title: A self-assembling short oligonucleotide duplex suitable for pretargeting.
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.
authors.affiliation: Molecular Pharmacology and Chemistry Program, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Prabodhika
authors.initials: P
authors.lastname: Mallikaratchy
authors.forename: Jeffery
authors.initials: J
authors.lastname: Gardner
authors.forename: Lars Ulrik R
authors.initials: LU
authors.lastname: Nordstrøm
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Veomett
authors.forename: Michael R
authors.initials: MR
authors.lastname: McDevitt
authors.forename: Mark L
authors.initials: ML
authors.lastname: Heaney
authors.forename: David A
authors.initials: DA
authors.lastname: Scheinberg
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000737:chemistry* / Q000276:immunology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D006207:Half-Life; D007205:Indium Radioisotopes; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods*; D009690:Nucleic Acid Conformation; D009693:Nucleic Acid Hybridization; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000235:genetics; D009843:Oligoribonucleotides / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000235:genetics; D020871:RNA Stability; D011869:Radioligand Assay; D000069283:Rituximab
chemical_list: D018033:Antibodies, Bispecific; D058846:Antibodies, Monoclonal, Murine-Derived; D007205:Indium Radioisotopes; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D009843:Oligoribonucleotides; C477371:locked nucleic acid; D000069283:Rituximab