsMAb) that binds to the tumor and to the isotope carrier (e.g., a hapten-peptide) is pre-administered some time earlier. The pretargeting procedure has been shown repeatedly to improve tumor localization as compared to directly radiolabeled antibodies, thereby enhancing both imaging and therapy. In this article, we review the progress our group has made toward developing and testing bsMAb pretargeting systems for cancer detection and therapy. [ABSTRACT FROM AUTHOR]

Purpose: 99mTc-DI-DD-3B6/22-80B3 (Thromboview, hereafter abbreviated to 99mTc-DI-80B3 Fab′) is a humanised, radiolabelled monoclonal antibody Fab′ fragment with high affinity and specificity for the D-dimer domain of cross-linked fibrin. The purpose of this study was to evaluate the safety, pharmacokinetics and dosimetry of four increasing doses of 99mTc-DI-80B3 Fab′ in healthy volunteers. Methods: Thirty-two healthy volunteers (18.70 years; 16 male, 16 female) received a single intravenous injection of 0.5, 1.0, 2.0 or 4.0 mg of 99mTc-DI-80B3 Fab′. Safety outcomes (vital signs, electrocardiography, haematology, biochemistry, adverse events and development of human anti-human antibodies) were assessed up to 30 days post injection. Blood and urine samples were collected up to 48 h post injection. Gamma camera images were acquired at 0.5, 1, 2, 4, 6 and 24 h post injection. Dosimetry was performed using standard MIRD methodology. Results: No adverse events considered to be drug related were observed. Human anti-human antibody was not detectable in any subject during the follow-up period. 99mTc-DI-80B3 Fab′ had a rapid initial plasma clearance (t1/2α=1 h). The pharmacokinetic profile of the Fab′ fragment was generally linear across the four dose cohorts. By 24 h, 30.35% of the administered radioactivity appeared in the urine. There was marked renal accumulation with time, but no specific uptake was identified within other normal tissues. The effective dose was 9 mSv/750 MBq. Conclusions: 99mTc-DI-80B3 Fab′ is well tolerated, is rapidly cleared and exhibits clinically acceptable dosimetry. characteristics well suited to a potential thrombus imaging agent. [ABSTRACT FROM AUTHOR]

MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high-affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody-directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1 with technetium-99m was developed for the purpose of determining tumour localisation of MFECP1 in a phase I ADEPT clinical study. The method used was 99mTc-carbonyl [99mTc(H2O)3(CO)3]+ (abbreviated to TcCO) mediated labelling of 99mTc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was labelled with TcCO under a variety of conditions, and this was shown to be a relatively simple and robust method. Tissue biodistribution was assessed in a CEA-expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and for measurement of CPG2 enzyme levels. The amount of radioactivity retained by the tumour proved to be an accurate estimation of actual measured enzyme activity, indicating that this radiolabelling method does not appear to damage the antibody–antigen binding or the enzyme activity of MFECP1. However, correlation between CPG2 enzyme activity and measured radioactivity in liver, spleen and kidney was poor, indicating retention of radioactivity in non-tumour sites but loss of enzyme activity. The high retention of technetium radioisotope in normal tissues may limit the clinical applicability of this radiolabelling method for MFECP1; however, these results suggest that this technique does have applicability for measuring the biodistribution of His-tagged recombinant proteins. [ABSTRACT FROM AUTHOR]

A mouse monoclonal antibody (MoAb), S74 against a human scirrhous gastric carcinoma cell line was developed. The radioiodinated antibody bound preferentially in vivo to xenografted tumors rather than to normal tissue, whereas tumor uptake of normal mouse IgG did not occur. Thus this MoAb was able to selectively localize a human tumor in an animal model, and clinically it may enable immunotherapy against scirrhous carcinoma of the stomach. [ABSTRACT FROM AUTHOR]

To develop a new method of radioimmunodetection for thyroid cancer, we tested the binding ability of a human antithyroglobulin monoclonal antibody, VB5, to primary culture of human thyroid cancer cells. VB5 was able to immunostain cytoplasmic thyroglobulin (Tg) in the acetone-fixed cancer cells when used in a labeled streptavidin-biotin method but not in a conventional indirect immunoperoxidase technique. The antibody was readily labeled with I-125 in the standard chloramin-T method, and showed specific binding to the antigen on cultured malignant thyrocytes displaceable with non-labeled VB5 or with excess Tg antigen. Although these initial results in vitro are encouraging, the observed low specific binding (about 1% at room temperature) to intact cells with a single monoclonal antibody seems insufficient to conduct any in vivo immunolocalization experiments in animals. To obtain more binding, we would need a cocktail of several monoclonal antibodies to different epitopes, and also fragmentation of antibody molecules to penetrate into cytoplasm. [ABSTRACT FROM AUTHOR]

We evaluated the intravenous infusion of a cocktail of I-131 anti-CEA and anti-C A19-9 monoclonal antibody F(ab')2 (IMACIS-1) in patients with gastrointestinal neoplasm and liver metastases in order to assess its efficacy in detecting the presence of cancer. Seven patients with primary or recurrent gastrointestinal cancer in whom liver metastases were also detected were studied. Accumulation of radioactivity in the primary tumor was seen in only one patient. Visualization of the liver metastases was achieved in all patients. Thus detection of liver metastasis was better than in primary or recurrent tumors. While tumor visualization was most often seen in the 3 day image, optimal visualization of the tumor was seen at 5-7 days. There was no correlation between the serum concentration of CEA or CA19-9 and the visualization of tumors. Serum kinetics of I-131IMACIS-1 showed biexponential components with a 1st phase T of 5.0 hours and 2nd phase T of 34.7 hours. The mean whole body (I-131) half-life determined from the whole-body scans was 1.95 days. The mean urinary excretion of I-131 in 7 days was 85%. This value agreed closely with total radioactivity retention detected by scanning. This series of studies demonstrated the potential utility of a cocktail of antibodies consisting of an anti-CEA and an anti-CA19-9 monoclonal F(ab'). [ABSTRACT FROM AUTHOR]

The potential of DU-PAN II, monoclonal antibody (IgM), which was raised against the human tumor cell line, was evaluated for radioimmunodetection of human pancreatic tumors (PAN-5-JCK and EXP-58) grown in nude mice.I-labeled DU-PAN II was accumulated into PAN-5-JCK producing DU-PAN II antigen with a tumor-to-blood ratio of 2.72±3.00, but it did not localize in EXP-58 because of insufficient DU-PAN II. There was no significant uptake ofI-nonimmunized IgM in PAN-5-ICK. These facts indicated the specific tumor uptake of DU-PAN II. Excellent images of the tumor PAN-5-JCK were obtained 3 days after the injection ofI-DU-PAN II. Gel chromatography was also investigated with respect to the plasma taken from mice injected with antibody, or incubated with antibody in vitro. The results indicate that circulating antigen affected the tumor uptake of DU-PAN II : The more the tumor grew, the higher the amount of antigen excreted into the blood, leading to the degradation of DU-PAN II before it reached the tumor sites. Consequently, the immunoscintigram of the small tumor was remarkably clear. The catabolism and the radiolysis of the labeled IgM injected are critical points in applying immunoscintigraphy. [ABSTRACT FROM AUTHOR]

This paper reviews the development of cancer imaging with radiolabeled antibodies to carcinoembryonic antigen and the current status and challenges for cancer therapy with radiolabeled antibodies. Advances in antibody preparations, choice of isotope and labeling methods, as well as imaging methods have resulted in rapid and sensitive radioimmunodetection agents that can affect the management of cancer patients. Radioimmunotherapy faces other problems, but advances in antibody engineering and control of dose-limiting myelotoxicity may result in reproducible clinical responses similar to the encouraging results being obtained in the radioimmunotherapy of lymphomas. Copyright © 1995 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This editorial reviews the development, current status, and future prospects of cancer imaging with radioactive antibodies, termed radioimmunodetection (RAID). There has been a slow and steady development of this field for more than 35 years, with more recent activity and progress resulting from the identification of human tumor-associated antibodies and suitable human tumor xenograft models, the demonstration that circulating antigens do not prevent radioantibody localization in tumor, the development of computer-assisted and biological methods for reducing non-target background radioactivity, and the advent of hybridoma-produced monoclonal antibodies. At the present time, tumor sites in the range of 1.5 to 2.0 cm can be imaged, with the best resolution of 0.4-0.5 cm being reported with new chelates of Tc. A number of factors, including character of the radioantibody and its bioavailability, the tumor antigen site and bioavailability, the character of the radiolabel, and the target tumor's size, location and vascularization, contribute to the sensitivity, specificity, accuracy, and resolution of the method. Already at this early stage of development, RAID has been shown to have, in certain tumor types and with particular antibody and imaging systems, an accuracy of tumor site detection of over 90%, with the disclosure of occult lesions. Carefully designed prospective trials are needed to fully assess the role of this new modality in the management of cancer patients, particularly in early detection of primary and recurrent tumors. [ABSTRACT FROM AUTHOR]

The localization of a radiolabeled murine monoclonal antibody reactive with choriocarcinomas to human choriocarcinoma xenografts following intravenous and subcutaneous injection was evaluated by gamma scanning and tissue sampling. Tumor xenografts were established in the popliteal node region of athymic nude mice after repeated innoculations of the hind foot pads with BEWO choriocarcinoma cells. In dual label specific antibody studies, tumor/non tumor uptake ratios following subcutaneous (resulting in considerable intralymphatic uptake) injection of I-5F9.3 were significantly higher than those achieved post simultaneous intravenous injection of I-5F9.3. Double label experiments with I-5F9.3 and a nonspecific antibody, I-UPC-10, following subcutaneous injection, demonstrated that the high localization to popliteal region tumors was largely due to antibody specificity. Gamma scans following subcutaneous antibody administration of specific antibody to tumor bearing animals showed tumors soon after subcutaneous injection, at times earlier than those typically seen following intravenous delivery. Similar subcutaneous injections showed little normal nodal uptake in BALB/c control animals on gamma scans. No correlation was seen between tumor localization by specific antibody between the intravenous and intralymphatic routes, implying a difference in the mechanisms of tumor uptake of antibody by these two routes. The subcutaneous approach to antibody delivery offers advantages over intravenous delivery in tumors of human origin, including higher tumor/non tumor ratios and earlier imaging times. This was true even though these tumors were many times larger than normal lymph nodes. This subcutaneous delivery advantage should be exploitable in imaging nodal metastases of human tumors. [ABSTRACT FROM AUTHOR]

LL2 is an anti-CD22 pan-B-cell monoclonal antibody which, when radiolabeled, has a high sensitivity for detecting B-cell, non-Hodgkin’s lymphoma (NHL), as well as an antitumor efficacy in therapeutic applications. The aim of this study was to determine whether intracellularly retained radiolabels have an advantage in the diagnosis and therapy of lymphoma with LL2. In vitro studies showed that iodinated LL2 is intracellularly catabolized, with a rapid release of the radioiodine from the cell. In contrast, residualizing radiolabels, such as radioactive metals, are retained intracellularly for substantially longer. In vivo studies were performed using LL2-labeled with radioiodine by a non-residualizing (chloramine-T) or a residualizing method (dilactitol-tyramine, DLT), or with a radioactive metal (111In). The biodistribution of a mixture of 125I (non-residualizing chloramine-T compared to residualizing DLT), 111In-labeled LL2 murine IgG2a or its fragments [F(ab′)2, Fab′], as well as its humanized, CDR-grafted form, was studied in nude mice bearing the RL human B-cell NHL cell line. Radiation doses were calculated from the biodistribution data according to the Medical International Radiation Dose scheme to assess the potential advantage for therapeutic applications. At all assay times, tumor uptake was higher with the residualizing labels (i.e., 111In and DLT-125I) than with the non-residualizing iodine label. For example, tumor/blood ratios of 111In-labeled IgG were 3.2-, 3.5- and 2.8-fold higher than for non-residualizing iodinated IgG on days 3, 7 and 14, respectively. Similar results were obtained for DLT-labeled IgG and fragments with residualized radiolabels. Tumor/organ ratios also were higher with residualizing labels. No significant differences in tumor, blood and organ uptake were observed between murine and humanized LL2. The conventionally iodinated anti-CD20 antibody, 1F5, had tumor uptake values comparable to those of iodinated LL2, the uptake of both antibodies being strongly dependent on tumor size. These data suggest that, with internalizing antibodies such as LL2, labeling with intracellularly retained isotopes has an advantage over released ones, which justifies further clinical trials with residualizing 111In-labeled LL2 for diagnosis, and residualizing 131I and 90Y labels for therapy. [ABSTRACT FROM AUTHOR]

The monoclonal antibody (MoAb) KIS1 has been shown to react specifically with an antigen of human squamous cell carcinoma (SCC); however, a major problem in its clinical application is that the intact murine antibody induces a human anti-mouse antibody (HAMA). To overcome this problem, we produced the KIS1 F(ab')2 fragment, then radioiodinated the intact KIS1 antibody and its F(ab')2 fragment. Nude mice bearing human esophageal SCC implants were injected with 100μCi of131I-intact, KIS1 or131I-KIS1 F(ab')2, and images were obtained using a gamma camera. Radioimmunotherapy (RIT) was performed by injecting the tumor-bearing nude mice with131I-intact KIS1 or131I-KIS1 F(ab')2 at a dosage of 300μCi, following which 7 or 3 days were required to produce high quality tumor images by scintigraphy. The tumor-bearing mice treated with131I-KIS1 F(ab')2 showed significant tumor growth inhibition, about 5.4 times greater than that of the control group and 1.8 times greater than that of the131I-intact KIS1 group 21 days after the injection. These results indicate that the KIS1 F(ab')2 fragment is superior to intact KIS1, and that it may be clinically useful for radioimmunodetection followed by tumor targeting therapy for patients with SCC of the esophagus. [ABSTRACT FROM AUTHOR]

In 12 consecutive patients with suspected metastatic carcinoma of the liver, we evaluated the sensitivity of radiolabeled antibodies to tumor antigens, magnetic resonance imaging, and X-ray computed tomography imaging in the detection of hepatic malignancies. Studies were performed with I labeled antibodies to CEA and/or CSAp; polyclonal, monoclonal and F(ab′) antibodies were used. Nontarget radioactivity was diminished by administration of Tc reagents simulating nontumor distribution and use of a computer substraction method. In nine patients with confirmed liver neoplasms, radioimunodetection disclosed the foci of hepatic malignancies. In three patients with suspected liver neoplasms, the antibody studies were positive, but at this time have not been confirmed. X-ray computed tomography each disclosed mass lesions in five patients and magnetic resonance in three. These findings suggest that radioimmunodetection provides greater accuracy in the detection and localization of cancer than other diagnostic modalities currently used. [ABSTRACT FROM AUTHOR]

The biodistribution of a radiolabelled monoclonal antibody (I-NDOG) was studied in patients with ovarian tumour. It was found that the uptake patterns in known tumour sites was variable and that the clearance of the agent from the vascular pool was due to renal excretion of the radionuclide and the redistribution of the radioactively labelled compound into other compartments. The mean (±SD) plasma clearance time was 20.8 (±2.3) h and the ratios of target (tumour) to background (thigh) ranged between 1.4 and 4.8. The ratio between the plasma radioactivity at either 3.5 or 20 h after administration was calculated relative to the initial plasma radioactivity. These values (0.79 and 0.48, respectively) were incorporated into an image-subtraction technique that allowed for redistribution outside the vascular pool. A whole-body dose equivalent to 16.3 μSv MBq (60.4 mrem.mCi) was calculated. [ABSTRACT FROM AUTHOR]

Conjugates of the chelating agents DTPA and TTHA with a monoclonal anti-HCG were prepared. The tissue distribution of the In-labelled conjugates and also In-citrate was studied in mice bearing human choriocarcinoma xenografts. The antibody conjugates both gave high liver and spleen radionuclide accumulation. Elevated femur levels were observed for the TTHA conjugate and In-citrate. Generally the DTPA conjugate showed the highest tumor/tissue ratios, although its tumor/blood ratio was lower than the other two materials. The results infer that the DTPA conjugate has the greatest utility as an imaging agent but that it would require a background subtraction technique. [ABSTRACT FROM AUTHOR]