Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates

Marnix Lameijer, Tina Binderup, Mandy M.T. Van Leent, Max L. Senders, Francois Fay, Joost Malkus, Brenda L. Sanchez-Gaytan, Abraham J.P. Teunissen, Nicolas Karakatsanis, Philip Robson, Xianxiao Zhou, Yuxiang Ye, Gregory Wojtkiewicz, Jun Tang, Tom T.P. Seijkens, Jeffrey Kroon, Erik S.G. Stroes, Andreas Kjaer, Jordi Ochando, Thomas ReinerCarlos Pérez-Medina, Claudia Calcagno, Edward A. Fischer, Bin Zhang, Ryan E. Temel, Filip K. Swirski, Matthias Nahrendorf, Zahi A. Fayad, Esther Lutgens, Willem J.M. Mulder, Raphaël Duivenvoorden

Research output: Contribution to journalArticlepeer-review


Macrophage accumulation in atherosclerosis is directly linked to the destabilization and rupture of plaque, causing acute atherothrombotic events. Circulating monocytes enter the plaque and differentiate into macrophages, where they are activated by CD4+ T lymphocytes through CD40-CD40 ligand signalling. Here, we report the development and multiparametric evaluation of a nanoimmunotherapy that moderates CD40-CD40 ligand signalling in monocytes and macrophages by blocking the interaction between CD40 and tumour necrosis factor receptor-associated factor 6 (TRAF6). We evaluated the biodistribution characteristics of the nanoimmunotherapy in apolipoprotein E-deficient (Apoe -/-) mice and in non-human primates by in vivo positron-emission tomography imaging. In Apoe -/- mice, a 1-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, which was due to the impaired migration capacity of monocytes, as established by a transcriptome analysis. The rapid reduction of plaque inflammation by the TRAF6-targeted nanoimmunotherapy and its favourable toxicity profiles in both mice and non-human primates highlights the translational potential of this strategy for the treatment of atherosclerosis.

Original languageEnglish (US)
Pages (from-to)279-292
Number of pages14
JournalNature Biomedical Engineering
Issue number5
StatePublished - May 1 2018

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Medicine (miscellaneous)
  • Biomedical Engineering
  • Computer Science Applications


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