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Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab
Uppsala Univ, Dept Med Chem, SE-75283 Uppsala, Sweden.;Uppsala Univ, Sci Life Lab, Uppsala, Sweden..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.ORCID iD: 0000-0003-1598-8894
Uppsala Univ, Dept Med Chem, SE-75283 Uppsala, Sweden..
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
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2018 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 8, p. 3394-3403Article in journal (Refereed) Published
Abstract [en]

Human epidermal growth factor receptor type 3 (HER3) is recognized to be involved in resistance to HER targeting therapies. A number of HER3-targeting monoclonal antibodies are under clinical investigation as potential cancer therapeutics. Smaller high-affinity scaffold proteins are attractive non-Fc containing alternatives to antibodies. A previous study indicated that anti-HER3 affibody molecules could delay the growth of xenografted HER3-positive tumors. Here, we designed a second-generation HER3-targeting construct (TAM-HER3), containing two HER3-specific affibody molecules bridged by an albumin-binding domain (ABD) for extension of blood circulation. Receptor blocking activity was demonstrated in vitro. In mice bearing BxPC-3 xenografts, the therapeutic efficacy of TAM-HER3 was compared to the HER3-specific monoclonal antibody seribantumab (MM-121). TAM-HER3 inhibited heregulin-induced phosphorylation in a panel of HER3-expressing cancer cells and was found to be equally as potent as seribantumab in terms of therapeutic efficacy in vivo and with a similar safety profile. Median survival times were 60 days for TAM-HER3, 54 days for seribantumab, and 41 days for the control group. No pathological changes were observed in cytopathological examination. The multimeric HER3-binding affibody molecule in fusion to ABD seems promising for further evaluation as candidate therapeutics for treatment of HER3-overexpressing tumors.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 15, no 8, p. 3394-3403
Keywords [en]
affibody molecule, HER3, targeting therapy, preclinical
National Category
Clinical Medicine
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URN: urn:nbn:se:kth:diva-233605DOI: 10.1021/acs.molpharmaceut.8b00393ISI: 000441476800049PubMedID: 29995421Scopus ID: 2-s2.0-85049877449OAI: oai:DiVA.org:kth-233605DiVA, id: diva2:1242061
Note

QC 20180827

Available from: 2018-08-27 Created: 2018-08-27 Last updated: 2018-09-03Bibliographically approved

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Bass, TarekLöfblom, JohnStåhl, Stefan

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