Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers

Angelo Moreno, George A. Pitoc, Nancy J. Ganson, Juliana M. Layzer, Michael S. Hershfield, Alice F. Tarantal, Bruce A. Sullenger

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

Biopharmaceuticals have become increasingly attractive therapeutic agents and are often PEGylated to enhance their pharmacokinetics and reduce their immunogenicity. However, recent human clinical trials have demonstrated that administration of PEGylated compounds can evoke anti-PEG antibodies. Considering the ubiquity of PEG in commercial products and the presence of pre-existing anti-PEG antibodies in patients in large clinical trials evaluating a PEG-modified aptamer, we investigated how anti-PEG antibodies effect the therapeutic activities of PEGylated RNA aptamers. We demonstrate that anti-PEG antibodies can directly bind to and inhibit anticoagulant aptamer function in vitro and in vivo. Moreover, in parallel studies we detected the presence of anti-PEG antibodies in nonhuman primates after a single administration of a PEGylated aptamer. Our results suggest that anti-PEG antibodies can limit the activity of PEGylated drugs and potentially compromise the activity of otherwise effective therapeutic agents. The most common approach for pharmacokinetic enhancement of biologically inspired therapies is PEGylation; however, possible limitations of this formulation strategy have arisen. Here, we describe how anti-PEG antibodies can inhibit the therapeutic efficacy of a PEGylated RNA aptamer. These findings further highlight emerging issues between the immune system and PEGylated therapeutics.

Original languageEnglish (US)
Pages (from-to)634-644.e3
JournalCell Chemical Biology
Volume26
Issue number5
DOIs
StatePublished - May 16 2019
Externally publishedYes

Keywords

  • anti-PEG antibodies
  • aptamer
  • aPTT (activated partial thromboplastin time)
  • ELISA (enzyme-linked immunosorbent assay)
  • hypersensitivity
  • PEG (polyethylene glycol)
  • PEGylation
  • RB006
  • REGULATE-PCI
  • rhesus monkeys

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint Dive into the research topics of 'Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers'. Together they form a unique fingerprint.

  • Cite this

    Moreno, A., Pitoc, G. A., Ganson, N. J., Layzer, J. M., Hershfield, M. S., Tarantal, A. F., & Sullenger, B. A. (2019). Anti-PEG Antibodies Inhibit the Anticoagulant Activity of PEGylated Aptamers. Cell Chemical Biology, 26(5), 634-644.e3. https://doi.org/10.1016/j.chembiol.2019.02.001