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LIBRIS Formathandbok  (Information om MARC21)
FältnamnIndikatorerMetadata
00007513naa a2200709 4500
001oai:DiVA.org:kth-276626
003SwePub
008200623s2020 | |||||||||||000 ||eng|
009oai:DiVA.org:uu-414292
009oai:lup.lub.lu.se:27901384-07e7-4b87-8e20-97d0133ec44b
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-2766262 URI
0247 a https://doi.org/10.3390/pharmaceutics120403912 DOI
0247 a https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4142922 URI
0247 a https://lup.lub.lu.se/record/27901384-07e7-4b87-8e20-97d0133ec44b2 URI
040 a (SwePub)kthd (SwePub)uud (SwePub)lu
041 a engb eng
042 9 SwePub
072 7a ref2 swepub-contenttype
072 7a art2 swepub-publicationtype
1001 a Ding, Haozhongu KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u18o3ynm
2451 0a HER2-Specific Pseudomonas Exotoxin A PE25 Based Fusions :b Influence of Targeting Domain on Target Binding, Toxicity, and In Vivo Biodistribution
264 c 2020-04-24
264 1b MDPI AG,c 2020
338 a print2 rdacarrier
500 a QC 20200623
520 a The human epidermal growth factor receptor 2 (HER2) is a clinically validated target for cancer therapy, and targeted therapies are often used in regimens for patients with a high HER2 expression level. Despite the success of current drugs, a number of patients succumb to their disease, which motivates development of novel drugs with other modes of action. We have previously shown that an albumin binding domain-derived affinity protein with specific affinity for HER2, ADAPT(6), can be used to deliver the highly cytotoxic protein domain PE25, a derivative of Pseudomonas exotoxin A, to HER2 overexpressing malignant cells, leading to potent and specific cell killing. In this study we expanded the investigation for an optimal targeting domain and constructed two fusion toxins where a HER2-binding affibody molecule, Z(HER2:2891), or the dual-HER2-binding hybrid Z(HER2:2891)-ADAPT(6) were used for cancer cell targeting. We found that both targeting domains conferred strong binding to HER2; both to the purified extracellular domain and to the HER2 overexpressing cell line SKOV3. This resulted in fusion toxins with high cytotoxic potency toward cell lines with high expression levels of HER2, with EC50 values between 10 and 100 pM. For extension of the plasma half-life, an albumin binding domain was also included. Intravenous injection of the fusion toxins into mice showed a profound influence of the targeting domain on biodistribution. Compared to previous results, with ADAPT(6) as targeting domain, Z(HER2:2891) gave rise to further extension of the plasma half-life and also shifted the clearance route of the fusion toxin from the liver to the kidneys. Collectively, the results show that the targeting domain has a major impact on uptake of PE25-based fusion toxins in different organs. The results also show that PE25-based fusion toxins with high affinity to HER2 do not necessarily increase the cytotoxicity beyond a certain point in affinity. In conclusion, Z(HER2:2891) has the most favorable characteristics as targeting domain for PE25.
650 7a NATURVETENSKAPx Biologix Mikrobiologi0 (SwePub)106062 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Microbiology0 (SwePub)106062 hsv//eng
650 7a NATURVETENSKAPx Biologix Biokemi och molekylärbiologi0 (SwePub)106022 hsv//swe
650 7a NATURAL SCIENCESx Biological Sciencesx Biochemistry and Molecular Biology0 (SwePub)106022 hsv//eng
650 7a MEDICIN OCH HÄLSOVETENSKAPx Medicinska och farmaceutiska grundvetenskaperx Farmaceutiska vetenskaper0 (SwePub)301012 hsv//swe
650 7a MEDICAL AND HEALTH SCIENCESx Basic Medicinex Pharmaceutical Sciences0 (SwePub)301012 hsv//eng
653 a pseudomonas exotoxin A
653 a affibody molecule
653 a half-life extension
653 a cancer
653 a HER2
653 a Affibody molecule
653 a Cancer
653 a Half-life extension
653 a HER2
653 a Pseudomonas exotoxin A
7001 a Altai, Mohamedu Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,LUCC: Lund University Cancer Centre,Other Strong Research Environments4 aut0 (Swepub:lu)mo8753al
7001 a Yin, Wenu KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u1ne6bok
7001 a Lindbo, Sarahu KTH Royal Institute of Technology,KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u1d07egv
7001 a Liu, Haou KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u17qdh9c
7001 a Garousi, Javadu Uppsala University,Uppsala universitet,Medicinsk strålningsvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.4 aut0 (Swepub:uu)javga723
7001 a Xu, Tianqiu Uppsala University,Uppsala universitet,Medicinsk strålningsvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.4 aut0 (Swepub:uu)tiaxu272
7001 a Orlova, Annau Uppsala University,Uppsala universitet,Theranostics,Uppsala Univ, Dept Med Chem, Dag Hammarskjolds Vag 14C, S-75123 Uppsala, Sweden.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.,Tomsk Polytechnic University4 aut0 (Swepub:uu)annaorlo
7001 a Tolmachev, Vladimiru Uppsala University,Uppsala universitet,Medicinsk strålningsvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.;Tomsk Polytech Univ, Res Sch Chem & Appl Biomed Sci, Res Ctr Oncotheranost, Tomsk 634050, Russia.,Tomsk Polytechnic University4 aut0 (Swepub:uu)vladtolm
7001 a Hober, Sophia,d 1965-u KTH Royal Institute of Technology,KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u11qqzc1
7001 a Gräslund, Torbjörnu KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.4 aut0 (Swepub:kth)u1dl39rj
7102 a KTHb Proteinvetenskap4 org
7730 t Pharmaceuticsd : MDPI AGg 12:4q 12:4x 1999-4923
8564 u https://doi.org/10.3390/pharmaceutics12040391y Fulltext
8564 u https://www.mdpi.com/1999-4923/12/4/391/pdf
8564 u https://uu.diva-portal.org/smash/get/diva2:1455629/FULLTEXT01.pdfx primaryx Raw objecty fulltext:print
8564 u http://dx.doi.org/10.3390/pharmaceutics12040391x freey FULLTEXT
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-276626
8564 8u https://doi.org/10.3390/pharmaceutics12040391
8564 8u https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-414292
8564 8u https://lup.lub.lu.se/record/27901384-07e7-4b87-8e20-97d0133ec44b

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