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Targeting Tumor Cel...
Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules
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- Rinne, Sara S. (author)
- Uppsala universitet,Theranostics,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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- Yin, Wen, 1993- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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- Mestre Borras, Anna, 1994- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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- Abouzayed, Ayman (author)
- Uppsala universitet,Theranostics
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- Leitao, Charles Dahlsson, 1992- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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- Vorobyeva, Anzhelika (author)
- Uppsala universitet,Medicinsk strålningsvetenskap
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- Löfblom, John, 1977- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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- Ståhl, Stefan, 1961- (author)
- KTH,Proteinteknologi
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- Orlova, Anna, 1960- (author)
- Uppsala universitet,Medicinsk strålningsvetenskap,Theranostics,Science for Life Laboratory, SciLifeLab
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- Gräslund, Torbjörn, 1970- (author)
- KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, S-11417 Stockholm, Sweden.
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(creator_code:org_t)
- 2022-05-31
- 2022
- English.
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In: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:6
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Abstract
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- Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin-binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K-D 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [99mTc]Tc-ZHER3-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 +/- 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that ZHER3-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Biomedicinsk laboratorievetenskap/teknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Biomedical Laboratory Science/Technology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Keyword
- affibody molecule
- human epidermal growth factor receptor 3 (HER3)
- BxPC-3
- emtansine
- DM1
- albumin binding domain
- affibody drug conjugate (AffiDC)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Rinne, Sara S.
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Yin, Wen, 1993-
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Mestre Borras, A ...
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Abouzayed, Ayman
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Leitao, Charles ...
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Vorobyeva, Anzhe ...
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Löfblom, John, 1 ...
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Ståhl, Stefan, 1 ...
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Orlova, Anna, 19 ...
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Gräslund, Torbjö ...
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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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MEDICAL AND HEAL ...
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MEDICAL AND HEAL ...
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- Articles in the publication
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Biomedicines
- By the university
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Royal Institute of Technology
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Uppsala University