A self-assembling short oligonucleotide duplex suitable for pretargeting

Prabodhika Mallikaratchy, Jeffery Gardner, Lars Ulrik R. Nordstrøm, Nicholas J. Veomett, Michael R. McDevitt, Mark L. Heaney, David A. Scheinberg

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)289-299
Number of pages11
JournalNucleic Acid Therapeutics
Volume23
Issue number4
DOIs
Publication statusPublished - Aug 1 2013
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery

Cite this

Mallikaratchy, P., Gardner, J., Nordstrøm, L. U. R., Veomett, N. J., McDevitt, M. R., Heaney, M. L., & Scheinberg, D. A. (2013). A self-assembling short oligonucleotide duplex suitable for pretargeting. Nucleic Acid Therapeutics, 23(4), 289-299. https://doi.org/10.1089/nat.2013.0425