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Preclinical Evaluation of HER2-Targeting DARPin G3: Impact of Albumin-Binding Domain (ABD) Fusion

Deyev, Sergey M. (författare)
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,Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.
Oroujeni, Maryam, PhD, 1982- (författare)
Uppsala universitet,Cancerprecisionsmedicin,Affibody AB, S-17165 Solna, Sweden.
Garousi, Javad (författare)
Uppsala universitet,KTH,Proteinvetenskap,Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden,Cancerprecisionsmedicin,KTH Royal Inst Technol, Dept Prot Sci, S-10691 Stockholm, Sweden.
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Gräslund, Torbjörn, 1970- (författare)
KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, S-10691 Stockholm, Sweden.
Li, Ruonan (författare)
KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, S-10691 Stockholm, Sweden.
Rosly, Alia Hani Binti (författare)
Uppsala universitet,Cancerprecisionsmedicin
Orlova, Anna, 1960- (författare)
Uppsala universitet,Theranostics
Konovalova, Elena (författare)
Molecular Immunology Laboratory, Shemyakin & Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, 117997, Russia,Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.
Schulga, Alexey (författare)
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,Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.
Vorobyeva, Anzhelika (författare)
Uppsala universitet,Cancerprecisionsmedicin
Tolmachev, Vladimir (författare)
Uppsala universitet,Cancerprecisionsmedicin
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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 Russian Acad Sci, Shemyakin & Ovchinnikov Inst Bioorgan Chem, Mol Immunol Lab, Moscow 117997, Russia;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia. (creator_code:org_t)
Multidisciplinary Digital Publishing Institute (MDPI), 2024
2024
Engelska.
Ingår i: International Journal of Molecular Sciences. - : Multidisciplinary Digital Publishing Institute (MDPI). - 1661-6596 .- 1422-0067. ; 25:8
Relaterad länk:
https://doi.org/10.3...
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https://doi.org/10.3...
https://urn.kb.se/re...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
Stäng  
  • 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Radiologi och bildbehandling (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Radiology, Nuclear Medicine and Medical Imaging (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Medicinal Chemistry (hsv//eng)

Nyckelord

albumin-binding domain (ABD)
DARPin G3
HER2
Lutetium-177 ( Lu) 177
SKOV-3 xenograft
SPECT imaging

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