Clinical management of multiple sclerosis and neuromyelitis optica with therapeutic monoclonal antibodies: approved therapies and emerging candidates

Dubey, Divyanshu; Kieseier, Bernd C.; Hartung, Hans Peter; Hemmer, Bernhard; Miller-Little, William A.; Stüve, Olaf

doi:10.1586/1744666x.2015.992881

Cited by 17 publications

(21 citation statements)

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“…In addition, clinically, AxD, especially type 2, shows stepwise or stroke-like progression, which is similar to the typical progression of other white matter diseases involving oligodendrocytes, MS and NMO. These findings suggest that the neuroinflammatory process promoted by proinflammatory astrocytes may be involved in the pathogenesis of AxD, and that immunomodulation approaches [33] targeting astrocytopathy would be a candidate therapy for AxD. Recent studies showed that astrocytes themselves can secrete cytokines and have responsibility for extrinsic factors, including LPS [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Kondo

Funayama

Miyake

et al. 2017

Journal of the Neurological Sciences

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Alexander disease is a fatal neurological illness characterized by white-matter degeneration and formation of Rosenthal fibers, which contain glial fibrillary acidic protein as astrocytic inclusion. Alexander disease is mainly caused by a gene mutation encoding glial fibrillary acidic protein, although the underlying pathomechanism remains unclear. We established induced pluripotent stem cells from Alexander disease patients, and differentiated induced pluripotent stem cells into astrocytes. Alexander disease patient astrocytes exhibited Rosenthal fiber-like structures, a key Alexander disease pathology, and increased inflammatory cytokine release compared to healthy control. These results suggested that Alexander disease astrocytes contribute to leukodystrophy and a variety of symptoms as an inflammatory source in the Alexander disease patient brain. Astrocytes, differentiated from induced pluripotent stem cells of Alexander disease, could be a cellular model for future translational medicine.

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Section: Discussionmentioning

confidence: 99%

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Kondo

Funayama

Miyake

et al. 2017

Journal of the Neurological Sciences

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“…Rituximab is a chimeric mouse–human IgG1k mAb that binds to the CD20 cell surface epitope on circulating B‐cells (Reff et al , ). It lyses peripheral B‐cell populations through a threefold mechanism of action: a combination of ADCC and CDC and possibly promotion of apoptosis (Dubey et al , ). Rituximab is approved for patients with non‐Hodgkin's lymphoma, chronic lymphocytic leukaemia, rheumatoid arthritis, granulomatous polyangiitis and microscopic polyangiitis (Gasperi et al , ).…”

Section: Mab Therapies For Relapsing Ms: Efficacy and Mechanisms Of Amentioning

confidence: 99%

Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B‐cell‐targeted therapies

Nguyen

Gresle

Marshall

et al. 2017

British J Pharmacology

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Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS, and one of the most common causes of disability in young adults. Over the last decade, new disease-modifying therapies have emerged, including monoclonal antibodies (mAbs) that provide highly targeted therapies with greater efficacy than platform therapies. In particular, monoclonal antibodies directed against CD20-positive B cells have shown remarkable results in recent clinical trials and renewed interest in the mechanism of B cell-depleting therapies to ameliorate relapse activity and progression in MS. Here, we review the mechanisms of action and clinical evidence of approved and emerging mAbs, with a focus on B cell-targeted therapies.

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“…Anti-CTLA-4 treatment increased clinical signs of EAE in animal models [145,146]. Abatacept has showed safety and favorable immunological effects in a phase I clinical trial in patients with RRMS [147], while an initial placebo-controlled phase II trial in 219 patients was halted prematurely because of an increased relapse rate and MRI activity in an abatacepttreated group [148]. However, a post-hoc analysis revealed that patients in this treatment arm had a higher baseline activity at the time of study inclusion, providing the rationale for another attempt a few years later.…”

Section: Anti-ctla-4-directed Therapy (Abatacept)mentioning

confidence: 99%

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

Bittner

Wiendl

2016

Neurotherapeutics

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Therapeutic options for multiple sclerosis (MS) have significantly increased over the last few years. T lymphocytes are considered to play a central role in initiating and perpetuating the pathological immune response. Currently approved therapies for MS target T lymphocytes, either in an unspecific manner or directly by interference with specific Tcell pathways. While the concept of BT-cell-specific therapyî mplies specificity and selectivity, currently approved approaches come from a general shaping of the immune system towards anti-inflammatory immune responses by non-T-cellselective immune suppression or immune modulation (e.g., interferons-immune modulation approach) to a depletion of immune cell populations involving T cells (e.g., anti-CD52, alemtuzumab-immune selective depletion approach), or a selective inhibition of distinct molecular pathways in order to sequester leucocytes (e.g., natalizumab-leukocyte sequestration approach). This review will highlight the rationale and results of different T-cell-directed therapeutic approaches coming from basic animal experiments to clinical trials. We will first discuss the pathophysiological rationale for targeting T lymphocytes in MS leading to currently approved treatments acting on T lymphocytes. Furthermore, we will disuss previous promising concepts that have failed to show efficacy in clinical trials or were halted as a result of unexpected adverse events. Learning from the discrepancies between expectations and failures in practical outcomes helps to optimize future research approaches and clinical study designs. As our current view of MS pathogenesis and patient needs is rapidly evolving, novel therapeutic approaches targeting T lymphocytes will also be discussed, including specific molecular interventions such as cytokine-directed treatments or strategies enhancing immunoregulatory mechanisms. Based on clinical experience and novel pathophysiological approaches, T-cell-based strategies will remain a pillarstone of MS therapy.

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Clinical management of multiple sclerosis and neuromyelitis optica with therapeutic monoclonal antibodies: approved therapies and emerging candidates

Cited by 17 publications

References 100 publications

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Modeling Alexander disease with patient IPSCS reveals cellular and molecular pathology of astrocytes

Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B‐cell‐targeted therapies

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

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