Temelimab works. HERVs clearly implicated.

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frodo
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Temelimab works. HERVs clearly implicated.

Post by frodo » Mon May 20, 2019 11:38 am

Efficacy and Safety of Temelimab, an Antibody Antagonist of the Human Endogenous Retrovirus Type-W env Protein, in Participants with Relapsing Remitting Multiple Sclerosis: A Double-Blind, Randomised, Placebo-Controlled Phase 2b Clinical Trial

https://papers.ssrn.com/sol3/papers.cfm ... id=3388820

Abstract

Background: The envelope protein encoded by pathogenic Human Endogenous Retrovirus type-W (pHERV W-env) has been involved in the pathophysiology of MS. In pre-clinical studies pHERV-W-env directly activated microglia and inhibited remyelination; both mechanisms contribute to MS-related CNS damage. Temelimab (GNbAC1) is a humanised, IgG4-kappa monoclonal antibody that targets pHERV-W-env, neutralising its effects in preclinical models. The aim of this Phase 2 study was to evaluate efficacy and safety of three doses of temelimab in participants with relapsing-remitting MS.

Methods: A 24-week randomised, double-blind, placebo-controlled Period 1 was followed by a 24 week randomised, dose-controlled Period 2 (NCT02782858). Placebo-treated subjects from Period 1 were re-randomised to one of the active treatment arms for Period 2. Six injections were repeated in both periods. Primary endpoint was the cumulative number of Gd-enhancing T1 lesions in monthly brain MRIs from week 12 to 24. Secondary and exploratory endpoints were: hypointense T1 lesion number/volume, T2 lesion number/volume, change in brain volume, change in magnetisation transfer ratio (MTR), clinical relapse, and disability at weeks 24 and 48.

Findings: 270 participants were randomised. The primary endpoint was not met at week 24 (comparison ratio 0.90 (95% CI=0.49-1.64) highest dose vs placebo). 247 participants (91.5% of original cohort) entered Period 2; 236 (87.4%) completed week 48 evaluations. A dose-related decrease of brain atrophy and positive effects on T1 hypointense lesion number and MTR in the 18 mg/kg group were observed at week 48. No safety issue emerged.

Interpretation: This is the first clinical efficacy study of temelimab, a specific anti-HERV-directed therapy. No benefit was seen on inflammatory measures at week 24; however, week 48 data suggests dose-dependent effects of temelimab on 3 neurodegeneration measures: brain atrophy, MTR and T1 hypointense lesions. Temelimab has further development potential as a neuroprotective treatment that specifically blocks deleterious CNS effects of pHERV-W-env in MS.

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How are HERVs implicated?

Post by frodo » Mon Jun 24, 2019 12:45 am

Let's call this "the Kremer's paper" because it seems that it will be cited a lot from now on.

pHERV-W envelope protein fuels microglial cell-dependent damage of myelinated axons in multiple sclerosis

https://www.pnas.org/content/early/2019 ... 3116.short

Significance

There is a broad repertoire of immunomodulatory drugs that effectively treat the inflammatory aspects of relapsing multiple sclerosis (MS). However, axonal degeneration, which occurs mainly in progressive MS, is still not understood and cannot be treated pharmaceutically.

As it is the major factor contributing to clinical disability in MS, it represents an unmet clinical need. A recently completed phase IIb study has demonstrated that anti-pathogenic human endogenous retrovirus type W (pHERV-W) envelope protein (ENV) treatment results in a significant decrease of neurodegenerative brain atrophy in treated MS patients.

For these results, the work presented here offers an explanation by demonstrating that, via myeloid cells, pHERV-W ENV directly harms axons.

Abstract

Axonal degeneration is central to clinical disability and disease progression in multiple sclerosis (MS). Myeloid cells such as brain-resident microglia and blood-borne monocytes are thought to be critically involved in this degenerative process. However, the exact underlying mechanisms have still not been clarified. We have previously demonstrated that human endogenous retrovirus type W (HERV-W) negatively affects oligodendroglial precursor cell (OPC) differentiation and remyelination via its envelope protein pathogenic HERV-W (pHERV-W) ENV (formerly MS-associated retrovirus [MSRV]-ENV). In this current study, we investigated whether pHERV-W ENV also plays a role in axonal injury in MS.

We found that in MS lesions, pHERV-W ENV is present in myeloid cells associated with axons. Focusing on progressive disease stages, we could then demonstrate that pHERV-W ENV induces a degenerative phenotype in microglial cells, driving them toward a close spatial association with myelinated axons. Moreover, in pHERV-W ENV-stimulated myelinated cocultures, microglia were found to structurally damage myelinated axons. Taken together, our data suggest that pHERV-W ENV-mediated microglial polarization contributes to neurodegeneration in MS.

Thus, this analysis provides a neurobiological rationale for a recently completed clinical study in MS patients showing that antibody-mediated neutralization of pHERV-W ENV exerts neuroprotective effects.

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answer to the Kremers paper

Post by frodo » Sun Sep 01, 2019 11:11 am

there is an answer to the Kremers paper

On the origin of a pathogenic HERV-W envelopeprotein present in multiple sclerosis lesions

https://www.pnas.org/content/pnas/early ... 6.full.pdf

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Re: Temelimab works. HERVs clearly implicated.

Post by frodo » Sun Sep 01, 2019 11:13 am

And here an answer to the answer, from the Kremer's team.

https://www.pnas.org/content/pnas/early ... 6.full.pdf

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Re: Temelimab works. HERVs clearly implicated.

Post by frodo » Sun Sep 01, 2019 11:14 am

And here a new review about the role of HERVs in microglia activation, following Kremer's paper from last May.

This researchers confirm again the previously reported associations: A specific HERV (pHEV-W), activated microglia and demyelination, like Kremer's model predicted.

https://www.pnas.org/content/early/2019 ... 1909786116

The pHEV-W envelope protein has been described in the CNS in patients with MS (23, 24) and is confirmed in this study, with the protein being found in the extracellular parenchyma and within activated microglia.

The microglia seem to be closely associated with demyelinating axons. This protein can inhibit development of oligodendrocytes (OL), the cells that elaborate and maintain myelin as an extension and modification of their plasma membrane, and antibody to that protein can neutralize the inhibitory effect (25, 26).

Pathology represents a “snapshot” in time, how would one prove or support a causative role for activated microglia that have apparently phagocytized the envelope protein. Kremer et al. (13) have performed a series of elegant in vitro studies demonstrating that, at least in vitro, the microglia respond to the envelope protein as a proinflammatory stimulus. The microglia, in turn, produce proinflammatory cytokines which can further cause damage to myelin and axons and fail to produce protective factors.

[...]

What other ways might pHEV-W protein be involved in MS pathogenesis? How does the possible involvement of pHEV-W square with evidence for other viruses in MS, particularly EBV?

There is a role for EBV and other viruses in MS, as they can serve to activate the gene for HEV-W, leading to increased expression of the envelope protein (7, 35). It is still not clear that pHEV-W is first activated within the CNS or whether activation in the CNS is initiated by infiltrating inflammatory cells which have been shown to express the envelope protein.

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