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HER2-Specific Pseud...
HER2-Specific Pseudomonas Exotoxin A PE25 Based Fusions : Influence of Targeting Domain on Target Binding, Toxicity, and In Vivo Biodistribution
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- Ding, Haozhong (author)
- KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Altai, Mohamed (author)
- 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 Environments
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- Yin, Wen (author)
- KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Lindbo, Sarah (author)
- KTH Royal Institute of Technology,KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Liu, Hao (author)
- KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Garousi, Javad (author)
- Uppsala University,Uppsala universitet,Medicinsk strålningsvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.
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- Xu, Tianqi (author)
- Uppsala University,Uppsala universitet,Medicinsk strålningsvetenskap,Uppsala Univ, Dept Immunol Genet & Pathol, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden.
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- Orlova, Anna (author)
- 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 University
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- Tolmachev, Vladimir (author)
- 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 University
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- Hober, Sophia, 1965- (author)
- KTH Royal Institute of Technology,KTH,Proteinteknologi,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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- Gräslund, Torbjörn (author)
- KTH Royal Institute of Technology,KTH,Proteinvetenskap,KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
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(creator_code:org_t)
- 2020-04-24
- 2020
- English.
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In: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 12:4
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Abstract
Subject headings
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- 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.
Subject headings
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- pseudomonas exotoxin A
- affibody molecule
- half-life extension
- cancer
- HER2
- Affibody molecule
- Cancer
- Half-life extension
- HER2
- Pseudomonas exotoxin A
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Ding, Haozhong
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Altai, Mohamed
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Yin, Wen
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Lindbo, Sarah
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Liu, Hao
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Garousi, Javad
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Xu, Tianqi
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Orlova, Anna
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Tolmachev, Vladi ...
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Hober, Sophia, 1 ...
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Gräslund, Torbjö ...
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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 Microbiology
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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 ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- 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
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Lund University