Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies

BMC Clinical Pharmacology

Christoph Coch⁵  Gunther Hartmann⁵  Marcus Müller³  Stefan Holdenrieder⁵  Julia Stingl⁴  Roberto Viviani¹  Rolf Fimmers²  Verena Dykstra⁵  Julian Zimmermann³  Bastian Lüdenbach⁵  Christine Fuhrmann⁵  Martin Mengel⁴  Annette Viktoria Hinze⁴  Martin Coenen⁵ 

[1]Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany

[2]Institute of Medical Biometrics, Informatics and Epidemiology, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53127, Germany

[3]Deparment of Neurology, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53127, Germany

[4]Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, Bonn, 53175, Germany

[5]Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, Bonn, 53127, Germany

关键词: Cytokines;    miRNA;    RIG-I;    Phase I study;    Dose calculation;    Multiple sclerosis;    Tumor immune therapy;    Immune response;    Interferon-beta;   

Others  :  1226057
DOI  :  10.1186/s40360-015-0025-x

 received in 2015-05-07, accepted in 2015-09-11,  发布年份 2015

【 摘 要 】

Background

The innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand.

Methods/Design

ResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables.

Discussion

The ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system.

Trial registration

clinicaltrials.gov ID NCT02364986

【 授权许可】

   
2015 Coenen et al.

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