TY - JOUR
T1 - A self-assembling short oligonucleotide duplex suitable for pretargeting
AU - Mallikaratchy, Prabodhika
AU - Gardner, Jeffery
AU - Nordstrøm, Lars Ulrik R.
AU - Veomett, Nicholas J.
AU - McDevitt, Michael R.
AU - Heaney, Mark L.
AU - Scheinberg, David A.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84881175157&partnerID=8YFLogxK
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U2 - 10.1089/nat.2013.0425
DO - 10.1089/nat.2013.0425
M3 - Article
C2 - 23848521
AN - SCOPUS:84881175157
SN - 2159-3337
VL - 23
SP - 289
EP - 299
JO - Nucleic Acid Therapeutics
JF - Nucleic Acid Therapeutics
IS - 4
ER -