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

Authors: Mallikaratchy, P. R.; Ruggiero, A.; Gardner, J. R.; Kuryavyi, V.; Maguire, W. F.; Heaney, M. L.; McDevitt, M. R.; Patel, D. J.; Scheinberg, D. A.
Article Title: A multivalent DNA aptamer specific for the B-cell receptor on human lymphoma and leukemia
Abstract: 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. © The Author(s) 2010. Published by Oxford University Press.
Keywords: controlled study; leukemia; unclassified drug; human cell; nonhuman; binding affinity; protein conformation; animal cell; mouse; animals; mice; protein targeting; protein binding; in vivo study; in vitro study; cell line, tumor; b lymphocyte; cell specificity; lymphoma, b-cell; nonhodgkin lymphoma; mice, nude; nuclease; cell interaction; macrogol; biomedical engineering; aptamer; aptamers, nucleotide; oligonucleotides; immunoglobulin m; trypsin; protein nucleic acid interaction; locked nucleic acid; enzyme stability; receptors, antigen, b-cell; b lymphocyte receptor; multivalent dna aptamer; leukemia, b-cell
Journal Title: Nucleic Acids Research
Volume: 39
Issue: 6
ISSN: 0305-1048
Publisher: Oxford University Press  
Date Published: 2011-03-01
Start Page: 2458
End Page: 2469
Language: English
DOI: 10.1093/nar/gkq996
PROVIDER: scopus
PMCID: PMC3064813
PUBMED: 21030439
Notes: --- - "Export Date: 23 June 2011" - "CODEN: NARHA" - "Source: Scopus"
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MSK Authors
  1. Mark L Heaney
    85 Heaney
  2. Michael R Mcdevitt
    117 Mcdevitt
  3. Dinshaw J Patel
    379 Patel
  4. Jeffrey Gardner
    32 Gardner