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Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells

Tissue factor (TF) has been confirmed to be specifically expressed by vascular endothelial cells (VECs) in solid tumors and certain types of malignant tumor cells. Coagulation factor VII (FVII) can specifically bind to TF with high affinity, so the FVII-TF interaction provides an ideal target for tu...

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Autores principales: Ma, Liping, Wang, Guanru, Liu, Sijia, Bi, Feng, Liu, Ming, Wang, Gang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181131/
https://www.ncbi.nlm.nih.gov/pubmed/34109110
http://dx.doi.org/10.3389/fonc.2021.638591
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author Ma, Liping
Wang, Guanru
Liu, Sijia
Bi, Feng
Liu, Ming
Wang, Gang
author_facet Ma, Liping
Wang, Guanru
Liu, Sijia
Bi, Feng
Liu, Ming
Wang, Gang
author_sort Ma, Liping
collection PubMed
description Tissue factor (TF) has been confirmed to be specifically expressed by vascular endothelial cells (VECs) in solid tumors and certain types of malignant tumor cells. Coagulation factor VII (FVII) can specifically bind to TF with high affinity, so the FVII-TF interaction provides an ideal target for tumor therapy. Expression of proteins in skeletal muscles is a simple and economical avenue for continuous production of therapeutic molecules. However, it is difficult to treat solid tumors till now due to the limited number of therapeutic proteins produced by the intramuscular gene expression system. Herein, we strived to explore whether anti-tumor effects can be achieved via intramuscular delivery of a plasmid encoding a FVII-guided immunoconjugate (Icon) molecule by a previously established Pluronic L64/electropulse (L/E) technique. Our study exhibited several interesting outcomes. 1) The mouse light chain of FVII (mLFVII) molecule could guide red fluorescent protein (RFP) to accumulate predominantly at tumor sites in a TF-dependent manner. 2) Intramuscular expression of mLFVII-hFc (human IgG1 Fc) Icon could significantly inhibit the growth of both liver and lung cancers in nude mice, and the inhibition extent was proportional to the level of tumor-expressed TF. 3) The number of blood vessels and the amount of blood flow in tumors were significantly decreased in mLFVII-hFc Icon-treated mice. 4) This immunotherapy system did not display obvious side effects. Our study provided an efficient and economical system for tumor immunotherapy by targeting both blood vessels and tumor cells. It is also an open system for synergistic therapy by conveniently integrating other anticancer regimens.
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spelling pubmed-81811312021-06-08 Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells Ma, Liping Wang, Guanru Liu, Sijia Bi, Feng Liu, Ming Wang, Gang Front Oncol Oncology Tissue factor (TF) has been confirmed to be specifically expressed by vascular endothelial cells (VECs) in solid tumors and certain types of malignant tumor cells. Coagulation factor VII (FVII) can specifically bind to TF with high affinity, so the FVII-TF interaction provides an ideal target for tumor therapy. Expression of proteins in skeletal muscles is a simple and economical avenue for continuous production of therapeutic molecules. However, it is difficult to treat solid tumors till now due to the limited number of therapeutic proteins produced by the intramuscular gene expression system. Herein, we strived to explore whether anti-tumor effects can be achieved via intramuscular delivery of a plasmid encoding a FVII-guided immunoconjugate (Icon) molecule by a previously established Pluronic L64/electropulse (L/E) technique. Our study exhibited several interesting outcomes. 1) The mouse light chain of FVII (mLFVII) molecule could guide red fluorescent protein (RFP) to accumulate predominantly at tumor sites in a TF-dependent manner. 2) Intramuscular expression of mLFVII-hFc (human IgG1 Fc) Icon could significantly inhibit the growth of both liver and lung cancers in nude mice, and the inhibition extent was proportional to the level of tumor-expressed TF. 3) The number of blood vessels and the amount of blood flow in tumors were significantly decreased in mLFVII-hFc Icon-treated mice. 4) This immunotherapy system did not display obvious side effects. Our study provided an efficient and economical system for tumor immunotherapy by targeting both blood vessels and tumor cells. It is also an open system for synergistic therapy by conveniently integrating other anticancer regimens. Frontiers Media S.A. 2021-05-24 /pmc/articles/PMC8181131/ /pubmed/34109110 http://dx.doi.org/10.3389/fonc.2021.638591 Text en Copyright © 2021 Ma, Wang, Liu, Bi, Liu and Wang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Ma, Liping
Wang, Guanru
Liu, Sijia
Bi, Feng
Liu, Ming
Wang, Gang
Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title_full Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title_fullStr Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title_full_unstemmed Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title_short Intramuscular Expression of Plasmid-Encoded FVII-Fc Immunoconjugate for Tumor Immunotherapy by Targeting Tumoral Blood Vessels and Cells
title_sort intramuscular expression of plasmid-encoded fvii-fc immunoconjugate for tumor immunotherapy by targeting tumoral blood vessels and cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181131/
https://www.ncbi.nlm.nih.gov/pubmed/34109110
http://dx.doi.org/10.3389/fonc.2021.638591
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