Dataset Information

Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context.

ABSTRACT:

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-? 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.

SUBMITTER: Kapp K

PROVIDER: S-EPMC5134728 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Publications

Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context.

Kapp Kerstin K Schneider Jacqueline J Schneider Lisa L Gollinge Nadine N Jänsch Stefanie S Schroff Matthias M Wittig Burghardt B Kleuss Christiane C

Immunity, inflammation and disease 20161018 4

<h4>Introduction</h4>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 ...[more]

PMID: 27980779

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Dataset Information

Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context.

Introduction

Methods

Results and conclusions

Publications

Distinct immunological activation profiles of dSLIM® and ProMune® depend on their different structural context.

Similar Datasets

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