MIS-416(MIS-416) - 药物靶点：NOD2 x TLR9_专利_临床

概要

基本信息

药物类型

预防性疫苗

别名

靶点

NOD2 x TLR9

作用机制

NOD2拮抗剂(核苷酸结合寡聚化结构域蛋白-2拮抗剂)、TLR9拮抗剂(Toll样受体9拮抗剂)

治疗领域

免疫系统疾病神经系统疾病其他疾病+ [2]

在研适应症-

非在研适应症

感染慢性进行性多发性硬化原发性进行性多发性硬化+ [3]

原研机构

Amplia Therapeutics Ltd.

在研机构-

非在研机构

Amplia Therapeutics Ltd.

最高研发阶段无进展临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

5

项与 MIS-416 相关的临床试验

NCT02228213 / Completed临床2期

A Phase 2B Randomised, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of MIS416 in the Treatment of Subjects With Secondary Progressive Multiple Sclerosis

The purpose of this study is to determine whether MIS416 administered once weekly over 12 months is safe, tolerable, and improves a range of signs and symptoms associated with secondary progressive multiple sclerosis.

开始日期2014-10-01

申办/合作机构

Amplia Therapeutics Ltd.

[+1]

JPRN-UMIN000008007 / Completed临床1期IIT

Phase I study on the combination therapy of IMF-001 and MIS416 for the treatment of patients with NY-ESO-1 expressing malignant solid tumor. - Phase I study on the combination therapy of IMF-001 and MIS416 for the treatment of patients with NY-ESO-1 expressing malignant solid tumor.

开始日期2012-06-01

申办/合作机构-

JPRN-UMIN000008006 / Completed临床1期IIT

Phase I Clinical Study on the Long-term Combination Therapy of CHP-NY-ESO-1 Cancer Vaccine and MIS416 for the Treatment of Patients with NY-ESO-1-expressing Refractory Solid tumor. - Phase I Clinical Study on the Long-term Combination Therapy of CHP-NY-ESO-1 Cancer Vaccine and MIS416 for the Treatment of Patients with NY-ESO-1-expressing Refractory Solid Tumor.

开始日期2012-05-01

申办/合作机构-

100 项与 MIS-416 相关的临床结果

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100 项与 MIS-416 相关的转化医学

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100 项与 MIS-416 相关的专利（医药）

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14

项与 MIS-416 相关的文献（医药）

2020-12-01·Acta Neuropathologica Communications2区 · 医学

Innate signaling within the central nervous system recruits protective neutrophils

2区 · 医学

ArticleOA

作者: Owens, Trevor ; Kavan, Stephanie ; Hansen, Christian Rønn ; Thomassen, Mads ; Webster, Gill A ; Khorooshi, Reza ; Kruse, Torben ; Burton, Mark ; Dieu, Ruthe Storgaard ; Wais, Vian ; Marczynska, Joanna

AbstractThere is great interest in understanding how the central nervous system (CNS) communicates with the immune system for recruitment of protective responses. Infiltrating phagocytic monocytes and granulocytes are implicated in neuroinflammation in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). To investigate how CNS endogenous signals can be harnessed to promote anti-inflammatory programs, we have used a particulate Toll-like receptor 9 and nucleotide-oligomerization domain 2 bispecific innate ligand (MIS416), to address whether its phagocytosis within the CNS recruits protective myeloid cells. We find that MIS416 injected intrathecally into the cerebrospinal fluid via the cisterna magna induced a local chemokine response that recruited blood-derived monocytes and neutrophils to the CNS. These cells phagocytosed MIS416. The increase in EAE severity normally seen from time of onset did not occur in mice receiving MIS416. This suppression of disease symptoms was dependent on expression of the type I interferon receptor (IFNAR). Transfer of intrathecal MIS416-induced neutrophils suppressed EAE in recipient mice, while monocytes did not transfer protection. MIS416-induced neutrophils showed increased IL-10 expression that was IFNAR1-driven. In contrast to intrathecal administration, intravenous administration of MIS416 led to monocyte but not neutrophil infiltration to the CNS. We thus identify a CNS-intrinsic and -specific phagocytosis-induced recruitment of anti-inflammatory neutrophils that contribute to CNS homeostasis and may have therapeutic potential.

2020-04-01·Cancer Immunology, Immunotherapy2区 · 医学

First-in-human phase I clinical trial of the NY-ESO-1 protein cancer vaccine with NOD2 and TLR9 stimulants in patients with NY-ESO-1-expressing refractory solid tumors

2区 · 医学

Article

作者: Kageyama, Shinichi ; Mizuno, Toshiro ; Ishihara, Mikiya ; Harada, Naozumi ; Ikeda, Hiroaki ; Shiku, Hiroshi ; Shiraishi, Taizo ; Sato, Eiichi ; Katayama, Naoyuki ; Kanda, Hideki ; Sasaki, Takeshi ; Muraoka, Daisuke ; Hori, Yasuhide ; Miyahara, Yoshihiro ; Tono, Yasutaka ; Sugimura, Yoshiki ; Webster, Gill A ; Soga, Norihito ; Uchida, Katsunori

AbstractCholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (μg/μg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4–5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step.

2019-09-01·Journal of Allergy and Clinical Immunology1区 · 医学

Toll-like receptor 9–dependent interferon production prevents group 2 innate lymphoid cell–driven airway hyperreactivity

1区 · 医学

Article

作者: Lai, Alan Chuan-Ying ; Chi, Po-Yu ; Webster, Gill ; Thio, Christina Li-Ping ; Chang, Ya-Jen

BACKGROUNDGroup 2 innate lymphoid cells (ILC2s) are important mediators of allergic asthma. Bacterial components, such as unmethylated CpG DNA, a Toll-like receptor (TLR) 9 agonist, are known to possess beneficial immunomodulatory effects in patients with T cell-mediated chronic asthma. However, their roles in regulating ILC2s remain unclear.OBJECTIVEWe sought to determine the role of TLR9 activation in regulating ILC2 function and to evaluate the therapeutic utility of an immunomodulatory microparticle containing natural TLR9 ligand (MIS416).METHODSWe evaluated the immunomodulatory effects of CpG A in IL-33-induced airway hyperreactivity (AHR) and airway inflammation. The roles of interferons were examined in vivo and in vitro by using signal transducer and activator of transcription 1 (Stat1)^-/- mice and neutralizing antibodies against IFN-γ and IFN-α/β receptor subunit 1, and their cellular sources were identified. The therapeutic utility of MIS416 was investigated in the Alternaria alternata model of allergic asthma and in humanized NSG mice.RESULTSWe show that TLR9 activation by CpG A suppresses IL-33-mediated AHR and airway inflammation through inhibition of ILC2s. Activation of TLR9 leads to production of IFN-α, which drives IFN-γ production by natural killer cells. Importantly, IFN-γ is essential for TLR9-driven suppression, and IFN-α cannot compensate for impaired IFN-γ signaling. We further show that IFN-γ directly inhibits ILC2 function through a STAT1-dependent mechanism. Finally, we demonstrate the therapeutic potential of MIS416 in A alternata-induced airway inflammation and validated these findings in human subjects.CONCLUSIONTLR9 activation alleviates ILC2-driven AHR and airway inflammation through direct suppression of cell function. Microparticle-based delivery of TLR9 ligands might serve as a therapeutic strategy for asthma treatment.

100 项与 MIS-416 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	MIS-416	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
继发进展型多发性硬化	临床2期	新西兰	Amplia Therapeutics Ltd.	2014-10-01
继发进展型多发性硬化	临床2期	澳大利亚	Amplia Therapeutics Ltd.	2014-10-01
慢性进行性多发性硬化	临床2期	新西兰	Amplia Therapeutics Ltd.	2010-08-01
原发性进行性多发性硬化	临床2期	新西兰	Amplia Therapeutics Ltd.	2010-08-01
感染	临床2期	新西兰	Amplia Therapeutics Ltd.	-
肿瘤	临床2期	新西兰	Amplia Therapeutics Ltd.	-
实体瘤	临床2期	日本	Amplia Therapeutics Ltd.	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01191996 (Phase 2B trial for the treatment of secondary progressive multiple sclerosis, AAN2017)	临床2期	继发进展型多发性硬化 EPO \| VEGF \| HGF ... 更多	15	MIS416 500 mg	衊襯壓遞膚艱築簾繭襯(壓製願願鹹顧齋衊憲獵) = 鹹顧艱窪齋壓遞觸壓網窪簾鬱簾夢積遞衊積衊 (醖艱憲顧壓網顧衊鹽醖 ) 更多	积极	2017-04-18
NCT01191996 (Pubmed)	临床2期	慢性进行性多发性硬化	34	MIS416	(蓋齋築築壓願廠築艱衊) = 獵範願製範醖淵築築顧製選積淵衊願製遞鏇繭 (夢獵築製憲觸齋觸鑰選 ) 更多	-	2015-09-01