期刊
NUCLEIC ACID THERAPEUTICS
卷 23, 期 4, 页码 289-299出版社
MARY ANN LIEBERT, INC
DOI: 10.1089/nat.2013.0425
关键词
-
资金
- NIH [R01 CA55349, P01 33049, R21 CA128406]
- Lymphoma Research Foundation Research Fellow Grant
- Lymphoma Foundation
- Tudor Fund
- Glades Fund
Monoclonal antibodies (mAbs) have naturally evolved as suitable, high affinity and specificity targeting molecules. However, the large size of full-length mAbs yields poor pharmacokinetic properties. A solution to this issue is the use of a multistep administration approach, in which the slower clearing mAb is administered first and allowed to reach the target site selectively, followed by administration of a rapidly clearing small molecule carrier of the cytotoxic or imaging ligand, which bears a cognate receptor for the mAb. Here, we introduce a novel pretargetable RNA based system comprised of locked nucleic acids (LNA) and 2'O-Methyloligoribonucleotides (2'OMe-RNA). The duplex shows fast hybridization, high melting temperatures, excellent affinity, and high nuclease stability in plasma. Using a prototype model system with rituximab conjugated to 2'OMe-RNA (oligo), we demonstrate that LNA-based complementary strand (c-oligo) effectively hybridizes with rituximab-oligo, which is slowly circulating in vivo, despite the high clearance rates of c-oligo.
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