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Sökning: WFRF:(Heskamp Sandra)

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1.
  • Garousi, Javad, et al. (författare)
  • Comparative evaluation of affibody- and antibody fragments-based CAIX imaging probes in mice bearing renal cell carcinoma xenografts
  • 2019
  • Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Carbonic anhydrase IX (CAIX) is a cancer-associated molecular target for several classes of therapeutics. CAIX is overexpressed in a large fraction of renal cell carcinomas (RCC). Radionuclide molecular imaging of CAIX-expression might offer a non-invasive methodology for stratification of patients with disseminated RCC for CAIX-targeting therapeutics. Radiolabeled monoclonal antibodies and their fragments are actively investigated for imaging of CAIX expression. Promising alternatives are small non-immunoglobulin scaffold proteins, such as affibody molecules. A CAIX-targeting affibody ZCAIX:2 was re-designed with the aim to decrease off-target interactions and increase imaging contrast. The new tracer, DOTA-HE3-ZCAIX:2, was labeled with In-111 and characterized in vitro. Tumor-targeting properties of [In-111]In-DOTA-HE3-ZCAIX:2 were compared head-to-head with properties of the parental variant, [(99)mTc]Tc(CO)(3)-HE3-ZCAIX:2, and the most promising antibody fragment-based tracer, [In-111]In-DTPA-G250(Fab')(2), in the same batch of nude mice bearing CAIX-expressing RCC xenografts. Compared to the (99)mTc-labeled parental variant, [In-111]In-DOTA-HE3-ZCAIX:2 provides significantly higher tumor-to-lung, tumor-to-bone and tumor-to-liver ratios, which is essential for imaging of CAIX expression in the major metastatic sites of RCC. [In-111]In-DOTA-HE3-ZCAIX:2 offers significantly higher tumor-to-organ ratios compared with [In-111]In-G250(Fab']2. In conclusion, [In-111]In-DOTA-HE3-ZCAIX:2 can be considered as a highly promising tracer for imaging of CAIX expression in RCC metastases based on our results and literature data.
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2.
  • Heskamp, Sandra, et al. (författare)
  • Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with (18)F-Labeled Affibody Molecule Z(HER2:2395) in a Mouse Model for Ovarian Cancer
  • 2012
  • Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 53:1, s. 146-153
  • Tidskriftsartikel (refereegranskat)abstract
    • Affibody molecules are small (7 kDa) proteins with subnanomolar targeting affinity. Previous SPECT studies in xenografts have shown that the Affibody molecule (111)In-DOTA-Z(HER2:2395) can discriminate between high and low human epidermal growth factor receptor type 2 (HER2)-expressing tumors, indicating that radiolabeled Affibody molecules have potential for patient selection for HER2-targeted therapy. Compared with SPECT, PET with positron-emitting radionuclides, such as (18)F, may improve imaging of HER2 expression because of higher sensitivity and improved quantification of PET. The aim of the present study was to determine whether the (18)F-labeled NOTA-conjugated Affibody molecule Z(HER2:2395) is a suitable agent for imaging of HER2 expression. The tumor-targeting properties of (18)F-labeled Z(HER2:2395) were compared with (111)In- and (68)Ga-labeled Z(HER2:2395) in mice with HER2-expressing SK-OV-3 xenografts. Methods: Z(HER2:2395) was conjugated with NOTA and radiolabeled with (18)F, (68)Ga, and (111)In. Radiolabeling with (18)F was based on the complexation of Al(18)F by NOTA. The 50% inhibitory concentration values for NOTA-Z(HER2:2395) labeled with (19)F, (69)Ga, and (115)In were determined in a competitive cell-binding assay using SK-OV-3 cells. Mice bearing subcutaneous SK-OV-3 xenografts were injected intravenously with radiolabeled NOTA-Z(HER2:2395). One and 4 h after injection, PET/CT or SPECT/CT images were acquired, and the biodistribution was determined by ex vivo measurement. Results: The 50% inhibitory concentration values for (19)F-, (69)Ga-, and (115)In-NOTA-Z(HER2:2395) were 5.0, 6.3, and 5.3 nM, respectively. One hour after injection, tumor uptake was 4.4 +/- 0.8 percentage injected dose per gram (% ID/g), 5.6 +/- 1.6 % ID/g, and 7.1 +/- 1.4 % ID/g for (18)F-, (68)Ga-, and (111)In-NOTA-Z(HER2:2395), respectively, and the respective tumor-to-blood ratios were 7.4 +/- 1.8, 8.0 +/- 1.3, and 4.8 +/- 1.3. Tumor uptake was specific, because uptake could be blocked efficiently by coinjection of an excess of unlabeled Z(HER2:2395). PET/CT and SPECT/CT images clearly visualized HER2-expressing SK-OV-3 xenografts. Conclusion: This study showed that (18)F-NOTA-Z(HER2:2395) is a promising new imaging agent for HER2 expression in tumors. Affibody molecules were successfully labeled with (18)F within 30 min, based on the complexation of Al(18)F by NOTA. Further research is needed to determine whether this technique can be used for patient selection for HER2-targeted therapy.
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3.
  • Heskamp, Sandra, et al. (författare)
  • Imaging of Human Epidermal Growth Factor Receptor Type 2 Expression with 18F-Labeled Affibody Molecule ZHER2:2395 in a Mouse Model for Ovarian Cancer
  • 2012
  • Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 53:1, s. 146-153
  • Tidskriftsartikel (refereegranskat)abstract
    • Affibody molecules are small (7 kDa) proteins with subnanomolar targeting affinity. Previous SPECT studies in xenografts have shown that the Affibody molecule 111In-DOTA-ZHER2:2395 can discriminate between high and low human epidermal growth factor receptor type 2 (HER2)–expressing tumors, indicating that radiolabeled Affibody molecules have potential for patient selection for HER2-targeted therapy. Compared with SPECT, PET with positron-emitting radionuclides, such as 18F, may improve imaging of HER2 expression because of higher sensitivity and improved quantification of PET. The aim of the present study was to determine whether the 18F-labeled NOTA-conjugated Affibody molecule ZHER2:2395 is a suitable agent for imaging of HER2 expression. The tumor-targeting properties of 18F-labeled ZHER2:2395 were compared with 111In- and 68Ga-labeled ZHER2:2395 in mice with HER2-expressing SK-OV-3 xenografts. Methods: ZHER2:2395 was conjugated with NOTA and radiolabeled with 18F, 68Ga, and 111In. Radiolabeling with 18F was based on the complexation of Al18F by NOTA. The 50% inhibitory concentration values for NOTA-ZHER2:2395 labeled with 19F, 69Ga, and 115In were determined in a competitive cell-binding assay using SK-OV-3 cells. Mice bearing subcutaneous SK-OV-3 xenografts were injected intravenously with radiolabeled NOTA-ZHER2:2395. One and 4 h after injection, PET/CT or SPECT/CT images were acquired, and the biodistribution was determined by ex vivo measurement. Results: The 50% inhibitory concentration values for 19F-, 69Ga-, and 115In-NOTA-ZHER2:2395 were 5.0, 6.3, and 5.3 nM, respectively. One hour after injection, tumor uptake was 4.4 ± 0.8 percentage injected dose per gram (%ID/g), 5.6 ± 1.6 %ID/g, and 7.1 ± 1.4 %ID/g for 18F-, 68Ga-, and 111In-NOTA-ZHER2:2395, respectively, and the respective tumor-to-blood ratios were 7.4 ± 1.8, 8.0 ± 1.3, and 4.8 ± 1.3. Tumor uptake was specific, because uptake could be blocked efficiently by coinjection of an excess of unlabeled ZHER2:2395. PET/CT and SPECT/CT images clearly visualized HER2-expressing SK-OV-3 xenografts. Conclusion: This study showed that 18F-NOTA-ZHER2:2395 is a promising new imaging agent for HER2 expression in tumors. Affibody molecules were successfully labeled with 18F within 30 min, based on the complexation of Al18F by NOTA. Further research is needed to determine whether this technique can be used for patient selection for HER2-targeted therapy.
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4.
  • Huizing, Fokko J., et al. (författare)
  • CAIX-targeting radiotracers for hypoxia imaging in head and neck cancer models
  • 2019
  • Ingår i: Scientific Reports. - 2045-2322. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypoxia-induced carbonic anhydrase IX (CAIX) expression is a prognostic marker in solid tumors. In recent years many radiotracers have been developed, but a fair comparison of these compounds is not possible because of the diversity in tumor models and other experimental parameters. In this study we performed a direct in vivo comparison of three promising CAIX targeting radiotracers in xenografted head and neck cancer models. The biodistribution of [In-111]In-DOTA-ZCAIX:2 was directly compared with [In-111]In-DTPA-G250-F(ab')(2) and [In-111] In-DTPA-G250 in female BALB/C nu/nu mice bearing two HNSCC xenografts with different levels of CAIX expression. In vivo biodistribution was quantified by means of microSPECT/CT scans and ex vivo biodistribution was determined with the use of gamma-counter. Tumors were snap frozen and sections were stained for CAIX expression, vessels, hypoxia (pimonidazole) and tumor blood perfusion. Tracer uptake was significantly higher in SSCNij153 tumors compared to SCCNij185 tumors for [In-111]In-DOTA-HE3-ZCAIX:2: 0.32 +/- 0.03 versus 0.18 +/- 0.01%ID/g,(p = 0.003) 4 h p.i., for [In-111]In-DTPA-girentuximab-F(ab')(2): 3.0 +/- 0.5%ID/g and 1.2 +/- 0.1%ID/g (p = 0.03), 24 h p.i. and for [In-111]In-DTPA-girentuximab: 30 +/- 2.1%ID/g and 7.0 +/- 1.0%ID/g (p = 0.0002) 72 h p.i. SPECT imaging with both [In-111]In-DTPA-girentuximab-F(ab') 2 and [111In]In-DTPA-girentuximab showed a clear difference in tracer distribution between the two tumor models. The whole IgG, i.e. [In-111]In-DTPA-girentuximab, showed the highest tumor-to-muscle ratio. We showed that different CAIX-targeting radiotracers can discriminate a low CAIX-expressing tumor from a high CAIX-expressing head and neck cancer xenografts model. In these hypoxic head and neck xenograft models [In-111]In-DTPA-girentuximab showed the most promising results.
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