@article{7ce7412a4472455dbf78509482c60a52,
title = "Evaluation of the Therapeutic Potential of a HER3-Binding Affibody Construct TAM-HER3 in Comparison with a Monoclonal Antibody, Seribantumab",
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.",
keywords = "affibody molecule, HER3, preclinical, targeting therapy",
author = "Anna Orlova and Bass, {Tarek Z.} and Rinne, {Sara S.} and Leitao, {Charles Dahlsson} and Maria Rosestedt and Christina Atterby and Lindvi Gudmundsdotter and Frejd, {Fredrik Y.} and John L{\"o}fblom and Vladimir Tolmachev and Stefan St{\aa}hl",
note = "Funding Information: *Address: Department of Medicinal Chemistry, Uppsala University, SE-75283, Uppsala, Sweden. Phone: +46 (0)18 4715303-: anna.orlova@ilk.uu.se. *Address: Department of Protein Science, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SE-106 91 Stockholm, Sweden. Phone: +46 8 790 9626. E-mail: ssta@kth.se. ORCID Anna Orlova: 0000-0001-6120-2683 John L{\"o}fblom: 0000-0001-9423-0541 Author Contributions #These authors contributed equally to this work. Funding This work was supported by the Swedish Cancer Society (grants CAN2016-463 (S.S.), CAN2014-474, CAN 2017/425 (A.O.), and CAN2015/350 (V.T.)), the Swedish Research Council (grants 621-2012-5236 (S.S.), 2015-02509 (A.O.), and 2015-02353 (V.T.)), the Wallenberg Center for Protein Technology, and the ESCAPE Cancer grant from VINNOVA (2016-04060, A.O.). Notes The authors declare the following competing financial interest(s): F.Y.F. and L.G. are employees of Affibody AB. V.T., J.L., A.O., and S.S. are members of the scientific advisory board of Affibody AB. S.S., F.Y.F., L.G., V.T., and A.O. own stock in Affibody AB. T.Z.B., S.S.R., C.D.L., M.R., and C.A. declare no potential conflict of interest. Publisher Copyright: Copyright {\textcopyright} 2018 American Chemical Society. Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2018",
month = aug,
day = "6",
doi = "10.1021/acs.molpharmaceut.8b00393",
language = "English",
volume = "15",
pages = "3394--3403",
journal = "Molecular Pharmaceutics",
issn = "1543-8384",
publisher = "American Chemical Society",
number = "8",
}