title: Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context.
abstract: DNA-based TLR9 agonists are potent activators of the immune system. ProMune® and dSLIM® belong to different families of TLR9 agonists and both have been established as cancer immunotherapeutics in clinical proof-of-concept studies. Unfortunately, ProMune® failed in pivotal oncological trials. dSLIM®, the active ingredient of Lefitolimod (MGN1703), successfully finished a double-blinded, placebo-controlled phase II study in patients with advanced colorectal cancer, exhibiting improved progression-free survival and durable disease control.
  
  
  
  To explain the different systemic efficacies of dSLIM® and ProMune®, both TLR9 agonists and chimeric molecules thereof are analyzed side-by-side in a panel of in vitro assays for immune activation.
  
  
  
  Indeed, dSLIM® exposure results in an IFN-α dependent broad activation of immune cells whereas ProMune® strongly stimulates B cells. Moreover, all functional effects of dSLIM® strictly depend on the presence of CG-motifs within its dumbbell-shaped, covalently closed structural context. Conversely, several immunological effects of ProMune® like IL-8 secretion are independent of CG-motifs and could be ascribed to the phosphorothioate-modifications of its DNA backbone, which may have caused the side effects of ProMune® in clinical trials. Finally, we showed that the implementation of ProMune® (ODN2006) base sequence into the characteristic dSLIM® dumbbell form resulted in dSLIM2006 with all beneficial effects for immunostimulation combined from both TLR9 classes without any CG-independent effects.
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kapp
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schneider
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Schneider
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Gollinge
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Jänsch
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schroff
authors.affiliation: Foundation Institute Molecular Biology and Bioinformatics Freie Universitaet Berlin Berlin Germany.
authors.forename: Burghardt
authors.initials: B
authors.lastname: Wittig
authors.affiliation: Mologen AG Berlin Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kleuss
mesh_terms: D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001483:Base Sequence; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D016207:Cytokines; D003713:Dendritic Cells; D006801:Humans; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology*; D051217:Toll-Like Receptor 9
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; C483020:ProMune; D051217:Toll-Like Receptor 9
keywords: Cancer immunotherapy; plasmacytoid dendritic cells; structure‐function relationship