Assessment of the Molecular Mechanism of Action of SB3, a Trastuzumab Biosimilar

Background SB3, a biosimilar of Herceptin ® (trastuzumab, hereinafter referred to as reference product) is currently approved in the EU, Korea, Australia, the USA, and Brazil for the treatment of human epidermal growth factor receptor (HER) 2-positive early and metastatic breast cancer and HER2-posi...

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Published in:BioDrugs : clinical immunotherapeutics, biopharmaceuticals, and gene therapy biopharmaceuticals, and gene therapy, 2019-12, Vol.33 (6), p.661-671
Main Authors: Paek, Kyungyeol, Kim, Go-woon, Ahn, So Yeong, Lim, Joon Hyuk, Jung, Dongkeum, Kim, Seokkyun, Lee, Jae Hee
Format: Article
Language:English
Subjects:
AKT protein
Angiogenesis
Antibodies
Antibody-Dependent Cell Cytotoxicity - drug effects
Antibody-dependent cell-mediated cytotoxicity
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Apoptosis
Biological products
Biomedical and Life Sciences
Biomedicine
Biosimilar Pharmaceuticals - pharmacology
Breast cancer
Breast Neoplasms - drug therapy
Breast Neoplasms - metabolism
Cancer Research
Cancer therapies
Cell growth
Cell Line
Cell Line, Tumor
Cytotoxicity
Dimerization
Epidermal growth factor
ErbB-2 protein
FDA approval
Female
Flow cytometry
Gastric cancer
Humans
Intracellular
Kinases
Metastases
Metastasis
Molecular Medicine
Monoclonal antibodies
Original
Original Research Article
Phagocytosis
Pharmacotherapy
Phosphorylation
Receptor, ErbB-2 - metabolism
Signal transduction
Stomach Neoplasms - drug therapy
Stomach Neoplasms - metabolism
Targeted cancer therapy
Trastuzumab
Trastuzumab - pharmacology
Tumor cell lines
Vascular endothelial growth factor
Vascular Endothelial Growth Factor A - metabolism
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Summary:Background SB3, a biosimilar of Herceptin ® (trastuzumab, hereinafter referred to as reference product) is currently approved in the EU, Korea, Australia, the USA, and Brazil for the treatment of human epidermal growth factor receptor (HER) 2-positive early and metastatic breast cancer and HER2-positive metastatic gastric cancer. Previously, the biological similarity of SB3 to EU- or US-sourced reference product was assessed using various cell-based and binding assays. Objective In this paper, as a part of its similarity assessment, SB3 was evaluated for additional characteristics related to its molecular mechanism of action (MoA). Methods For extracellular effects of SB3, HER2-overexpressing cancer cell lines were used to assess expression of surface HER2, shedding of the extracellular domain of HER2, and antibody-dependent cell-mediated phagocytosis (ADCP) activity. For intracellular effects, Akt phosphorylation and vascular endothelial growth factor (VEGF) release were assessed. Additionally, in vitro docetaxel or pertuzumab combination experiments were performed for further characterization; anti-proliferation, HER2/HER3 dimerization inhibition, apoptosis, and antibody-dependent cell-mediated cytotoxicity (ADCC) assays were used. Results It was confirmed that SB3 is highly similar to the reference products on quality attributes related to extracellular/intracellular efficacy. This similarity was also confirmed during combination studies with docetaxel and pertuzumab. Conclusion Overall, the equivalence of SB3 with reference product in MoA-related qualities in in vitro mono- and combination therapy experiments may support clinical bioequivalence of the two substances.
ISSN:1173-8804
1179-190X
DOI:10.1007/s40259-019-00381-2