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

Autor: Xu T; Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden., Schulga A; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, Tomsk 634050, Russia.; Molecular Immunology Laboratory, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia., Konovalova E; Molecular Immunology Laboratory, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia., Rinne SS; Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden., Zhang H; Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden., Vorontsova O; Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden., Orlova A; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, Tomsk 634050, Russia.; Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.; Science for Life Laboratory, Uppsala University, 751 23 Uppsala, Sweden., Deyev SM; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, Tomsk 634050, Russia.; Molecular Immunology Laboratory, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia.; Bio-Nanophotonic Laboratory, Institute of Engineering Physics for Biomedicine (PhysBio), National Research Nuclear University 'MEPhI', Moscow 115409, Russia.; Center of Biomedical Engineering, Sechenov University, Moscow 119991, Russia., Tolmachev V; Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.; Research Centrum for Oncotheranostics, Research School of Chemistry and Applied Biomedical Sciences, National Research Tomsk Polytechnic University, Tomsk 634050, Russia., Vorobyeva A; Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 Feb 02; Vol. 24 (3). Date of Electronic Publication: 2023 Feb 02.
DOI: 10.3390/ijms24032838
Abstrakt: 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 99m Tc(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.
Databáze: MEDLINE
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