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A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia

Long-term survival still eludes most patients with leukemia and non-Hodgkin’s lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and o...

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Autores principales: Mallikaratchy, Prabodhika R., Ruggiero, Alessandro, Gardner, Jeffrey R., Kuryavyi, Vitaly, Maguire, William F., Heaney, Mark L., McDevitt, Michael R., Patel, Dinshaw J., Scheinberg, David A.
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064813/
https://www.ncbi.nlm.nih.gov/pubmed/21030439
http://dx.doi.org/10.1093/nar/gkq996
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author Mallikaratchy, Prabodhika R.
Ruggiero, Alessandro
Gardner, Jeffrey R.
Kuryavyi, Vitaly
Maguire, William F.
Heaney, Mark L.
McDevitt, Michael R.
Patel, Dinshaw J.
Scheinberg, David A.
author_facet Mallikaratchy, Prabodhika R.
Ruggiero, Alessandro
Gardner, Jeffrey R.
Kuryavyi, Vitaly
Maguire, William F.
Heaney, Mark L.
McDevitt, Michael R.
Patel, Dinshaw J.
Scheinberg, David A.
author_sort Mallikaratchy, Prabodhika R.
collection PubMed
description Long-term survival still eludes most patients with leukemia and non-Hodgkin’s lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications.
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spelling pubmed-30648132011-03-28 A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia Mallikaratchy, Prabodhika R. Ruggiero, Alessandro Gardner, Jeffrey R. Kuryavyi, Vitaly Maguire, William F. Heaney, Mark L. McDevitt, Michael R. Patel, Dinshaw J. Scheinberg, David A. Nucleic Acids Res Synthetic Biology and Chemistry Long-term survival still eludes most patients with leukemia and non-Hodgkin’s lymphoma. No approved therapies target the hallmark of the B cell, its mIgM, also known as the B-cell receptor (BCR). Aptamers are small oligonucleotides that can specifically bind to a wide range of target molecules and offer some advantages over antibodies as therapeutic agents. Here, we report the rational engineering of aptamer TD05 into multimeric forms reactive with the BCR that may be useful in biomedical applications. Systematic truncation of TD05 coupled with modification with locked nucleic acids (LNA) increased conformational stability and nuclease resistance. Trimeric and tetrameric versions with optimized polyethyleneglycol (PEG) linker lengths exhibited high avidity at physiological temperatures both in vitro and in vivo. Competition and protease studies showed that the multimeric, optimized aptamer bound to membrane-associated human mIgM, but not with soluble IgM in plasma, allowing the possibility of targeting leukemias and lymphomas in vivo. The B-cell specificity of the multivalent aptamer was confirmed on lymphoma cell lines and fresh clinical leukemia samples. The chemically engineered aptamers, with significantly improved kinetic and biochemical features, unique specificity and desirable pharmacological properties, may be useful in biomedical applications. Oxford University Press 2011-03 2010-10-28 /pmc/articles/PMC3064813/ /pubmed/21030439 http://dx.doi.org/10.1093/nar/gkq996 Text en © The Author(s) 2010. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/2.5 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Synthetic Biology and Chemistry
Mallikaratchy, Prabodhika R.
Ruggiero, Alessandro
Gardner, Jeffrey R.
Kuryavyi, Vitaly
Maguire, William F.
Heaney, Mark L.
McDevitt, Michael R.
Patel, Dinshaw J.
Scheinberg, David A.
A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title_full A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title_fullStr A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title_full_unstemmed A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title_short A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
title_sort multivalent dna aptamer specific for the b-cell receptor on human lymphoma and leukemia
topic Synthetic Biology and Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3064813/
https://www.ncbi.nlm.nih.gov/pubmed/21030439
http://dx.doi.org/10.1093/nar/gkq996
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