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Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus

Modified measles virus (MV) has effective oncolytic activity preclinically and is currently being investigated in clinical trials for various types of cancer. We investigated the use of cystine knot proteins (CKPs) to direct MV activity. CKPs are short polypeptides that bind their targets with high...

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Autores principales: Lal, Sangeet, Raffel, Corey
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771132/
https://www.ncbi.nlm.nih.gov/pubmed/29367943
http://dx.doi.org/10.1016/j.omto.2017.09.005
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author Lal, Sangeet
Raffel, Corey
author_facet Lal, Sangeet
Raffel, Corey
author_sort Lal, Sangeet
collection PubMed
description Modified measles virus (MV) has effective oncolytic activity preclinically and is currently being investigated in clinical trials for various types of cancer. We investigated the use of cystine knot proteins (CKPs) to direct MV activity. CKPs are short polypeptides that bind their targets with high affinity. We used a CKP that binds αvβ3, αvβ5, and α5β1 integrins with single-digit nanomolar affinity to retarget MV to the integrins (MV-CKPint). MV-CKPint infected, replicated in, and killed human glioblastoma, medulloblastoma, diffuse intrinsic pontine glioma (DIPG), and melanoma cancer cells in vitro, all of which express the target integrins. MV-CKPint activity was competitively blocked by echistatin, an integrin binding peptide. When the CKP was cleaved from the viral H protein at an included protease site, virus activity was abrogated. When delivered intravenously (i.v.), the retargeted virus reached a subcutaneous glioblastoma tumor bed and produced cytopathic effects similar to that shown by intratumoral injection of the virus. Because these target integrins are overexpressed by tumor vascular endothelium, MV-CKPint may allow for effective therapy with i.v. injection. These results indicate for the first time that CKPs can be used to retarget MV for a receptor of choice. In addition, MV-CKPint provides proof of principle for the use of a CKP of interest to retarget any enveloped virus for both oncolytic and gene therapy purposes.
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spelling pubmed-57711322018-01-24 Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus Lal, Sangeet Raffel, Corey Mol Ther Oncolytics Article Modified measles virus (MV) has effective oncolytic activity preclinically and is currently being investigated in clinical trials for various types of cancer. We investigated the use of cystine knot proteins (CKPs) to direct MV activity. CKPs are short polypeptides that bind their targets with high affinity. We used a CKP that binds αvβ3, αvβ5, and α5β1 integrins with single-digit nanomolar affinity to retarget MV to the integrins (MV-CKPint). MV-CKPint infected, replicated in, and killed human glioblastoma, medulloblastoma, diffuse intrinsic pontine glioma (DIPG), and melanoma cancer cells in vitro, all of which express the target integrins. MV-CKPint activity was competitively blocked by echistatin, an integrin binding peptide. When the CKP was cleaved from the viral H protein at an included protease site, virus activity was abrogated. When delivered intravenously (i.v.), the retargeted virus reached a subcutaneous glioblastoma tumor bed and produced cytopathic effects similar to that shown by intratumoral injection of the virus. Because these target integrins are overexpressed by tumor vascular endothelium, MV-CKPint may allow for effective therapy with i.v. injection. These results indicate for the first time that CKPs can be used to retarget MV for a receptor of choice. In addition, MV-CKPint provides proof of principle for the use of a CKP of interest to retarget any enveloped virus for both oncolytic and gene therapy purposes. American Society of Gene & Cell Therapy 2017-09-29 /pmc/articles/PMC5771132/ /pubmed/29367943 http://dx.doi.org/10.1016/j.omto.2017.09.005 Text en © 2017. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Lal, Sangeet
Raffel, Corey
Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title_full Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title_fullStr Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title_full_unstemmed Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title_short Using Cystine Knot Proteins as a Novel Approach to Retarget Oncolytic Measles Virus
title_sort using cystine knot proteins as a novel approach to retarget oncolytic measles virus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771132/
https://www.ncbi.nlm.nih.gov/pubmed/29367943
http://dx.doi.org/10.1016/j.omto.2017.09.005
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