α2-Macroglobulin binds CpG oligodeoxynucleotides and enhances their immunostimulatory properties by a receptor-dependent mechanism

Ryan B. Anderson, George J. Cianciolo, Margaret N. Kennedy, Salvatore V. Pizzo

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

CpG oligodeoxynucleotides (ODN) stimulate the immune system and are under evaluation as treatments and vaccine adjuvants for infectious diseases, cancer, and immune system disorders. Although they have shown promising results in numerous clinical trials, the ultimate use of CpG ODN-based therapeutics may hinge on improved pharmacokinetics and reduced systemic side-effects. CpG ODN efficacy and potency might be enhanced greatly by packaging them into particles that protect them from degradation and specifically target them for uptake by immune-competent cells. The plasma proteinase inhibitor α2- macroglobulin (α2M) binds numerous biologically active macromolecules, including cytokines, chemokines, and growth factors, and can modulate their activity. Molecules bound to α2M are protected from interactions with neighboring macromolecules and are targeted for receptor-mediated uptake by immune-competent cells. Here, we report that activated α2M (α2M*) binds CpG ODN and enhances their immunostimulatory properties significantly. Murine macrophages treated with α2M*-ODN complexes respond more rapidly and produce a greater cytokine response than induced by free CpG ODN. Using human PBMC, α2M*-ODN complexes exhibit fourfold enhanced potency and 15-fold greater efficacy for stimulating production of inflammatory cytokines. α2M* targets delivery of CpG ODN specifically to immunecompetent cells, which endocytose the complexes sixfold more rapidly than free CpG ODN. CpG ODN bound to α2M* are also protected from degradation by nucleases. This novel targeting technology may improve CpG ODN-based therapeutics by increasing efficacy at reduced doses, thus reducing side-effects and cost.

Original languageEnglish (US)
Pages (from-to)381-392
Number of pages12
JournalJournal of Leukocyte Biology
Volume83
Issue number2
DOIs
StatePublished - Feb 2 2008
Externally publishedYes

Keywords

  • Dendritic cells
  • LRP
  • TLR9
  • Vaccine adjuvant

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Cell Biology

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