Mattias Sandström
Uppsala University
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Featured researches published by Mattias Sandström.
The Journal of Nuclear Medicine | 2014
Jens Nørkær Sørensen; Dan Sandberg; Mattias Sandström; Anders Wennborg; Joachim Feldwisch; Vladimir Tolmachev; Gunnar Åström; Mark Lubberink; Ulrike Garske-Román; Henrik Lindman
The expression status of human epidermal growth factor receptor type 2 (HER2) predicts the response of HER2-targeted therapy in breast cancer. ABY-025 is a small reengineered Affibody molecule targeting a unique epitope of the HER2 receptor, not occupied by current therapeutic agents. This study evaluated the distribution, safety, dosimetry, and efficacy of 111In-ABY-025 for determining the HER2 status in metastatic breast cancer. Methods: Seven patients with metastatic breast cancer and HER2-positive (n = 5) or -negative (n = 2) primary tumors received an intravenous injection of approximately 100 μg (∼140 MBq) of 111In-ABY-025. Planar γ-camera imaging was performed after 30 min, followed by SPECT/CT after 4, 24, and 48 h. Blood levels of radioactivity, antibodies, shed serum HER2, and toxicity markers were evaluated. Lesional HER2 status was verified by biopsies. The metastases were located by 18F-FDG PET/CT 5 d before 111In-ABY-025 imaging. Results: Injection of 111In-ABY-025 yielded a mean effective dose of 0.15 mSv/MBq and was safe, well tolerated, and without drug-related adverse events. Fast blood clearance allowed high-contrast HER2 images within 4–24 h. No anti–ABY-025 antibodies were observed. When metastatic uptake at 24 h was normalized to uptake at 4 h, the ratio increased in HER2-positive metastases and decreased in negative ones (P < 0.05), with no overlap and confirmation by biopsies. In 1 patient, with HER2-positive primary tumor, 111In-ABY-025 imaging correctly suggested a HER2-negative status of the metastases. The highest normal-tissue uptake was in the kidneys, followed by the liver and spleen. Conclusion: 111In-ABY-025 appears safe for use in humans and is a promising noninvasive tool for discriminating HER2 status in metastatic breast cancer, regardless of ongoing HER2-targeted antibody treatment.
European Journal of Nuclear Medicine and Molecular Imaging | 2010
Vladimir Tolmachev; Daniel Rosik; Helena Wållberg; Anna Sjöberg; Mattias Sandström; Monika Hansson; Anders Wennborg; Anna Orlova
IntroductionOverexpression of epidermal growth factor receptor (EGFR) is a prognostic and predictive biomarker in a number of malignant tumours. Radionuclide molecular imaging of EGFR expression in cancer could influence patient management. However, EGFR expression in normal tissues might complicate in vivo imaging. The aim of this study was to evaluate if optimization of the injected protein dose might improve imaging of EGFR expression in tumours using a novel EGFR-targeting protein, the DOTA-ZEGFR:2377 Affibody molecule.MethodsAn anti-EGFR Affibody molecule, ZEGFR:2377, was labelled with 111In via the DOTA chelator site-specifically conjugated to a C-terminal cysteine. The affinity of DOTA-ZEGFR:2377 for murine and human EGFR was measured by surface plasmon resonance. The cellular processing of 111In-DOTA-ZEGFR:2377 was evaluated in vitro. The biodistribution of radiolabelled Affibody molecules injected in a broad range of injected Affibody protein doses was evaluated in mice bearing EGFR-expressing A431 xenografts.ResultsSite-specific coupling of DOTA provided a uniform conjugate possessing equal affinity for human and murine EGFR. The internalization of 111In-DOTA-ZEGFR:2377 by A431 cells was slow. In vivo, the conjugate accumulated specifically in xenografts and in EGFR-expressing tissues. The curve representing the dependence of tumour uptake on the injected Affibody protein dose was bell-shaped. The highest specific radioactivity (lowest injected protein dose) provided a suboptimal tumour-to-blood ratio. The results of the biodistribution study were confirmed by γ-camera imaging.ConclusionThe 111In-DOTA-ZEGFR:2377 Affibody molecule is a promising tracer for radionuclide molecular imaging of EGFR expression in malignant tumours. Careful optimization of protein dose is required for high-contrast imaging of EGFR expression in vivo.
Bioconjugate Chemistry | 2008
Sara Ahlgren; Anna Orlova; Daniel Rosik; Mattias Sandström; Anna Sjöberg; Barbro Baastrup; Olof Widmark; Gunilla Fant; Joachim Feldwisch; Vladimir Tolmachev
Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i.
The Journal of Nuclear Medicine | 2009
Vladimir Tolmachev; Mikaela Friedman; Mattias Sandström; Tove L.J. Eriksson; Daniel Rosik; Monika Hodik; Stefan Ståhl; Fredrik Y. Frejd; Anna Orlova
Noninvasive detection of epidermal growth factor receptor (EGFR) expression in malignant tumors by radionuclide molecular imaging may provide diagnostic information influencing patient management. The aim of this study was to evaluate a novel EGFR-targeting protein, the ZEGFR:1907 Affibody molecule, for radionuclide imaging of EGFR expression, to determine a suitable tracer format (dimer or monomer) and optimal label. Methods: An EGFR-specific Affibody molecule, ZEGFR:1907, and its dimeric form, (ZEGFR:1907)2, were labeled with 111In using benzyl-diethylenetriaminepentaacetic acid and with 125I using p-iodobenzoate. Affinity and cellular retention of conjugates were evaluated in vitro. Biodistribution of radiolabeled Affibody molecules was compared in mice bearing EGFR-expressing A431 xenografts. Specificity of EGFR targeting was confirmed by comparison with biodistribution of non–EGFR-specific counterparts. Results: Head-to-tail dimerization of the Affibody molecule improved the dissociation rate. In vitro, dimeric forms demonstrated superior cellular retention of radioactivity. For both molecular set-ups, retention was better for the 111In-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFR-expressing tissues. The retention of radioactivity in tumors was better in vivo for dimeric forms; however, the absolute uptake values were higher for monomeric tracers. The best tracer, 111In-labeled ZEGFR:1907, provided a tumor-to-blood ratio of 100 (24 h after injection). Conclusion: The radiometal-labeled monomeric Affibody molecule ZEGFR:1907 has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.
The Journal of Nuclear Medicine | 2013
Mattias Sandström; Ulrike Garske-Roman; Dan Granberg; Silvia Johansson; Charles Widström; Barbro Eriksson; Anders Sundin; Hans Lundqvist; Mark Lubberink
The organs at risk in radionuclide therapy with 177Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys. Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of 177Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT. Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of 177Lu-octreotate could be administered before the upper dose limit for the individual patient was reached. Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of 177Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.
Journal of Applied Physiology | 2012
João Batista Borges; Fernando Suarez-Sipmann; Stephan H. Bohm; Gerardo Tusman; Alexandre Melo; Enn Maripuu; Mattias Sandström; Marcelo Park; Eduardo Leite Vieira Costa; Göran Hedenstierna; Marcelo B. P. Amato
The assessment of the regional match between alveolar ventilation and perfusion in critically ill patients requires simultaneous measurements of both parameters. Ideally, assessment of lung perfusion should be performed in real-time with an imaging technology that provides, through fast acquisition of sequential images, information about the regional dynamics or regional kinetics of an appropriate tracer. We present a novel electrical impedance tomography (EIT)-based method that quantitatively estimates regional lung perfusion based on first-pass kinetics of a bolus of hypertonic saline contrast. Pulmonary blood flow was measured in six piglets during control and unilateral or bilateral lung collapse conditions. The first-pass kinetics method showed good agreement with the estimates obtained by single-photon-emission computerized tomography (SPECT). The mean difference (SPECT minus EIT) between fractional blood flow to lung areas suffering atelectasis was -0.6%, with a SD of 2.9%. This method outperformed the estimates of lung perfusion based on impedance pulsatility. In conclusion, we describe a novel method based on EIT for estimating regional lung perfusion at the bedside. In both healthy and injured lung conditions, the distribution of pulmonary blood flow as assessed by EIT agreed well with the one obtained by SPECT. The method proposed in this study has the potential to contribute to a better understanding of the behavior of regional perfusion under different lung and therapeutic conditions.
The Journal of Nuclear Medicine | 2010
Sara Ahlgren; Anna Orlova; Helena Wållberg; Monika Hansson; Mattias Sandström; Richard Lewsley; Anders Wennborg; Lars Abrahmsén; Vladimir Tolmachev; Joachim Feldwisch
Overexpression of the human epidermal growth factor receptor type 2 (HER2) in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a nonimmunoglobulin scaffold have demonstrated a high potential for in vivo molecular imaging of HER2-expressing tumors. The reengineering of the molecular scaffold has led to a second generation of optimized Affibody molecules that have a surface distinctly different from the parental protein domain from staphylococcal protein A. Compared with the parental molecule, the new tracer showed a further increased melting point, stability, and overall hydrophilicity and was more amenable to chemical peptide synthesis. The goal of this study was to assess the potential effects of this extensive reengineering on HER2 targeting, using ABY-025, a DOTA-conjugated variant of the novel tracer. Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, rats, and cynomolgus macaques (Macaca fascicularis). Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats, and macaques. A highly specific tumor uptake of 16.7 ± 2.5 percentage injected activity per gram of tissue was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h and 88 at 4 h and increased up to 3 d after injection. γ-camera imaging of tumors was already possible at 0.5 h after injection. Furthermore, the repeated intravenous administration of ABY-025 did not induce antibody formation in rats. Conclusion: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound reengineering of the nonbinding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor-bearing mice, leading to high tumor-to-organ-ratios and high-contrast imaging shortly after injection.
The Journal of Nuclear Medicine | 2014
Irina Velikyan; Anders Sundin; Jens Nørkær Sørensen; Mark Lubberink; Mattias Sandström; Ulrike Garske-Román; Hans Lundqvist; Dan Granberg; Barbro Eriksson
Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). 177Lu-DOTATATE and 68Ga-DOTATOC/68Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of 68Ga-DOTATOC and 68Ga-DOTATATE in the context of subsequent PRRT with 177Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression. Methods: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (Ki) was calculated according to the Patlak method for 3 tumors per patient. Results: There were no significant differences in lesion count, lesion SUV, Ki, functional tumor volume, or SSTR volume between 68Ga-DOTATOC and 68Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of 68Ga-DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. 68Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P = 0.018). The tumor-to-liver ratio was marginally higher for 68Ga-DOTATOC at the 3-h time point (P = 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with Ki linearly and achieved saturation for a Ki of greater than 0.2 mL/cm3/min, corresponding to an SUV of more than 25. Conclusion: 68Ga-DOTATOC and 68Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with 177Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render 68Ga-DOTATATE preferable. SUV did not correlate linearly with Ki and thus may not reflect the SSTR density accurately at its higher values, whereas Ki might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome.
Bioconjugate Chemistry | 2010
Vladimir Tolmachev; Camilla Hofström; Jennie Malmberg; Sara Ahlgren; Seyed Jalal Hosseinimehr; Mattias Sandström; Lars Abrahmsén; Anna Orlova; Torbjörn Gräslund
Affibody molecules are a class of small (ca. 7 kDa) robust scaffold proteins suitable for radionuclide molecular imaging of therapeutic targets in vivo. A hexahistidine tag at the N-terminus streamlines development of new imaging probes by enabling facile purification using immobilized metal ion affinity chromatography (IMAC), as well as convenient [⁹⁹(m)Tc(CO)₃](+)-labeling. However, previous studies in mice have demonstrated that Affibody molecules labeled by this method yield higher liver accumulation of radioactivity, compared to the same tracer lacking the hexahistidine tag and labeled by an alternative method. Two variants of the HER2-binding Affibody molecule Z(HER)₂(:)₃₄₂ were made in an attempt to create a tagged tracer that could be purified by immobilized metal affinity chromatography, yet would not result in anomalous hepatic radioactivity accumulation following labeling with [⁹⁹(m)Tc(CO)₃](+). In one construct, the hexahistidine tag was moved to the C-terminus. In the other construct, every second histidine residue in the hexahistidine tag was replaced by the more hydrophilic glutamate, resulting in a HEHEHE-tag. Both variants, denoted Z(HER)₂(:)₃₄₂-H₆ and (HE)₃-Z(HER)₂(:)₃₄₂, respectively, could be efficiently purified using IMAC and stably labeled with [⁹⁹(m)Tc(CO)₃](+) and were subsequently compared with the parental H₆-Z(HER)₂(:)₃₄₂ having an N-terminal hexahistidine tag. All three variants were demonstrated to specifically bind to HER2-expressing cells in vitro. The hepatic accumulation of radioactivity in a murine model was 2-fold lower with [⁹⁹(m)Tc(CO)₃](+)-Z(HER2:342)-H₆ compared to [⁹⁹(m)Tc(CO)₃](+)-H₆-Z(HER)₂(:)₃₄₂, and more than 10-fold lower with [⁹⁹(m)Tc(CO)₃](+)-(HE)₃-Z(HER)₂(:)₃₄₂. These differences translated into appreciably superior tumor-to-liver ratio for [⁹⁹(m)Tc(CO)₃](+)-(HE)₃-Z(HER)₂(:)₃₄₂ compared to the alternative conjugates. This information might be useful for development of other scaffold-based molecular imaging probes.
Theranostics | 2016
Jens Nørkær Sørensen; Irina Velikyan; Dan Sandberg; Anders Wennborg; Joachim Feldwisch; Vladimir Tolmachev; Anna Orlova; Mattias Sandström; Mark Lubberink; Helena Olofsson; Henrik Lindman
Purpose: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with 68Ga-gallium ([68Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology. Experimental design: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [68Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [68Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [68Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization. Results: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [68Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients. Conclusion: [68Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer.