Advertisement

A High-dose Pharmacokinetic Study of a New IgG4 Monoclonal Antibody Temelimab/GNbAC1 Antagonist of an Endogenous Retroviral Protein pHERV-W Env

      Abstract

      Purpose

      Temelimab/GNbAC1 is a humanized immunoglobulin G4 monoclonal antibody antagonist of the human endogenous retrovirus W envelope protein, which is associated with multiple sclerosis (MS) pathophysiology and possibly with other autoimmune disorders. Human endogenous retrovirus W envelope protein is expressed in the central nervous system of patients with MS, and sufficient amount of temelimab must reach the target. The safety of very high dosages of temelimab should be tested to support further clinical trials in MS.

      Methods

      This randomized, placebo-controlled, dose-escalation study evaluated the safety and pharmacokinetic profile of temelimab in 24 healthy volunteers after a single intravenous infusion at doses of 36, 60, 85, and 110 mg/kg administered sequentially.

      Findings

      Temelimab was well tolerated, with no particular adverse drug reactions at any dose. The maximal dose of 110 mg/kg could be administered, and no antidrug antibodies were induced. After administration of 36–110 mg/kg, mean temelimab Cmax increased from 859 to 2450 μg/mL, and AUC values increased from 319,900 to 1,030,000 μg·h/mL. There was an approximate dose-proportional increase in exposure, similar to observations at lower doses.

      Implications

      The favorable data in terms of safety and pharmacokinetic variables support temelimab use at high doses in future MS trials to optimally neutralize the temelimab target in the central nervous system. ClinicalTrials.gov identifier: NCT03574428.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Curtin F.
        • Perron H.
        • Kromminga A.
        • Porchet H.
        • Lang A.B.
        Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein.
        MAbs. 2015; 7: 265-275
        • Levet S.
        • Medina J.
        • Joanou J.
        • et al.
        An ancestral retroviral protein identified as a therapeutic target in type-1 diabetes.
        JCI Insight. 2017 Sep 7; (pii: 94387): 2
        • Kremer D.
        • Schichel T.
        • Förster M.
        • et al.
        Human endogenous retrovirus type W envelope protein inhibits oligodendroglial precursor cell differentiation.
        Ann Neurol. 2013; 74: 721-732
        • Göttle P.
        • Förster M.
        • Gruchot J.
        • et al.
        Rescuing the negative impact of human endogenous retrovirus envelope protein on oligodendroglial differentiation and myelination.
        Glia. 2019 Jan; 67: 160-170
        • Kremer D.
        • Gruchot J.
        • Weyers V.
        • et al.
        Microglial-dependent Neurodegeneration in Multiple Sclerosis Is Fueled by pHERV-W Envelope Protein.
        Charcot Foundation Annual Meeting, Baveno, Italia2018
        • Kremer D.
        • Förster M.
        • Schichel T.
        • et al.
        The neutralizing antibody GNbAC1 abrogates HERV-W envelope protein-mediated oligodendroglial maturation blockade.
        Mult Scler. 2015 Aug; 21: 1200-1203
        • Curtin F.
        • Bernard C.
        • Levet S.
        • et al.
        A new therapeutic approach for type 1 diabetes: rationale for GNbAC1, an anti-HERV-W-Env monoclonal antibody.
        Diabetes Obes Metab. 2018 Sep; 20: 2075-2084
        • Hartung H.P.
        • Curtin F.
        • Schneble H.M.
        • et al.
        • on behalf of the GNC-003 Investigators
        Barkhof F. CHANGE-MS End-of-Study (Week 48) Results.
        ECTRIMS, Berlin2018
        • Curtin F.
        • Vidal V.
        • Bernard C.
        • Kromminga A.
        • Lang A.B.
        • Porchet H.
        Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: a Phase 1 study.
        MAbs. 2016 Jul; 8: 854-860
        • Derfuss T.
        • Curtin F.
        • Guebelin C.
        • et al.
        A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients—a twelve month follow-up.
        J Neuroimmunol. 2015 Aug 15; 285: 68-70
        • Curtin F.
        • Lang A.B.
        • Perron H.
        • et al.
        GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis-associated endogenous retrovirus: a first-in-humans randomized clinical study.
        Clin Ther. 2012 Dec; 34: 2268-2278
        • Fischbach F.
        • Dunning M.B.
        A Manual of Laboratory and Diagnostic Tests.
        8th ed. Wolters Kluwer/Lippincott Williams and Wilkins, Philadelphia2009: 333
        • Tran J.Q.
        • Rana J.
        • Barkhof F.
        • et al.
        Randomized phase I trials of the safety/tolerability of anti-LINGO-1 monoclonal antibody BIIB033.
        Neurol Neuroimmunol Neuroinflamm. 2014 Aug 21; 1: e18
        • Jankovic J.
        • Goodman I.
        • Safirstein B.
        • et al.
        Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-α-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial.
        JAMA Neurol. 2018 Oct 1; 75: 1206-1214
        • Lim J.J.
        • Derby M.A.
        • Zhang Y.
        • et al.
        A Phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study to investigate the safety, tolerability, and pharmacokinetics of an anti-influenza B virus monoclonal antibody, MHAB5553A, in healthy volunteers.
        Antimicrob Agents Chemother. 2017 Jul 25; (pii: e00279-17): 61
        • Keizer R.J.
        • Huitema A.D.
        • Schellens J.H.
        • Beijnen J.H.
        Clinical pharmacokinetics of therapeutic monoclonal antibodies.
        Clin Pharmacokinet. 2010 Aug; 49: 493-507
        • Derfuss T.
        • Curtin F.
        • Guebelin C.
        • et al.
        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.
        Mult Scler. 2015 Jun; 21: 885-893
      1. Gamunex UK SMPC Consulted on January 14, 2019: https://www.medicines.org.uk/emc/product/4854/smpc.