Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab

Anna Orlova, Tarek Z. Bass, Sara S. Rinne, Charles Dahlsson Leitao, Maria Rosestedt, Christina Atterby, Lindvi Gudmundsdotter, Fredrik Y. Frejd, John Löfblom, Vladimir Tolmachev, Stefan Ståhl

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3394-3403
Number of pages10
JournalMolecular Pharmaceutics
Volume15
Issue number8
DOIs
Publication statusPublished - 6 Aug 2018
Externally publishedYes

Keywords

  • affibody molecule
  • HER3
  • preclinical
  • targeting therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

Fingerprint Dive into the research topics of 'Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab'. Together they form a unique fingerprint.

Cite this