288 results on '"Oroujeni, Maryam"'
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2. Comparison of approaches for increasing affinity of affibody molecules for imaging of B7-H3: dimerization and affinity maturation
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Oroujeni, Maryam, Carlqvist, Matilda, Ryer, Eva, Orlova, Anna, Tolmachev, Vladimir, and Frejd, Fredrik Y.
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- 2024
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3. Evaluation of affinity matured Affibody molecules for imaging of the immune checkpoint protein B7-H3
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Oroujeni, Maryam, Bezverkhniaia, Ekaterina A., Xu, Tianqi, Liu, Yongsheng, Plotnikov, Evgenii V., Klint, Susanne, Ryer, Eva, Karlberg, Ida, Orlova, Anna, Frejd, Fredrik Y., and Tolmachev, Vladimir
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- 2023
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4. Conditionally activated affibody-based prodrug targeting EGFR demonstrates improved tumour selectivity
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Dahlsson Leitao, Charles, Mestre Borras, Anna, Xu, Tianqi, Oroujeni, Maryam, Liu, Yongsheng, Westerberg, Cornelia, Clinton, Jacob, Tolmachev, Vladimir, Orlova, Anna, Ståhl, Stefan, Vorobyeva, Anzhelika, and Löfblom, John
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- 2023
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5. Comparison of HER2-targeted affibody conjugates loaded with auristatin- and maytansine-derived drugs
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Yin, Wen, Xu, Tianqi, Ding, Haozhong, Zhang, Jie, Bodenko, Vitalina, Tretyakova, Maria S., Belousov, Mikhail V., Liu, Yongsheng, Oroujeni, Maryam, Orlova, Anna, Tolmachev, Vladimir, Gräslund, Torbjörn, and Vorobyeva, Anzhelika
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- 2023
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6. Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion
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Deyev, Sergey M., primary, Oroujeni, Maryam, additional, Garousi, Javad, additional, Gräslund, Torbjörn, additional, Li, Ruonan, additional, Rosly, Alia Hani Binti, additional, Orlova, Anna, additional, Konovalova, Elena, additional, Schulga, Alexey, additional, Vorobyeva, Anzhelika, additional, and Tolmachev, Vladimir, additional
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- 2024
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7. Reduction of renal activity retention of radiolabeled albumin binding domain-derived affinity proteins using a non-residualizing label strategy compared with a cleavable glycine-leucine-glycine-lysine-linker
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Lundmark, Fanny, Vorobyeva, Anzhelika, Liu, Yongsheng, Lindbo, Sarah, Xu, Tianqi, Oroujeni, Maryam, Rinne, Sara S., Rosenström, Ulrika, Garousi, Javad, Lundmark, Fanny, Vorobyeva, Anzhelika, Liu, Yongsheng, Lindbo, Sarah, Xu, Tianqi, Oroujeni, Maryam, Rinne, Sara S., Rosenström, Ulrika, and Garousi, Javad
- Abstract
The feasibility of targeted imaging and therapy using radiolabeled albumin-binding domain-derived affinity proteins (ADAPTs) has been demonstrated. However, high renal uptake of radioactivity limits the maximum tolerated dose. Successful reduction of renal retention of radiolabeled Fab fragments has been demonstrated by incorporating a cleavable linker between the targeting agent and the radiometal chelator. The present study investigated if the introduction of a glycine-leucine-glycine-lysine (GLGK)-linker would reduce the kidney uptake of radiolabeled ADAPT6 and also compared it with the non-residualizing [125I]I-[(4-hydroxyphenyl)ethyl]maleimide ([125I]I-HPEM) labeling strategy. GLGK was site-specifically coupled to human epidermal growth factor receptor 2 (HER2)-targeting ADAPT6. Conjugates without the cleavable linker were used as controls and all constructs were labeled with lutetium-177 (177Lu). [125I]I-HPEM was coupled to ADAPT6 at the C-terminus. Biodistribution of all constructs was evaluated in NMRI mice 4 h after injection. Specific binding to HER2-expressing cells in vitro was demonstrated for all constructs. No significant difference in kidney uptake was observed between the [177Lu]Lu-2,2 ',2",2"'-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid-GLGK-conjugates and the controls. The renal activity of [125I]I-HPEM-ADAPT6 was significantly lower compared with all other constructs. In conclusion, the incorporation of the cleavable GLGK-linker did not result in lower renal retention. Therefore, the present study emphasized that, in order to achieve a reduction of renal retention, alternative molecular design strategies may be required for different targeting agents.
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- 2024
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8. Preclinical Evaluation of HER2-Targeting DARPin G3 : Impact of Albumin-Binding Domain (ABD) Fusion
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Deyev, Sergey M., Oroujeni, Maryam, Garousi, Javad, Graeslund, Torbjoern, Li, Ruonan, Rosly, Alia Hani Binti, Orlova, Anna, Konovalova, Elena, Schulga, Alexey, Vorobyeva, Anzhelika, Tolmachev, Vladimir, Deyev, Sergey M., Oroujeni, Maryam, Garousi, Javad, Graeslund, Torbjoern, Li, Ruonan, Rosly, Alia Hani Binti, Orlova, Anna, Konovalova, Elena, Schulga, Alexey, Vorobyeva, Anzhelika, and Tolmachev, Vladimir
- Abstract
Designed ankyrin repeat protein (DARPin) G3 is an engineered scaffold protein. This small (14.5 kDa) targeting protein binds with high affinity to human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in several cancers. The use of the DARPin G3 for radionuclide therapy is complicated by its high renal reabsorption after clearance via the glomeruli. We tested the hypothesis that a fusion of the DARPin G3 with an albumin-binding domain (ABD) would prevent rapid renal excretion and high renal reabsorption resulting in better tumour targeting. Two fusion proteins were produced, one with the ABD at the C-terminus (G3-ABD) and another at the N-terminus (ABD-G3). Both variants were labelled with Lu-177. The binding properties of the novel constructs were evaluated in vitro and their biodistribution was compared in mice with implanted human HER2-expressing tumours. Fusion with the ABD increased the retention time of both constructs in blood compared with the non-ABD-fused control. The effect of fusion with the ABD depended strongly on the order of the domains in the constructs, resulting in appreciably better targeting properties of [Lu-177]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins., The two first authors contributed equally.Corresponding author: Vladimir Tolmachev
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- 2024
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9. Radionuclide therapy using ABD-fused ADAPT scaffold protein: Proof of Principle
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Garousi, Javad, von Witting, Emma, Borin, Jesper, Vorobyeva, Anzhelika, Altai, Mohamed, Vorontsova, Olga, Konijnenberg, Mark W., Oroujeni, Maryam, Orlova, Anna, Tolmachev, Vladimir, and Hober, Sophia
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- 2021
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10. Reduction of renal activity retention of radiolabeled albumin binding domain‑derived affinity proteins using a non‑residualizing label strategy compared with a cleavable glycine‑leucine‑glycine‑lysine‑linker
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Lundmark, Fanny, primary, Vorobyeva, Anzhelika, additional, Liu, Yongsheng, additional, Lindbo, Sarah, additional, Xu, Tianqi, additional, Oroujeni, Maryam, additional, Rinne, Sara, additional, Rosenström, Ulrika, additional, and Garousi, Javad, additional
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- 2023
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11. Preclinical Evaluation of a Novel High-Affinity Radioligand [99mTc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA)
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Bezverkhniaia, Ekaterina, primary, Kanellopoulos, Panagiotis, additional, Abouzayed, Ayman, additional, Larkina, Mariia, additional, Oroujeni, Maryam, additional, Vorobyeva, Anzhelika, additional, Rosenström, Ulrika, additional, Tolmachev, Vladimir, additional, and Orlova, Anna, additional
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- 2023
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12. HER2-specific Affibody Molecule [99mTc]Tc-ZHER2:41071: phase I clinical trial
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Tolmachev, Vladimir, primary, Bragina, Olga, additional, Chernov, Vladimir, additional, Larkina, Maria, additional, Rybina, Anastasiya, additional, Zelchan, Roman, additional, Oroujeni, Maryam, additional, Loftenius, Annika, additional, Orlova, Anna, additional, Sorensen, Jens, additional, and Frejd, Fredrik, additional
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- 2023
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13. 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry
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Abouzayed, Ayman, primary, Seitova, Kamila, additional, Lundmark, Fanny, additional, Bodenko, Vitalina, additional, Oroujeni, Maryam, additional, Tolmachev, Vladimir, additional, Rosenström, Ulrika, additional, and Orlova, Anna, additional
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- 2023
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14. Conjugation of cyclodextrin to magnetic Fe3O4 nanoparticles via polydopamine coating for drug delivery
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Oroujeni, Maryam, Kaboudin, Babak, Xia, Wei, Jönsson, Petra, and Ossipov, Dmitri A.
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- 2018
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15. Conditionally activated affibody-based prodrug targeting EGFR demonstrates improved tumour selectivity
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Leitao, Charles Dahlsson, Borras, Anna Mestre, Xu, Tianqi, Oroujeni, Maryam, Liu, Yongsheng, Westerberg, Cornelia, Clinton, Jacob, Tolmachev, Vladimir, Orlova, Anna, Stahl, Stefan, Vorobyeva, Anzhelika, Lofblom, John, Leitao, Charles Dahlsson, Borras, Anna Mestre, Xu, Tianqi, Oroujeni, Maryam, Liu, Yongsheng, Westerberg, Cornelia, Clinton, Jacob, Tolmachev, Vladimir, Orlova, Anna, Stahl, Stefan, Vorobyeva, Anzhelika, and Lofblom, John
- Abstract
Safety and efficacy of cancer-targeting treatments can be improved by conditional activation enabled by the distinct milieu of the tumour microenvironment. Proteases are intricately involved in tumourigenesis and commonly dysregulated with elevated expression and activity. Design of prodrug molecules with protease -dependent activation has the potential to increase tumour-selective targeting while decreasing exposure to healthy tissues, thus improving the safety profile for patients. Higher selectivity could also allow for adminis-tration of higher doses or use of more aggressive treatment options, leading to higher therapeutic efficacy. We have previously developed an affibody-based prodrug with conditional targeting of EGFR conferred by an anti-idiotypic affibody masking domain (ZB05). We could show that binding to endogenous EGFR on cancer cells in vitro was restored following proteolytic removal of ZB05. In this study we evaluate a novel affibody-based pro -drug design, which incorporates a protease substrate sequence recognized by cancer-associated proteases and demonstrate the potential of this approach for selective tumour-targeting and shielded uptake in healthy tissues in vivo using tumour-bearing mice. This may widen the therapeutic index of cytotoxic EGFR-targeted thera-peutics by decreasing side effects, improving selectivity of drug delivery, and enabling the use of more potent cytotoxic drugs.
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- 2023
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16. 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry
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Abouzayed, Ayman, Seitova, Kamila, Lundmark, Fanny, Bodenko, Vitalina, Oroujeni, Maryam, Tolmachev, Vladimir, Rosenström, Ulrika, Orlova, Anna, Abouzayed, Ayman, Seitova, Kamila, Lundmark, Fanny, Bodenko, Vitalina, Oroujeni, Maryam, Tolmachev, Vladimir, Rosenström, Ulrika, and Orlova, Anna
- Abstract
Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMA-expression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that Lu-177-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy.Methods: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [Lu-177]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [Lu-177]Lu-PSMA-617 was simultaneously evaluated for comparison.Results: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [Lu-177]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities K-D1 = 3.8 nM and K-D2 = 25 nM. The half-maximal inhibitory concentration for Lu-nat-BQ7876 was 59 nM that is equal to 61 nM for Lu-nat-PSMA-617. Cellular processing of [Lu-177]Lu-BQ7876 was accompanied by slow internalization. [Lu-177]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 +/- 3%ID/g) di
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- 2023
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17. Phase I clinical evaluation of 99mTc-labeled Affibody molecule for imaging HER2 expression in breast cancer
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Bragina, Olga, Chernov, Vladimir, Larkina, Mariia, Rybina, Anstasiya, Zelchan, Roman, Garbukov, Eugeniy, Oroujeni, Maryam, Loftenius, Annika, Orlova, Anna, Sörensen, Jens, Frejd, Fredrik Y., Tolmachev, Vladimir, Bragina, Olga, Chernov, Vladimir, Larkina, Mariia, Rybina, Anstasiya, Zelchan, Roman, Garbukov, Eugeniy, Oroujeni, Maryam, Loftenius, Annika, Orlova, Anna, Sörensen, Jens, Frejd, Fredrik Y., and Tolmachev, Vladimir
- Abstract
The determination of tumor human epidermal growth factor receptor type 2 (HER2) status is of increasing importance with the recent approval of more efficacious HER2-targeted treatments. There is a lack of suitable methods for clinical in vivo HER2 expression assessment. Affibody molecules are small affinity proteins ideal for imaging detection of receptors, which are engineered using a small (molecular weight 6.5 kDa) nonimmunoglobulin scaffold. Labeling of Affibody molecules with positron emitters enabled the development of sensitive and specific agents for molecular imaging. The development of probes for SPECT would permit the use of Affibody-based imaging in regions where PET is not available. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the Tc-99m-ZHER2:41071 Affibody molecule developed for SPECT/CT imaging of HER2 expression.Methods: Thirty-one patients with primary breast cancer were enrolled and divided into three cohorts (injected with 500, 1000, or 1500 mu g ZHER2:41071) comprising at least five patients with high (positive) HER2 tumor expression (IHC score 3+ or 2+ and ISH positive) and five patients with low (IHC score 2+ or 1+ and ISH negative) or absent HER2 tumor expression. Patients were injected with 451 +/- 71 MBq Tc-99m-ZHER2:4107. Planar scintigraphy was performed after 2, 4, 6 and 24 h, and SPECT/CT imaging followed planar imaging 2, 4 and 6 h after injection.Results: Injections of Tc-99m-ZHER2:41071 were well tolerated and not associated with adverse events. Normal organs with the highest accumulation were the kidney and liver. The effective dose was 0.019 +/- 0.004 mSv/MBq. Injection of 1000 mu g provided the best standard discrimination between HER2-positive and HER2-low or HER2-negative tumors 2 h after injection (SUVmax 16.9 +/- 7.6 vs. 3.6 +/- 1.4, p < 0.005). The Tc-99m-ZHER2:41071 uptake in HER2-positive lymph node metastases (SUVmax 6.9 +/- 2.4, n = 5) was significantly (p < 0.05) higher
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- 2023
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18. Preclinical Evaluation of a Novel High-Affinity Radioligand [99mTc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA)
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Bezverkhniaia, Ekaterina, Kanellopoulos, Panagiotis, Abouzayed, Ayman, Larkina, Mariia, Oroujeni, Maryam, Vorobyeva, Anzhelika, Rosenström, Ulrika, Tolmachev, Vladimir, Orlova, Anna, Bezverkhniaia, Ekaterina, Kanellopoulos, Panagiotis, Abouzayed, Ayman, Larkina, Mariia, Oroujeni, Maryam, Vorobyeva, Anzhelika, Rosenström, Ulrika, Tolmachev, Vladimir, and Orlova, Anna
- Abstract
Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl-triglutamate chelator for labeling with Tc-99m (designated as BQ0413). The purpose of this study was to evaluate the imaging properties of [Tc-99m]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [Tc-99m]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [Tc-99m]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 +/- 15 pM. In tumor-bearing mice, the tumor uptake of [Tc-99m]Tc-BQ0413 (38 +/- 6 %IA/g in PC3-pip 3 h after the injection of 40 pmol) was dependent on PSMA expression (3 +/- 2 %IA/g and 0.9 +/- 0.3 %IA/g in PSMA-negative PC-3 and SKOV-3 tumors, respectively). We show that both unlabeled BQ0413 and the commonly used binder PSMA-11 enable the blocking of [Tc-99m]Tc-BQ0413 uptake in normal PSMA-expressing tissues without blocking the uptake in tumors. This resulted in an appreciable increase in tumor-to-organ ratios. At the same injected mass (5 nmol), the use of BQ0413 was more efficient in suppressing renal uptake than the use of PSMA-11. In conclusion, [Tc-99m]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT).
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- 2023
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19. Preclinical Evaluation of a Novel High-Affinity Radioligand [ 99m Tc]Tc-BQ0413 Targeting Prostate-Specific Membrane Antigen (PSMA).
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Bezverkhniaia, Ekaterina, Kanellopoulos, Panagiotis, Abouzayed, Ayman, Larkina, Mariia, Oroujeni, Maryam, Vorobyeva, Anzhelika, Rosenström, Ulrika, Tolmachev, Vladimir, and Orlova, Anna
- Subjects
SINGLE-photon emission computed tomography ,RADIONUCLIDE imaging - Abstract
Radionuclide imaging using radiolabeled inhibitors of prostate-specific membrane antigen (PSMA) can be used for the staging of prostate cancer. Previously, we optimized the Glu-urea-Lys binding moiety using a linker structure containing 2-napththyl-L-alanine and L-tyrosine. We have now designed a molecule that contains mercaptoacetyl–triglutamate chelator for labeling with Tc-99m (designated as BQ0413). The purpose of this study was to evaluate the imaging properties of [
99m Tc]Tc-BQ0413. PSMA-transfected PC3-pip cells were used to evaluate the specificity and affinity of [99m Tc]Tc-BQ0413 binding in vitro. PC3-pip tumor-bearing BALB/C nu/nu mice were used as an in vivo model. [99m Tc]Tc-BQ0413 bound specifically to PC3-pip cells with an affinity of 33 ± 15 pM. In tumor-bearing mice, the tumor uptake of [99m Tc]Tc-BQ0413 (38 ± 6 %IA/g in PC3-pip 3 h after the injection of 40 pmol) was dependent on PSMA expression (3 ± 2 %IA/g and 0.9 ± 0.3 %IA/g in PSMA-negative PC-3 and SKOV-3 tumors, respectively). We show that both unlabeled BQ0413 and the commonly used binder PSMA-11 enable the blocking of [99m Tc]Tc-BQ0413 uptake in normal PSMA-expressing tissues without blocking the uptake in tumors. This resulted in an appreciable increase in tumor-to-organ ratios. At the same injected mass (5 nmol), the use of BQ0413 was more efficient in suppressing renal uptake than the use of PSMA-11. In conclusion, [99m Tc]Tc-BQ0413 is a promising probe for the visualization of PSMA-positive lesions using single-photon emission computed tomography (SPECT). [ABSTRACT FROM AUTHOR]- Published
- 2023
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20. 177Lu-labeled PSMA targeting therapeutic with optimized linker for treatment of disseminated prostate cancer; evaluation of biodistribution and dosimetry.
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Abouzayed, Ayman, Seitova, Kamila, Lundmark, Fanny, Bodenko, Vitalina, Oroujeni, Maryam, Tolmachev, Vladimir, Rosenström, Ulrika, and Orlova, Anna
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MEDICAL dosimetry ,CASTRATION-resistant prostate cancer ,PROSTATE cancer ,RADIONUCLIDE imaging ,ANDROGEN receptors ,PROSTATE-specific membrane antigen ,ABSORBED dose ,RADIOTHERAPY safety - Abstract
Introduction: Prostate specific membrane antigen (PSMA), highly expressed in metastatic castration-resistant prostate cancer (mCRPC), is an established therapeutic target. Theranostic PSMA-targeting agents are widely used in patient management and has shown improved outcomes for mCRPC patients. Earlier, we optimized a urea-based probe for radionuclide visualization of PSMAexpression in vivo using computer modeling. With the purpose to develop a targeting agent equally suitable for radionuclide imaging and therapy, the agent containing DOTA chelator was designed (BQ7876). The aim of the study was to test the hypothesis that 177Lu-labeled BQ7876 possesses target binding and biodistribution properties potentially enabling its use for radiotherapy. Methods: BQ7876 was synthesized and labeled with Lu-177. Specificity and affinity of [177Lu]Lu-BQ7876 to PSMA-expressing PC3-pip cells was evaluated and its processing after binding to cells was studied. Animal studies in mice were performed to assess its biodistribution in vivo, target specificity and dosimetry. [177Lu]Lu-PSMA-617 was simultaneously evaluated for comparison. Results: BQ7876 was labeled with Lu-177 with radiochemical yield >99%. Its binding to PSMA was specific in vitro and in vivo when tested in antigen saturation conditions as well as in PSMA-negative PC-3 tumors. The binding of [177Lu]Lu-BQ7876 to living cells was characterized by rapid association, while the dissociation included a rapid and a slow phase with affinities KD1 = 3.8 nM and KD2 = 25 nM. The half-maximal inhibitory concentration for natLu-BQ7876 was 59 nM that is equal to 61 nM for natLu-PSMA-617. Cellular processing of [177Lu]Lu-BQ7876 was accompanied by slow internalization. [177Lu]Lu-BQ7876 was cleared from blood and normal tissues rapidly. Initial elevated uptake in kidneys decreased rapidly, and by 3 h post injection, the renal uptake (13 ± 3% Frontiers in ID/g) did not differ significantly from tumor uptake (9 ± 3%ID/g). Tumor uptake was stable between 1 and 3 h followed by a slow decline. The highest absorbed dose was in kidneys, followed by organs and tissues in abdomen. Discussion: Biodistribution studies in mice demonstrated that targeting properties of [177Lu]Lu-BQ7876 are not inferior to properties of [177Lu]Lu-PSMA-617, but do not offer any decisive advantages. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Influence of composition of cysteine-containing peptide-based chelators on biodistribution of 99mTc-labeled anti-EGFR affibody molecules
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Oroujeni, Maryam, Andersson, Ken G., Steinhardt, Xenia, Altai, Mohamed, Orlova, Anna, Mitran, Bogdan, Vorobyeva, Anzhelika, Garousi, Javad, Tolmachev, Vladimir, and Löfblom, John
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- 2018
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22. P-185 - HER2-specific Affibody Molecule [99mTc]Tc-ZHER2:41071: phase I clinical trial
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Tolmachev, Vladimir, Bragina, Olga, Chernov, Vladimir, Larkina, Maria, Rybina, Anastasiya, Zelchan, Roman, Oroujeni, Maryam, Loftenius, Annika, Orlova, Anna, Sorensen, Jens, and Frejd, Fredrik
- Published
- 2023
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23. Phase I clinical evaluation of 99mTc-labeled Affibody molecule for imaging HER2 expression in breast cancer
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Bragina, Olga, primary, Chernov, Vladimir, additional, Larkina, Mariia, additional, Rybina, Anstasiya, additional, Zelchan, Roman, additional, Garbukov, Eugeniy, additional, Oroujeni, Maryam, additional, Loftenius, Annika, additional, Orlova, Anna, additional, Sörensen, Jens, additional, Frejd, Fredrik Y., additional, and Tolmachev, Vladimir, additional
- Published
- 2023
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24. Phase I clinical evaluation of 99mTc-labeled Affibody molecule for imaging HER2 expression in breast cancer.
- Author
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Bragina, Olga, Chernov, Vladimir, Larkina, Mariia, Rybina, Anstasiya, Zelchan, Roman, Garbukov, Eugeniy, Oroujeni, Maryam, Loftenius, Annika, Orlova, Anna, Sörensen, Jens, Frejd, Fredrik Y., and Tolmachev, Vladimir
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- 2023
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25. Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
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Tolmachev, Vladimir, primary, Bodenko, Vitalina, additional, Oroujeni, Maryam, additional, Deyev, Sergey, additional, Konovalova, Elena, additional, Schulga, Alexey, additional, Lindbo, Sarah, additional, Hober, Sophia, additional, Bragina, Olga, additional, Orlova, Anna, additional, and Vorobyeva, Anzhelika, additional
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- 2022
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26. Direct in Vivo Comparison of 99mTc-labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
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Tolmachev, Vladimir, Bodenko, Vitalina, Oroujeni, Maryam, Deyev, Sergey, Konovalova, Elena, Schulga, Alexey, Lindbo, Sarah, Hober, Sophia, Bragina, Olga, Orlova, Anna, and Vorobyeva, Anzhelika
- Subjects
scaffold proteins ,DARPin ,ADAPT6 ,HER2 ,preclinical ,Radiologi och bildbehandling ,radionuclide molecular imaging ,technetium-99m ,Radiology, Nuclear Medicine and Medical Imaging ,pharmacology_toxicology - Abstract
Non-invasive radionuclide molecular visualization of human epidermal growth factor receptor type 2 (HER2) can provide stratification of patients for HER2-targeting therapy. This method can also enable monitoring of the response to such therapies, thereby making treatment personalized and more efficient. Clinical evaluation in a phase I study demonstrated that injections of two scaffold protein-based imaging probes, [99mTc]Tc-(HE)3-G3 and [99mTc]Tc-ADAPT6, are safe, well-tolerated and cause a low level of radioactivity in healthy tissue. The goal of this preclinical study was to select the best probe for stratification of patients and response monitoring. Biodistribution of both tracers was compared in mice bearing SKOV-3 xenografts with high HER2 expression or MDA-MB-468 xenografts with very low expression. Changes in accumulation of the probes in SKOV-3 tumors 24 h after injection of trastuzumab were evaluated. Both [99mTc]Tc-ADAPT6 and [99mTc]Tc-(HE)3-G3 permitted high contrast imaging of HER2-expressing tumors and a clear discrimination between tumors with high and low HER2 expression. However, [99mTc]Tc-ADAPT6 has better preconditions for higher sensitivity and specificity of stratification. On the other hand, [99mTc]Tc-(HE)3-G3 is capable of detecting the decrease of HER2 expression on response to trastuzumab therapy only 24 h after injection of the loading dose. This indicates that the [99mTc]Tc-(HE)3-G3 tracer would be better for monitoring early response to such treatment. The results of this study should be considered in planning of further clinical development of HER2 imaging probes. Title in Web of Science: Direct In Vivo Comparison of Tc-99m-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
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- 2022
27. Evaluation of an Affibody-Based Binder for Imaging of Immune Check-Point Molecule B7-H3
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Oroujeni, Maryam, primary, Bezverkhniaia, Ekaterina A., additional, Xu, Tianqi, additional, Liu, Yongsheng, additional, Plotnikov, Evgenii V., additional, Karlberg, Ida, additional, Ryer, Eva, additional, Orlova, Anna, additional, Tolmachev, Vladimir, additional, and Frejd, Fredrik Y., additional
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- 2022
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28. Preclinical Evaluation of a New Format of 68Ga- and 111In-Labeled Affibody Molecule ZIGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT
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Liu, Yongsheng, primary, Yu, Shengze, additional, Xu, Tianqi, additional, Bodenko, Vitalina, additional, Orlova, Anna, additional, Oroujeni, Maryam, additional, Rinne, Sara S., additional, Tolmachev, Vladimir, additional, Vorobyeva, Anzhelika, additional, and Gräslund, Torbjörn, additional
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- 2022
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29. Evaluation of an Affibody-Based Binder for Imaging of Immune Check-Point Molecule B7-H3
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Oroujeni, Maryam, Bezverkhniaia, Ekaterina A., Xu, Tianqi, Liu, Yongsheng, Plotnikov, Evgenii, V, Karlberg, Ida, Ryer, Eva, Orlova, Anna, Tolmachev, Vladimir, Frejd, Fredrik Y., Oroujeni, Maryam, Bezverkhniaia, Ekaterina A., Xu, Tianqi, Liu, Yongsheng, Plotnikov, Evgenii, V, Karlberg, Ida, Ryer, Eva, Orlova, Anna, Tolmachev, Vladimir, and Frejd, Fredrik Y.
- Abstract
Radionuclide molecular imaging could provide an accurate assessment of the expression of molecular targets in disseminated cancers enabling stratification of patients for specific therapies. B7-H3 (CD276) is a transmembrane protein belonging to the B7 superfamily. This protein is overexpressed in different types of human malignancies and such upregulation is generally associated with a poor clinical prognosis. In this study, targeting properties of an Affibody-based probe, AC12, containing a -GGGC amino acid sequence as a chelator (designated as AC12-GGGC) labelled with technetium-99m (Tc-99m) were evaluated for imaging of B7-H3-expressing tumours. AC12-GGGC was efficiently labelled with Tc-99m. [Tc-99m]Tc-AC12-GGGC bound specifically to B7-H3 expressing cells in vitro with affinities in nanomolar range. In mice bearing B7-H3-expressing xenografts, [Tc-99m]Tc-AC12-GGGC showed tumour uptake of 2.1 +/- 0.5 %ID/g at 2 h after injection. Its clearance from blood, normal organs and tissues was very rapid. This new targeting agent, [Tc-99m]Tc-AC12-GGGC, provided high tumour-to-blood ratio already at 2 h (8.2 +/- 1.9), which increased to 11.0 +/- 0.5 at 4 h after injection. Significantly (p < 0.05) higher tumour-to-liver and higher tumour-to-bone ratios at 2 h in comparison with 4 h after injection were observed. Thus, [Tc-99m]Tc-AC12-GGGC could be a promising candidate for further development.
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- 2022
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30. Affibody-Mediated PNA-Based Pretargeted Cotreatment Improves Survival of Trastuzumab-Treated Mice Bearing HER2-Expressing Xenografts
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Oroujeni, Maryam, Tano, Hanna, Vorobyeva, Anzhelika, Liu, Yongsheng, Vorontsova, Olga, Xu, Tianqi, Westerlund, Kristina, Orlova, Anna, Tolmachev, Vladimir, Karlstrom, Amelie Eriksson, Oroujeni, Maryam, Tano, Hanna, Vorobyeva, Anzhelika, Liu, Yongsheng, Vorontsova, Olga, Xu, Tianqi, Westerlund, Kristina, Orlova, Anna, Tolmachev, Vladimir, and Karlstrom, Amelie Eriksson
- Abstract
Treatment of patients with human epidermal growth factor receptor 2 (HER2)-expressing tumors using the monoclonal antibody trastuzumab increases survival. The Affibody-based peptide nucleic acid (PNA)-mediated pretargeted radionuclide therapy has demonstrated efficacy against HER2-expressing xenografts in mice. Structural studies suggest that Affibody molecules and trastuzumab bind to different epitopes on HER2. The aim of this study was to test the hypothesis that a combination of PNA-mediated pretargeted radionuclide therapy and trastuzumab treatment of HER2-expressing xenografts can extend survival compared with monotherapies. Methods: Mutual interference of the primary pretargeting probe Z(HER2:342)-SR-HP1 and trastuzumab in binding to HER2-expressing cell lines was investigated in vitro. Experimental therapy evaluated the survival of mice bearing HER2-expressing SKOV-3 xenografts after treatment with vehicle, trastuzumab only, pretargeting using Affibody-PNA chimera Z(HER2:342)-SR-HP1 and complementary probe Lu-177-HP2, and combination of trastuzumab and pretargeting. The ethical permit limited the study to 90 d. The animals'weightsweremonitored during the study. After study termination, samples of liver and kidneys were evaluated by a veterinary pathologist for toxicity signs. Results: The presence of a large molar excess of trastuzumab had no influence on the affinity of Z(HER2:342)-SR-HP1 binding to HER2-expressing cells in vitro. The affinity of trastuzumab was not affected by a large excess of Z(HER2:342)-SR-HP1. Themedian survival of mice treated with trastuzumab (75.5 d) was significantly longer than the survival of mice treated with a vehicle (59.5 d). Median survival of mice treated with pretargeting was not reached by day 90. Six mice of 10 in this group survived, and 2 had complete remission. All mice in the combination treatment group survived, and tumors in 7 mice had disappeared at study termination. There was no significant difference between ani
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- 2022
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31. Preclinical Evaluation of a New Format of Ga-68- and In-111-Labeled Affibody Molecule Z(IGF-1R:4551) for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT
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Liu, Yongsheng, Yu, Shengze, Xu, Tianqi, Bodenko, Vitalina, Orlova, Anna, Oroujeni, Maryam, Rinne, Sara S., Tolmachev, Vladimir, Vorobyeva, Anzhelika, Gräslund, Torbjörn, Liu, Yongsheng, Yu, Shengze, Xu, Tianqi, Bodenko, Vitalina, Orlova, Anna, Oroujeni, Maryam, Rinne, Sara S., Tolmachev, Vladimir, Vorobyeva, Anzhelika, and Gräslund, Torbjörn
- Abstract
The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule Z(IGF-1R:4551) binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the Ga-68 and In-111-labeled affibody construct NODAGA-(HE)(3)-Z(IGF-1R:4551) for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [Ga-68]Ga-NODAGA-(HE)(3)-Z(IGF-1R:4551) and [In-111]In-NODAGA-(HE)(3)-Z(IGF-1R:4551), demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 +/- 0.2 and 8.0 +/- 0.6 for [Ga-68]Ga-NODAGA-(HE)(3)-Z(IGF-1R:4551) and [In-111]In-NODAGA-(HE)(3)-Z(IGF-1R:4551), respectively. In conclusion, a molecular design of the Z(IGF-1R:4551) affibody molecule, including placement of a (HE)(3)-tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT.
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- 2022
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32. Effect of Inter-Domain Linker Composition on Biodistribution of ABD-Fused Affibody-Drug Conjugates Targeting HER2
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Xu, Tianqi, Zhang, Jie, Oroujeni, Maryam, Tretyakova, Maria S., Bodenko, Vitalina, Belousov, Mikhail, V, Orlova, Anna, Tolmachev, Vladimir, Vorobyeva, Anzhelika, Gräslund, Torbjörn, Xu, Tianqi, Zhang, Jie, Oroujeni, Maryam, Tretyakova, Maria S., Bodenko, Vitalina, Belousov, Mikhail, V, Orlova, Anna, Tolmachev, Vladimir, Vorobyeva, Anzhelika, and Gräslund, Torbjörn
- Abstract
Targeted drug conjugates based on Affibody molecules fused to an albumin-binding domain (ABD) for half-life extension have demonstrated potent anti-tumor activity in preclinical therapeutic studies. Furthermore, optimization of their molecular design might increase the cytotoxic effect on tumors and minimize systemic toxicity. This study aimed to investigate the influence of length and composition of a linker between the human epidermal growth factor receptor 2 (HER2)-targeted affibody molecule (Z(HER2:2891)) and the ABD domain on functionality and biodistribution of affibody-drug conjugates containing a microtubulin inhibitor mertansin (mcDM1) (AffiDCs). Two conjugates, having a trimeric (S(3)G)(3) linker or a trimeric (G(3)S)(3) linker were produced, radiolabeled with Tc-99m(CO)(3), and compared side-by-side in vitro and in vivo with the original Z(HER2:2891)-G(4)S-ABD-mcDM1 conjugate having a monomeric G(4)S linker. Both conjugates with longer linkers had a decreased affinity to HER2 and mouse and human serum albumin in vitro, however, no differences in blood retention were observed in NMRI mice up to 24 h post injection. The use of both (S(3)G)(3) and (G(3)S)(3) linkers reduced liver uptake of AffiDCs by approximately 1.2-fold compared with the use of a G(4)S linker. This finding provides important insights into the molecular design for the development of targeted drug conjugates with reduced hepatic uptake., De två första författarna delar förstaförfattarskapet.
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- 2022
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33. Direct In Vivo Comparison of Tc-99m-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
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Tolmachev, Vladimir, Bodenko, Vitalina, Oroujeni, Maryam, Deyev, Sergey, Konovalova, Elena, Schulga, Alexey, Lindbo, Sarah, Hober, Sophia, Bragina, Olga, Orlova, Anna, Vorobyeva, Anzhelika, Tolmachev, Vladimir, Bodenko, Vitalina, Oroujeni, Maryam, Deyev, Sergey, Konovalova, Elena, Schulga, Alexey, Lindbo, Sarah, Hober, Sophia, Bragina, Olga, Orlova, Anna, and Vorobyeva, Anzhelika
- Abstract
Non-invasive radionuclide molecular visualization of human epidermal growth factor receptor type 2 (HER2) can provide stratification of patients for HER2-targeting therapy. This method can also enable monitoring of the response to such therapies, thereby making treatment personalized and more efficient. Clinical evaluation in a phase I study demonstrated that injections of two scaffold protein-based imaging probes, [Tc-99m]Tc-(HE)(3)-G3 and [Tc-99m]Tc-ADAPT6, are safe, well-tolerated and cause a low level of radioactivity in healthy tissue. The goal of this preclinical study was to select the best probe for stratification of patients and response monitoring. Biodistribution of both tracers was compared in mice bearing SKOV-3 xenografts with high HER2 expression or MDA-MB-468 xenografts with very low expression. Changes in accumulation of the probes in SKOV-3 tumors 24 h after injection of trastuzumab were evaluated. Both [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3 permitted high contrast imaging of HER2-expressing tumors and a clear discrimination between tumors with high and low HER2 expression. However, [Tc-99m]Tc-ADAPT6 has better preconditions for higher sensitivity and specificity of stratification. On the other hand, [Tc-99m]Tc-(HE)(3)-G3 is capable of detecting the decrease of HER2 expression on response to trastuzumab therapy only 24 h after injection of the loading dose. This indicates that the [Tc-99m]Tc-(HE)(3)-G3 tracer would be better for monitoring early response to such treatment. The results of this study should be considered in planning of further clinical development of HER2 imaging probes., QC 20230109
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- 2022
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34. Effect of Inter-Domain Linker Composition on Biodistribution of ABD-Fused Affibody-Drug Conjugates Targeting HER2
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Xu, Tianqi, primary, Zhang, Jie, additional, Oroujeni, Maryam, additional, Tretyakova, Maria S., additional, Bodenko, Vitalina, additional, Belousov, Mikhail V., additional, Orlova, Anna, additional, Tolmachev, Vladimir, additional, Vorobyeva, Anzhelika, additional, and Gräslund, Torbjörn, additional
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- 2022
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35. Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
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Garousi, Javad, Ding, Haozhong, Witting, Emma von, Xu, Tianqi, Vorobyeva, Anzhelika, Oroujeni, Maryam, Orlova, Anna, Hober, Sophia, Gräslund, Torbjörn, and Tolmachev, Vladimir
- Subjects
RS1-441 ,Pharmacy and materia medica ,HER2 ,Biochemistry and Molecular Biology ,human epidermal growth factor receptor 2 ,ADAPT ,DM1 ,Article ,Biokemi och molekylärbiologi ,albumin binding domain - Abstract
Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusion with an albumin binding domain (ABD), and armed it with the highly cytotoxic payload mertansine (DM1) for an investigation of its properties in vitro and in vivo. The resulting drug conjugate, ADAPT6-ABD-mcDM1, retained binding to its intended targets, namely HER2 and serum albumins. Further, it was able to specifically bind to cells with high HER2 expression, get internalized, and showed potent toxicity, with IC50 values ranging from 5 to 80 nM. Conversely, no toxic effect was found for cells with low HER2 expression. In vivo, ADAPT6-ABD-mcDM1, radiolabeled with 99mTc, was characterized by low uptake in most normal organs, and the main excretion route was shown to be through the kidneys. The tumor uptake was 5.5% ID/g after 24 h, which was higher than the uptake in all normal organs at this time point except for the kidneys. The uptake in the tumors was blockable by pre-injection of an excess of the monoclonal antibody trastuzumab (having an overlapping epitope on the HER2 receptor). In conclusion, half-life extended drug conjugates based on the ADAPT platform of affinity proteins holds promise for further development towards targeted cancer therapy.
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- 2021
36. The Influence of Domain Permutations of an Albumin-Binding Domain-Fused HER2-Targeting Affibody-Based Drug Conjugate on Tumor Cell Proliferation and Therapy Efficacy
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Yin, Wen, primary, Xu, Tianqi, additional, Altai, Mohamed, additional, Oroujeni, Maryam, additional, Zhang, Jie, additional, Vorobyeva, Anzhelika, additional, Vorontsova, Olga, additional, Vtorushin, Sergey V., additional, Tolmachev, Vladimir, additional, Gräslund, Torbjörn, additional, and Orlova, Anna, additional
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- 2021
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37. Affibody-Mediated PNA-Based Pretargeted Cotreatment Improves Survival of Trastuzumab-Treated Mice Bearing HER2-Expressing Xenografts
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Oroujeni, Maryam, primary, Tano, Hanna, additional, Vorobyeva, Anzhelika, additional, Liu, Yongsheng, additional, Vorontsova, Olga, additional, Xu, Tianqi, additional, Westerlund, Kristina, additional, Orlova, Anna, additional, Tolmachev, Vladimir, additional, and Karlström, Amelie Eriksson, additional
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- 2021
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38. Direct In Vivo Comparison of 99m Tc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy.
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Tolmachev, Vladimir, Bodenko, Vitalina, Oroujeni, Maryam, Deyev, Sergey, Konovalova, Elena, Schulga, Alexey, Lindbo, Sarah, Hober, Sophia, Bragina, Olga, Orlova, Anna, and Vorobyeva, Anzhelika
- Subjects
SCAFFOLD proteins ,EPIDERMAL growth factor receptors ,TREATMENT effectiveness - Abstract
Non-invasive radionuclide molecular visualization of human epidermal growth factor receptor type 2 (HER2) can provide stratification of patients for HER2-targeting therapy. This method can also enable monitoring of the response to such therapies, thereby making treatment personalized and more efficient. Clinical evaluation in a phase I study demonstrated that injections of two scaffold protein-based imaging probes, [
99m Tc]Tc-(HE)3 -G3 and [99m Tc]Tc-ADAPT6, are safe, well-tolerated and cause a low level of radioactivity in healthy tissue. The goal of this preclinical study was to select the best probe for stratification of patients and response monitoring. Biodistribution of both tracers was compared in mice bearing SKOV-3 xenografts with high HER2 expression or MDA-MB-468 xenografts with very low expression. Changes in accumulation of the probes in SKOV-3 tumors 24 h after injection of trastuzumab were evaluated. Both [99m Tc]Tc-ADAPT6 and [99m Tc]Tc-(HE)3 -G3 permitted high contrast imaging of HER2-expressing tumors and a clear discrimination between tumors with high and low HER2 expression. However, [99m Tc]Tc-ADAPT6 has better preconditions for higher sensitivity and specificity of stratification. On the other hand, [99m Tc]Tc-(HE)3 -G3 is capable of detecting the decrease of HER2 expression on response to trastuzumab therapy only 24 h after injection of the loading dose. This indicates that the [99m Tc]Tc-(HE)3 -G3 tracer would be better for monitoring early response to such treatment. The results of this study should be considered in planning of further clinical development of HER2 imaging probes. [ABSTRACT FROM AUTHOR]- Published
- 2022
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39. Evaluation of a novel 177Lu-labelled therapeutic Affibody molecule with a deimmunized ABD domain and improved biodistribution profile.
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Liu, Yongsheng, Oroujeni, Maryam, Liao, Yunqi, Vorobyeva, Anzhelika, Bodenko, Vitalina, Orlova, Anna, Konijnenberg, Mark, Carlqvist, Matilda, Wahlberg, Elisabet, Loftenius, Annika, Frejd, Fredrik Y, and Tolmachev, Vladimir
- Subjects
- *
HEPATOTOXICOLOGY , *NEPHROTOXICOLOGY , *MOLECULES , *SURVIVAL rate , *TRASTUZUMAB - Abstract
Purpose: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required.The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177Lu. Affinity, specificity, and in vivo targeting properties of [177Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated.The maximum molar activity of 52 GBq/µmol [177Lu]Lu-PEP49989 was obtained. [177Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [177Lu]Lu-PEP49989 was similar to the affinity of [177Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [177Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [177Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [177Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [177Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild.In preclinical studies, [177Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab.Methods: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required.The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177Lu. Affinity, specificity, and in vivo targeting properties of [177Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated.The maximum molar activity of 52 GBq/µmol [177Lu]Lu-PEP49989 was obtained. [177Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [177Lu]Lu-PEP49989 was similar to the affinity of [177Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [177Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [177Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [177Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [177Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild.In preclinical studies, [177Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab.Results: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required.The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177Lu. Affinity, specificity, and in vivo targeting properties of [177Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated.The maximum molar activity of 52 GBq/µmol [177Lu]Lu-PEP49989 was obtained. [177Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [177Lu]Lu-PEP49989 was similar to the affinity of [177Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [177Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [177Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [177Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [177Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild.In preclinical studies, [177Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab.Conclusion: Fusion of Affibody molecules with an albumin-binding domain (ABD) provides targeting agents, which are suitable for radionuclide therapy. To facilitate clinical translation, the low immunogenic potential of such constructs with targeting properties conserved is required.The HER2-targeting Affibody molecule ZHER2:2891 was fused with a deimmunized ABD variant and DOTA was conjugated to a unique C-terminal cysteine. The novel construct, PEP49989, was labelled with 177Lu. Affinity, specificity, and in vivo targeting properties of [177Lu]Lu-PEP49989 were characterised. Experimental therapy in mice with human HER2-expressing xenografts was evaluated.The maximum molar activity of 52 GBq/µmol [177Lu]Lu-PEP49989 was obtained. [177Lu]Lu-PEP49989 bound specifically to HER2-expressing cells in vitro and in vivo. The HER2 binding affinity of [177Lu]Lu-PEP49989 was similar to the affinity of [177Lu]Lu-ABY-027 containing the parental ABD035 variant. The renal uptake of [177Lu]Lu-PEP49989 was 1.4-fold higher, but hepatic and splenic uptake was 1.7-2-fold lower than the uptake of [177Lu]Lu-ABY-027. The median survival of xenograft-bearing mice treated with 21 MBq [177Lu]Lu-PEP49989 (> 90 days) was significantly longer than the survival of mice treated with vehicle (38 days) or trastuzumab (45 days). Treatment using a combination of [177Lu]Lu-PEP49989 and trastuzumab increased the number of complete tumour remissions. The renal and hepatic toxicity was minimal to mild.In preclinical studies, [177Lu]Lu-PEP49989 demonstrated favourable biodistribution and a strong antitumour effect, which was further enhanced by co-treatment with trastuzumab. [ABSTRACT FROM AUTHOR]
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- 2024
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40. The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR : 2377 Affibody Molecule
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Oroujeni, Maryam, Xu, Tianqi, Gagnon, Katherine, Rinne, Sara S., Weis, Jan, Garousi, Javad, Andersson, Ken G, Löfblom, John, Orlova, Anna, Tolmachev, Vladimir, Oroujeni, Maryam, Xu, Tianqi, Gagnon, Katherine, Rinne, Sara S., Weis, Jan, Garousi, Javad, Andersson, Ken G, Löfblom, John, Orlova, Anna, and Tolmachev, Vladimir
- Abstract
Epidermal growth factor receptor (EGFR) is overexpressed in many malignancies. EGFR-targeted therapy extends survival of patients with disseminated cancers. Radionuclide molecular imaging of EGFR expression would make EGFR-directed treatment more personalized and therefore more efficient. A previous study demonstrated that affibody molecule [68Ga]Ga-DFO-ZEGFR:2377 permits specific positron-emission tomography (PET) imaging of EGFR expression in xenografts at 3 h after injection. We anticipated that imaging at 24 h after injection would provide higher contrast, but this is prevented by the short half-life of 68Ga (67.6 min). Here, we therefore tested the hypothesis that the use of the non-conventional long-lived positron emitter 66Ga (T1/2 = 9.49 h, β+ = 56.5%) would permit imaging with higher contrast. 66Ga was produced by the 66Zn(p,n)66Ga nuclear reaction and DFO-ZEGFR:2377 was efficiently labelled with 66Ga with preserved binding specificity in vitro and in vivo. At 24 h after injection, [66Ga]Ga-DFO-ZEGFR:2377 provided 3.9-fold higher tumor-to-blood ratio and 2.3-fold higher tumor-to-liver ratio than [68Ga]Ga-DFO-ZEGFR:2377 at 3 h after injection. At the same time point, [66Ga]Ga-DFO-ZEGFR:2377 provided 1.8-fold higher tumor-to-blood ratio, 3-fold higher tumor-to-liver ratio, 1.9-fold higher tumor-to-muscle ratio and 2.3-fold higher tumor-to-bone ratio than [89Zr]Zr-DFO-ZEGFR:2377. Biodistribution data were confirmed by whole body PET combined with magnetic resonance imaging (PET/MRI). The use of the positron emitter 66Ga for labelling of DFO-ZEGFR:2377 permits PET imaging of EGFR expression at 24 h after injection and improves imaging contrast.
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- 2021
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41. Drug Conjugates Based on a Monovalent Affibody Targeting Vector Can Efficiently Eradicate HER2 Positive Human Tumors in an Experimental Mouse Model
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Xu, Tianqi, Ding, Haozhong, Vorobyeva, Anzhelika, Oroujeni, Maryam, Orlova, Anna, Tolmachev, Vladimir, Gräslund, Torbjörn, Xu, Tianqi, Ding, Haozhong, Vorobyeva, Anzhelika, Oroujeni, Maryam, Orlova, Anna, Tolmachev, Vladimir, and Gräslund, Torbjörn
- Abstract
The human epidermal growth factor receptor 2 (HER2) is frequently overexpressed in a variety of cancers and therapies targeting HER2 are routinely used in the clinic. Recently, small engineered scaffold proteins, such as affibody molecules, have shown promise as carriers of cytotoxic drugs, and these drug conjugates may become complements or alternatives to the current HER2-targeting therapies. Here, we investigated if a monovalent HER2-binding affibody molecule, Z(HER2:2891), fused with a plasma half-life extending albumin binding domain (ABD), may be used as carrier of the cytotoxic maytansine derivate mcDM1. We found that the resulting drug conjugate, Z(HER2:2891)-ABD-E-3-mcDM1, had strong affinity for its cognate molecular targets: HER2 and serum albumin. Z(HER2:2891)-ABD-E-3-mcDM1 displayed potent cytotoxic activity towards cells with high HER2 expression, with IC50 values ranging from 0.6 to 33 nM. In vivo, an unspecific increase in uptake in the liver, imparted by the hydrophobic mcDM1, was counteracted by incorporation of hydrophilic and negatively charged glutamate residues near the site of mcDM1 conjugation. A dose-escalation experiment showed that increasing doses up to 15.1 mg/kg gave a proportional increase in uptake in xenografted HER2-overexpressing SKOV3 tumors, after which the tumors became saturated. Experimental therapy with four once-weekly injection of 10.3 or 15.1 mg/kg led to efficient regression of tumors in all animals and complete regression in some. Weight loss was detected for some animals in the group receiving the highest dose, suggesting that it was close to the maximum tolerated dose. In conclusion, the monovalent HER2-targeting affibody drug conjugate presented herein have potent anti-tumor activity in vivo., QC 20210203
- Published
- 2021
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42. The Influence of Domain Permutations of an Albumin-Binding Domain-Fused HER2-Targeting Affibody-Based Drug Conjugate on Tumor Cell Proliferation and Therapy Efficacy
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Yin, Wen, Xu, Tianqi, Altai, Mohamed, Oroujeni, Maryam, Zhang, Jie, Vorobyeva, Anzhelika, Vorontsova, Olga, Vtorushin, Sergey V., Tolmachev, Vladimir, Graslund, Torbjorn, Orlova, Anna, Yin, Wen, Xu, Tianqi, Altai, Mohamed, Oroujeni, Maryam, Zhang, Jie, Vorobyeva, Anzhelika, Vorontsova, Olga, Vtorushin, Sergey V., Tolmachev, Vladimir, Graslund, Torbjorn, and Orlova, Anna
- Abstract
Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had longer blood retention and lower hepatic uptake than the dimeric ones. A dimeric construct, specifically ABD-Z-Z, could stimulate the proliferation of HER2 expressing SKOV-3 cells in vitro and the growth of tumors in vivo, whereas the monomeric construct Z-ABD could not. These two constructs demonstrated a therapeutic effect when coupled to mcDM1; however, the effect was more pronounced for the non-stimulating Z-ABD. The median survival of the mice treated with Z-ABD-mcDM1 was 63 days compared to the 37 days for those treated with ABD-Z-Z-mcDM1 or for the control animals. Domain permutation of an ABD-fused HER2-targeting affibody-based drug conjugate significantly influences tumor cell proliferation and therapy efficacy. The monomeric conjugate Z-ABD is the most promising format for targeted delivery of the cytotoxic drug DM1.
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- 2021
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43. Radiolabelled affibody molecules for imaging EGFR expression in tumours
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Oroujeni, Maryam and Oroujeni, Maryam
- Abstract
Affibody molecules are promising scaffold-based targeting proteins for radionuclide imaging and cancer therapy. This thesis is based on 5 original research articles (Papers I-V), with the primary focus being placed on the optimization of molecular design of EGFR-binding affibody variants for high contrast imaging of epidermal growth factor receptor (EGFR) expression in tumours. The goal of my studies was to investigate the effect of labelling chemistry on the targeting properties of the anti-EGFR affibody molecule ZEGFR:2377 labelled with technetium-99m (99mTc) for single-photon emission computed tomography (SPECT), gallium-68 (68Ga), zirconium-89 (89Zr) and gallium-66 (66Ga) for positron-emission tomography (PET) to select radiolabelled variants providing the best imaging contrast. In Paper I, we showed the feasibility of stably labelling the anti-EGFR affibody molecule ZEGFR:2377 with 99mTc using a peptide-based cysteine-containing chelator and evaluated the imaging of EGFR expression in tumours using the [99mTc]Tc-ZEGFR:2377 affibody molecule. In Paper II, the effect of the composition of cysteine-containing peptide-based chelators on the biodistribution of 99mTc-labelled anti-EGFR affibody molecules was investigated. We evaluated whether the use of glutamate-based chelators improved the imaging properties of 99mTc-labelled ZEGFR:2377. In Paper III, the use of cyclic (FSC) versus noncyclic chelators (DFO) as bifunctional chelators for radiolabelling the anti-EGFR affibody molecule ZEGFR:2377 with 89Zr was investigated. The in vitro and in vivo properties of the resulting DFO- and FSC-ZEGFR:2377 molecules labelled with 89Zr were studied. In Paper IV, the targeting properties of [68Ga]Ga-DFO-ZEGFR:2377 were evaluated and compared directly with the properties of [89Zr]Zr-DFO-ZEGFR:2377 at 3 h after injection. In Paper V, the targeting properties of [66Ga]Ga-DFO-ZEGFR:2377 were evaluated and compared directly with the properties of [68Ga]Ga-DFO-ZEGFR:2377 and [89Zr]Z, No
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- 2021
44. Preclinical Evaluation of Tc-99m-ZHER2:41071, a Second-Generation Affibody-Based HER2-Visualizing Imaging Probe with a Low Renal Uptake
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Oroujeni, Maryam, Rinne, Sara S., Vorobyeva, Anzhelika, Loftenius, Annika, Feldwisch, Joachim, Jonasson, Per, Chernov, Vladimir, Orlova, Anna, Frejd, Fredrik Y., Tolmachev, Vladimir, Oroujeni, Maryam, Rinne, Sara S., Vorobyeva, Anzhelika, Loftenius, Annika, Feldwisch, Joachim, Jonasson, Per, Chernov, Vladimir, Orlova, Anna, Frejd, Fredrik Y., and Tolmachev, Vladimir
- Abstract
Radionuclide imaging of HER2 expression in tumours may enable stratification of patients with breast, ovarian, and gastroesophageal cancers for HER2-targeting therapies. A first-generation HER2-binding affibody molecule [Tc-99m]Tc-ZHER2:V2 demonstrated favorable imaging properties in preclinical studies. Thereafter, the affibody scaffold has been extensively modified, which increased its melting point, improved storage stability, and increased hydrophilicity of the surface. In this study, a second-generation affibody molecule (designated ZHER2:41071) with a new improved scaffold has been prepared and characterized. HER2-binding, biodistribution, and tumour-targeting properties of [Tc-99m]Tc-labelled ZHER2:41071 were investigated. These properties were compared with properties of the first-generation affibody molecules, [Tc-99m]Tc-ZHER2:V2 and [Tc-99m]Tc-ZHER2:2395. [Tc-99m]Tc-ZHER2:41071 bound specifically to HER2 expressing cells with an affinity of 58 +/- 2 pM. The renal uptake for [Tc-99m]Tc-ZHER2:41071 and [Tc-99m]Tc-ZHER2:V2 was 25-30 fold lower when compared with [Tc-99m]Tc-ZHER2:2395. The uptake in tumour and kidney for [Tc-99m]Tc-ZHER2:41071 and [Tc-99m]Tc-ZHER2:V2 in SKOV-3 xenografts was similar. In conclusion, an extensive re-engineering of the scaffold did not compromise imaging properties of the affibody molecule labelled with Tc-99m using a GGGC chelator. The new probe, [Tc-99m]Tc-ZHER2:41071 provided the best tumour-to-blood ratio compared to HER2-imaging probes for single photon emission computed tomography (SPECT) described in the literature so far. [Tc-99m]Tc-ZHER2:41071 is a promising candidate for further clinical translation studies.
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- 2021
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45. Affibody-Derived Drug Conjugates Targeting HER2 : Effect of Drug Load on Cytotoxicity and Biodistribution
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Ding, Haozhong, Xu, Tianqi, Zhang, Jie, Tolmachev, Vladimir, Oroujeni, Maryam, Orlova, Anna, Gräslund, Torbjörn, Vorobyeva, Anzhelika, Ding, Haozhong, Xu, Tianqi, Zhang, Jie, Tolmachev, Vladimir, Oroujeni, Maryam, Orlova, Anna, Gräslund, Torbjörn, and Vorobyeva, Anzhelika
- Abstract
Affibody molecules hold great promise as carriers of cytotoxic drugs for cancer therapy due to their typically high affinity, easy production, and inherent control of the drug molecules’ loading and spatial arrangement. Here, the impact of increasing the drug load from one to three on the properties of an affibody drug conjugate targeting the human epidermal growth factor receptor 2 (HER2) was investigated. The affibody carrier was recombinantly expressed as a fusion to an albumin-binding domain (ABD) for plasma half-life extension. One or three cysteine amino acids were placed at the C-terminus to which cytotoxic mcDM1 molecules were conjugated. The resulting drug conjugates, ZHER2–ABD–mcDM1 and ZHER2–ABD–mcDM13, were characterized in vitro, and their biodistribution in mice carrying HER2-overexpressing SKOV3 xenografts was determined. Increasing the drug load from one to three led to a decrease in affinity for HER2, but a significantly more potent cytotoxic effect on SKOV3 cells with high HER2 expression. The difference in cytotoxic effect on other cell lines with high HER2 expression was not significant. In vivo, an increase in drug load led to a 1.45-fold higher amount of cytotoxic mcDM1 delivered to the tumors. The increase in drug load also led to more rapid hepatic clearance, warranting further optimization of the molecular design., De två första författarna delar förstaförfattarskapet
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- 2021
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46. Comparative Evaluation of Novel Lu-177-Labeled PNA Probes for Affibody-Mediated PNA-Based Pretargeting
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Tano, Hanna, Oroujeni, Maryam, Vorobyeva, Anzhelika, Westerlund, Kristina, Liu, Yongsheng, Xu, Tianqi, Vasconcelos, Daniel, Orlova, Anna, Karlstrom, Amelie Eriksson, Tolmachev, Vladimir, Tano, Hanna, Oroujeni, Maryam, Vorobyeva, Anzhelika, Westerlund, Kristina, Liu, Yongsheng, Xu, Tianqi, Vasconcelos, Daniel, Orlova, Anna, Karlstrom, Amelie Eriksson, and Tolmachev, Vladimir
- Abstract
Simple Summary Affibody molecules are small, engineered affinity proteins based on a nonimmunoglobulin scaffold. Affibody-based radionuclide imaging probes have demonstrated excellent tumor targeting. However, the renal clearance of affibody molecules is accompanied by high reabsorption and retention of activity in the kidney, which prevents their use for radionuclide therapy. We have previously shown the feasibility of overcoming the high renal uptake using a pretargeting approach for affibody-mediated therapy based on peptide nucleic acid (PNA) hybridization. In this study, we test the hypothesis that shortening the PNA pretargeting probes would further increase the difference between the accumulation of radiometals in tumor xenografts and in kidneys. A series of novel PNA probes has been designed and evaluated in vitro and in vivo. We have found that a variant containing 9 nucleobases enables a two-fold increase of the tumor-to-kidney dose ratio compared with a variant containing 15 nucleobases. This creates preconditions for more efficient therapy of cancer. Affibody-mediated PNA-based pretargeting is a promising approach to radionuclide therapy of HER2-expressing tumors. In this study, we test the hypothesis that shortening the PNA pretargeting probes would increase the tumor-to-kidney dose ratio. The primary probe Z(HER2:342)-SR-HP15 and the complementary secondary probes HP16, HP17, and HP18, containing 9, 12, and 15 nucleobases, respectively, and carrying a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator were designed, synthesized, characterized in vitro, and labeled with Lu-177. In vitro pretargeting was studied in HER2-expressing SKOV3 and BT474 cell lines. The biodistribution of these novel probes was evaluated in immunodeficient mice bearing SKOV3 xenografts and compared to the previously studied [Lu-177]Lu-HP2. Characterization confirmed the formation of high-affinity duplexes between HP15 and the secondary probes, with the affi
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- 2021
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47. Preclinical Evaluation of a New Format of 68 Ga- and 111 In-Labeled Affibody Molecule Z IGF-1R:4551 for the Visualization of IGF-1R Expression in Malignant Tumors Using PET and SPECT.
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Liu, Yongsheng, Yu, Shengze, Xu, Tianqi, Bodenko, Vitalina, Orlova, Anna, Oroujeni, Maryam, Rinne, Sara S., Tolmachev, Vladimir, Vorobyeva, Anzhelika, and Gräslund, Torbjörn
- Subjects
SINGLE-photon emission computed tomography ,CARDIAC radionuclide imaging ,COMPUTED tomography ,MONOCLONAL antibodies ,VISUALIZATION ,DRUG target ,MOLECULES - Abstract
The Insulin-like growth factor-1 receptor (IGF-1R) is a molecular target for several monoclonal antibodies undergoing clinical evaluation as anticancer therapeutics. The non-invasive detection of IGF-1R expression in tumors might enable stratification of patients for specific treatment and improve the outcome of both clinical trials and routine treatment. The affibody molecule Z
IGF-1R:4551 binds specifically to IGF-1R with subnanomolar affinity. The goal of this study was to evaluate the68 Ga and111 In-labeled affibody construct NODAGA-(HE)3 -ZIGF-1R:4551 for the imaging of IGF-1R expression, using PET and SPECT. The labeling was efficient and provided stable coupling of both radionuclides. The two imaging probes, [68 Ga]Ga-NODAGA-(HE)3 -ZIGF-1R:4551 and [111 In]In-NODAGA-(HE)3 -ZIGF-1R:4551 , demonstrated specific binding to IGF-1R-expressing human cancer cell lines in vitro and to IGF-1R-expressing xenografts in mice. Preclinical PET and SPECT/CT imaging demonstrated visualization of IGF-1R-expressing xenografts already one hour after injection. The tumor-to-blood ratios at 3 h after injection were 7.8 ± 0.2 and 8.0 ± 0.6 for [68 Ga]Ga-NODAGA-(HE)3 -ZIGF-1R:4551 and [111 In]In-NODAGA-(HE)3 -ZIGF-1R:4551 , respectively. In conclusion, a molecular design of the ZIGF-1R:4551 affibody molecule, including placement of a (HE)3 -tag on the N-terminus and site-specific coupling of a NODAGA chelator on the C-terminus, provides a tracer with improved imaging properties for visualization of IGF-1R in malignant tumors, using PET and SPECT. [ABSTRACT FROM AUTHOR]- Published
- 2022
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48. Affibody-Derived Drug Conjugates Targeting HER2: Effect of Drug Load on Cytotoxicity and Biodistribution
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Ding, Haozhong, primary, Xu, Tianqi, additional, Zhang, Jie, additional, Tolmachev, Vladimir, additional, Oroujeni, Maryam, additional, Orlova, Anna, additional, Gräslund, Torbjörn, additional, and Vorobyeva, Anzhelika, additional
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- 2021
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49. Preclinical Evaluation of 99mTc-ZHER2:41071, a Second-Generation Affibody-Based HER2-Visualizing Imaging Probe with a Low Renal Uptake
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Oroujeni, Maryam, primary, Rinne, Sara S., additional, Vorobyeva, Anzhelika, additional, Loftenius, Annika, additional, Feldwisch, Joachim, additional, Jonasson, Per, additional, Chernov, Vladimir, additional, Orlova, Anna, additional, Frejd, Fredrik Y., additional, and Tolmachev, Vladimir, additional
- Published
- 2021
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50. The Use of a Non-Conventional Long-Lived Gallium Radioisotope 66Ga Improves Imaging Contrast of EGFR Expression in Malignant Tumours Using DFO-ZEGFR:2377 Affibody Molecule
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Oroujeni, Maryam, primary, Xu, Tianqi, additional, Gagnon, Katherine, additional, Rinne, Sara S., additional, Weis, Jan, additional, Garousi, Javad, additional, Andersson, Ken G., additional, Löfblom, John, additional, Orlova, Anna, additional, and Tolmachev, Vladimir, additional
- Published
- 2021
- Full Text
- View/download PDF
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