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In vivo evaluation of a novel format of a bivalent HER3-targeting and albumin- binding therapeutic affibody construct
KTH, School of Biotechnology (BIO), Protein Technology.ORCID iD: 0000-0003-1598-8894
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, 43118Article in journal (Refereed) Published
Abstract [en]

Overexpression of human epidermal growth factor receptor 3 (HER3) is involved in resistance to several therapies for malignant tumours. Currently, several anti-HER3 monoclonal antibodies are under clinical development. We introduce an alternative approach to HER3-targeted therapy based on engineered scaffold proteins, i.e. affibody molecules. We designed a small construct (22.5 kDa, denoted 3A3), consisting of two high-affinity anti-HER3 affibody molecules flanking an albumin-binding domain ABD, which was introduced for prolonged residence in circulation. In vitro, 3A3 efficiently inhibited growth of HER3-expressing BxPC-3 cells. Biodistribution in mice was measured using 3A3 that was site-specifically labelled with In-111 via a DOTA chelator. The residence time of In-111-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-111-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-111-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-111-DOTA-TAT, most likely due to sequestering of 3A3 by mErbB3, the murine counterpart of HER3. Repeated dosing and increase of injected protein dose decreased uptake of In-111-DOTA-3A3 in mErbB3-expressing tissues. Encouragingly, growth of BxPC-3 xenografts in mice was delayed in an experimental (pilot-scale) therapy study using 3A3. We conclude that the 3A3 affibody format seems promising for treatment of HER3-overexpressing tumours.

Place, publisher, year, edition, pages
Nature Publishing Group, 2017. Vol. 7, 43118
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:kth:diva-204078DOI: 10.1038/srep43118ISI: 000394748000001PubMedID: 28230065Scopus ID: 2-s2.0-85013769093OAI: oai:DiVA.org:kth-204078DiVA: diva2:1085476
Note

QC 20170329

Available from: 2017-03-29 Created: 2017-03-29 Last updated: 2017-03-30Bibliographically approved
In thesis
1. Affibody molecules targeting HER3 for cancer therapy
Open this publication in new window or tab >>Affibody molecules targeting HER3 for cancer therapy
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of targeted therapy has contributed tremendously to the treatment of patients with cancer. The use of highly specific affinity proteins to target cancer cells has become a standard in treatment strategies for several different cancers. In light of this, many cancer cell markers are investigated for their potential use in diagnostics and therapy. One such marker is the human epidermal growth factor receptor 3, HER3. It has been established as an important contributor to many cancer types. The function of HER3 is to relay cell growth signals from outside of the cell to the inside. Interfering with- and inhibit- ing the function of HER3 has emerged as an interesting strategy for cancer therapeutics. The studies presented in this thesis aim to target HER3 with small, engineered affinity domain proteins for therapeutic purposes. Monomeric affibody molecules have previously been engineered to bind and inhibit HER3 in vitro. Due to the relatively low expression of HER3, an increase in valency appears promising to strengthen the therapeutic potential. Affibody molecules targeting the receptor were thus linked to form bivalent and bispecific constructs and evaluated both in vitro and in vivo. In the first study of this thesis affibody molecules specific for HER3 and HER2 were fused to an albumin binding domain to form bivalent and bispecific construct. The constructs inhibited ligand-induced receptor phos- phorylation of both HER2 and HER3 more efficiently than monomeric affibody molecules. A second approach to enhance the potential of affibody molecules in tumor targeting is described in the second study, where monomeric HER3-binding affibody molecules were engineered to increase their affinity for HER3. The resulting variants showed a 20-fold in- creased affinity and higher capacity to inhibit cancer cell growth. Combining the findings of the first two studies, the third study describes the evaluation of a HER3-targeting bivalent affibody construct for potential application as a therapeutic. Here, the bivalent construct inhibited cancer cell growth in vitro and was found to slow down tumor growth in mice, while being well tolerated and showing no visible toxicity. The fourth study built upon these findings and compares a very similar bivalent construct to the clinically-investigated HER3-specific monoclonal antibody seribantumab. The affibody construct showed very comparable efficacy with the antibody in terms of decreasing tumor growth rate and ex- tending mouse survival. Collectively, these works describe for the first time the use of alternative affinity protein constructs with therapeutic potential targeting HER3.

Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2017. 87 p.
Keyword
Affibody molecule, cancer therapy, epidermal growth factor receptors, ErbB3, HER3, protein engineering
National Category
Other Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-204593 (URN)
Public defence
2017-05-12, FR4, Roslagstullsbacken 21, Stockholm, 10:00 (English)
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Supervisors
Note

QC 20170330

Available from: 2017-03-30 Created: 2017-03-29 Last updated: 2017-03-30Bibliographically approved

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