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IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.

ABSTRACT: BACKGROUND:The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC-/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. METHODS:We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30, and 45?mg/kg) and clinical disease course was evaluated up to 35?days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed. RESULTS:We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30?mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. CONCLUSIONS:These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

SUBMITTER: Desu HL

PROVIDER: S-EPMC7199312 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.

Desu Haritha L HL Plastini Melanie M Illiano Placido P Bramlett Helen M HM Dietrich W Dalton WD de Rivero Vaccari Juan Pablo JP Brambilla Roberta R Keane Robert W RW

Journal of neuroinflammation 20200504 1

<h4>Background</h4>The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC<sup>-/-</sup> mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of ou ...[more]

PMID: 32366256

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Project description:Therapeutic approaches to multiple sclerosis (MS) are based on altering the functions of the immune system, either by using broad immunosuppressive drugs used for transplantation rejection and rheumatology, or by modulating them more discreetly with beta interferon and synthetic amino-acid copolymers. These strategies are only partially successful, have important safety and tolerability limitations, and have shown to be mostly effective in earlier stages of the disease, in which acute relapses dominate the clinical picture. For progressive phenotypes of MS there are currently no effective therapeutic options. As very specific and potent immunosuppressive agents, monoclonal antibodies (mAbs) may offer considerable advantages over other therapies for MS. During the last decade, anti-a4 integrin natalizumab became the first approved mAb for treatment of relapsing MS, after convincingly demonstrating clinically significant effects on two large Phase 3 trials. Moreover, the concept of disease remission was introduced for the first time, to describe patients that show no signs of clinical or imaging markers of disease activity during therapy with natalizumab. Of the mAbs under development for MS, alemtuzumab and rituximab have also shown promising evidence of effectiveness, and potentially expanded the therapeutic horizon to reversal of disease progression in early relapsing patients, and progressive patients who previously had not been studied. However, the appearance of progressive multifocal leukoencephalopathy (PML) in natalizumab-treated MS patients, as well as in patients with lymphoma, lupus and rheumatoid arthritis treated with rituximab, and autoimmune-type complications in alemtuzumab-treated MS patients underlines the fact that extended efficacy comes with significant clinical risks. The challenge is then how best to utilize therapies that have evidently superior efficacy in a chronic disease of young adults, to obtain the best benefit-risk ratio, and how to monitor and prevent emergent safety concerns.

Dataset Information

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.

Publications

IC100: a novel anti-ASC monoclonal antibody improves functional outcomes in an animal model of multiple sclerosis.

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