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Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin
KTH, School of Biotechnology (BIO), Protein Technology.
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2016 (English)In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, p. 1185-1194Article in journal (Refereed) Published
Abstract [en]

Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide In-111. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)(3) purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, In-111-(HE)(3)-Z(HER2)-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

Place, publisher, year, edition, pages
2016. Vol. 49, no 3, p. 1185-1194
Keywords [en]
Affibody molecule, immunotoxin, albumin binding domain, PE38, HER2, biodistribution, In-111
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-192970DOI: 10.3892/ijo.2016.3614ISI: 000382447300034PubMedID: 27573289Scopus ID: 2-s2.0-84978531659OAI: oai:DiVA.org:kth-192970DiVA, id: diva2:1004306
Funder
Swedish Research CouncilSwedish Cancer Society
Note

QC 20160930

Available from: 2016-09-30 Created: 2016-09-23 Last updated: 2018-05-16Bibliographically 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)
Opponent
Supervisors
Note

QC 20180517

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

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