Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.GeNeuro SA, Geneva, Switzerlandhttp://www.tandfonline.com/loi/kmab202016-01-31hb201

A high-dose pharmacokinetic study of a new IgG4 monoclonal antibody temelimab/GNbAC1 antagonist of an endogenous retroviral protein pHERV-W Env

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.GeNeuro SAhttps://www.journals.elsevier.com/clinical-therapeutics2020-09-01hj2020Pharmacolog

A new therapeutic approach for type 1 diabetes : rationale for GNbAC1, an anti‐HERV‐W‐Env monoclonal antibody

We describe a newly identified therapeutic target for type 1 diabetes (T1D): an envelope protein of endogenous retroviral origin, human endogenous retrovirus W envelope (HERV‐W‐Env). HERV‐W‐Env was found to be detected in the blood of ~60% of patients with T1D and is expressed in acinar pancreatic cells of 75% of patients with T1D at post mortem examination. Preclinical experiments showed that this protein displays direct cytotoxicity on human β‐islet cells. In vivo HERV‐W‐Env impairs the insulin and glucose metabolism in transgenic mice expressing HERV‐W‐Env. GNbAC1, an IgG4 monoclonal antibody, has been developed to specifically target HERV‐W‐Env and to neutralize the effect of HERV‐W‐Env in vitro and in vivo. GNbAC1 is currently in clinical development for multiple sclerosis and > 300 subjects have been administered with GNbAC1 so far. GNbAC1 is now being tested in T1D in the RAINBOW‐T1D study, which is a randomized placebo‐controlled study with the objective of showing the safety and pharmacodynamic response of GNbAC1 in patients who have had T1D with a maximum of 4 years' duration. GNbAC1 is being tested vs placebo at the dose of 6 mg/kg in 60 patients during six repeated administrations for 6 months; a 6‐month open‐label extension will follow. The primary endpoint is to assess safety, and secondary endpoints are the pharmacodynamic responses to GNbAC1. GNbAC1 targeting HERV‐W‐Env is currently in clinical development in T1D, with the first safety and pharmacodynamic study. If the study results are positive, this may open the door to the development of an innovative non‐immunomodulatory disease‐modifying treatment for T1D.The RAINBOW-T1D study is financed by GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.http://wileyonlinelibrary.com/journal/dom2019-09-01hj2018Pharmacolog

Preclinical and early clinical development of GNbAC1, a humanized IgG4 monoclonal antibody targeting endogenous retroviral MSRV-Env protein

Monoclonal antibodies (mAbs) play an increasing important role in the therapeutic armamentarium against multiple sclerosis (MS), an inflammatory and degenerative disorder of the central nervous system. Most of the mAbs currently developed for MS are immunomodulators blocking the inflammatory immune process. In contrast with mAbs targeting immune function, GNbAC1, a humanized IgG4 mAb, targets the multiple sclerosis associated retrovirus envelope (MSRVEnv) protein, an upstream factor in the pathophysiology of MS. MSRV-Env protein is of endogenous retroviral origin, expressed in MS brain lesions, and it is pro-inflammatory and toxic to the remyelination process, by preventing the differentiation of oligodendrocyte precursor cells. We present the preclinical and early clinical development results of GNbAC1. The specificity of GNbAC1 for its endogenous retroviral target is described. Efficacy of different mAb versions of GNbAC1 were assessed in MSRV-Env induced experimental allergic encephalitis (EAE), an animal model of MS. Because the target MSRV-Env is not expressed in animals, no relevant animal model exists for a proper in vivo toxicological program. An off-target 2-week toxicity study in mice was thus performed, and it showed an absence of safety risk. Additional in vitro analyses showed an absence of complement or antibody-dependent cytotoxicity as well as a low level of cross-reactivity to human tissues. The first-in-man clinical study in 33 healthy subjects and a long-term clinical study in 10 MS patients showed that GNbAC1 is well tolerated in humans without induction of immunogenicity and that it induces a pharmacodynamic response on MSRV biomarkers. These initial results suggest that the mAb GNbAC1 could be a safe long-term treatment for patients with MS with a unique therapeutic mechanism of action.GeNeuro SA, Geneva, Switzerlandhttp://www.tandfonline.com/loi/kmab202016-01-31hb201

A randomised placebo-controlled study to investigate GNbAC1 an anti-HERV-W-Env monoclonal antibody in patients with recent onset of type 1 diabetes : rationale and design

AIMS : Human endogenous retroviruses (HERVs) elements, remnants of ancestral viral genomic insertions, are emerging targets in several autoimmune diseases. In type 1 diabetes (T1D) patients, the envelope protein of HERV-W (HERV-W-Env) is detected in 70% of sera and is found expressed by acinar cells in 75% of T1D pancreata. HERV-W-Env pathogenic properties include inhibition of insulin secretion by pancreatic beta cells, and hyperglycemia associated with decreased levels of insulin in a transgenic mouse model, suggesting the involvement of HERV-W-Env in T1D pathogenesis. GNbAC1, a humanised monoclonal antibody targeting specifically HERV-W-Env is tested for the first time in T1D patients. METHOD/DESIGN : This trial is a randomised placebo controlled 2-arm study with the objective of showing the safety and pharmacodynamics response of GNbAC1 in T1D patients. Sixty T1D patients are planned to be included. GNbAC1 will be tested versus placebo at the dose of 6 mg/kg administered intravenously; 6 drug administrations will be performed at 4-week intervals. The primary endpoint will record adverse events, physical examination and vital signs as well as clinical laboratory data. Secondary endpoints will be: glycated haemoglobin blood levels; C-peptide levels up to 2 hours after mixed meal tolerance test; fasting and postprandial blood glucose; change from baseline in percentage of subjects not requiring insulin; daily use of insulin. T1D and autoimmune related antibodies will be assessed. CONCLUSIONS : This first safety and pharmacodynamics study of the monoclonal antibody GNbAC1 in T1D patients, if positive, may open the door for the development of an innovative non-immunomodulatory disease modifying drug for T1D. REGISTRATION : clinicalTrials.gov Identifier: NCT03179423GeNeuro Australia Pty Ltd, a subsidiary of GeNeuro SA, Switzerland.https://onlinelibrary.wiley.com/journal/146454912019-08-31hj2018Pharmacolog

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

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

Efficacy and safety of temelimab in multiple sclerosis: Results of a randomized phase 2b and extension study

Background: The envelope protein of human endogenous retrovirus W (HERV-W-Env) is expressed by macrophages and microglia, mediating axonal damage in chronic active MS lesions. Objective and Methods: This phase 2, double-blind, 48-week trial in relapsing-remitting MS with 48-week extension phase assessed the efficacy and safety of temelimab; a monoclonal antibody neutralizing HERV-W-Env. The primary endpoint was the reduction of cumulative gadolinium-enhancing T1-lesions in brain magnetic resonance imaging (MRI) scans at week 24. Additional endpoints included numbers of T2 and T1-hypointense lesions, magnetization transfer ratio, and brain atrophy. In total, 270 participants were randomized to receive monthly intravenous temelimab (6, 12, or 18 mg/kg) or placebo for 24 weeks; at week 24 placebo-treated participants were re-randomized to treatment groups. Results: The primary endpoint was not met. At week 48, participants treated with 18 mg/kg temelimab had fewer new T1-hypointense lesions (p = 0.014) and showed consistent, however statistically non-significant, reductions in brain atrophy and magnetization transfer ratio decrease, as compared with the placebo/comparator group. These latter two trends were sustained over 96 weeks. No safety issues emerged. Conclusion: Temelimab failed to show an effect on features of acute inflammation but demonstrated preliminary radiological signs of possible anti-neurodegenerative effects. Current data support the development of temelimab for progressive MS. Trial registration: CHANGE-MS: ClinicalTrials.gov: NCT02782858, EudraCT: 2015-004059-29; ANGEL-MS: ClinicalTrials.gov: NCT03239860, EudraCT: 2016-004935-18