Search: onr:"swepub:oai:DiVA.org:kth-308520" >
Targeting tumor cel...
Targeting tumor cells overexpressing the human epidermal growth factor receptor 3 with potent drug conjugates based on affibody molecules
-
Rinne, Sara (author)
-
- Yin, Wen, 1993- (author)
- KTH,Proteinvetenskap,Torbjörn Gräslund
-
Borras, Anna Mestre (author)
-
show more...
-
Abouzaed, Ayman (author)
-
Leitao, Charles Dahlsson (author)
-
Vorobyeva, Anzhelika (author)
-
- Löfblom, John (author)
- KTH,Proteinvetenskap
-
Stähl, Stefan (author)
-
Orlova, Anna (author)
-
- Gräslund, Torbjörn (author)
- KTH,Proteinvetenskap
-
show less...
-
(creator_code:org_t)
- English.
- Related links:
-
https://urn.kb.se/re...
Abstract
Subject headings
Close
- 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 have 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 strong affinity to the extracellular domain of HER3 (KD 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic cancer cell line, BxPC3. The drug conjugate showed a potent cytotoxic effect on BxPC3 cells with an IC50 value of 7 nM. Further in vitro evaluation of a radiolabeled version [99mTc]Tc-ZHER3-ABD-mcDM1, showed that it had a relatively high rate of internalization into HER3-expressing BxPC-3 as well as DU145 (prostate cancer) cells, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could specifically target BxPC-3 and DU145-derived xenografts in mice, with an uptake peaking at 6.3 ± 0.4 %ID/g at 6 h post-injection for the BxPC-3-derived xenografts. The general biodistribution showed uptake in liver, lung, salivary gland, stomach, and small intestine, organs known to express HER3 naturally. The results from the study show that ZHER3-ABD- mcDM1 is a highly potent and specific drug conjugate, that may be further developed towards HER3-targeted cancer therapy.
Subject headings
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Publication and Content Type
- vet (subject category)
- ovr (subject category)
To the university's database
- By the author/editor
-
Rinne, Sara
-
Yin, Wen, 1993-
-
Borras, Anna Mes ...
-
Abouzaed, Ayman
-
Leitao, Charles ...
-
Vorobyeva, Anzhe ...
-
show more...
-
Löfblom, John
-
Stähl, Stefan
-
Orlova, Anna
-
Gräslund, Torbjö ...
-
show less...
- About the subject
-
- NATURAL SCIENCES
-
NATURAL SCIENCES
-
and Biological Scien ...
-
and Microbiology
- By the university
-
Royal Institute of Technology