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Article

Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model

by
Tianqi Xu
1,
Alexey Schulga
2,3,
Elena Konovalova
3,
Sara S. Rinne
4,
Hongchao Zhang
1,
Olga Vorontsova
1,
Anna Orlova
2,4,5,
Sergey M. Deyev
2,3,6,7,
Vladimir Tolmachev
1,2 and
Anzhelika Vorobyeva
1,*
1
Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden
2
Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, Tomsk 634050, Russia
3
Molecular Immunology Laboratory, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia
4
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden
5
Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden
6
Bio-Nanophotonic Laboratory, Institute of Engineering Physics for Biomedicine (PhysBio), National Research Nuclear University ‘MEPhI’, Moscow 115409, Russia
7
Center of Biomedical Engineering, Sechenov University, Moscow 119991, Russia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2023, 24(3), 2838; https://doi.org/10.3390/ijms24032838
Submission received: 14 November 2022 / Revised: 25 January 2023 / Accepted: 31 January 2023 / Published: 2 February 2023
(This article belongs to the Special Issue Bacterial Toxins and Cancer)
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Abstract

Pancreatic cancer (PC) is one of the most aggressive malignancies. A combination of targeted therapies could increase the therapeutic efficacy in tumors with heterogeneous target expression. Overexpression of the human epidermal growth factor receptor type 3 (HER3) and the epithelial cell adhesion molecule (EpCAM) in up to 40% and 30% of PCs, respectively, is associated with poor prognosis and highlights the relevance of these targets. Designed ankyrin repeat protein (DARPin) Ec1 fused with the low immunogenic bacterial toxin LoPE provides specific and potent cytotoxicity against EpCAM-expressing cancer cells. Here, we investigated whether the co-targeting of HER3 using the monoclonal antibody seribantumab (MM-121) and of EpCAM using Ec1–LoPE would improve the therapeutic efficacy in comparison to the individual agents. Radiolabeled 99mTc(CO)3-Ec1–LoPE showed specific binding with rapid internalization in EpCAM-expressing PC cells. MM-121 did not interfere with the binding of Ec1–LoPE to EpCAM. Evaluation of cytotoxicity indicated synergism between Ec1–LoPE and MM-121 in vitro. An experimental therapy study using Ec1–LoPE and MM-121 in mice bearing EpCAM- and HER3-expressing BxPC3 xenografts demonstrated the feasibility of the therapy. Further development of the co-targeting approach using HER3 and EpCAM could therefore be justified.
Keywords: pancreatic cancer; targeted therapy; HER3; MM-121; DARPin; EpCAM; pseudomonas exotoxin A; combination treatment pancreatic cancer; targeted therapy; HER3; MM-121; DARPin; EpCAM; pseudomonas exotoxin A; combination treatment

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MDPI and ACS Style

Xu, T.; Schulga, A.; Konovalova, E.; Rinne, S.S.; Zhang, H.; Vorontsova, O.; Orlova, A.; Deyev, S.M.; Tolmachev, V.; Vorobyeva, A. Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model. Int. J. Mol. Sci. 2023, 24, 2838. https://doi.org/10.3390/ijms24032838

AMA Style

Xu T, Schulga A, Konovalova E, Rinne SS, Zhang H, Vorontsova O, Orlova A, Deyev SM, Tolmachev V, Vorobyeva A. Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model. International Journal of Molecular Sciences. 2023; 24(3):2838. https://doi.org/10.3390/ijms24032838

Chicago/Turabian Style

Xu, Tianqi, Alexey Schulga, Elena Konovalova, Sara S. Rinne, Hongchao Zhang, Olga Vorontsova, Anna Orlova, Sergey M. Deyev, Vladimir Tolmachev, and Anzhelika Vorobyeva. 2023. "Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model" International Journal of Molecular Sciences 24, no. 3: 2838. https://doi.org/10.3390/ijms24032838

APA Style

Xu, T., Schulga, A., Konovalova, E., Rinne, S. S., Zhang, H., Vorontsova, O., Orlova, A., Deyev, S. M., Tolmachev, V., & Vorobyeva, A. (2023). Feasibility of Co-Targeting HER3 and EpCAM Using Seribantumab and DARPin–Toxin Fusion in a Pancreatic Cancer Xenograft Model. International Journal of Molecular Sciences, 24(3), 2838. https://doi.org/10.3390/ijms24032838

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