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Effect of Inter-Dom...
Effect of Inter-Domain Linker Composition on Biodistribution of ABD-Fused Affibody-Drug Conjugates Targeting HER2
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- Xu, Tianqi (author)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Zhang, Jie (author)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Oroujeni, Maryam, PhD, 1982- (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Affibody AB, Dept Sci & Dev, S-17165 Solna, Sweden.
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- Tretyakova, Maria S. (author)
- Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.;Russian Acad Sci, Tomsk Natl Res Med Ctr, Canc Res Inst, Tomsk 634009, Russia.
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- Bodenko, Vitalina (author)
- Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.
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- Belousov, Mikhail, V (author)
- Siberian State Med Univ, Dept Pharmaceut Anal, Minist Hlth Russian Federat, Tomsk 634050, Russia.;Natl Res Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.
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- Orlova, Anna, 1960- (author)
- Uppsala universitet,Theranostics,Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.
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- Tolmachev, Vladimir (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.
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- Vorobyeva, Anzhelika (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, Tomsk 634050, Russia.
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- Gräslund, Torbjörn (author)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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(creator_code:org_t)
- 2022-02-26
- 2022
- English.
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:3, s. 522-
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- affibody molecule
- human epidermal growth factor receptor 2
- HER2
- SKOV3
- emtansine
- DM1
- albumin binding domain
- affibody drug conjugate
- AffiDC
Publication and Content Type
- ref (subject category)
- art (subject category)
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Xu, Tianqi
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Zhang, Jie
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Oroujeni, Maryam ...
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Tretyakova, Mari ...
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Bodenko, Vitalin ...
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Belousov, Mikhai ...
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Orlova, Anna, 19 ...
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Tolmachev, Vladi ...
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Vorobyeva, Anzhe ...
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Gräslund, Torbjö ...
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- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Pharmaceutics
- By the university
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Royal Institute of Technology
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Uppsala University