Granzyme B-based cytolytic fusion protein targeting EpCAM specifically kills triple negative breast cancer cells in vitro and inhibits tumor growth in a subcutaneous mouse tumor model

Autor: Thomas Nachreiner, Fabian Kiessling, Alessa Pardo, Dmitrij Hristodorov, Anh-Tuan Pham, Theophilus Thepen, Manal Amoury, Wijnand Helfrich, Katharina Kolberg, Stefano Di Fiore, Stefan Barth, Ahmad Fawzi Hussain, Rainer Fischer, Radoslav Mladenov
Přispěvatelé: Translational Immunology Groningen (TRIGR), Targeted Gynaecologic Oncology (TARGON), Publica
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
medicine.medical_treatment
ANTITUMOR-ACTIVITY
Triple Negative Breast Neoplasms
Granzymes
Targeted therapy
SUBTYPES
chemistry.chemical_compound
0302 clinical medicine
Antibody Specificity
Immunotoxin
Tissue Distribution
Triple negative breast cancer
DRUG-DELIVERY
IMMUNOTOXIN
ADHESION MOLECULE
Triple-negative breast cancer
GENE-EXPRESSION
Mice
Inbred BALB C
biology
Granzyme B
Immunotoxins
Epithelial cell adhesion molecule
Epithelial Cell Adhesion Molecule
Tumor Burden
APOPTOSIS
Oncology
030220 oncology & carcinogenesis
Female
TRIAL
Immunotherapy
Antibody
Recombinant Fusion Proteins
Medical biotechnology
Mice
Nude
Transfection
03 medical and health sciences
Antigens
Neoplasm
Cancer stem cell
Cell Line
Tumor
medicine
Animals
Humans
Cell Proliferation
Human cytolytic fusion protein
Xenograft Model Antitumor Assays
Molecular biology
HEK293 Cells
030104 developmental biology
chemistry
Mutation
Cancer research
biology.protein
OVEREXPRESSION
MONOCLONAL-ANTIBODIES
Cell Adhesion Molecules
Single-Chain Antibodies
Zdroj: Cancer letters, 372(2), 201-209. ELSEVIER IRELAND LTD
ISSN: 0304-3835
Popis: Triple-negative breast cancer (TNBC) is associated with poor prognosis and high prevalence among young premenopausal women. Unlike in other breast cancer subtypes, no targeted therapy is currently available. Overexpression of epithelial cell adhesion molecule (EpCAM) in 60% of TNBC tumors correlates with poorer prognosis and is associated with cancer stem cell phenotype. Thus, selective elimination of EpCAM(+) TNBC tumor cells is of clinical importance.Therefore, we constructed a fully human targeted cytolytic fusion protein, designated GbR201K-alpha EpCAM(scFv), in which an EpCAM-selective single-chain antibody fragment (scFv) is genetically fused to a granzyme B (Gb) mutant with reduced sensitivity to its natural inhibitor serpin B9. In vitro studies confirmed its specific binding, internalization and cytotoxicity toward a panel of EpCAM-expressing TNBC cells. Biodistribution kinetics and tumor-targeting efficacy using MDA-MB-468 cells in a human TNBC xenograft model in mice revealed selective accumulation of GbR201K-aEpCAM(scFv) in the tumors after i.v. injection. Moreover, treatment of tumor-bearing mice demonstrated a prominent inhibition of tumor growth of up to 50 % in this proof-of-concept study. Taken together, our results indicate that GbR201K-alpha EpCAM(scFv) is a promising novel targeted therapeutic for the treatment of TNBC. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Databáze: OpenAIRE
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