Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context
| Autor: | Lisa Schneider, Jacqueline Schneider, Nadine Gollinge, Stefanie Jänsch, Burghardt Wittig, Kerstin Kapp, Christiane Kleuss, Matthias Schroff |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Immunology Alpha interferon Cancer immunotherapy Antineoplastic Agents Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system medicine Humans Immunology and Allergy Secretion Cells Cultured Original Research Base Sequence In vitro toxicology Interferon-alpha Cancer TLR9 Dendritic Cells medicine.disease 030104 developmental biology Oligodeoxyribonucleotides chemistry plasmacytoid dendritic cells Toll-Like Receptor 9 Cancer research Cytokines structure‐function relationship Colorectal Neoplasms DNA 030215 immunology |
| Zdroj: | Immunity, Inflammation and Disease |
| ISSN: | 2050-4527 |
| Popis: | Introduction 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. Methods 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. Results and conclusions 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. |
| Databáze: | OpenAIRE |
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