Design and Structural Requirements of the Potent and Safe TLR-9 Agonistic Immunomodulator MGN1703
Schmidt, Manuel (Mologen AG (Berlin, Alemanya))
Hagner, Nicole (Freie Universitaet)
Marco Valle, Alberto (Universitat Autònoma de Barcelona. Departament de Sanitat i d'Anatomia Animals)
König-Merediz, Sven A. (Vivotecnia)
Schroff, Matthias (Mologen AG (Berlin, Alemanya))
Wittig, Burghardt (Freie Universitaet)

Data:	2015
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Nucleic Acid Therapeutics, Vol. 25 (june 2015) , p. 130-140, ISSN 2159-3345

DOI: 10.1089/nat.2015.0533
PMID: 25826686

11 p, 1.0 MB

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