A phase IIa randomised clinical study of GNbAC1, a humanised monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus in multiple sclerosis patients

Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell dif...

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Bibliographic Details
Published in:Multiple sclerosis 2015-06, Vol.21 (7), p.885-893
Main Authors: Derfuss, Tobias, Curtin, François, Guebelin, Claudia, Bridel, Claire, Rasenack, Maria, Matthey, Alain, Du Pasquier, Renaud, Schluep, Myriam, Desmeules, Jules, Lang, Alois B, Perron, Hervé, Faucard, Raphael, Porchet, Hervé, Hartung, Hans-Peter, Kappos, Ludwig, Lalive, Patrice H
Format: Article
Language:English
Subjects:
Adult
Antibodies, Monoclonal, Humanized - pharmacokinetics
Antibodies, Monoclonal, Humanized - therapeutic use
Brain - pathology
Double-Blind Method
Endogenous Retroviruses
Female
Gene Products, env - antagonists & inhibitors
Humans
Magnetic Resonance Imaging
Male
Middle Aged
Multiple Sclerosis - drug therapy
Multiple Sclerosis - pathology
Multiple Sclerosis - virology
Polymerase Chain Reaction
RNA, Viral - analysis
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Summary:Background: GNbAC1 is an immunoglobulin (IgG4) humanised monoclonal antibody against multiple sclerosis-associated retrovirus (MSRV)-Env, a protein of endogenous retroviral origin, expressed in multiple sclerosis (MS) lesions, which is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. Objective: This is a randomised, double-blind placebo-controlled dose-escalation study followed by a six-month open-label phase to test GNbAC1 in MS patients. The primary objective was to assess GNbAC1 safety in MS patients, and the other objectives were pharmacokinetic and pharmacodynamic assessments. Methods: Ten MS patients were randomised into two cohorts to receive a single intravenous infusion of GNbAC1/placebo at doses of 2 or 6 mg/kg. Then all patients received five infusions of GNbAC1 at 2 or 6 mg/kg at four-week intervals in an open-label setting. Safety, brain magnetic resonance imaging (MRI), pharmacokinetics, immunogenicity, cytokines and MSRV RNA expression were studied. Results: All patients completed the study. GNbAC1 was well tolerated in all patients. GNbAC1 pharmacokinetics is dose-linear with mean elimination half-life of 27–37 d. Anti-GNbAC1 antibodies were not detected. Cytokine analysis did not indicate an adverse effect. MSRV-transcripts showed a decline after the start of treatment. Nine patients had stable brain lesions at MRI. Conclusion: The safety, pharmacokinetic profile, and pharmacodynamic responses to GNbAC1 are favourable in MS patients over a six-month treatment period.
ISSN:1352-4585
1477-0970
DOI:10.1177/1352458514554052