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Targeting HER2 Expr...
Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein
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- Garousi, Javad (author)
- Uppsala universitet,KTH,Proteinvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, SE-75185 Uppsala, Sweden.,Medicinsk strålningsvetenskap,KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
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- Ding, Haozhong (author)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
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- von Witting, Emma (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
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- Xu, Tianqi (author)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Vorobyeva, Anzhelika (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Res Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, RU-634050 Tomsk, Russia.
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- Oroujeni, Maryam, PhD, 1982- (author)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Orlova, Anna, 1960- (author)
- Uppsala universitet,Theranostics,Res Tomsk Polytech Univ, Res Ctr Oncotheranost, Res Sch Chem & Appl Biomed Sci, RU-634050 Tomsk, Russia.
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- Hober, Sophia, Professor, 1965- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
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- Gräslund, Torbjörn (author)
- KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, SE-10691 Stockholm, Sweden.
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- Tolmachev, Vladimir (author)
- Uppsala universitet,Medicinsk strålningsvetenskap
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(creator_code:org_t)
- 2021-11-03
- 2021
- English.
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 13:11, s. 1847-
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Abstract
Subject headings
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- 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 Tc-99m, 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- ADAPT
- human epidermal growth factor receptor 2
- HER2
- DM1
- albumin binding domain
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Garousi, Javad
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Ding, Haozhong
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von Witting, Emm ...
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Xu, Tianqi
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Vorobyeva, Anzhe ...
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Oroujeni, Maryam ...
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Orlova, Anna, 19 ...
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Hober, Sophia, P ...
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Gräslund, Torbjö ...
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Tolmachev, Vladi ...
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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