TY - JOUR
T1 - Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates
AU - Lameijer, Marnix
AU - Binderup, Tina
AU - van Leent, Mandy M. T.
AU - Senders, Max L.
AU - Fay, Francois
AU - Malkus, Joost
AU - Sanchez-Gaytan, Brenda L.
AU - Teunissen, Abraham J. P.
AU - Karakatsanis, Nicolas
AU - Robson, Philip
AU - Zhou, Xianxiao
AU - Ye, Yuxiang
AU - Wojtkiewicz, Gregory
AU - Tang, Jun
AU - Seijkens, Tom T. P.
AU - Kroon, Jeffrey
AU - Stroes, Erik S. G.
AU - Kjaer, Andreas
AU - Ochando, Jordi
AU - Reiner, Thomas
AU - Pérez-Medina, Carlos
AU - Calcagno, Claudia
AU - Fischer, Edward A.
AU - Zhang, Bin
AU - Temel, Ryan E.
AU - Swirski, Filip K.
AU - Nahrendorf, Matthias
AU - Fayad, Zahi A.
AU - Lutgens, Esther
AU - Mulder, Willem J. M.
AU - Duivenvoorden, Raphaël
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85045445754&origin=inward
U2 - https://doi.org/10.1038/s41551-018-0221-2
DO - https://doi.org/10.1038/s41551-018-0221-2
M3 - Article
C2 - 30936448
SN - 2157-846X
VL - 2
SP - 279
EP - 292
JO - Nature Biomedical Engineering
JF - Nature Biomedical Engineering
IS - 5
ER -