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  • 1.
    Aitken, Candice L.
    et al.
    New York University.
    McGuinness, Georgeann
    New York University.
    Siddiqui, Faaiza
    New York University.
    Ton, Anthony
    New York University.
    Kramer, Elissa L
    New York University.
    Maguire Jr., Gerald Q.
    KTH, Tidigare Institutioner, Teleinformatik.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Tumor localization and image registration of 18-FDG SPECT scans with CT scans1999Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 40, nr 5, s. 290P-291PArtikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    The aim of this study was to determine the feasibility of registering routine clinical F-18 fluorodeoxyglucose (FDG) coincidence detection (CD) scans with computed tomographic (CT) scans for radiation treatment planning and case management.

    METHODS:

    F-18 FDG CD and chest CT scans, performed in 10 randomly selected patients with confirmed or possible adenocarcinoma of the lung, were evaluated. The quality of the matches was verified by comparisons of the center-to-center distance between a region of interest (ROI) manually drawn on the CT slice and warped onto the CD slice with an ROI drawn manually directly on the CD slice. In addition, the overlap between the two ROIs was calculated.

    RESULTS:

    All 10 F-18 FDG CD and CT scans were registered with good superimposition of soft tissue density on increased radionuclide activity. The center-to-center distance between the ROIs ranged from 0.29 mm to 8.08 mm, with an average center-to-center distance of 3.89 mm +/- 2.42 mm (0.69 pixels +/- 0.34 pixels). The ROI overlap ranged from 77% to 99%, with an average of 90% +/- 5.6%.

    CONCLUSIONS:

    Although the use of F-18 FDG CD shows great promise for the identification of tumors, it shares the same drawbacks as those associated with radiolabeled monoclonal antibody SPECT and ligand-based positron emission tomographic scans in that anatomic markers are limited. This study shows that image registration is feasible and may improve the clinical relevance of CD images.

  • 2. Altai, Mohamed
    et al.
    Perols, Anna
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Tsourma, Maria
    Mitran, Bogdan
    Honarvar, Hadis
    Robillard, Marc
    Rossin, Raffaella
    ten Hoeve, Wolter
    Lubberink, Mark
    Orlova, Anna
    Karlström, Amelie Eriksson
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Tolmachev, Vladimir
    Feasibility of Affibody-Based Bioorthogonal Chemistry Mediated Radionuclide Pretargeting2016Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 57, nr 3, s. 431-436Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules constitute a new class of probes for radionuclide tumor targeting. The small size of Affibody molecules is favorable for rapid localization in tumors and clearance from circulation. However, high renal reabsorption of Affibody molecules prevents the use of residualizing radiometals, including several promising low-energy (beta- and alpha-emitters, for radionuclide therapy. We tested a hypothesis that Affibody-based pretargeting mediated by a bioorthogonal interaction between trans-cyclooctene (TCO) and tetrazine would provide higher accumulation of radiometals in tumor xenografts than in the kidneys. Methods: TCO was conjugated to the anti-human epidermal growth factor receptor 2 (HER2) Affibody molecule Z(2395). DOTA-tetrazine was labeled with In-111 and Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV-3 and BT474 cell lines. In vivo studies were performed on BALB/C nu/nu mice bearing SKOV-3 xenografts. Results: I-125-Z(2395)-TCO bound specifically to HER2-expressing cells in vitro with an affinity of 45 +/- 16 pM. In-111-tetrazine bound specifically and selectively to Z(2325)-TCO pretreated cells. In vivo studies demonstrated HER2-specific I-125-Z(2395)-TCO accumulation in xenografts. TCO-mediated In-111-tetrazine localization was shown in tumors, when the radiolabeled tracer was injected 4 h after an injection of Z(2395)-TCO. At 1 h after injection, the tumor uptake of In-111-tetrazine and Lu-177-tetrazine was approximately 2-fold higher than the renal uptake. Pretargeting provided more than a 56-fold reduction of renal uptake of In-111 in comparison with direct targeting. Conclusion: The feasibility of Affibody-based bioorthogonal chemistry-mediated pretargeting was demonstrated. The use of pre-targeting provides a substantial reduction of radiometal accumulation in kidneys, creating preconditions for palliative radionuclide therapy.

  • 3. Altai, Mohamed
    et al.
    Wållberg, Helena
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Honarvar, Hadis
    Strand, Joanna
    Orlova, Anna
    Varasteh, Zohreh
    Sandström, Mattias
    Löfblom, John
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Larsson, Erik
    Strand, Sven-Erik
    Lubberink, Mark
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi. Uppsala University, Sweden.
    Tolmachev, Vladimir
    Re-188-Z(HER2:V2), a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment2014Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 55, nr 11, s. 1842-1848Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small (7 kDa) nonimmunoglobulin scaffold proteins with favorable tumor-targeting properties. Studies concerning the influence of chelators on biodistribution of Tc-99m-labeled Affibody molecules demonstrated that the variant with a C-terminal glycyl-glycyl-glycyl-cysteine peptide-based chelator (designated Z(HER2:V2)) has the best biodistribution profile in vivo and the lowest renal retention of radioactivity. The aim of this study was to evaluate Re-188-Z(HER2:v2) as a potential candidate for radionuclide therapy of human epidermal growth factor receptor type 2 (HER2)-expressing tumors. Methods: Z(HER2:V2) was labeled with Re-188 using a gluconate-containing kit. Targeting of HER2-overexpressing SKOV-3 ovarian carcinoma xenografts in nude mice was studied for a dosimetry assessment. Results: Binding of Re-188-Z(HER2:V2) to living SKOV-3 cells was demonstrated to be specific, with an affinity of 6.4 +/- 0.4 pM. The biodistribution study showed a rapid blood clearance (1.4 +/- 0.1 percentage injected activity per gram [%ID/g] at 1 h after injection). The tumor uptake was 14 +/- 2, 12 +/- 2, 5 +/- 2, and 1.8 +/- 0.5 %IA/g at 1, 4, 24, and 48 h after injection, respectively. The in vivo targeting of HER2-expressing xenografts was specific. Already at 4 h after injection, tumor uptake exceeded kidney uptake (2.1 +/- 0.2 %IA/g). Scintillation-camera imaging showed that tumor xenografts were the only sites with prominent accumulation of radioactivity at 4 h after injection. Based on the biokinetics, a dosimetry evaluation for humans suggests that Re-188-Z(HER2:v2) would provide an absorbed dose to tumor of 79 Gy without exceeding absorbed doses of 23 Gy to kidneys and 2 Gy to bone marrow. This indicates that future human radiotherapy studies may be feasible. Conclusion: (188)ReZ(HER2:v2) can deliver high absorbed doses to tumors without exceeding kidney and bone marrow toxicity limits.

  • 4.
    Chapnick, Jeffrey V
    et al.
    New York University.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    Sanger, Joseph J.
    New York University.
    Megibow, Alec J.
    New York University.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Oratz, R.
    New York University, Department of Radiology.
    Birnbaum, Bernard A.
    New York University.
    Martino, J.
    New York University, Department of Radiology.
    Fusion of Functional Spect Images with Structural CT/MRI Images1991Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 32, s. 1135-Artikkel i tidsskrift (Fagfellevurdert)
  • 5. Heskamp, Sandra
    et al.
    Laverman, Peter
    Rosik, Daniel
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Boschetti, Frederic
    van der Graaf, Winette T. A.
    Oyen, Wim J. G.
    van Laarhoven, Hanneke W. M.
    Tolmachev, Vladimir
    Boerman, Otto C.
    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 Cancer2012Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 1, s. 146-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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.

  • 6.
    Kramer, Elissa L.
    et al.
    New York University.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Sanger, Joseph J.
    New York University.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    Megibow, Alec J.
    New York University.
    CT/SPECT Fusion for Correlation of Monoclonal-antibody (MOAB) SPECT and Abdominal CT1988Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 29, nr 7, s. 1313-Artikkel i tidsskrift (Annet vitenskapelig)
  • 7.
    Lindbo, Sarah
    et al.
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Garousi, Javad
    Mitran, Bogdan
    Altai, Mohamed
    Buijs, Jos
    Orlova, Anna
    Hober, Sophia
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Tolmachev, Vladimir
    Radionuclide Tumor Targeting Using ADAPT Scaffold Proteins: Aspects of Label Positioning and Residualizing Properties of the Label2018Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, nr 1, s. 93-99Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Visualization of cancer-associated alterations of molecular phenotype using radionuclide imaging is a noninvasive approach to stratifying patients for targeted therapies. The engineered albumin-binding domain-derived affinity protein (ADAPT) is a promising tracer for radionuclide molecular imaging because of its small size (6.5 kDa), which satisfies the precondition for efficient tumor penetration and rapid clearance. Previous studies demonstrated that the human epidermal growth factor receptor type 2 (HER2)-targeting ADAPT6 labeled with radiometals at the N terminus is able to image HER2 expression in xenografts a few hours after injection. The aim of this study was to evaluate whether the use of a non-residualizing label or placement of the labels at the C terminus would further improve the targeting properties of ADAPT6. Methods: Two constructs, Cys(2)-ADAPT6 and Cys(59)-ADAPT6, having the (HE)(3)DANS sequence at the N terminus were produced and site-specifically labeled using In-111-DOTA or I-125-iodo-((4-hydroxyphenyl) ethyl) maleimide (HPEM). The conjugates were compared in vitro and in vivo. HER2-targeting properties and biodistribution were evaluated in BALB/C nu/nu mice bearing ovarian carcinoma cell (SKOV-3) xenografts. Results: Specific HER2 binding and high affinity were preserved after labeling. Both Cys(2)-ADAPT6 and Cys59-ADAPT6 were internalized slowly by HER2-expressing cancer cells. Depending on the label position, uptake at 4 h after injection varied from 10% to 22% of the injected dose per gram of tumor tissue. Regardless of terminus position, the I-125-HPEM label provided more than 140-fold lower renal uptake than the In-111-DOTA label at 4 after injection. The tumor-to-organ ratios were, in contrast, higher for both of the (111)InDOTA- labeled ADAPT variants in other organs. Tumor-to-blood ratios for In-111-labeled Cys(2)-ADAPT6 and Cys(59)-ADAPT6 did not differ significantly (250-280), but In-111-DOTA-Cys(59)-ADAPT6 provided significantly higher tumor-to-lung, tumor-to-liver, tumor-to-spleen, and tumor-to-muscle ratios. Radioiodinated variants had similar tumor-to-organ ratios, but I-125-HPEM-Cys(59)-ADAPT6 had significantly higher tumor uptake and a higher tumor-to-kidney ratio. Conclusion: Residualizing properties of the label strongly influence the targeting properties of ADAPT6. The position of the radiolabel influences targeting as well, although to a lesser extent. Placement of a label at the C terminus yields the best biodistribution features for both radiometal and radiohalogen labels. Low renal retention of the radioiodine label creates a precondition for radionuclide therapy using I-131-labeled HPEM-Cys(59)-ADAPT6.

  • 8.
    Moy, Linda
    et al.
    New York University, Department of Radiology.
    Ponzo, Fabio
    New York University, Department of Radiology.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Kommunikationssystem, CoS.
    Murphy-Walcott, Antoinette D.
    New York University, Department of Radiology.
    Deans, Abby E.
    New York University, Department of Radiology.
    Kitazono, Mary T.
    New York University, Department of RadiologyNew York University, Department of Radiology.
    Travascio, Laura
    New York University, Department of Radiology.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Improving specificity of breast MRI using prone PET and fused MRI and PET 3D volume datasets2007Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 48, nr 4, s. 528-537Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    MRI is a sensitive method for detecting invasive breast cancer, but it lacks specificity. To examine the effect of combining PET with MRI on breast lesion characterization, a prototype positioning device was fabricated to allow PET scans to be acquired in the same position as MRI scans-that is, prone. Methods: To test the hypothesis that fusion of 18F-FDG PET and MRI scans improves detection of breast cancer, 23 patients with suspected recurrent or new breast cancer underwent a routine whole-body PET scan, a prone PET scan of the chest, and a routine breast MRJ scan. The attenuation-corrected prone PET and MRI clatasets were registered twice by different operators. The fusion results were judged for quality by visual inspection and statistical analysis. A joint reading of the MRI and PET scans side by side and integrated images was performed by a nuclear medicine physician and a radiologist. Sensitivity and specificity of MRI and combined MRI and PET scans were calculated on the basis of pathology reports or at least 1 y of clinical and radiologic follow-up. Results: All fusions were verified to be well matched using specific anatomic criteria. A total of 45 lesions was assessed. Lesion size range was 0.6 to 10.0 cm. Of the 44 breasts examined, 29 were suspicious for cancer, of which 15 were found to be positive on surgical excision. In lesion-by-lesion analysis, sensitivity and specificity of MRI alone were 92% and 52%, respectively; after MRI and PETfusion, they were 63% and 95%, respectively. The positive predictive value and the negative predictive value for MRI alone were 69% and 85%, respectively; after MRI and PET fusion, they were 94% and 69%, respectively. Conclusion: Acquisition of prone PET scans using the new positioning device permitted acquisition of prone scans suitable for fusion with breast MRI scans. Fused PET and MRI scans increased the specificity of MRI but decreased the sensitivity in this small group of patients. Additional data are needed to confirm the statistical significance of these preliminary findings.

  • 9.
    Noz, Marilyn E.
    et al.
    New York University, Department of Radiology.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    McGee, S. A.
    Sanger, Joseph J.
    New York University.
    Schwimmer, J. J.
    New York University.
    Bae, R.
    New York University.
    An Integrated Approach to Estimating Biodistribution and Radiation Absorbed Dose from Planar Scintigraphic Views of Radiolabeled Monoclonal Antibodies1992Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 33, s. 925-Artikkel i tidsskrift (Fagfellevurdert)
  • 10.
    Noz, Marilyn E.
    et al.
    New York University.
    Kramer, Elissa L.
    New York University.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Scence.
    Sanger, Joseph J.
    New York University.
    An Integrated Approach to Estimating Biodistribution and Radiation Absorbed Dose from Radiolabeled Monoclonal Antibodies-II1993Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 34, nr 5, s. P128-Artikkel i tidsskrift (Fagfellevurdert)
  • 11.
    Noz, Marilyn E.
    et al.
    New York University, Department of Radiology.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Kommunikationssystem, CoS.
    Sanger, Joseph J
    New York University.
    Approach to Estimating Biodistribution and Radiation Absorbed Dose from Planar Scintigraphic Views of Radiolabeled Monoclonal Antibodies - II1993Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 34, nr 5, s. 128 Supplement S-Artikkel i tidsskrift (Fagfellevurdert)
  • 12.
    Noz, Marilyn E.
    et al.
    New York University, Department of Radiology.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    Columbia University, Department of Computer Science.
    Sanger, Joseph J.
    New York University.
    Chapnick, Jeffrey V
    New York University.
    Megibow, Alec J.
    New York University.
    Birnbaum, Bernard A.
    New York University.
    Fusion of Radiolabeled Monoclonal Antibody SPECT Images with CT/MRI Images1992Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 33, s. 960-Artikkel i tidsskrift (Fagfellevurdert)
  • 13.
    Noz, Marilyn E.
    et al.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Kommunikationssystem, CoS, Radio Systems Laboratory (RS Lab).
    F-18-FDG PET in detecting primary breast cancer: Reply2007Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 48, nr 10, s. 1752-1752Artikkel i tidsskrift (Annet vitenskapelig)
  • 14. Orlova, A.
    et al.
    Jonsson, Anders
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Rosik, Daniel
    KTH, Skolan för bioteknologi (BIO), Proteinteknologi.
    Lundqvist, H.
    Lindborg, M.
    Abrahmsen, L.
    Ekblad, C.
    Frejd, F. Y.
    Tolmachev, V.
    Site-specific radiometal labeling and improved biodistribution using ABY-027, a novel HER2-targeting affibody molecule-albumin-binding domain fusion protein2013Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 54, nr 6, s. 961-968Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Because of their better penetration, smaller targeting proteins may be superior to antibodies for radioimmunotherapy of solid tumors. Therefore, Affibody molecules (6.5 kDa) have a potential for being suitable as targeted moiety for radiolabeled therapeutic proteins. Previous studies have demonstrated that a fusion of an Affibody molecule with an albumin-binding domain (ABD) provides a strong noncovalent binding to albumin in vivo. This strong noncovalent binding can be used for reduction of the renal uptake of the Affibody molecule while maintaining a size smaller than that of an antibody, which is important when using residualizing radionuclide labels conjugated to Affibody molecules. The goal of this study was to design and evaluate a new targeting Affibody - ABD fusion protein with improved biodistribution properties for radionuclide therapy. Methods: A novel Affibody-based construct, Z HER2:2891-ABD035-DOTA (ABY-027), was created by fusion of the reengineered HER2-binding Affibody molecule ZHER2:2891 to the N terminus of the high-affinity ABD035, and a maleimido-derivative of DOTA was conjugated at the C terminus of the construct. Binding and processing of 177Lu-ABY-027 by HER2-expressing cells were evaluated in vitro. Targeting of HER2-expressing SKOV-3 xenografts was evaluated in BALB/C nu/nu mice and compared with targeting of previously reported ABD-(Z HER2:342)2. Results: The binding affinity (dissociation constant) of ABY-027 to HER2 (74 pM) was the same as for the parental Z HER2:2891 (76 pM). ABY-027 was stably labeled with 177Lu and 111In with preserved specific binding to HER2-expressing cells in vitro. In vivo receptor saturation experiments demonstrated that targeting of SKOV-3 xenografts in BALB/C nu/nu mice was HER2-specific. 177Lu-ABY- 027 demonstrated substantially (2- to 3-fold) lower renal and hepatic uptake than previously assessed HER2-specific Affibody-based albumin-binding agents. Tumor uptake of radiolabeled ABY-027 at 48 h after injection was 2-fold higher than that for previously reported ABD-(ZHER2:342)2. Conclusion: An optimized molecular design of an ABD fusion protein resulted in an Affibody molecule construct with better properties for therapy. Fully preserved in vivo targeting of the fusion protein was shown in xenografted mice. Site-specific coupling of DOTA provides a uniform conjugate and creates the potential for labeling with a broad range of therapeutic radionuclides. The biodistribution of 177Lu-ABY-027 in a murine model suggests it is more suitable for therapy than alternative approaches.

  • 15. Orlova, Anna
    et al.
    Nilsson, Fredrik Y.
    Wikman, Maria
    Widstrom, Charles
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Carlsson, Jorgen
    Tolmachev, Vladimir
    Comparative in vivo evaluation of technetium and iodine labels on an anti-HER2 Affibody for single-photon imaging of HER2 expression in tumors2006Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 47, nr 3, s. 512-519Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In vivo diagnosis with cancer-specific targeting agents that have optimal characteristics for imaging is an important development in treatment planning for cancer patients. Overexpression of the HER2 antigen is high in several types of carcinomas and has predictive and prognostic value, especially for breast cancer. A new type of targeting agent, the Affibody molecule, was described recently. An Affibody dimer, HiS(6)-(ZHER(2:4))(2) (15.4 kDa), binds to HER2 with an affinity of 3 nmol/L and might be used for the imaging of HER2 expression. The use of Tc-99m might improve the availability of the labeled conjugate, and Tc(l)-carbonyl chemistry enables the site-specific labeling of the histidine tag on the Affibody molecule. The goals of the present study were to prepare Tc-99m-labeled Hi0S(6)-(Z(HER2:4))(2) and to evaluate its targeting properties compared with the targeting properties of I-125 -4-iodobenzoate-HiS(6)-(Z(HER2:4))(2) [I-125-HiS(6)-(Z(HER2:4))(2)]- Methods: The labeling of HiS6-(Z(HER2:4))2 with Tc-99m was performed with an IsoLink kit. The specificity of Tc-99m-HiS(6)-(Z(HER2:4))(2) binding to HER2 was evaluated in vitro with SK-OV-3 ovarian carcinoma cells. The comparative biodistributions of Tc-99m-HiS(6)-(Z(HER2,4))(2) and I-125-HiS(6)-(Z(HER2:4))(2) in tumor-bearing BALB/c nulnu mice were determined. Results: The labeling yield for Tc-99m-HIS6(Z(HER2:4))(2) was similar to 60% (50 degrees C), and the radiochernical purity was greater than 97%. The conjugate was stable during storage and under histicline and cysteine challenges and demonstrated receptor-specific binding. The biodistribution study demonstrated tumor-specific uptake levels (percentage injected activity per gram of tissue [%]A/gj) of 2.6 %IA/g for Tc-99m-HiS(6)-(Z(HER2:4))(2) and 2.3 % IA/g for I-125-HiS6-(Z(HER2:4))(2) at 4 h after injection. Both conjugates provided clear imaging of SK-OV-3 xenografts at 6 h after injection. The tumor-to-nontumor ratios were much more favorable for the radioiodinated Affibody. Conclusion: The use of Tc(l)-carbonyl chemistry enabled us to prepare a stable, site-specifically labeled 99mTc-HiS(6)-(Z(HER2:4))(2) conjugate that was able to bind to HER2-expressing cells in vitro and in vivo. The indirectly radioiodinated conjugate provided better tumor-to-liver ratios. The labeling of Affibody molecules with Tc-99m should be investigated further.

  • 16. Orlova, Anna
    et al.
    Wållberg, Helena
    Stone-Elander, Sharon
    Tolmachev, Vladimir
    On the Selection of a Tracer for PET Imaging of HER2-Expressing Tumors: Direct Comparison of a (124)I-Labeled Affibody Molecule and Trastuzumab in a Murine Xenograft Model2009Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, nr 3, s. 417-425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human epidermal growth factor receptor type 2 (HER2) is a tyrosine kinase, which is often overexpressed in many carcinomas. Imaging HER2 expression in malignant tumors can provide important prognostic and predictive diagnostic information. The use of anti-HER2 tracers labeled with positron-emitting radionuclides may increase the sensitivity of HER2 imaging. The goal of this study was to compare directly 2 approaches for developing anti-HER2 PET tracers: a (124)I-labeled monoclonal antibody and a small (7-kDa) scaffold protein, the Affibody molecule, Methods: The anti-HER2 Affibody Z(HER2:342) and humanized monoclonal antibody trastuzumab were labeled with (124/125)I using p-iodobenzoate (PIB) as a linker. Cellular processing of both tracers by HER2-expressing cells was investigated. The biodistributions of (124)I-PIB-Z(HER2:342) and (125)I-PIB-trastuzumab were compared in BALB/C nu/nu mice bearing HER2-expressing NCI-N87 xenografts using paired labels. Small-animal PET of (124)I-PIB-Z(HER2:342) and (124)I-PIB-trastuzumab in tumor-bearing mice was performed at 6, 24, and 72 h after injection. Results: Both radioiodinated Z(HER2:342) and trastuzumab bound specifically to HER2-expressing cells in vitro and specifically targeted HER2-expressing xenografts in vivo. Radioiodinated trastuzumab was more rapidly internalized and degraded, which resulted in better retention of radioactivity delivered by Z(HER2:342). Total uptake of trastuzumab in tumors was higher than that of (124)I-PIB-Z(HER2:342). However, tumor-to-organ ratios were appreciably higher for (124)I-PIB-Z(HER2:342) due to the more rapid clearance of radioactivity from blood and normal organs. The ex vivo results were confirmed by small-animal PET. Conclusion: The use of the small scaffold targeting Affibody provides better contrast in HER2 imaging than does the monoclonal antibody.

  • 17.
    Ponzo, Fabio
    et al.
    New York University, Department of Radiology.
    Moy, Linda
    New York University, Department of Radiology.
    Murphy-Walcott, Antoinette D.
    New York University, Department of Radiology.
    Kitazono, M.
    New York University, Department of Radiology.
    Deans, Abby E.
    New York University, Department of Radiology.
    Noz, Marilyn E.
    New York University, Department of Radiology.
    Maguire Jr., Gerald Q.
    KTH, Skolan för informations- och kommunikationsteknik (ICT), Kommunikationssystem, CoS.
    Kramer, Elissa L.
    New York University, Department of Radiology.
    Improving specificity of breast MRI using a new mammoPET apparatus and fused MRI/PET 3D data sets2006Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 47, nr Supp1, s. 396P-Artikkel i tidsskrift (Fagfellevurdert)
  • 18.
    Tolmachev, Vladimir
    et al.
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Friedman, Mikaela
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Sandström, Mattias
    Section of Hospital Physics, Department of Oncology, Uppsala University Hospital.
    Eriksson, Tove L. J.
    Affibody AB, Bromma.
    Rosik, Daniel
    Affibody AB, Bromma.
    Hodik, Monika
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Frejd, Fredrik Y.
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Orlova, Anna
    Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University.
    Affibody Molecules for Epidermal Growth Factor Receptor Targeting In Vivo: Aspects of Dimerization and Labeling Chemistry2009Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, nr 2, s. 274-283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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 Z(EGFR: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, (Z(EGFR:1907))(2), were labeled with In-111 using benzyl-diethylenetriaminepentaacetic acid and with I-125 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 In-111-labeled tracer than for the radioiodinated counterpart. In vivo, all conjugates accumulated specifically in xenografts and in EGFRexpressing 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, In-111-labeled Z(EGFR:1907), provided a tumor-to-blood ratio of 100 (24 h after injection). Conclusion: The radiometal-labeled monomeric Aff ibody molecule Z(EGFR:1907) has a potential for radionuclide molecular imaging of EGFR expression in malignant tumors.

  • 19. Tolmachev, Vladimir
    et al.
    Malmberg, Jennie
    Hofström, Camilla
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Abrahmsén, Lars
    Bergman, Thomas
    Sjöberg, Anna
    Sandström, Mattias
    Gräslund, Torbjörn
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Orlova, Anna
    Imaging of Insulinlike Growth Factor Type 1 Receptor in Prostate Cancer Xenografts Using the Affibody Molecule (111)In-DOTA-Z(IGF1R:4551)2012Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 1, s. 90-97Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One of the pathways leading to androgen independence in prostate cancer involves upregulation of insulinlike growth factor type 1 receptor (IGF-1R). Radionuclide imaging of IGF-1R in tumors might be used for selection of patients who would most likely benefit from IGF-1R-targeted therapy. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of IGF-1R expression in prostate cancer xenografts using a small nonimmunoglobulin-derived binding protein called an Affibody molecule. Methods: The IGF-1R-binding Z(IGF1R:4551) Affibody molecule was site-specifically conjugated with a maleimido derivative of DOTA and labeled with (111)In. The binding of radiolabeled Z(IGF1R:4551) to IGF-1R-expressing cells was evaluated in vitro and in vivo. Results: DOTA-Z(IGF1R:4551) can be stably labeled with (111)In with preserved specific binding to IGF-1R-expressing cells in vitro. In mice, (111)In-DOTAZ(IGF1R):(4551) accumulated in IGF-1R-expressing organs (pancreas, stomach, lung, and salivary gland). Receptor saturation experiments demonstrated that targeting of DU-145 prostate cancer xenografts in NMRI nu/nu mice was IGF-1R-specific. The tumor uptake was 1.1 +/- 0.3 percentage injected dose per gram, and the tumor-to-blood ratio was 3.2 +/- 0.2 at 8 h after injection. Conclusion: This study demonstrates the feasibility of in vivo targeting of IGF-1R-expressing prostate cancer xenografts using an Affibody molecule. Further development of radiolabeled Affibody molecules might provide a useful clinical tool for stratification of patients with prostate cancer for IGF-1R-targeting therapy.

  • 20. Tolmachev, Vladimir
    et al.
    Tran, Thuy A.
    Rosik, Daniel
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Sjöberg, Anna
    Abrahmsén, Lars
    Orlova, Anna
    Tumor Targeting Using Affibody Molecules: Interplay of Affinity, Target Expression Level, and Binding Site Composition2012Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 6, s. 953-960Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radionuclide imaging of cancer-associated molecular alterations may contribute to patient stratification for targeting therapy. Scaffold high-affinity proteins, such as Affibody molecules, are a new, promising class of probes for in vivo imaging. Methods. The effects of human epidermal growth factor receptor 2 (HER2) affinity and binding site composition of HER2-binding Affibody molecules, and of the HER2 density on the tumor targeting, were studied in vivo. The tumor uptake and tumor-to-organ ratios of Affibody molecules with moderate (dissociation constant [K-D)] 10(-9) M) or high (K-D = 10(-10) M) affinity were compared between tumor xenografts with a high (SKOV-3) and low (LS174T) HER2 expression level in BALB/C nu/nu mice. Two Affibody molecules with similar affinity (K-D = 10(-10) M) but having alternative amino acids in the binding site were compared. Results. In SKOV-3 xenografts, uptake was independent of affinity at 4 h after injection, but high-affinity binders provided 2-fold-higher tumor radioactivity retention at 24 h. In LS174T xenografts, uptake of high-affinity probes was already severalfold higher at 4 h after injection, and the difference was increased at 24 h. The clearance rate and tumor-to-organ ratios were influenced by the amino acid composition of the binding surface of the tracer protein. Conclusion. The optimal affinity of HER2-binding Affibody molecules depends on the expression of a molecular target. At a high expression level (>10(6) receptors per cell), an affinity in the low-nanomolar range is sufficient. At moderate expression, subnanomolar affinity is desirable. The binding site composition can influence the imaging contrast. This information may be useful for development of imaging agents based on scaffold affinity proteins.

  • 21.
    Westerlund, Kristina
    et al.
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Protein Engineering.
    Altai, Mohamed
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    Mitran, Bogdan
    Uppsala Univ, Div Mol Imaging, Dept Med Chem, Uppsala, Sweden..
    Konijnenberg, Mark
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Oroujeni, Maryam
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    Atterby, Christina
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    de Jong, Marion
    Erasmus MC, Dept Radiol & Nucl Med, Rotterdam, Netherlands..
    Orlova, Anna
    Uppsala Univ, Div Mol Imaging, Dept Med Chem, Uppsala, Sweden..
    Mattsson, Johanna
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    Micke, Patrick
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    Eriksson Karlström, Amelie
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Protein Engineering.
    Tolmachev, Vladimir
    Uppsala Univ, Dept Immunol Genet & Pathol, SE-75181 Uppsala, Sweden..
    Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle2018Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, nr 7, s. 1092-1098Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are small proteins engineered using a nonanti-body scaffold. Radiolabeled Affibody molecules are excellent imaging probes, but their application to radionuclide therapy has been prevented by high renal reabsorption. The aim of this study was to test the hypothesis that Affibody-based peptide nucleic acid (PNA)-mediated pretargeted therapy of human epidermal growth factor receptor 2 (HER2)-expressing cancer extends survival without accompanying renal toxicity. Methods: A HER2-targeting Affibody molecule ligated with an AGTCGTGATGTAGTC PNA hybridization probe (Z(HER2:342)-SR-HP1) was used as the primary pretargeting agent. A complementary AGTCGTGATGTAGTC PNA conjugated to the chelator DOTA and labeled with the radionuclide Lu-177 (Lu-177-HP2) was used as the secondary agent. The influence of different factors on pretargeting was investigated. Experimental radionuclide therapy in mice bearing SKOV-3 xenografts was performed in 6 cycles separated by 7 d. Results: Optimal tumor targeting was achieved when 16 MBq/3.5 mu g (0.65 nmol) of Lu-177-HP2 was injected 16 h after injection of 100 mu g (7.7 nmol) of Z(HER2:342)-SR-HP1. The calculated absorbed dose to tumors was 1,075 mGy/MBq, whereas the absorbed dose to kidneys was 206 mGy/MBq and the absorbed dose to blood (surrogate of bone marrow) was 4 mGy/MBq. Survival of mice was significantly longer (P < 0.05) in the treatment group (66 d) than in the control groups treated with the same amount of Z(HER2:342)-SR-HP1 only (37 d), the same amount and activity of Lu-177-HP2 only (32 d), or phosphate-buffered saline (37 d). Conclusion: The studied pretargeting system can deliver an absorbed dose to tumors appreciably exceeding absorbed doses to critical organs, making Affibody-based PNA-mediated pretargeted radionuclide therapy highly attractive.

  • 22.
    Wållberg, Helena
    et al.
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Grafström, Jonas
    Cheng, Qing
    Lu, Li
    Ahlzén, Hanna-Stina Martinsson
    Samén, Erik
    Thorell, Jan-Olov
    Johansson, Katarina
    Dunås, Finn
    Olofsson, Maria Hägg
    Stone-Elander, Sharon
    Arnér, Elias S. J.
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    HER2-Positive Tumors Imaged Within 1 Hour Using a Site-Specifically C-11-Labeled Sel-Tagged Affibody Molecule2012Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 53, nr 9, s. 1446-1453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A rapid, reliable method for distinguishing tumors or metastases that overexpress human epidermal growth factor receptor 2 (HER2) from those that do not is highly desired for individualizing therapy and predicting prognoses. In vivo imaging methods are available but not yet in clinical practice; new methodologies improving speed, sensitivity, and specificity are required. Methods: A HER2-binding Affibody molecule, Z(HER2:342), was recombinantly fused with a C-terminal selenocysteine-containing tetrapeptide Sel-tag, allowing site-specific labeling with either C-11 or Ga-68, followed by biodistribution studies with small-animal PET. Dosimetry data for the 2 radiotracers were compared. Imaging of HER2-expressing human tumor xenografts was performed using the C-11-labeled Affibody molecule. Results: Both the C-11- and Ga-68-labeled tracers initially cleared rapidly from the blood, followed by a slower decrease to 4-5 percentage injected dose per gram of tissue at 1 h. Final retention in the kidneys was much lower (>5-fold) for the C-11-labeled protein, and its overall absorbed dose was considerably lower. C-11-Z(HER2:342) showed excellent tumor-targeting capability, with almost 10 percentage injected dose per gram of tissue in HER2-expressing tumors within 1 h. Specificity was demonstrated by preblocking binding sites with excess ligand, yielding significantly reduced radiotracer uptake (P = 0.002), comparable to uptake in tumors with low HER2 expression. Conclusion: To our knowledge, the Sel-tagging technique is the first that enables site-specific C-11-radiolabeling of proteins. Here we present the finding that, in a favorable combination between radionuclide half-life and in vivo pharmacokinetics of the Affibody molecules, C-11-labeled Set-tagged Z(HER2:342) can successfully be used for rapid and repeated PET studies of HER2 expression in tumors.

  • 23.
    Wållberg, Helena
    et al.
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Orlova, Anna
    Altai, Mohammed
    Hosseinimehr, Seyed Jalal
    Widström, Charles
    Malmberg, Jennie
    Ståhl, Stefan
    KTH, Skolan för bioteknologi (BIO), Molekylär Bioteknologi.
    Tolmachev, Vladimir
    Molecular Design and Optimization of Tc-99m-Labeled Recombinant Affibody Molecules Improves Their Biodistribution and Imaging Properties2011Inngår i: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 52, nr 3, s. 461-469Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Affibody molecules are a recently developed class of targeting proteins based on a nonimmunoglobulin scaffold. The small size (7 kDa) and subnanomolar affinity of Affibody molecules enables high-contrast imaging of tumor-associated molecular targets, particularly human epidermal growth factor receptor type 2 (HER2). Tc-99m as a label offers advantages in clinical practice, and earlier studies demonstrated that Tc-99m-labeled recombinant Affibody molecules with a C-terminal cysteine could be used for HER2 imaging. However, the renal retention of radioactivity exceeded tumor uptake, which might complicate imaging of metastases in the lumbar region. The aim of this study was to develop an agent with low renal uptake and preserved tumor targeting. Methods: A series of recombinant derivatives of the HER2-binding Z(HER2:342) Affibody molecule with a C-terminal chelating sequence, -GXXC (X denoting glycine, serine, lysine, or glutamate), was designed. The constructs were labeled with Tc-99m and evaluated in vitro and in vivo. Results: All variants were stably labeled with Tc-99m, with preserved capacity to bind specifically to HER2-expressing cells in vitro and in vivo. The composition of the chelating sequence had a clear influence on the cellular processing and biodistribution properties of the Affibody molecules. The best variant, Tc-99m-Z(HER2:V2), with the C-terminal chelating sequence -GGGC, provided the lowest radioactivity retention in all normal organs and tissues including the kidneys. Tc-99m-Z(HER2:V2) displayed high uptake of radioactivity in HER2-expressing xenografts, 22.6 +/- 4.0 and 7.7 +/- 1.5 percentage injected activity per gram of tissue at 4 h after injection in SKOV-3 (high HER2 expression) and DU-145 (low HER2 expression) tumors, respectively. In both models, the tumor uptake exceeded the renal uptake. Conclusion: These results demonstrate that the biodistribution properties of recombinant Tc-99m-labeled Affibody molecules can be optimized by modification of the C-terminal cysteine-containing chelating sequence. Tc-99m-Z(HER2:V2) is a promising candidate for further development as a diagnostic radiopharmaceutical for imaging of HER2-expressing tumors. These results may be useful for the development of imaging agents based on other Affibody molecules and, hopefully, other scaffolds.

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