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

Abstract

In atherosclerosis, macrophage accumulation 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 PET imaging. In Apoe−/− mice, a one-week nanoimmunotherapy treatment regimen achieved significant anti-inflammatory effects, caused by the impaired migration capacity of monocytes, as established by 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.

Defining trained immunity and its role in health and disease

“…Notably, preventing trained immunity rebalanced the myeloid cell compartment from proinflammatory to anti-inflammatory, while the adaptive immune system was characterized by an increased frequency of regulatory T cells. Co-treatment with a nanoimmunotherapeutic agent that prevents CD40-CD40L co-stimulation 186 led to the induction of tolerance. these observations highlight that the innate and adaptive immune systems work in conjunction, and that immune memory can be best considered a feature relevant to phagocytes and lymphocytes 187 .…”

Therapeutic targeting of trained immunity

“…We previously ventured into applying nanomaterials to engage immune cells, particularly myeloid cells, in cardiovascular disease 104,114,[130][131][132] , cancer 133,134 and graft transplantation 113 . In these studies, we used so-called high-density lipoprotein (HDL) nanobiologics as immunotherapeutic agents to exert therapeutic benefits both systematically and locally, for example, at an atherosclerotic lesion 101 .…”

“…Intravenous administration of mTORi-HDL to mice on the day they received a heart allograft, as well as 2 and 5 days post-transplantation, markedly increased survival from 8 to 60 days, and a subset of mice survived up to 100 days. However, a combination treatment of co-injected mTORi-HDL and a nanobiologic (tumour necrosis factor receptor-associated factor 6 inhibitor (TRAF6i)-HDL) 132 that impairs CD40 co-stimulation further increased allograft survival to 90 days. The immune response underlying organ rejection involves T cell activation through a cascade that includes alloantigen presentation (signal 1), costimulation (signal 2) and soluble cytokine secretion (signal 3).…”

High density lipoprotein mimicking nanoparticles for atherosclerosis

“…The anti-atherosclerotic efficacy of TRAF6-rHDL NPs was due to their ability to impair the migration capacity of monocytes and decrease monocyte recruitment by downregulating the genes involved in regulating monocyte migration but upregulating the genes associated with lymphocyte homing and cell adhesion for athero-protective function. For the nonhuman primate model, large amounts of TRAF6-rHDL NPs were found to accumulate in the liver and kidneys 72 h after infusions [50].…”