Abstract
Single-stranded oligodeoxynucleotides (ODN), containing nonmethylated cytosine–guanine motifs (CpG ODN), are recognized by the innate immune system as “danger signals.” CpG ODN are efficacious immunomodulators but require phosphorothioate (PT) or other backbone modifications for metabolic stability, which cause toxicities in mice and primates. We therefore designed a covalently closed DNA molecule (dSLIM®) where two single-stranded loops containing CG motifs are connected through a double-stranded stem in the absence of any nonnatural DNA component. The most promising immunomodulator, MGN1703, comprises two loops of 30 nucleotides containing three CG motifs each, and a connecting stem stem of 28 base pairs. MGN1703 stimulates cytokine secretion [interferon (IFN)-α, IFN-γ, interleukin (IL)-12, IL-6, and IL-2] and activates immune cells by increased expression of CD80, CD40, human leukocyte antigen (HLA)-DR and ICAM-1. Efficacy of immunomodulation strictly depends on the descriptive dumbbell shape and size of the molecule. Variations in stem length and loop size lead to reduced potency of the respective members of the dSLIM® class. In a representative mouse model, toxicities from injections of high amounts of a CpG ODN-PT and of MGN1703 were evaluated. The CpG ODN-PT group showed severe organ damage, whereas no such or other pathologies were found in the MGN1703 group. Oncological clinical trials of MGN1703 already confirmed our design.
Highlights
Oligodeoxynucleotides containing nonmethylated cytosine moieties within cytosine–guanine sequence motifs (CpG ODN) are potent immunomodulators [1,2]
CpG ODN bind and activate Toll-like receptor 9 (TLR-9), which in the human immune system is located in the endoplasmic reticulum of plasmacytoid dendritic cells and B cells [6]
This results in the production of proinflammatory cytokines and the type 1 interferon response, leading to the activation and maturation of dendritic cells (Langerhans cells, plasmacytoid dendritic cells (pDC), myeloid dendritic cells mDC), the proliferation of B cells, and to the proliferation and activation of innate effector cells [e.g., natural killer (NK) cells and invariant NKT cells] among others
Summary
Oligodeoxynucleotides containing nonmethylated cytosine moieties within cytosine–guanine sequence motifs (CpG ODN) are potent immunomodulators [1,2]. TLR-9 activation subsequently triggers a signaling cascade involving MyD88, IRAK, and TRAF-6 leading to the activation of NF–kB and IRF7 pathways [1,2,7,8,9]. This results in the production of proinflammatory cytokines and the type 1 interferon response, leading to the activation and maturation of dendritic cells (Langerhans cells, pDC, myeloid dendritic cells mDC), the proliferation of B cells, and to the proliferation and activation of innate effector cells [e.g., natural killer (NK) cells and invariant NKT cells] among others. Through the bridging function of mature, activated DC the adaptive immune system responds [10,11,12]
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