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 Reiner; Carlos Pérez-medina; Claudia Calcagno; Edward A. Fisher; Bin Zhang; Ryan E. Temel; Filip K. Swirski; Matthias Nahrendorf; Zahi A. Fayad; Esther Lutgens; Willem J. M. Mulder; Raphaël Duivenvoorden

doi:10.1038/s41551-018-0221-2

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. Fisher, Bin Zhang, Ryan E. Temel, Filip K. Swirski, Matthias Nahrendorf, Zahi A. Fayad, Esther Lutgens, Willem J. M. Mulder, Raphaël Duivenvoorden

Department of Clinical Medicine

47 Citations (Scopus)

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.

Original language	English
Journal	Nature Biomedical Engineering
Volume	2
Pages (from-to)	279-292
DOIs	https://doi.org/10.1038/s41551-018-0221-2
Publication status	Published - 1 May 2018

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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., ... Duivenvoorden, R. (2018). Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates. Nature Biomedical Engineering, 2, 279-292. https://doi.org/10.1038/s41551-018-0221-2

Lameijer, M, Binderup, T, Van Leent, MMT, Senders, ML, Fay, F, Malkus, J, Sanchez-gaytan, BL, Teunissen, AJP, Karakatsanis, N, Robson, P, Zhou, X, Ye, Y, Wojtkiewicz, G, Tang, J, Seijkens, TTP, Kroon, J, Stroes, ESG, Kjaer, A, Ochando, J, Reiner, T, Pérez-medina, C, Calcagno, C, Fisher, EA, Zhang, B, Temel, RE, Swirski, FK, Nahrendorf, M, Fayad, ZA, Lutgens, E, Mulder, WJM & Duivenvoorden, R 2018, 'Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates', Nature Biomedical Engineering, vol. 2, pp. 279-292. https://doi.org/10.1038/s41551-018-0221-2

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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.",

author = "Marnix Lameijer and Tina Binderup and {Van Leent}, {Mandy M. T.} and Senders, {Max L.} and Francois Fay and Joost Malkus and Sanchez-gaytan, {Brenda L.} and Teunissen, {Abraham J. P.} and Nicolas Karakatsanis and Philip Robson and Xianxiao Zhou and Yuxiang Ye and Gregory Wojtkiewicz and Jun Tang and Seijkens, {Tom T. P.} and Jeffrey Kroon and Stroes, {Erik S. G.} and Andreas Kjaer and Jordi Ochando and Thomas Reiner and Carlos P{\'e}rez-medina and Claudia Calcagno and Fisher, {Edward A.} and Bin Zhang and Temel, {Ryan E.} and Swirski, {Filip K.} and Matthias Nahrendorf and Fayad, {Zahi A.} and Esther Lutgens and Mulder, {Willem J. M.} and Rapha{\"e}l Duivenvoorden",

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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 - Fisher, 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 - 2018/5/1

Y1 - 2018/5/1

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.

U2 - 10.1038/s41551-018-0221-2

DO - 10.1038/s41551-018-0221-2

M3 - Journal article

C2 - 30936448

SN - 2157-846X

VL - 2

SP - 279

EP - 292

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

ER -

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

Abstract

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