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Vorobyeva, A., Bragina, O., Altai, M., Mitran, B., Orlova, A., Shulga, A., . . . Deyev, S. (2018). Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors. Contrast Media & Molecular Imaging, Article ID 6930425.
Open this publication in new window or tab >>Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors
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2018 (English)In: Contrast Media & Molecular Imaging, ISSN 1555-4309, E-ISSN 1555-4317, article id 6930425Article in journal (Refereed) Published
Abstract [en]

High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2-targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [Tc-99m] Tc(CO)(3) using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [I-125] I-DARPin 9_29 and [Tc-99m] Tc(CO)(3)-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 +/- 0.7 % ID/g and 2.9 +/- 0.7 % ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 +/- 0.09 % ID/g and 0.30 +/- 0.05 % ID/g, respectively. Retention of [I-125] I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [Tc-99m] Tc(CO)(3)-DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29.

Place, publisher, year, edition, pages
WILEY-HINDAWI, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-359679 (URN)10.1155/2018/6930425 (DOI)000435897100001 ()29977173 (PubMedID)
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509VINNOVA, 2016-04060Swedish Cancer Society, 2015/350Swedish Cancer Society, 2017/425Swedish Society for Medical Research (SSMF)
Available from: 2018-09-06 Created: 2018-09-06 Last updated: 2018-09-06Bibliographically approved
Summer, D., Garousi, J., Oroujeni, M., Mitran, B., Andersson, K. G., Vorobyeva, A., . . . Decristoforo, C. (2018). Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression. Molecular Pharmaceutics, 15(1), 175-185
Open this publication in new window or tab >>Cyclic versus Noncyclic Chelating Scaffold for Zr-89-Labeled ZEGFR:2377 Affibody Bioconjugates Targeting Epidermal Growth Factor Receptor Overexpression
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 175-185Article in journal (Refereed) Published
Abstract [en]

Zirconium-89 is an emerging radionuclide for positron emission tomography (PET) especially for biomolecules with slow e pharmacokinetics as due to its longer half-life, in comparison to fluorine 18 and gallium-68, imaging at late time points is feasible. Desferrioxamine B (DFO), a linear bifunctional chelator (BFC) is mostly used for this radionuclide so far but shows limitations regarding stability. Our group recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study was designed to compare FSC and DFO head-to head as bifunctional chelators for "Zr-radiolabeled EGFR-targeting ZEGFR:2377 affibody bioconjugates. FSC-ZEGFR:2377 and DFOZEGFR:2377 were evaluated regarding radiolabeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution, and microPET-CT imaging. Both conjugates were efficiently labeled with zirconium-89 at room temperature but radiochemical yields increased substantially at elevated temperature, 85 degrees C. Both 89Zr-FSC-ZEGFR:2377 and Zr-89-DFO-ZEGFR:2377 revealed remarkable specificity, affinity and slow cell-line dependent internalization. Radiolabeling at 85 degrees C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake. In comparison 89ZrDFO-ZEGFR:2377, radiolabeled at room temperature, showed a significant difference regarding tumor-to-organ ratios. MicroPET-CT imaging studies of Zr-89-FSC-ZEGFR:2377 as well as Zr-89-DFO-ZEGFR:2377 confirmed these findings. In summary we were able to show that FSC is a suitable alternative to DFO for radiolabeling of biomolecules with zirconium-89. Furthermore, our findings indicate that Zr-89-radiolabeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
Keywords
FSC, DFO, zirconium-89, EGFR, affibody, PET
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-341305 (URN)10.1021/acs.molpharmaceut.7b00787 (DOI)000419419800017 ()29160082 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/474, CAN2015/350Swedish Research Council, VR 2015-02509, VR 2015-02353Knut and Alice Wallenberg Foundation
Available from: 2018-02-07 Created: 2018-02-07 Last updated: 2018-02-07Bibliographically approved
Vorobyeva, A., Westerlund, K., Mitran, B., Altai, M., Rinne, S., Sörensen, J., . . . Karlström, A. E. (2018). Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy. Scientific Reports, 8, Article ID 9643.
Open this publication in new window or tab >>Development of an optimal imaging strategy for selection of patients for affibody-based PNA-mediated radionuclide therapy
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 9643Article in journal (Refereed) Published
Abstract [en]

Affibody molecules are engineered scaffold proteins, which demonstrated excellent binding to selected tumor-associated molecular abnormalities in vivo and highly sensitive and specific radionuclide imaging of Her2-expressing tumors in clinics. Recently, we have shown that peptide nucleic acid (PNA)-mediated affibody-based pretargeted radionuclide therapy using beta-emitting radionuclide Lu-177 extended significantly survival of mice bearing human Her2-expressing tumor xenografts. In this study, we evaluated two approaches to use positron emission tomography (PET) for stratification of patients for affibody-based pretargeting therapy. The primary targeting probe Z(HER2:342)SR-HP1 and the secondary probe HP2 (both conjugated with DOTA chelator) were labeled with the positron-emitting radionuclide Ga. Biodistribution of both probes was measured in BALB/C nu/nu mice bearing either SKOV-3 xenografts with high Her2 expression or DU-145 xenografts with low Her2 expression. (68)GaHP2 was evaluated in the pretargeting setting. Tumor uptake of both probes was compared with the uptake of pretargeted Lu-177-HP2. The uptake of both Ga-68-Z(HER2:342)SR-HP1 and Ga-68-HP2 depended on Her2-expression level providing clear discrimination of between tumors with high and low Her2 expression. Tumor uptake of Ga-68-HP2 correlated better with the uptake of Lu-177-HP2 than the uptake of Ga-68 Z(HER2:342) SR-HP1. The use of Ga-68-HP2 as a theranostics counterpart would be preferable approach for clinical translation.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-360010 (URN)10.1038/s41598-018-27886-0 (DOI)000436078500006 ()29942011 (PubMedID)
Funder
Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Swedish Research Council, 2016-05207VINNOVA, 2015-02509Swedish Cancer Society, CAN 2015/350Swedish Cancer Society, 2014/474Swedish Society for Medical Research (SSMF)
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
Honarvar, H., Calce, E., Doti, N., Langella, E., Orlova, A., Buijs, J., . . . De Luca, S. (2018). Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe. Scientific Reports, 8, Article ID 2998.
Open this publication in new window or tab >>Evaluation of HER2-specific peptide ligand for its employment as radiolabeled imaging probe
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 2998Article in journal (Refereed) Published
Abstract [en]

HER2 transmembrane receptor is an important target in immunotherapy treatment of breast and gastroesophageal cancer. Molecular imaging of HER2 expression may provide essential prognostic and predictive information concerning disseminated cancer and aid in selection of an optimal therapy. Radiolabeled low molecular weight peptide ligands are particularly attractive as probes for molecular imaging, since they reach and bind to the target and clear from non-target organs and blood stream faster than bulky antibodies. In this study, we evaluated a potential HER2-imaging probe, an A9 nonapeptide, derived from the trastuzumab-Fab portion. Its cellular uptake was investigated by mass spectrometry analysis of the cytoplasmic cellular extracts. Moreover, based on in-silico modeling, DTPA chelator was conjugated to N-terminus of A9. In-111-labeled A9 demonstrated nanomolar affinity to HER2-expressing BT474 cells and favorable biodistribution profile in NMRI mice. This study suggests that the peptide A9 represents a good lead candidate for development of molecular probe, to be used for imaging purposes and for the delivery of cytotoxic agents.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-348106 (URN)10.1038/s41598-018-21283-3 (DOI)000424985800036 ()29445216 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-04-11Bibliographically approved
Orlova, A., Bass, T. Z., Rinne, S. S., Leitao, C. D., Rosestedt, M., Atterby, C., . . . Ståhl, S. (2018). Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab. Molecular Pharmaceutics, 15(8), 3394-3403
Open this publication in new window or tab >>Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 8, p. 3394-3403Article in journal (Refereed) Published
Abstract [en]

Human epidermal growth factor receptor type 3 (HER3) is recognized to be involved in resistance to HER targeting therapies. A number of HER3-targeting monoclonal antibodies are under clinical investigation as potential cancer therapeutics. Smaller high-affinity scaffold proteins are attractive non-Fc containing alternatives to antibodies. A previous study indicated that anti-HER3 affibody molecules could delay the growth of xenografted HER3-positive tumors. Here, we designed a second-generation HER3-targeting construct (TAM-HER3), containing two HER3-specific affibody molecules bridged by an albumin-binding domain (ABD) for extension of blood circulation. Receptor blocking activity was demonstrated in vitro. In mice bearing BxPC-3 xenografts, the therapeutic efficacy of TAM-HER3 was compared to the HER3-specific monoclonal antibody seribantumab (MM-121). TAM-HER3 inhibited heregulin-induced phosphorylation in a panel of HER3-expressing cancer cells and was found to be equally as potent as seribantumab in terms of therapeutic efficacy in vivo and with a similar safety profile. Median survival times were 60 days for TAM-HER3, 54 days for seribantumab, and 41 days for the control group. No pathological changes were observed in cytopathological examination. The multimeric HER3-binding affibody molecule in fusion to ABD seems promising for further evaluation as candidate therapeutics for treatment of HER3-overexpressing tumors.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
Keywords
affibody molecule, HER3, targeting therapy, preclinical
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-362844 (URN)10.1021/acs.molpharmaceut.8b00393 (DOI)000441476800049 ()29995421 (PubMedID)
Funder
Swedish Research Council, 621-2012-5236Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353VINNOVA, 2016-04060Swedish Cancer Society, CAN2016-463Swedish Cancer Society, CAN2014-474Swedish Cancer Society, CAN 2017/425Swedish Cancer Society, CAN2015/350
Available from: 2018-10-12 Created: 2018-10-12 Last updated: 2018-10-12Bibliographically approved
Oroujeni, M., Andersson, K. G., Steinhardt, X., Altai, M., Orlova, A., Mitran, B., . . . Löfblom, J. (2018). Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules. Amino Acids, 50(8), 981-994
Open this publication in new window or tab >>Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules
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2018 (English)In: Amino Acids, ISSN 0939-4451, E-ISSN 1438-2199, Vol. 50, no 8, p. 981-994Article in journal (Refereed) Published
Abstract [en]

Epidermal growth factor receptor (EGFR) is overexpressed in a number of cancers and is the molecular target for several anti-cancer therapeutics. Radionuclide molecular imaging of EGFR expression should enable personalization of anti-cancer treatment. Affibody molecule is a promising type of high-affinity imaging probes based on a non-immunoglobulin scaffold. A series of derivatives of the anti-EGFR affibody molecule ZEGFR:2377, having peptide-based cysteine-containing chelators for conjugation of Tc-99m, was designed and evaluated. It was found that glutamate-containing chelators Gly-Gly-Glu-Cys (GGEC), Gly-Glu-Glu-Cys (GEEC) and Glu-Glu-Glu-Cys (EEEC) provide the best labeling stability. The glutamate containing conjugates bound to EGFR-expressing cells specifically and with high affinity. Specific targeting of EGFR-expressing xenografts in mice was demonstrated. The number of glutamate residues in the chelator had strong influence on biodistribution of radiolabeled affibody molecules. Increase of glutamate content was associated with lower uptake in normal tissues. The Tc-99m-labeled variant containing the EEEC chelator provided the highest tumor-to-organ ratios. In conclusion, optimizing the composition of peptide-based chelators enhances contrast of imaging of EGFR-expression using affibody molecules.

Keywords
Affibody molecules, EGFR, Tc-99m, Peptide-based chelators, Glutamate
National Category
Cell and Molecular Biology Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-358029 (URN)10.1007/s00726-018-2571-1 (DOI)000438425500002 ()29728916 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-08-23Bibliographically approved
Tolmachev, V., Grönroos, T. J., Yim, C.-B., Garousi, J., Yue, Y., Grimm, S., . . . Karlström, A. E. (2018). Molecular design of radiocopper-labelled Affibody molecules. Scientific Reports, 8(1), Article ID 6542.
Open this publication in new window or tab >>Molecular design of radiocopper-labelled Affibody molecules
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, no 1, article id 6542Article in journal (Refereed) Published
Abstract [en]

Cu-CB-TE2A-GEEE-ZHER2:342 was 16 ± 6%ID/g and tumor-to-blood ratio was 181 ± 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu-Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption.

National Category
Cancer and Oncology Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-349813 (URN)10.1038/s41598-018-24785-2 (DOI)000430795000041 ()29695813 (PubMedID)
Funder
Swedish Cancer Society, CAN 2015/350Swedish Research Council, 2015-02353Swedish Research Council, 2015-02509Swedish Research Council, 2013-5135Swedish Cancer Society, 2014/474
Note

Vladimir Tolmachev and Tove J. Grönroos contributed equally to this work.

Available from: 2018-05-02 Created: 2018-05-02 Last updated: 2018-06-26Bibliographically approved
Lindbo, S., Garousi, J., Mitran, B., Vorobyeva, A., Oroujeni, M., Orlova, A., . . . Tolmachev, V. (2018). Optimized Molecular Design of ADAPT-Based HER2-Imaging Probes Labeled with 111In and 68Ga. Molecular Pharmaceutics, 15(7), 2674-2683
Open this publication in new window or tab >>Optimized Molecular Design of ADAPT-Based HER2-Imaging Probes Labeled with 111In and 68Ga
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 7, p. 2674-2683Article in journal (Refereed) Published
Abstract [en]

Radionuclide molecular imaging is a promising tool for visualization of cancer associated molecular abnormalities in vivo and stratification of patients for specific therapies. ADAPT is a new type of small engineered proteins based on the scaffold of an albumin binding domain of protein G. ADAPTs have been utilized to select and develop high affinity binders to different proteinaceous targets. ADAPT6 binds to human epidermal growth factor 2 (HER2) with low nanomolar affinity and can be used for its in vivo visualization. Molecular design of 111In-labeled anti-HER2 ADAPT has been optimized in several earlier studies. In this study, we made a direct comparison of two of the most promising variants, having either a DEAVDANS or a (HE)3DANS sequence at the N-terminus, conjugated with a maleimido derivative of DOTA to a GSSC amino acids sequence at the C-terminus. The variants (designated DOTA-C59-DEAVDANS-ADAPT6-GSSC and DOTA-C61-(HE)3DANS-ADAPT6-GSSC) were stably labeled with 111In for SPECT and 68Ga for PET. Biodistribution of labeled ADAPT variants was evaluated in nude mice bearing human tumor xenografts with different levels of HER2 expression. Both variants enabled clear discrimination between tumors with high and low levels of HER2 expression. 111In-labeled ADAPT6 derivatives provided higher tumor-to-organ ratios compared to 68Ga-labeled counterparts. The best performing variant was DOTA-C61-(HE)3DANS-ADAPT6-GSSC, which provided tumor-to-blood ratios of 208 ± 36 and 109 ± 17 at 3 h for 111In and 68Ga labels, respectively.

Keywords
ADAPT, DOTA, HER2, gallium-68, indium-111, radionuclide imaging
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-358055 (URN)10.1021/acs.molpharmaceut.8b00204 (DOI)29865791 (PubMedID)
Funder
Swedish Cancer Society, 2015/350Swedish Cancer Society, 2017/425VINNOVASwedish Research Council, 2015-02353Swedish Research Council, 2015-02509
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Summer, D., Garousi, J., Oroujeni, M., Mitran, B., Andersson, K. G., Vorobyeva, A., . . . Decristoforo, C. (2018). PP15 89Zr-Siderophore-Affibody conjugates for imaging EGFR expression. Paper presented at 33rd International Austrian Winter Symposium : Zell am See, Austria. 24-27 January 2018.. EJNMMI Research, 8(S1), Article ID 5.
Open this publication in new window or tab >>PP15 89Zr-Siderophore-Affibody conjugates for imaging EGFR expression
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2018 (English)In: EJNMMI Research, ISSN 2191-219X, E-ISSN 2191-219X, Vol. 8, no S1, article id 5Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Aim: Zirconium-89 has gained great interest for PET, when imaging at late time points is required. Desferrioxamine B (DFO), is mostly used for this radionuclide as bifunctional chelator (BFC) and we recently reported on fusarinine C (FSC) with similar zirconium-89 complexing properties but potentially higher stability related to its cyclic structure. This study reports on the comparison of FSC and DFO as BFCs for 89Zr labelling of the affibody ZEGFR:2377 targeting Epidermal Growth Factor Receptors (EGFR).

Methods: FSC-ZEGFR:2377 and DFO-ZEGFR:2377 were evaluated regarding labeling, in vitro stability, specificity, cell uptake, receptor affinity, biodistribution and microPET-CT imaging.

Results: Both conjugates showed increased labelling yields at elevated temperature (85°C). Both conjugates revealed remarkable specificity, affinity and slow cell-line dependent internalisation. Labeling at 85°C showed comparable results in A431 tumor xenografted mice with minor differences regarding blood clearance, tumor and liver uptake but clear improvement as compared to 89Zr-DFO-ZEGFR:2377, labeled at room temperature, which was confirmed by MicroPET-CT imaging.

Conclusion: We were able to show that FSC is a suitable alternative to DFO for labeling of biomolecules with zirconium-89. Furthermore our findings indicate that 89Zr- labeling of DFO conjugates at higher temperature reduces off-chelate binding leading to significantly improved tumor-to-organ ratios and therefore enhancing image contrast.

National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-358056 (URN)10.1186/s13550-017-0354-4 (DOI)29362999 (PubMedID)
Conference
33rd International Austrian Winter Symposium : Zell am See, Austria. 24-27 January 2018.
Available from: 2018-08-24 Created: 2018-08-24 Last updated: 2018-08-24Bibliographically approved
Westerlund, K., Altai, M., Mitran, B., Konijnenberg, M., Oroujeni, M., Atterby, C., . . . Tolmachev, V. (2018). Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle. Journal of Nuclear Medicine, 59(7), 1092-1098
Open this publication in new window or tab >>Radionuclide Therapy of HER2-Expressing Human Xenografts Using Affibody-Based Peptide Nucleic Acid-Mediated Pretargeting: In Vivo Proof of Principle
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2018 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 59, no 7, p. 1092-1098Article in journal (Refereed) Published
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.

Keywords
pretargeting, PNA, affibody molecules, radionuclide therapy, HER2
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-358030 (URN)10.2967/jnumed.118.208348 (DOI)000437237200028 ()29439013 (PubMedID)
Funder
Swedish Cancer SocietyVINNOVASwedish Research Council
Note

Kristina Westerlund and Mohamed Altai contributed equally. Amelie Eriksson Karlström and Vladimir Tolmachev contributed equally.

Available from: 2018-08-23 Created: 2018-08-23 Last updated: 2018-09-18Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6120-2683

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