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Affibody-derived Drug Conjugates: Potent Cytotoxic Drugs ForTreatment Of HER2 Over-Expressing Tumors
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Protein Engineering.
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences Engineering and Technology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-228013OAI: oai:DiVA.org:kth-228013DiVA, id: diva2:1206273
Note

QC 20180517

Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-05-17Bibliographically approved
In thesis
1. Tumor targeted delivery of cytotoxic payloads using affibody molecules and ABD-derived affinity proteins
Open this publication in new window or tab >>Tumor targeted delivery of cytotoxic payloads using affibody molecules and ABD-derived affinity proteins
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cancer treatment cost billions of dollars every year, but the mortality rate is still high. An ideal treatment is the so-called “magic bullets” that recognize and kill tumor cells while leaving normal cells untouched. In recent years, some nonimmunoglobulin alternative scaffold affinity proteins, such as affibody molecules and ADAPTs, have emerged and been used to specifically recognize different tumor antigens. In this thesis, I studied the properties and anti-tumor activities of affibody and ADAPT fusion toxins and affibody drug conjugates. In the first two papers, I studied a panel of recombinant affitoxins (affibody toxin fusion proteins) consisting of an anti-HER2 affibody molecule (ZHER2), an albumin binding domain (ABD) and a truncated version of Pseudomonas Exotoxin A(PE38X8). The affitoxins demonstrated specific anti-tumor activity on HER2-overexpressing tumor cells in vitro. A biodistribution experiment showed that addition of an ABD increased the blood retention by 28-fold and a (HE)3 N-terminal purification tag decreased hepatic uptake of the affitoxin compared with a His6 tag. In paper III, I studied immunotoxins consisting of an anti-HER2 ABD-derived affinity protein (ADAPT), an ABD and a minimized and deimmunized version of Pseudomonas exotoxin A (PE25). These immunotoxins demonstrated potent and specific cytotoxicity toward HER2 overexpressing tumor cells in vitro similar to affitoxins. In paper IV, I produced a panel of affibody drug conjugates consisting of ZHER2, ABD and malemidocaproylmertansine (mc-DM1). The conjugates had selective toxic activity on HER2-overexpressing tumor cells in vitro comparable with the approved drug trastuzumab emtansine. The conjugate, ZHER2-ZHER2-ABD-mc-DM1 was found to prolong the life span of tumor bearing mice and delayed the growth ofxenografted SKOV-3 tumors. In conclusion, affibody molecules and ADAPTs are promising alternatives to antibodies for targeted tumor therapy.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2018. p. 78
Series
TRITA-CBH-FOU ; 2018:26
Keywords
Targeted tumor therapy, immunotoxins, ADCs, affibody molecule, ADAPT, pseudomonas exotoxin A, maytansinoid
National Category
Biochemistry and Molecular Biology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-228015 (URN)978-91-7729-827-4 (ISBN)
Public defence
2018-06-14, Oskar Kleins Auditorium, Roslagstullsbacken 21, Albanova University Center,, Stockholm, 10:00 (English)
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Note

QC 20180517

Available from: 2018-05-17 Created: 2018-05-16 Last updated: 2018-05-17Bibliographically approved

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