Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Bispecific / administration & dosage
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Antibodies, Bispecific / chemistry*
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Antibodies, Bispecific / immunology
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Antibodies, Monoclonal, Murine-Derived / administration & dosage
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Antibodies, Monoclonal, Murine-Derived / chemistry
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Female
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Half-Life
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Indium Radioisotopes
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Mice
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Mice, SCID
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Molecular Targeted Therapy / methods*
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Nucleic Acid Conformation
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Nucleic Acid Hybridization
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Oligonucleotides / administration & dosage
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Oligonucleotides / chemistry*
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Oligonucleotides / genetics
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Oligonucleotides, Antisense / administration & dosage
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Oligonucleotides, Antisense / chemical synthesis*
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Oligonucleotides, Antisense / genetics
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Oligoribonucleotides / administration & dosage
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Oligoribonucleotides / chemical synthesis*
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Oligoribonucleotides / genetics
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RNA Stability
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Radioligand Assay
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Rituximab
Substances
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Antibodies, Bispecific
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Antibodies, Monoclonal, Murine-Derived
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Indium Radioisotopes
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Oligonucleotides
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Oligonucleotides, Antisense
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Oligoribonucleotides
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locked nucleic acid
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Rituximab