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In vivo evaluation ...
In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct
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- Bass, Tarek (författare)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
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- Rosestedt, Maria (författare)
- Uppsala universitet,Avdelningen för Molekylär Avbildning
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- Mitran, Bogdan (författare)
- Uppsala universitet,Avdelningen för Molekylär Avbildning
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- Frejd, Fredrik Y. (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap,Affibody AB, SE-17163 Solna, Sweden
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- Löfblom, John (författare)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
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- Tolmachev, Vladimir (författare)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Ståhl, Stefan (författare)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
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- Orlova, Anna (författare)
- Uppsala universitet,Avdelningen för Molekylär Avbildning
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(creator_code:org_t)
- 2017-02-23
- 2017
- Engelska.
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 7
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://www.nature.c...
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https://kth.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation. In vitro, 3A3 efficiently inhibited growth of HER3-expressing BxPC-3 cells. Biodistribution in mice was measured using 3A3 that was site-specifically labelled with In-111 via a DOTA chelator. The residence time of In-111-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-111-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-111-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-111-DOTA-TAT, most likely due to sequestering of 3A3 by mErbB3, the murine counterpart of HER3. Repeated dosing and increase of injected protein dose decreased uptake of In-111-DOTA-3A3 in mErbB3-expressing tissues. Encouragingly, growth of BxPC-3 xenografts in mice was delayed in an experimental (pilot-scale) therapy study using 3A3. We conclude that the 3A3 affibody format seems promising for treatment of HER3-overexpressing tumours.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
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