Established and Emerging Immunological Complications of Biological Therapeutics in Multiple Sclerosis

Soleimani, Babak; Murray, Katy; Hunt, David

doi:10.1007/s40264-019-00799-1

Cited by 15 publications

(12 citation statements)

References 174 publications

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“…These complications can affect the risk–benefit balance of biological agents. In 2018, daclizumab, an anti-CD25 monoclonal antibody, was withdrawn from the market due to concerns about the development of severe, unpredictable autoimmunity [2]. Other approaches, such as corticosteroid administration, also have restrictions, related to side-effects or a lack of efficiency.…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Лунин

Хренов

Глушкова

et al. 2019

IJMS

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Relapsing–remitting experimental autoimmune encephalomyelitis (rEAE) in mice is a model that closely resembles relapsing–remitting multiple sclerosis in humans. This study aims to investigate a new approach to modulation of the inflammatory response in rEAE mice using a thymic peptide thymulin bound to polybutylcyanoacrylate (PBCA) nanoparticles. PBCA nanoparticles were used to prolong the presence of thymulin in the blood. Cytokine levels in blood were measured by ELISA; NF-κB and SAPK/JNK cascade activation, as well as Hsp72 and p53 protein expression, were measured by Western blotting. Animal health statuses were estimated using severity scores. Results showed that the cytokine response in rEAE was multi-staged: an early phase was accompanied by an increase in plasma interferon-γ, while the interleukin (IL)-17 response was markedly increased at a later stage. The stages were attributed to rEAE induction and maintenance phases. Thymulin significantly alleviated symptoms of rEAE and lowered plasma cytokine levels both in early and later stages of rEAE, and decreased NF-κB and SAPK/JNK cascade activation. Thymulin modulated NF-kappaB pathway activity via site-specific phosphorylation of RelA/p65 protein (at Ser276 and Ser536). The effect of nanoparticle-bound thymulin was more pronounced than the effect of free thymulin. Therefore, PBCA–thymulin can be considered a prospective treatment for this pathology.

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Section: Introductionmentioning

confidence: 99%

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Лунин

Хренов

Глушкова

et al. 2019

IJMS

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“…Both corticosteroids and immunosuppressives are burdened with severe side effects, including but not limited to metabolic, hematologic, and immune-related adverse reactions [ 34 ]. The rapidly growing group of medicines used for the treatment of ADs are biological drugs, such as antibodies and receptors targeting cytokines and immune cells; however, also these agents are not always effective and may cause severe adverse effects [ 35 ]. Therefore, there is an urgent need for new effective and safe therapies of ADs.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases

et al. 2022

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Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were utilized to assess the efficacy of this compound, and its pharmacokinetics was investigated in mice and rats. A new PK/PD disease progression model of compound 34 was developed that satisfactorily predicted the clinical score-time courses in mice with experimental encephalomyelitis that is an animal model of MS. Compound 34 displayed a high efficacy in all three animal models of ADs. Simultaneous inhibition of PDE types located in immune cells may constitute an alternative treatment strategy of ADs. The PK/PD encephalomyelitis and arthritis progression models presented in this study may be used in future preclinical research, and, upon modifications, may enable translation of the results of preclinical investigations into the clinical settings.

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“…At least five of these patients had clinical symptoms compatible with DRESS syndrome with CNS involvement [ 41 , 44 ], while others demonstrated evidence of CNS vasculitis or were associated with anti-N-methyl-d-aspartate (anti-NMDA) or anti-glial fbrillary acidic protein (anti-GFAP) antibodies [ 37 , 43 , 45 ]. One encephalitis have also been reported months after stopping treatment, suggesting that vigilance for secondary autoimmunity may need to be extended for many months after drug cessation [ 46 ].…”

Section: Failed Mabs In Relapsing Multiple Sclerosismentioning

confidence: 99%

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

Krämer

Wiendl

2022

Neurotherapeutics

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In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II–III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood–brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for ‘proof of concept’, time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.

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Established and Emerging Immunological Complications of Biological Therapeutics in Multiple Sclerosis

Cited by 15 publications

References 174 publications

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Protective Effect of PBCA Nanoparticles Loaded with Thymulin Against the Relapsing-Remitting Form of Experimental Autoimmune Encephalomyelitis in Mice

Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

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