Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates Journal Article
| Authors: | Lameijer, M.; Binderup, T.; van Leent, M. M. T.; Senders, M. L.; Fay, F.; Malkus, J.; Sanchez-Gaytan, B. L.; Teunissen, A. J. P.; Karakatsanis, N.; Robson, P.; Zhou, X.; Ye, Y.; Wojtkiewicz, G.; Tang, J.; Seijkens, T. T. P.; Kroon, J.; Stroes, E. S. G.; Kjaer, A.; Ochando, J.; Reiner, T.; Pérez-Medina, C.; Calcagno, C.; Ficher, E. A.; Zhang, B.; Temel, R. E.; Swirski, F. K.; Nahrendorf, M.; Fayad, Z. A.; Lutgens, E.; Mulder, W. J. M.; Duivenvoorden, R. |
| Article Title: | Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates |
| Abstract: | 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. © 2018 The Author(s). |
| Keywords: | positron emission tomography; ligands; body fluids; macrophages; mammals; diseases; non-human primate; apolipoprotein e; biodistributions; transcriptome analysis; anti-inflammatory effects; rapid reduction; necrosis factors; safety assessments |
| Journal Title: | Nature Biomedical Engineering |
| Volume: | 2 |
| Issue: | 5 |
| ISSN: | 2157-846X |
| Publisher: | Nature Publishing Group |
| Date Published: | 2018-05-01 |
| Start Page: | 279 |
| End Page: | 292 |
| Language: | English |
| DOI: | 10.1038/s41551-018-0221-2 |
| PROVIDER: | scopus |
| PMCID: | PMC6447057 |
| PUBMED: | 30936448 |
| DOI/URL: | |
| Notes: | Article -- Correction to the author list issued: 10.1038/s41551-018-0281-3 -- Export Date: 1 June 2018 -- Source: Scopus |
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