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...

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Bibliographic Details
Published in:Nucleic acids research 2011-03, Vol.39 (6), p.2458-2469
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Aptamers, Nucleotide - chemistry
Aptamers, Nucleotide - metabolism
Cell Line, Tumor
Female
Humans
Immunoglobulin M - metabolism
Leukemia, B-Cell - metabolism
Lymphoma, B-Cell - metabolism
Mice
Mice, Nude
Oligonucleotides - chemistry
Receptors, Antigen, B-Cell - metabolism
Synthetic Biology and Chemistry
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkq996