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Preclinical Evaluat...
Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion
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- Deyev, Sergey M. (author)
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
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- Oroujeni, Maryam (author)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden;; Affibody AB, 171 65 Solna, Sweden
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- Garousi, Javad (author)
- KTH,Proteinvetenskap,Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
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- Gräslund, Torbjörn, 1970- (author)
- KTH,Proteinvetenskap
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- Li, Ruonan (author)
- KTH,Proteinvetenskap
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- Rosly, Alia Hani Binti (author)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden;
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- Orlova, Anna (author)
- Department of Medicinal Chemistry, Uppsala University, 751 83 Uppsala, Sweden;
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- Konovalova, Elena (author)
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia
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- Schulga, Alexey (author)
- Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, Tomsk Polytechnic University, 634050 Tomsk, Russia
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- Vorobyeva, Anzhelika (author)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden;
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- Tolmachev, Vladimir (author)
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden;
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(creator_code:org_t)
- Multidisciplinary Digital Publishing Institute (MDPI), 2024
- 2024
- English.
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In: International Journal of Molecular Sciences. - : Multidisciplinary Digital Publishing Institute (MDPI). - 1661-6596 .- 1422-0067. ; 25:8
- Related links:
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https://doi.org/10.3...
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
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- 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 177Lu. 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 [177Lu]Lu-G3-ABD. Our data suggest that the order of domains is critical for the design of targeting constructs based on scaffold proteins.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
Keyword
- albumin-binding domain (ABD)
- DARPin G3
- HER2
- Lutetium-177 ( Lu) 177
- SKOV-3 xenograft
- SPECT imaging
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Deyev, Sergey M.
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Oroujeni, Maryam
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Garousi, Javad
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Gräslund, Torbjö ...
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Li, Ruonan
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Rosly, Alia Hani ...
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Orlova, Anna
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Konovalova, Elen ...
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Schulga, Alexey
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Vorobyeva, Anzhe ...
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Tolmachev, Vladi ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Radiology Nuclea ...
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Royal Institute of Technology