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Potent and specific fusion toxins consisting of a HER2-binding ABD-derived affinity protein (ADAPT), fused to truncated versions of Pseudomonas exotoxin A
KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Protein Engineering.
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Teknik och teknologier Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:kth:diva-228014OAI: oai:DiVA.org:kth-228014DiVA, id: diva2:1206275
Anmärkning

QC 20180517

Tillgänglig från: 2018-05-16 Skapad: 2018-05-16 Senast uppdaterad: 2018-05-17Bibliografiskt granskad
Ingår i avhandling
1. Tumor targeted delivery of cytotoxic payloads using affibody molecules and ABD-derived affinity proteins
Öppna denna publikation i ny flik eller fönster >>Tumor targeted delivery of cytotoxic payloads using affibody molecules and ABD-derived affinity proteins
2018 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
KTH Royal Institute of Technology, 2018. s. 78
Serie
TRITA-CBH-FOU ; 2018:26
Nyckelord
Targeted tumor therapy, immunotoxins, ADCs, affibody molecule, ADAPT, pseudomonas exotoxin A, maytansinoid
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
Bioteknologi
Identifikatorer
urn:nbn:se:kth:diva-228015 (URN)978-91-7729-827-4 (ISBN)
Disputation
2018-06-14, Oskar Kleins Auditorium, Roslagstullsbacken 21, Albanova University Center,, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

QC 20180517

Tillgänglig från: 2018-05-17 Skapad: 2018-05-16 Senast uppdaterad: 2018-05-17Bibliografiskt granskad

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Liu, Hao
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Protein Engineering
Teknik och teknologierMedicin och hälsovetenskap

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Totalt: 395 träffar
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