In Vivo Evaluation of a Novel Format of a Bivalent HER3-targeting and Albumin-binding Therapeutic Affibody Construct

Overview

Journal Sci Rep

Specialty Science

Date 2017 Feb 24

PMID 28230065

Citations 9

Authors

Tarek Z Bass

Maria Rosestedt

Bogdan Mitran

Fredrik Y Frejd

John Lofblom

Vladimir Tolmachev

Stefan Stahl

Anna Orlova

Affiliations

Soon will be listed here.

Abstract

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 via a DOTA chelator. The residence time of In-DOTA-3A3 in blood was extended when compared with the monomeric affibody molecule. In-DOTA-3A3 accumulated specifically in HER3-expressing BxPC-3 xenografts in mice. However, In-DOTA-3A3 cleared more rapidly from blood than a size-matched control construct In-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-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.

Citing Articles

Affibody-Drug Conjugates Targeting the Human Epidermal Growth Factor Receptor-3 Demonstrate Therapeutic Efficacy in Mice Bearing Low Expressing Xenografts.

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Engineering mono- and multi-valent inhibitors on a modular scaffold.

Diamante A, Chaturbedy P, Rowling P, Kumita J, Eapen R, McLaughlin S Chem Sci. 2021; 12(3):880-895.

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[Ga]ABY-028: an albumin-binding domain (ABD) protein-based imaging tracer for positron emission tomography (PET) studies of altered vascular permeability and predictions of albumin-drug conjugate transport.

Jussing E, Lu L, Grafstrom J, Tegnebratt T, Arnberg F, Rosik H EJNMMI Res. 2020; 10(1):106.

PMID: 32960353 PMC: 7509035. DOI: 10.1186/s13550-020-00694-2.

Benefit of Later-Time-Point PET Imaging of HER3 Expression Using Optimized Radiocobalt-Labeled Affibody Molecules.

Rinne S, Leitao C, Saleh-Nihad Z, Mitran B, Tolmachev V, Stahl S Int J Mol Sci. 2020; 21(6).

PMID: 32183096 PMC: 7139902. DOI: 10.3390/ijms21061972.

Increase in negative charge of Ga/chelator complex reduces unspecific hepatic uptake but does not improve imaging properties of HER3-targeting affibody molecules.

Rinne S, Leitao C, Gentry J, Mitran B, Abouzayed A, Tolmachev V Sci Rep. 2019; 9(1):17710.

PMID: 31776413 PMC: 6881397. DOI: 10.1038/s41598-019-54149-3.

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