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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]

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.

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]

ObjectiveLabeled oxidation-specific antibodies (Ox-AB) detect, quantify, and noninvasively image lipid-rich atherosclerotic lesions. However, it is unknown whether Ox-AB detect plaque stabilization.Methods and resultsThe aortic uptake of intravenously injected 125I-MDA2 (Ox-AB to malondialdehyde [MDA]-low-density lipoprotein [LDL]) was quantitated in: (1) LDL receptor-/- mice with established atherosclerosis continued on Western diet (Progression) or switched to chow (Regression) or chow+vitamins E and C (Regression-VIT) for 6 months; and (2) Watanabe rabbits (3- to 57-months old) with naturally evolved atherosclerotic lesions. In mice, the Progression group had more extensive atherosclerosis, higher 125I-MDA2 uptake, high concordance of Sudan (lipid)-staining and 125I-MDA2 uptake, and stronger oxidized LDL (OxLDL) and macrophage immunostaining than both Regression groups. In contrast, the Regression groups showed Sudan-positive lesions with focally diminished 125I-MDA2 uptake, which coincided with reduced OxLDL and macrophages but more smooth muscle cells (SMCs) and collagen. In rabbits, areas of increased 125I-MDA2 uptake were associated with high Sudan concordance and strong immunostaining for OxLDL and macrophages. Interestingly, advanced lesions with focally diminished 125I-MDA2 uptake showed stronger immunostaining for SMCs and collagen, particularly at the fibrous cap.ConclusionsOx-AB uptake is focally diminished in plaques displaying accepted features of plaque stability. Imaging techniques to detect the presence and depletion of OxLDL may be useful in assessing plaque stabilization.

One of the main challenges of PET imaging with 89 Zr-labeled monoclonal antibodies (mAbs) remains the long blood circulation of the radiolabeled mAbs, leading to high background signals, decreasing image quality. To overcome this limitation, here we report the use of a bioorthogonal linker cleavage approach (click-to-release chemistry) to selectively liberate [ 89 Zr]Zr-DFO from trans -cyclooctene-functionalized trastuzumab (TCO-Tmab) in blood, following the administration of a tetrazine compound (trigger) in BT-474 tumor-bearing mice. Methods: We created a series of TCO-DFO constructs and evaluated their performance in [ 89 Zr]Zr-DFO release from Tmab in vitro using different trigger compounds. The in vivo behavior of the best performing [ 89 Zr]Zr-TCO-Tmab was studied in healthy mice first to determine the optimal dose of the trigger. To find the optimal time for the trigger administration, the rate of [ 89 Zr]Zr-TCO-Tmab internalization was studied in BT-474 cancer cells. Finally, the trigger was administered 6 h or 24 h after [ 89 Zr]Zr-TCO-Tmab- administration in tumor-bearing mice to liberate the [ 89 Zr]Zr-DFO fragment. PET scans were obtained of tumor-bearing mice that received the trigger 6 h post-[ 89 Zr]Zr-TCO-Tmab administration. Results: The [ 89 Zr]Zr-TCO-Tmab and trigger pair with the best in vivo properties exhibited 83% release in 50% mouse plasma. In tumor-bearing mice the tumor-blood ratios were markedly increased from 1.0 ± 0.4 to 2.3 ± 0.6 (p = 0.0057) and from 2.5 ± 0.7 to 6.6 ± 0.9 (p < 0.0001) when the trigger was administered at 6 h and 24 h post-mAb, respectively. Same day PET imaging clearly showed uptake in the tumor combined with a strongly reduced background due to the fast clearance of the released [ 89 Zr]Zr-DFO-containing fragment from the circulation through the kidneys. Conclusions: This is the first demonstration of the use of trans -cyclooctene-tetrazine click-to-release chemistry to release a radioactive chelator from a mAb in mice to increase tumor-to-blood ratios. Our results suggest that click-cleavable radioimmunoimaging may allow for substantially shorter intervals in PET imaging with full mAbs, reducing radiation doses and potentially even enabling same day imaging., Competing Interests: Competing Interests: Maria Vlastara, Raffaella Rossin, Kim de Roode, Laurens Kleijn, and Marc Robillard are employees and/or shareholders of Tagworks. The other authors have no competing interests to declare., (© The author(s).)

In this study we wanted to present a case with the history of multiple previous neck explorations and persisting upper mediastinal ectopic parathyroid adenoma who underwent a successful operation with radioguided minimal invasive approach. [ABSTRACT FROM AUTHOR]

Radiolabeled antibody treatment with 131 I-omburtamab, administered intraventricularly into the cerebrospinal fluid (CSF) space, can deliver therapeutic absorbed doses to sites of leptomeningeal disease. Assessment of distribution and radiation dosimetry is a key element in optimizing such treatments. Using a theranostic approach, we performed pretreatment 131 I-omburtamab imaging and dosimetric analysis in patients before therapy. Methods: Whole-body planar images were acquired 3 ± 1, 23 ± 2, and 47 ± 2 h after intracranioventricular administration of 75 ± 5 MBq of 131 I-omburtamab via an Ommaya reservoir. Multiple blood samples were also obtained for kinetic analysis. Separate regions of interest (ROIs) were manually drawn to include the lateral ventricles, entire spinal canal CSF space, and over the whole body. Count data in the ROIs were corrected for background and physical decay, converted to activity, and subsequently fitted to an exponential clearance function. The radiation absorbed dose was estimated to the CSF, separately to the spinal column and ventricles, and to the whole body and blood. Biodistribution of the injected radiolabeled antibody was assessed for all patients. Results: Ninety-five patients were included in the analysis. Biodistribution showed prompt localization in the ventricles and spinal CSF space with low systemic distribution, noted primarily as hepatic, renal, and bladder activity after the first day. Using ROI analysis, the effective half-lives were 13 ± 11 h (range, 5-75 h) for CSF in the spinal column, 8 ± 3 h (range, 3-17 h) for ventricles, and 41 ± 11 (range, 23-81 h) for the whole body. Mean absorbed doses were 0.63 ± 0.38 cGy/MBq (range, 0.24-2.25 cGy/MBq) for CSF in the spinal column, 1.03 ± 0.69 cGy/MBq (range, 0.27-5.15 cGy/MBq) for the ventricular CSF, and 0.45 ± 0.32 mGy/MBq (range, 0.05-1.43 mGy/MBq) for the whole body. Conclusion: Pretherapeutic imaging with 131 I-omburtamab allows assessment of biodistribution and dosimetry before the administration of therapeutic activity. Absorbed doses to the CSF compartments and whole body derived from the widely applicable serial 131 I-omburtamab planar images had acceptable agreement with previously reported data determined from serial 124 I-omburtamab PET scans., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

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]

Se presenta un estudio experimental que tiene por objetivo evaluar la sensibilidad y especificidad de la detección de solución de continuidad del tracto gastrointestinal con la utilización de partículas pesadas marcadas con Tecnecio 99. Se diseñó un estudio experimental prospectivo triple ciego, con un cálculo de tamaño de muestra teniendo en cuenta una sensibilidad y especificidad superiores al 95%, con un error alfa del 0.05 y una precisión de 0.05. Inicialmente se evaluaron 4 conejos de la raza Nueva Zelanda para determinar: el anestésico y la dosis a utilizar, la capacidad del estómago en mililitros; los tiempos promedios de tránsito gastrointestinal, la capacidad de la cavidad abdominal en mililitros y la biodistribución del radiofármaco (absorción gastrointestinal, diseminación y distribución hemática y eliminación renal). Se utilizaron 40 conejos de la raza Nueva Zelanda y se analizaron en tres estaciones de trabajo independientes, asignando aleatoriamente 20 conejos en cada grupo de estudio (perforados y no perforados). El radiofármaco utilizado fue Tecnecio 99 sulfuro coloidal > 100 nm, 2.5 mCi a 140 -Kev de energía preparado en una dilución de solución salina al 0.9% quedando una concentración de 0.0025 mCi por mililitro. El rastreo se realizó con una sonda gamma a 10X. El análisis estadístico se realizó con el programa Episet V:1 aplicando la prueba de Chi Cuadrado. Todos los 20 conejos que tenían disrupción del estómago, presentaron una prueba positiva para detección de radioactividad en el líquido peritoneal analizado con un valor promedio de 467 y un rango de 37 a 1748. En los 20 conejos restantes que no tenían perforación de la pared gástrica la prueba fue negativa. La sensibilidad de la metodología diagnóstica fue de 0.98 y la especificidad de 0.98 con un intervalo de confianza de 0.92-1.0. El análisis comparativo del líquido peritoneal con la sonda Gamma en los grupos dio un valor de Chi Cuadrado de 37 con una p This study had the purpose of evaluating the sensibility and specificity of the radiommunoguided-detection of perforations of the gastrointestinal tract utilizing Tenecium 99. The design was a prospective, experimental triple blinded study, with an estimation of the size of the sample considering a 95% sensitivity and specificity, an alpha error of 0.05, and a precision of 0.05. There was an initial evaluation in four New Zealand rabbits in order to determine: type of anesthesia and doses, capacity of the stomach (ml), average time interval of intestinal transit, abdominal cavity capacity (ml) and the distribution of the radio material (intestinal absorption, blood dissemination and distribution, and renal excretion). Forty New Zealand rabbits were utilized for analysis in three independent work stations, randomizing 20 rabbits to each study group (perforated and nonperforated). The radio material was colloidal sulphur labeled with Tecnecium 99, >100 nm, 2.5 mCi, a 140 Kev energy prepared in 0.9% saline solution, which provided a concentration of 0.0025 mCi per ml. Scan was done with gamma 10X probe. Statistical analysis was done with the Episet V:1 and the chi square test. All rabbits with disruption of the stomach exhibited positive radiaton activity in the peritoneal fluid, analyzing an average value of 467 and a rank of 37 to 1748. In the remaining rabbits with no perforation of the gastric wall the scan was negative. The sensitivity of this diagnostic method was 0.98 and the specificity 0.98, with a confidence interval of 0.92-1.0. Comparative gamma probe analysis of the peritoneal fluid in the two groups gave 37 chi square with a p

Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions.

IntroducTION The availability of monoclonal antibodies in Cuba has facilitated development and application of innovative techniques (immunoscintigraphy and radioimmunotherapy) for cancer diagnosis and treatment. Objective Review immunoscintigraphy and radioimmunotherapy techniques and analyze their use in Cuba, based on the published literature. In this context, we describe the experience of Havana’s Clinical Research Center with labeled monoclonal antibodies for cancer diagnosis and treatment during the period 1993-2013. evidence ACQUISITION Basic concepts concerning cancer and monoclonal antibodies were reviewed, as well as relevant international and Cuban data. Forty-nine documents were reviewed, among them 2 textbooks, 34 articles by Cuban authors and 13 by international authors. All works published by the Clinical Research Center from 1993 through 2013 were included. Bibliography was obtained from the library of the Clinical Research Center and Infomed, Cuba’s national health telematics network, using the following keywords: monoclonal antibodies, immunoscintigraphy and radioimmunotherapy. Results Labeling the antibodies (ior t3, ior t1, ior cea 1, ior egf/ r3, ior c5, h-R3, 14F7 and rituximab) with radioactive isotopes was a basic line of research in Cuba and has fostered their use as diagnostic and therapeutic tools. The studies conducted demonstrated the good sensitivity and diagnostic precision of immunoscintigraphy for detecting various types of tumors (head and neck, ovarian, colon, breast, lymphoma, brain). Obtaining different radioimmune conjugates with radioactive isotopes such as 99mTc and 188Re made it possible to administer radioimmunotherapy to patients with several types of cancer (brain, lymphoma, breast). The objective of 60% of the clinical trials was to determine pharmacokinetics, internal dosimetry and adverse effects of monoclonal antibodies, as well as tumor response; there were few adverse effects, no damage to vital organs, and a positive tumor response in a substantial percentage of patients. Conclusions Cuba has experience with production and radiolabeling of monoclonal antibodies, which facilitates use of these agents. Studies in Cuba conducted by the Clinical Research Center over the past 20 years have yielded satisfactory results. Evidence obtained suggests promising potential of monoclonal antibodies and nuclear medicine, with immunoscintigraphy and radioimmunotherapy techniques providing alternatives for cancer diagnosis and treatment in Cuba. [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]

Abstract: Objectives: In tumors, hypoxia stimulates angiogenesis and correlates with treatment resistance and poor prognosis. We have previously demonstrated hypoxia in human renal cell carcinoma (RCC) via direct oxygen probe measurements. Carbonic anhydrase IX (CA IX) is a protein stimulated by hypoxia and involved in angiogenesis, and is a potential tumor target for imaging and therapies using cG250, a monoclonal antibody that recognizes CAIX. Our objectives were to characterize intratumoral hypoxia in a human RCC xenograft model using oxygen probe measurements; investigate if 124I-cG250 targets RCC correlating uptake on noninvasive positron emission tomography-computerized tomography (PET-CT) against traditional biodistribution studies, and investigate CAIX expression in this RCC model. Methods: BALB/c nude mice had human RCC (SK-RC-52) subcutaneously xenografted with oxygen levels measured by probe. Positron emission tomography (PET/CT) and biodistribution studies (124I-cG250) were correlated with oxygen measurements. Immunohistochemistry and autoradiography were performed on selected tumors to confirm CAIX expression Results: Oxygen tension in normal tissue (muscle) was 35.08 ± 2.41 mmHg (mean ± 95% CI), significantly greater compared to xenograft SK-RC-52 tumors at 5.02 ± 1.12 mmHg. Biodistribution studies of 124I-cG250 demonstrated isotope uptake in SK-RC-52 xenografts peaking at 23.45 ± 5.07% ID/g (mean ± SD) 48 hours after antibody injection, which was maintained for a further 2 days (19.43 ± 4.31 and 10.64 ± 5.64 % ID/g, respectively). PET studies demonstrated excellent localization of 124I-cG250 in tumor, and a significant correlation between SUVmean, SUVmax, and %/ID 124I-cG250. CAIX expression was present in all groups studied but there was no significant correlation between it and any oxygen parameter studied. Conclusion: Intratumoral hypoxia does exist within a human RCC xenograft model using invasive oxygen probe measurements. 124I-cG250 targets RCC with correlation between uptake on noninvasive PET-CT studies and traditional biodistribution studies opening the possibility of using PET/CT in future studies. Finally, CAIX expression was not related to hypoxia in this model, supporting the hypothesis that cell lines may subvert known hypoxia mechanisms in hypoxic environments. [Copyright &y& Elsevier]

Abstract: Detection of antigen 14C5, involved in substrate adhesion and highly expressed on the membrane of many carcinomas, including lung cancer, provides important diagnostic information that can influence patient management. The aim of this study was to evaluate the biodistribution and planar gamma camera imaging characteristics of radioiodinated F(ab′)2 and Fab fragments of monoclonal antibody (mAb) 14C5 in tumor-bearing mice. Methods: F(ab′)2 and Fab 14C5 fragments were radioiodinated using the Iodo-Gen method. In vitro stability, binding specificity and affinity of 125I-labeled 14C5 fragments were studied in A549 lung carcinoma cells. Biodistribution, blood clearance and tumor-targeting characteristics of 131I-labeled 14C5 fragments and intact mAb 14C5 were studied in Swiss nu/nu mice bearing A549 lung carcinoma tumors. Planar gamma imaging illustrated the potential use of these 123I-labeled 14C5 fragments for radioimmunodetection (RID). Results: Saturation binding experiments showed highest affinity for 125I-labeled F(ab′)2 fragments (K d=0.37±0.10 nmol/L) and lowest affinity for 125I-labeled Fab fragments (K d=2.25±0.44 nmol/L). Blood clearance studies showed that the alpha half-life (t½α) value for Fab, F(ab′)2 and mAb 14C5 was 14.9, 21 and 118 min, respectively. The beta half-life t½β value for Fab, F(ab′)2 and mAb 14C5 was 439, 627 and 4067 min, respectively. 131I-Fab fragments showed highest tumor uptake 3 h after injection (2.4±0.8 %ID/g), 131I-labeled F(ab′)2 showed highest tumor uptake 6 h after injection (4.7±0.7 %ID/g) and for 131I-labeled mAb highest tumor uptake was observed at 24 h (10.7±2.3 %ID/g). In planar gamma imaging, both labeled fragments gave better tumor-to-background contrast than 123I-mAb 14C5. Conclusion: Fab and F(ab′)2 fragments derived from intact mAb 14C5 have significant potential for diagnostic and therapeutic applications and may provide new tools in mAb-based radiopharmaceuticals for targeting non-small cell lung cancer. [Copyright &y& Elsevier]

Abstract: This article reviews recent preclinical and clinical advances in the use of pretargeting methods for the radioimmunodetection and radioimmunotherapy of cancer. Whereas directly labeled antibodies, fragments, and subfragments (minibodies and other constructs) have shown promise in both imaging and therapy applications over the past 25 years, their clinical adoption has not fulfilled the original expectations due to either poor image resolution and contrast in scanning or insufficient radiation doses delivered selectively to tumors for therapy. Pretargeting involves the separation of the localization of tumor with an anticancer antibody from the subsequent delivery of the imaging or therapeutic radionuclide. This has shown improvements in both imaging and therapy by overcoming the limitations of conventional, or one-step, radioimmunodetection or radioimmunotherapy. We focus herein on the use of bispecific antibodies followed by radiolabeled peptide haptens as a new modality of selective delivery of radionuclides for the imaging and therapy of cancer. Our particular emphasis in pretargeting is the use of bispecific trimeric (three Fab′s) recombinant constructs made by a modular method of antibody and protein engineering of fusion molecules called dock and lock (DNL). [Copyright &y& Elsevier]

Molecular imaging comprises a series of diagnostic modalities that provide information on the physiology and molecular composition of cells and tissues. One of these modalities, radioimmunodetection, uses radiolabeled monoclonal antibodies (mAbs) to image tissues. Two radioimmunodetection modalities are described in this article: immunoscintigraphy and radioimmunoguided surgery (RIGS). In immunoscintigraphy, the radioactivity is measured with the use of an external gamma camera and used to create images. In RIGS, the radioactivity is detected intraoperatively with the use of a handheld gamma probe to help the surgeon detect foci of otherwise occult disease. Both techniques have the potential to improve the preoperative and intraoperative localization of cancer. Multiple studies have been performed on the efficacy of RIGS on different malignancies, especially colorectal cancer. Despite the good sensitivity of the technique, some concerns revolve around the high rate of false positives and the real significance of leaving RIGS-positive tissue behind in terms of long-term outcomes and survival. More studies are warranted to further develop the technique and determine the specific role it will play on the diagnosis and management of surgical disease. Surgeons should actively participate in these studies and in expanding the applications of this promising technology. [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]