28 results on '"Cohrs, Susan"'
Search Results
2. Promising potential of [177Lu]Lu-DOTA-folate to enhance tumor response to immunotherapy—a preclinical study using a syngeneic breast cancer model
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Guzik, Patrycja, Siwowska, Klaudia, Fang, Hsin-Yu, Cohrs, Susan, Bernhardt, Peter, Schibli, Roger, and Müller, Cristina
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- 2021
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3. Evaluation of the first 44Sc-labeled Affibody molecule for imaging of HER2-expressing tumors
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Honarvar, Hadis, Müller, Cristina, Cohrs, Susan, Haller, Stephanie, Westerlund, Kristina, Karlström, Amelie Eriksson, van der Meulen, Nicholas P., Schibli, Roger, and Tolmachev, Vladimir
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- 2017
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4. Combination of lutetium-177 labelled anti-L1CAM antibody chCE7 with the clinically relevant protein kinase inhibitor MK1775: a novel combination against human ovarian carcinoma
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Lindenblatt, Dennis, Terraneo, Nastassja, Pellegrini, Giovanni, Cohrs, Susan, Spycher, Philipp René, Vukovic, David, Béhé, Martin, Schibli, Roger, and Grünberg, Jürgen
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- 2018
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5. Fluorinated quinazolinones as potential radiotracers for imaging kinesin spindle protein expression
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Holland, Jason P., Jones, Michael W., Cohrs, Susan, Schibli, Roger, and Fischer, Eliane
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- 2013
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6. Paclitaxel improved anti-L1CAM lutetium-177 radioimmunotherapy in an ovarian cancer xenograft model
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Lindenblatt, Dennis, Fischer, Eliane, Cohrs, Susan, Schibli, Roger, and Grünberg, Jürgen
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- 2014
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7. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model
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Grünberg, Jürgen, Lindenblatt, Dennis, Dorrer, Holger, Cohrs, Susan, Zhernosekov, Konstantin, Köster, Ulli, Türler, Andreas, Fischer, Eliane, and Schibli, Roger
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- 2014
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8. Implementing subtype‐specific pre‐clinical models of breast cancer to study pre‐treatment aspirin effects.
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Miller, Ian S., Khan, Sonja, Shiels, Liam P., Das, Sudipto, O' Farrell, Alice C., Connor, Kate, Lafferty, Adam, Moran, Bruce, Isella, Claudio, Loadman, Paul, Conroy, Emer, Cohrs, Susan, Schibli, Roger, Kerbel, Robert S., Gallagher, William M., Marangoni, Elisabetta, Bennett, Kathleen, O' Connor, Darran P., Dwyer, Róisín M., and Byrne, Annette T.
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ASPIRIN ,HER2 positive breast cancer ,ANIMAL models in research ,BREAST cancer ,TRIPLE-negative breast cancer ,SEVERE combined immunodeficiency - Abstract
Backgorund: Prior data suggest pre‐diagnostic aspirin use impacts breast tumour biology and patient outcome. Here, we employed faithful surgical resection models of HER2+ and triple‐negative breast cancer (TNBC), to study outcome and response mechanisms across breast cancer subtypes. Method: NOD/SCID mice were implanted with HER2+ MDA‐MB‐231/LN/2‐4/H2N, trastuzumab‐resistant HER2+ HCC1954 or a TNBC patient‐derived xenograft (PDX). A daily low‐dose aspirin regimen commenced until primary tumours reached ~250 mm3 and subsequently resected. MDA‐MB‐231/LN/2‐4/H2N mice were monitored for metastasis utilising imaging. To interrogate the survival benefit of pre‐treatment aspirin, 3 weeks post‐resection, HCC1954/TNBC animals received standard‐of‐care (SOC) chemotherapy for 6 weeks. Primary tumour response to aspirin was interrogated using immunohistochemistry. Results: Aspirin delayed time to metastasis in MDA‐MB‐231/LN/2‐4/H2N xenografts and decreased growth of HER2+/TNBC primary tumours. Lymphangiogenic factors and lymph vessels number were decreased in HER2+ tumours. However, no survival benefit was seen in aspirin pre‐treated animals (HCC1954/TNBC) that further received adjuvant SOC, compared with animals treated with SOC alone. In an effort to study mechanisms responsible for the observed reduction in lymphangiogenesis in HER2+ BC we utilised an in vitro co‐culture system of HCC1954 tumour cells and mesenchymal stromal cells (MSC). Aspirin abrogated the secretion of VEGF‐C in MSCs and also decreased the lymph/angiogenic potential of the MSCs and HCC1954 by tubule formation assay. Furthermore, aspirin decreased the secretion of uPA in HCC1954 cells potentially diminishing its metastatic capability. Conclusion: Our data employing clinically relevant models demonstrate that aspirin alters breast tumour biology. However, aspirin may not represent a robust chemo‐preventative agent in the HER2+ or TNBC setting. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Antibodies directed against L1-CAM synergize with Genistein in inhibiting growth and survival pathways in SKOV3ip human ovarian cancer cells
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Novak-Hofer, Ilse, Cohrs, Susan, Grünberg, Jürgen, Friedli, Alexandra, Schlatter, Monika C., Pfeifer, Marco, Altevogt, Peter, and Schubiger, P. August
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- 2008
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10. L1-CAM-targeted antibody therapy and 177Lu-radioimmunotherapy of disseminated ovarian cancer
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Fischer, Eliane, Grünberg, Jürgen, Cohrs, Susan, Hohn, Alexander, Waldner-Knogler, Karin, Jeger, Simone, Zimmermann, Kurt, Novak-Hofer, Ilse, and Schibli, Roger
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- 2012
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11. Identification of a PET Radiotracer for Imaging of the Folate Receptoralpha – A Potential Tool to Select Patients for Targeted Tumor Therapy.
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Guzik, Patrycja, Hsin-Yu Fang, Deberle, Luisa M., Benešová, Martina, Cohrs, Susan, Boss, Silvan D., Ametamey, Simon M., Schibli, Roger, and Müller, Cristina
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- 2021
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12. Identification of a PET Radiotracer for Imaging of the Folate Receptor-alpha – A Potential Tool to Select Patients for Targeted Tumor Therapy.
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Guzik, Patrycja, Hsin-Yu Fang, Deberle, Luisa M., Benešová, Martina, Cohrs, Susan, Boss, Silvan D., Ametamey, Simon M., Schibli, Roger, and Müller, Cristina
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- 2021
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13. Visualisation of interstitial lung disease by molecular imaging of integrin αvβ3 and somatostatin receptor 2.
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Schniering, Janine, Benešová, Martina, Brunner, Matthias, Haller, Stephanie, Cohrs, Susan, Frauenfelder, Thomas, Vrugt, Bart, Feghali-Bostwick, Carol A., Schibli, Roger, Distler, Oliver, Mueller, Cristina, and Maurer, Britta
- Abstract
Objective: To evaluate integrin αvβ3 (alpha-v-beta-3)-targeted and somatostatin receptor 2 (SSTR2)-targeted nuclear imaging for the visualisation of interstitial lung disease (ILD).Methods: The pulmonary expression of integrin αvβ3 and SSTR2 was analysed in patients with different forms of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. Single photon emission CT/CT (SPECT/CT) was performed on days 3, 7 and 14 after BLM instillation using the integrin αvβ3-targeting 177Lu-DOTA-RGD and the SSTR2-targeting 177Lu-DOTA-NOC radiotracer. The specific pulmonary accumulation of the radiotracers over time was assessed by in vivo and ex vivo SPECT/CT scans and by biodistribution studies.Results: Expression of integrin αvβ3 and SSTR2 was substantially increased in human ILD regardless of the subtype. Similarly, in lungs of BLM-challenged mice, but not of controls, both imaging targets were stage-specifically overexpressed. While integrin αvβ3 was most abundantly upregulated on day 7, the inflammatory stage of BLM-induced lung fibrosis, SSTR2 expression peaked on day 14, the established fibrotic stage. In agreement with the findings on tissue level, targeted nuclear imaging using SPECT/CT specifically detected both imaging targets ex vivo and in vivo, and thus visualised different stages of experimental ILD.Conclusion: Our preclinical proof-of-concept study suggests that specific visualisation of molecular processes in ILD by targeted nuclear imaging is feasible. If transferred into clinics, where imaging is considered an integral part of patients' management, the additional information derived from specific imaging tools could represent a first step towards precision medicine in ILD. [ABSTRACT FROM AUTHOR]- Published
- 2019
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14. Folate Receptor-Positive Gynecological Cancer Cells: In Vitro and In Vivo Characterization.
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Siwowska, Klaudia, Schmid, Raffaella M., Cohrs, Susan, Schibli, Roger, and Müller, Cristina
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FOLIC acid ,GYNECOLOGIC cancer ,CHORIOCARCINOMA ,CANCER chemotherapy ,XENOGRAFTS ,GENE expression ,IN vitro studies ,LABORATORY mice - Abstract
The folate receptor alpha (FR) is expressed in a variety of gynecological cancer types. It has been widely used for tumor targeting with folic acid conjugates of diagnostic and therapeutic probes. The cervical KB tumor cells have evolved as the standard model for preclinical investigations of folate-based (radio) conjugates. In this study, a panel of FR-expressing human cancer cell lines-- including cervical (HeLa, KB, KB-V1), ovarian (IGROV-1, SKOV-3, SKOV-3.ip), choriocarcinoma (JAR, BeWo) and endometrial (EFE-184) tumor cells--was investigated in vitro and for their ability to grow as xenografts in mice. FR-expression levels were compared in vitro and in vivo and the cell lines were characterized by determination of the sensitivity towards commonly-used chemotherapeutics and the expression of two additional, relevant tumor markers, HER2 and L1-CAM. It was found that, besides KB cells, its multiresistant KB-V1 subclone as well as the ovarian cancer cell lines, IGROV-1 and SKOV-3.ip, could be used as potentially more relevant preclinical models. They would allow addressing specific questions such as the therapeutic efficacy of FR-targeting agents in tumor (mouse) models of multi-resistance and in mouse models of metastases formation. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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15. Synthesis and Evaluation of Biphenyl Compounds as Kinesin Spindle Protein Inhibitors.
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Holland, Jason P., Kang, Albert, Cohrs, Susan, Selivanova, Svetlana V., Milicevic Sephton, Selena, Betzel, Thomas, Frey, Daniel, Wieser, Mara, Jaussi, Rolf, Kammerer, Richard A., Schibli, Roger, and Fischer, Eliane
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- 2013
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16. Transplantation and Tracking of Human-Induced Pluripotent Stem Cells in a Pig Model of Myocardial Infarction.
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Templin, Christian, Zweigerdt, Robert, Schwanke, Kristin, Olmer, Ruth, Ghadri, Jelena-Rima, Emmert, Maximilian Y., Müller, Ennio, Küest, Silke M., Cohrs, Susan, Schibli, Roger, Kronen, Peter, Hilbe, Monika, Reinisch, Andreas, Strunk, Dirk, Haverich, Axel, Hoerstrup, Simon, Lüscher, Thomas F., Kaufmann, Philipp A., Landmesser, Ulf, and Martin, Ulrich
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- 2012
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17. L1-CAM-targeted antibody therapy and 177Lu-radioimmunotherapy of disseminated ovarian cancer.
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Fischer, Eliane, Grünberg, Jürgen, Cohrs, Susan, Hohn, Alexander, Waldner-Knogler, Karin, Jeger, Simone, Zimmermann, Kurt, Novak-Hofer, Ilse, and Schibli, Roger
- Abstract
The L1-cell adhesion molecule (L1-CAM) is highly expressed in various cancer types including ovarian carcinoma but is absent from most normal tissue. A chimeric monoclonal antibody, chCE7, specifically binds to human L1-CAM and exhibits anti-proliferative effects on L1-CAM-expressing tumor cells. The goal of this study was to evaluate the efficacy of a novel
177 Lu-chCE7 radioimmunotherapeutic agent and to compare it to a treatment protocol with unlabeled, growth-inhibiting chCE7 in a mouse xenograft model of disseminated ovarian cancer. chCE7agl, an aglycosylated IgG1 variant with improved pharmacokinetics, was conjugated with 1,4,7,10-tetraazacyclododecane- N- N′- N′- N‴-tetraacetic acid (DOTA) and labeled with the low-energy β-emitter177 Lu. Tumor growth and survival were assessed after a single i.v. dose of 8 MBq (60 μg) radioimmunoconjugate in nude mice bearing either subcutaneous or intraperitoneal SKOV3.ip1 human ovarian cancer tumors. Therapeutic efficacy was compared with three times weekly i.p. administration of 10 mg/kg unconjugated chCE7. In vivo analysis of177 Lu-chCE7agl biodistribution demonstrated high and specific accumulation of radioactivity at the tumor site with maximal tumor uptake of up to 48.0 ± 8.1% ID/g at 168 h postinjection. A single treatment with177 Lu-DOTA-chCE7agl caused significant retardation of tumor growth and prolonged median survival from 33 to 71 days, while administration of a nontargeted177 Lu-immunoconjugate had no beneficial effect. Three times weekly i.p. application of unlabeled chCE7 10 mg/kg similarly increased survival from 44 to 72 days. We conclude that a single dose of177 Lu-DOTA-chCE7agl is as effective as repeated administration of nonradioactive chCE7 for treatment of small intraperitoneal tumors expressing L1-CAM. [ABSTRACT FROM AUTHOR]- Published
- 2012
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18. Simultaneous Visualization of 161 Tb- and 177 Lu-Labeled Somatostatin Analogues Using Dual-Isotope SPECT Imaging.
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Borgna, Francesca, Barritt, Patrick, Grundler, Pascal V., Talip, Zeynep, Cohrs, Susan, Zeevaart, Jan Rijn, Köster, Ulli, Schibli, Roger, van der Meulen, Nicholas P., Müller, Cristina, and Seimbille, Yann
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COMPUTED tomography ,SINGLE-photon emission computed tomography ,SOMATOSTATIN ,VISUALIZATION ,TERBIUM ,RADIOISOTOPES - Abstract
The decay of terbium-161 results in the emission of β¯-particles as well as conversion and Auger electrons, which makes terbium-161 interesting for therapeutic purposes. The aim of this study was to use dual-isotope SPECT imaging in order to demonstrate visually that terbium-161 and lutetium-177 are interchangeable without compromising the pharmacokinetic profile of the radiopharmaceutical. The
161 Tb- and177 Lu-labeled somatostatin (SST) analogues DOTATOC (agonist) and DOTA-LM3 (antagonist) were tested in vitro to demonstrate equal properties regarding distribution coefficients and cell uptake into SST receptor-positive AR42J tumor cells. The radiopeptides were further investigated in AR42J tumor-bearing nude mice using the method of dual-isotope (terbium-161/lutetium-177) SPECT/CT imaging to enable the visualization of their distribution profiles in the same animal. Equal pharmacokinetic profiles were demonstrated for either of the two peptides, irrespective of whether it was labeled with terbium-161 or lutetium-177. Moreover, the visualization of the sub-organ distribution confirmed similar behavior of161 Tb- and177 Lu-labeled SST analogues. The data were verified in quantitative biodistribution studies using either type of peptide labeled with terbium-161 or lutetium-177. While the radionuclide did not have an impact on the organ distribution, this study confirmed previous data of a considerably higher tumor uptake of radiolabeled DOTA-LM3 as compared to the radiolabeled DOTATOC. [ABSTRACT FROM AUTHOR]- Published
- 2021
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19. Combining Albumin-Binding Properties and Interaction with Pemetrexed to Improve the Tissue Distribution of Radiofolates.
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Müller, Cristina, Guzik, Patrycja, Siwowska, Klaudia, Cohrs, Susan, Schmid, Raffaella M., Schibli, Roger, Brust, Peter, and McPhee, Derek J.
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FOLIC acid ,JUNO protein ,PROTEIN binding ,PEMETREXED ,RADIOACTIVITY - Abstract
Folic-acid-based radioconjugates have been developed for nuclear imaging of folate receptor (FR)-positive tumors; however, high renal uptake was unfavorable in view of a therapeutic application. Previously, it was shown that pre-injection of pemetrexed (PMX) increased the tumor-to-kidney ratio of radiofolates several-fold. In this study, PMX was combined with the currently best performing radiofolate ([
177 Lu]cm13), which is outfitted with an albumin-binding entity. Biodistribution studies were carried out in mice bearing KB or IGROV-1 tumor xenografts, both FR-positive tumor types. SPECT/CT was performed with control mice injected with [177 Lu]folate only and with mice that received PMX in addition. Control mice showed high uptake of radioactivity in KB and IGROV-1 tumor xenografts, but retention in the kidneys was also high, resulting in tumor-to-kidney ratios of ~0.85 (4 h p.i.) and ~0.60 (24 h p.i.) or ~1.17 (4 h p.i.) and ~1.11 (24 h p.i.) respectively. Pre-injection of PMX improved the tumor-to-kidney ratio to values of ~1.13 (4 h p.i.) and ~0.92 (24 h p.i.) or ~1.79 (4 h p.i.) and ~1.59 (24 h p.i.), respectively, due to reduced uptake in the kidneys. It was found that a second injection of PMX—3 h or 7 h after administration of the radiofolate—improved the tumor-to-kidney ratio further to ~1.03 and ~0.99 or ~1.78 and ~1.62 at 24 h p.i. in KB and IGROV-1 tumor-bearing mice, respectively. SPECT/CT scans readily visualized the tumor xenografts, whereas accumulation of radioactivity in the kidneys was reduced in mice that received PMX. In this study, it was shown that PMX had a positive impact in terms of reducing the kidney uptake of albumin-binding radiofolates; hence, the administration of PMX resulted in ~1.3–1.7-fold higher tumor-to-kidney ratios. This is, however, a rather moderate effect in comparison to the previously shown effect of PMX on conventional radiofolates (without albumin binder), which led to 5–6-fold increased tumor-to-kidney ratios. An explanation for this result may be the different pharmacokinetic profiles of PMX and long-circulating radiofolates, respectively. Despite the promising potential of this concept, it is believed that a clinical translation would be challenging, particularly when PMX had to be injected more than once. [ABSTRACT FROM AUTHOR]- Published
- 2018
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20. The low-energy β− and electron emitter 161Tb as an alternative to 177Lu for targeted radionuclide therapy
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Lehenberger, Silvia, Barkhausen, Christoph, Cohrs, Susan, Fischer, Eliane, Grünberg, Jürgen, Hohn, Alexander, Köster, Ulli, Schibli, Roger, Türler, Andreas, and Zhernosekov, Konstantin
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LUTETIUM isotopes , *LOW energy electron diffraction , *RADIOISOTOPE therapy , *RADIOLABELING , *POSITRON emission tomography , *ION exchange chromatography ,TERBIUM isotopes - Abstract
Abstract: Introduction: The low-energy β− emitter 161Tb is very similar to 177Lu with respect to half-life, beta energy and chemical properties. However, 161Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to 177Lu. It also emits low-energy photons that are useful for gamma camera imaging. Methods: The 160Gd(n,γ)161Gd→161Tb production route was used to produce 161Tb by neutron irradiation of massive 160Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) 161Tb from the bulk of the 160Gd target and from its stable decay product 161Dy. 161Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. 177Lu. A 161Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera. Results: Up to 15 GBq of 161Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%–90% of the available 161Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The 161Tb obtained was of the quality required to prepare 161Tb–DOTA-Tyr3-octreotate. Conclusions: We were able to produce 161Tb in n.c.a. form by irradiating highly enriched 160Gd targets; it can be obtained in the quantity and quality required for the preparation of 161Tb-labeled therapeutic agents. [Copyright &y& Elsevier]
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- 2011
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21. The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor
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Friedli, Alexandra, Fischer, Eliane, Novak-Hofer, Ilse, Cohrs, Susan, Ballmer-Hofer, Kurt, Schubiger, P. August, Schibli, Roger, and Grünberg, Jürgen
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CELL adhesion molecules , *VASCULAR endothelial growth factors , *CANCER cell proliferation , *SERUM , *ASCITES , *OVARIAN cancer , *BIOCHEMISTRY - Abstract
Abstract: A soluble form of the L1 cell adhesion molecule (sL1) is released from various tumor cells and can be found in serum and ascites fluid of uterine and ovarian carcinoma patients. sL1 is a ligand for several Arg-Gly-Asp (RGD)-binding integrins and can be deposited in the extracellular matrix. In this study we describe a novel function of this physiologically relevant form of L1 as a pro-angiogenic factor. We demonstrated that the anti-L1 monoclonal antibody (mAb) chCE7 binds near or to the sixth Ig-like domain of human L1 which contains a single RGD sequence. mAb chCE7 inhibited the RGD-dependent adhesion of ovarian carcinoma cells to sL1 and reversed the sL1-induced proliferation, matrigel invasion and tube formation of bovine aortic endothelial (BAE) cells. A combination of sL1 with vascular endothelial growth factor-A (VEGF-A165), which is an important angiogenic inducer in tumors, strongly potentiated VEGF receptor-2 tyrosine phosphorylation in BAE cells. Chick chorioallantoic membrane (CAM) assays revealed the pro-angiogenic potency of sL1 in vivo which could be abolished by chCE7. These results indicate an important role of released L1 in tumor angiogenesis and represent a novel function of antibody chCE7 in tumor therapy. [Copyright &y& Elsevier]
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- 2009
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22. Future prospects for SPECT imaging using the radiolanthanide terbium-155 — production and preclinical evaluation in tumor-bearing mice.
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Müller, Cristina, Fischer, Eliane, Behe, Martin, Köster, Ulli, Dorrer, Holger, Reber, Josefine, Haller, Stephanie, Cohrs, Susan, Blanc, Alain, Grünberg, Jürgen, Bunka, Maruta, Zhernosekov, Konstantin, van der Meulen, Nicholas, Johnston, Karl, Türler, Andreas, and Schibli, Roger
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SINGLE-photon emission computed tomography , *RADIOLABELING , *RARE earth metals , *TERBIUM , *LABORATORY mice , *TUMOR diagnosis , *BIOMOLECULES - Abstract
Abstract: Introduction: We assessed the suitability of the radiolanthanide 155Tb (t1/2 =5.32days, Eγ =87keV (32%), 105keV (25%)) in combination with variable tumor targeted biomolecules using preclinical SPECT imaging. Methods: 155Tb was produced at ISOLDE (CERN, Geneva, Switzerland) by high-energy (~1.4GeV) proton irradiation of a tantalum target followed by ionization and on-line mass separation. 155Tb was separated from isobar and pseudo-isobar impurities by cation exchange chromatography. Four tumor targeting molecules – a somatostatin analog (DOTATATE), a minigastrin analog (MD), a folate derivative (cm09) and an anti-L1-CAM antibody (chCE7) – were radiolabeled with 155Tb. Imaging studies were performed in nude mice bearing AR42J, cholecystokinin-2 receptor expressing A431, KB, IGROV-1 and SKOV-3ip tumor xenografts using a dedicated small-animal SPECT/CT scanner. Results: The total yield of the two-step separation process of 155Tb was 86%. 155Tb was obtained in a physiological l-lactate solution suitable for direct labeling processes. The 155Tb-labeled tumor targeted biomolecules were obtained at a reasonable specific activity and high purity (>95%). 155Tb gave high quality, high resolution tomographic images. SPECT/CT experiments allowed excellent visualization of AR42J and CCK-2 receptor-expressing A431 tumors xenografts in mice after injection of 155Tb-DOTATATE and 155Tb-MD, respectively. The relatively long physical half-life of 155Tb matched in particular the biological half-lives of 155Tb-cm09 and 155Tb-DTPA-chCE7 allowing SPECT imaging of KB tumors, IGROV-1 and SKOV-3ip tumors even several days after administration. Conclusions: The radiolanthanide 155Tb may be of particular interest for low-dose SPECT prior to therapy with a therapeutic match such as the β--emitting radiolanthanides 177Lu, 161Tb, 166Ho, and the pseudo-radiolanthanide 90Y. [Copyright &y& Elsevier]
- Published
- 2014
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23. Identification of a PET Radiotracer for Imaging of the Folate Receptor-α: A Potential Tool to Select Patients for Targeted Tumor Therapy.
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Guzik P, Fang HY, Deberle LM, Benešová M, Cohrs S, Boss SD, Ametamey SM, Schibli R, and Müller C
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- Animals, Mice, Humans, Tissue Distribution, CHO Cells, Positron Emission Tomography Computed Tomography methods, Radioactive Tracers, Positron-Emission Tomography methods, Cell Line, Tumor, Radiopharmaceuticals pharmacokinetics, Molecular Targeted Therapy, Neoplasms diagnostic imaging, Neoplasms metabolism, Female, Folate Receptor 1 metabolism, Cricetulus
- Abstract
The aim of this study was to identify a folate receptor-α (FRα)-selective PET agent potentially suitable for the selection of patients who might profit from FRα-targeted therapies. The 6 R and 6 S isomers of
18 F-aza-5-methyltetrahydrofolate (MTHF) were assessed regarding their binding to FRα and FRβ, expressed on cancer and inflammatory cells, respectively, and compared with18 F-AzaFol, the folic acid-based analog. Methods: FR selectivity was investigated using FRα-transfected (RT16) and FRβ-transfected (D4) CHO cells. The cell uptake of18 F-folate tracers was investigated, and receptor-binding affinities were determined with the nonradioactive analogs. In vitro autoradiography of the18 F-folate tracers was performed using RT16 and D4 tissue sections. Biodistribution studies and PET/CT imaging of the radiotracers were performed on mice bearing RT16 and D4 xenografts. Results: The uptake of18 F-6 R -aza-5-MTHF was high when using RT16 cells (62% ± 10% of added activity) but much lower when using D4 cells (5% ± 2%). The FRα selectivity of18 F-6 R -aza-5-MTHF was further demonstrated by its approximately 43-fold higher binding affinity to FRα (half-maximal inhibitory concentration [IC50 ], 1.8 ± 0.1 nM) than to FRβ (IC50 , 77 ± 27 nM). The uptake of18 F-6 S -aza-5-MTHF and18 F-AzaFol was equal in both cell lines (52%-70%), with similar affinities to FRα (IC50 , 2.1 ± 0.4 nM and 0.6 ± 0.3 nM, respectively) and FRβ (0.8 ± 0.2 nM and 0.3 ± 0.1 nM, respectively). The autoradiography signal obtained with18 F-6 R -aza-5-MTHF was 11-fold more intense for RT16 than for D4 tissue sections. Biodistribution data showed high uptake of18 F-6 R -aza-5-MTHF in RT16 xenografts (81% ± 20% injected activity per gram [IA]/g 1 h after injection) but significantly lower accumulation in D4 xenografts (7.3% ± 2.1% IA/g 1 h after injection), which was also visualized using PET. The uptake of18 F-6 S -aza-5-MTHF and18 F-AzaFol was similar in RT16 (53% ± 10% IA/g and 45% ± 2% IA/g, respectively) and D4 xenografts (77% ± 10% IA/g and 52% ± 7% IA/g, respectively). Conclusion: This study demonstrated FRα selectivity for18 F-6 R -aza-5-MTHF but not for18 F-6 S -aza-5-MTHF or18 F-AzaFol. This characteristic, together with its favorable tissue distribution, makes18 F-6 R -aza-5-MTHF attractive for clinical translation to enable detection of FRα-positive cancer while preventing undesired accumulation in FRβ-expressing inflammatory cells., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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24. Combined Application of Albumin-Binding [ 177 Lu]Lu-PSMA-ALB-56 and Fast-Cleared PSMA Inhibitors: Optimization of the Pharmacokinetics.
- Author
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Borgna F, Deberle LM, Cohrs S, Schibli R, and Müller C
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- Animals, Cell Line, Tumor, Humans, Kidney metabolism, Male, Single Photon Emission Computed Tomography Computed Tomography, Organophosphorus Compounds chemistry, Organophosphorus Compounds pharmacokinetics, Prostatic Neoplasms metabolism
- Abstract
The strategy of using radioligands for targeting the prostate-specific membrane antigen (PSMA) revealed to be promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently developed albumin-binding PSMA radioligands showed a remarkably increased tumor uptake because of the enhanced blood circulation, but higher accumulation of activity was also observed in off-target organs and tissues. The aim of this study was to investigate the option of using fast-cleared, small-molecular-weight PSMA inhibitors (PSMA-11, 2-PMPA, and ZJ-43) to reduce the kidney uptake of [
177 Lu]Lu-PSMA-ALB-56, a previously developed albumin-binding PSMA radioligand. Dual-isotope SPECT/CT imaging was performed with tumor-bearing mice coinjected with [177 Lu]Lu-PSMA-ALB-56 and a 2.5-fold molar excess of [67 Ga]Ga-PSMA-11. At early timepoints after injection, the high renal uptake of [67 Ga]Ga-PSMA-11 reduced the accumulation of [177 Lu]Lu-PSMA-ALB-56 in the kidneys substantially, whereas the tumor uptake of [177 Lu]Lu-PSMA-ALB-56 was only slightly affected. These findings were confirmed in biodistribution studies, which revealed reduced uptake of [177 Lu]Lu-PSMA-ALB-56 in the kidneys due to coadministered unlabeled PSMA-11 (9.1 ± 0.8% IA/g vs 46 ± 11% IA/g; 1 h p.i.). The tumor uptake of [177 Lu]Lu-PSMA-ALB-56 was almost the same at 1 h p.i., irrespective of whether or not PSMA-11 was coinjected (24 ± 6% IA/g vs 27 ± 7% IA/g). The application of [177 Lu]Lu-PSMA-ALB-56 with 2-PMPA or ZJ-43, respectively, showed similar results in biodistribution studies. Among all three tested PSMA inhibitors, 2-PMPA, applied at a 2.5-fold molar excess relative to [177 Lu]Lu-PSMA-ALB-56, was most effective to improve the tumor-to-kidney ratios over the first hours after injection of [177 Lu]Lu-PSMA-ALB-56. The concept of using a PSMA inhibitor together with [177 Lu]Lu-PSMA-ALB-56 appears promising in view of a clinical translation of this and possibly other long-circulating PSMA radioligands.- Published
- 2020
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25. 18 F-AzaFol for Detection of Folate Receptor-β Positive Macrophages in Experimental Interstitial Lung Disease-A Proof-of-Concept Study.
- Author
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Schniering J, Benešová M, Brunner M, Haller S, Cohrs S, Frauenfelder T, Vrugt B, Feghali-Bostwick C, Schibli R, Distler O, Müller C, and Maurer B
- Subjects
- Animals, Bleomycin adverse effects, Bleomycin pharmacology, Female, Gene Expression Regulation drug effects, Gene Expression Regulation immunology, Humans, Mice, Proof of Concept Study, Fluorine Radioisotopes chemistry, Fluorine Radioisotopes pharmacology, Folate Receptor 2 immunology, Folic Acid analogs & derivatives, Folic Acid chemistry, Folic Acid pharmacology, Lung Diseases, Interstitial chemically induced, Lung Diseases, Interstitial diagnostic imaging, Lung Diseases, Interstitial immunology, Macrophages immunology, Positron Emission Tomography Computed Tomography, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacology
- Abstract
Background: Interstitial lung disease (ILD) is a common and severe complication in rheumatic diseases. Folate receptor-β is expressed on activated, but not resting macrophages which play a key role in dysregulated tissue repair including ILD. We therefore aimed to pre-clinically evaluate the potential of
18 F-AzaFol-based PET/CT (positron emission computed tomography/computed tomography) for the specific detection of macrophage-driven pathophysiologic processes in experimental ILD. Methods: The pulmonary expression of folate receptor-β was analyzed in patients with different subtypes of ILD as well as in bleomycin (BLM)-treated mice and respective controls using immunohistochemistry. PET/CT was performed at days 3, 7, and 14 after BLM instillation using the18 F-based folate radiotracer18 F-AzaFol. The specific pulmonary accumulation of the radiotracer was assessed by ex vivo PET/CT scans and quantified by ex vivo biodistribution studies. Results: Folate receptor-β expression was 3- to 4-fold increased in patients with fibrotic ILD, including idiopathic pulmonary fibrosis and connective tissue disease-related ILD, and significantly correlated with the degree of lung remodeling. A similar increase in the expression of folate receptor-β was observed in experimental lung fibrosis, where it also correlated with disease extent. In the mouse model of BLM-induced ILD, pulmonary accumulation of18 F-AzaFol reflected macrophage-related disease development with good correlation of folate receptor-β positivity with radiotracer uptake. In the ex vivo imaging and biodistribution studies, the maximum lung accumulation was observed at day 7 with a mean accumulation of 1.01 ± 0.30% injected activity/lung in BLM-treated vs. control animals (0.31 ± 0.06% % injected activity/lung; p < 0.01). Conclusion: Our preclinical proof-of-concept study demonstrated the potential of18 F-AzaFol as a novel imaging tool for the visualization of macrophage-driven fibrotic lung diseases., (Copyright © 2019 Schniering, Benešová, Brunner, Haller, Cohrs, Frauenfelder, Vrugt, Feghali-Bostwick, Schibli, Distler, Müller and Maurer.)- Published
- 2019
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26. In Vivo Labeling of Plasma Proteins for Imaging of Enhanced Vascular Permeability in the Lungs.
- Author
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Schniering J, Borgna F, Siwowska K, Benešová M, Cohrs S, Hasler R, van der Meulen NP, Maurer B, Schibli R, and Müller C
- Subjects
- Acute Lung Injury chemically induced, Animals, Aza Compounds chemistry, Bleomycin administration & dosage, Bleomycin toxicity, Capillary Permeability, Disease Models, Animal, Female, Heterocyclic Compounds, 1-Ring chemistry, Humans, Lung blood supply, Lung diagnostic imaging, Lung drug effects, Lung metabolism, Lutetium administration & dosage, Lutetium chemistry, Lutetium pharmacokinetics, Mice, Mice, Inbred C57BL, Positron-Emission Tomography methods, Prealbumin chemistry, Radioisotopes administration & dosage, Radioisotopes chemistry, Radioisotopes pharmacokinetics, Radiopharmaceuticals chemistry, Radiopharmaceuticals pharmacokinetics, Scandium administration & dosage, Scandium chemistry, Scandium pharmacokinetics, Serum Albumin, Human chemistry, Tissue Distribution, Tomography, Emission-Computed, Single-Photon methods, Acute Lung Injury diagnostic imaging, Molecular Imaging methods, Prealbumin metabolism, Radiopharmaceuticals administration & dosage, Serum Albumin, Human metabolism
- Abstract
Increased vascular permeability is an important hallmark of many diseases, including cancer, cerebral ischemia, and severe inflammatory disorders. In this regard, the noninvasive assessment of pathologically increased vascular permeability in vivo is of great interest. In this study, the potential of albumin- and transthyretin-binding radioligands was evaluated for imaging of vascular hyperpermeability. For this purpose, the bleomycin-induced lung injury model was used as a model of inflammation-associated vascular leakage. The plasma protein-binding ligands, which bind to albumin (DOTA-PPB-01) and transthyretin (DOTA-PPB-03), were radiolabeled and used for nuclear imaging and biodistribution studies. In this regard,
177 Lu was employed as a surrogate nuclide for detailed preclinical investigations, including single-photon emission computed tomography (SPECT) studies, whereas44 Sc was proposed as a radionuclide for positron emission tomography (PET), which may be relevant for future clinical translation. Mice were administered with these radioligands 6-9 days after intratracheal instillation of bleomycin or saline. Bleomycin-treated mice developed pronounced lung inflammation with enhanced vascular permeability that was reflected in significantly increased lung size and weight due to edema and infiltration with inflammatory cells. Biodistribution studies revealed significantly higher accumulation of177 Lu-DOTA-PPB-01 in injured lungs as compared to lungs of control animals at all investigated time points (4-48 h p.i.). The best contrast was achieved at late time points (16.1 ± 2.91% IA/g vs 2.03 ± 1.22% IA/g, 48 h p.i.) when the blood activity levels were ∼7.5% IA/g. Injection of177 Lu-DOTA-PPB-03 also resulted in increased lung accumulation in bleomycin-treated mice at all investigated time points (2-8 h p.i.). The pharmacokinetics was significantly faster, however, resulting in good contrast already at 8 h p.i. (4.32 ± 0.85% IA/g vs 1.06 ± 0.10% IA/g) when blood activity levels were ∼2% IA/g. The absolute lung accumulation of177 Lu-DOTA-PPB-03 was significantly lower than that of177 Lu-DOTA-PPB-01. PET/CT scans performed with44 Sc-DOTA-PPB-01 distinguished injured from healthy lungs only at late time points (20 h p.i.), whereas44 Sc-DOTA-PPB-03 already allowed the differentiation at 4 h p.i. due to its faster clearance. The investigated radioligands,44 Sc/177 Lu-DOTA-PPB-01 and44 Sc/177 Lu-DOTA-PPB-03, hold promise for the visualization of vascular leakage in a variety of pathological conditions.44 Sc would be the radionuclide of choice for clinical application as it can be stably coordinated with a DOTA chelator and enables PET imaging over extended periods.- Published
- 2018
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27. The low-energy β(-) and electron emitter (161)Tb as an alternative to (177)Lu for targeted radionuclide therapy.
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Lehenberger S, Barkhausen C, Cohrs S, Fischer E, Grünberg J, Hohn A, Köster U, Schibli R, Türler A, and Zhernosekov K
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- Humans, Lutetium isolation & purification, Lutetium therapeutic use, Nuclear Reactors, Octreotide analogs & derivatives, Octreotide blood, Organometallic Compounds blood, Radioisotopes isolation & purification, Radioisotopes therapeutic use, Terbium isolation & purification, Terbium therapeutic use, Beta Particles therapeutic use, Electrons, Lutetium chemistry, Radiochemistry methods, Radioisotopes chemistry, Radiotherapy methods, Terbium chemistry
- Abstract
Introduction: The low-energy β(-) emitter (161)Tb is very similar to (177)Lu with respect to half-life, beta energy and chemical properties. However, (161)Tb also emits a significant amount of conversion and Auger electrons. Greater therapeutic effect can therefore be expected in comparison to (177)Lu. It also emits low-energy photons that are useful for gamma camera imaging., Methods: The (160)Gd(n,γ)(161)Gd→(161)Tb production route was used to produce (161)Tb by neutron irradiation of massive (160)Gd targets (up to 40 mg) in nuclear reactors. A semiautomated procedure based on cation exchange chromatography was developed and applied to isolate no carrier added (n.c.a.) (161)Tb from the bulk of the (160)Gd target and from its stable decay product (161)Dy. (161)Tb was used for radiolabeling DOTA-Tyr3-octreotate; the radiolabeling profile was compared to the commercially available n.c.a. (177)Lu. A (161)Tb Derenzo phantom was imaged using a small-animal single-photon emission computed tomography camera., Results: Up to 15 GBq of (161)Tb was produced by long-term irradiation of Gd targets. Using a cation exchange resin, we obtained 80%-90% of the available (161)Tb with high specific activity, radionuclide and chemical purity and in quantities sufficient for therapeutic applications. The (161)Tb obtained was of the quality required to prepare (161)Tb-DOTA-Tyr3-octreotate., Conclusions: We were able to produce (161)Tb in n.c.a. form by irradiating highly enriched (160)Gd targets; it can be obtained in the quantity and quality required for the preparation of (161)Tb-labeled therapeutic agents., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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28. Copper-67 radioimmunotherapy and growth inhibition by anti-L1-cell adhesion molecule monoclonal antibodies in a therapy model of ovarian cancer metastasis.
- Author
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Knogler K, Grünberg J, Zimmermann K, Cohrs S, Honer M, Ametamey S, Altevogt P, Fogel M, Schubiger PA, and Novak-Hofer I
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Mice, Mice, Nude, Mutation, Neoplasm Metastasis, Plasmids metabolism, Positron-Emission Tomography methods, Antibodies, Monoclonal therapeutic use, Copper Radioisotopes therapeutic use, Neural Cell Adhesion Molecule L1 immunology, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Radioimmunotherapy methods
- Abstract
Purpose: We examined the tumor-targeting and therapeutic effects of (67)Cu-labeled single amino acid mutant forms of anti-L1 monoclonal antibody chCE7 in nude mice with orthotopically implanted SKOV3ip human ovarian carcinoma cells., Experimental Design: For radioimmunotherapy, chCE7 antibodies with a mutation of histidine 310 to alanine (chCE7H310A) and a mutation of asparagine 297 to glutamine (chCE7agl) were generated to achieve more rapid blood clearance. Biodistributions of (67)Cu-4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrachloride (CPTA)-labeled mutant antibodies were measured in nude mice bearing SKOV3ip human ovarian cancer metastases. The effects of single i.v. injections of (67)Cu-chCE7agl alone on tumor reduction and survival were investigated. In addition, a combination of low-dose (67)Cu-radioimmunotherapy with unlabeled anti-L1 antibody L1-11A on survival was investigated., Results: (67)Cu-CPTA-chCE7agl showed high (up to 49% ID/g) and persistent (up to 168 h) uptake in SKOV3ip metastases, with low levels in normal tissues. (67)Cu-CPTA-chCE7H310A revealed a shorter half-life in the blood and a lower tumor uptake and retention. A single low dose of 4 MBq of (67)Cu-chCE7agl reduced tumor growth but did not prolong survival significantly, whereas a single 10.5 MBq dose of (67)Cu-chCE7agl reduced tumor growth and prolonged survival significantly. The combination of unlabeled monoclonal antibody L1-11A with a subtherapeutic dose of (67)Cu-radioimmunotherapy also prolonged survival significantly., Conclusion: The results show improved pharmacokinetics and biodistributions as well as the therapeutic effect of the (67)Cu-labeled single amino acid mutant chCE7agl. Therapeutic data indicate, for the first time, the feasibility of combining anti-L1-directed growth inhibition and (67)Cu-radioimmunotherapy, thereby increasing the efficiency of antibody treatment of metastatic ovarian carcinoma.
- Published
- 2007
- Full Text
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