Journal
NUCLEIC ACIDS RESEARCH
Volume 39, Issue 6, Pages 2458-2469Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkq996
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Funding
- National Institutes of Health [R01 CA55349, P01 33049, R21 CA128406, R25T CA096945, R01, PO1]
- Laurie Straus Leukemia Foundation
- Lymphoma Research Foundation
- Lymphoma Foundation
- Tudor and Glades Funds
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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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