E WE thrombin(Aronora, Inc.)(E WE thrombin(Aronora, Inc.)) - 药物靶点：protein C_专利_临床

概要

基本信息

药物类型

酶

别名

E WE thrombin、EWE-thrombin、ProCase

+ [4]

靶点

protein C

作用方式

刺激剂

作用机制

protein C刺激剂(依赖于维生素K的C蛋白刺激剂)

治疗领域

心血管疾病泌尿生殖系统疾病

在研适应症-

非在研适应症

终末期肾脏病血栓形成

原研机构

Aronora, Inc.

在研机构-

非在研机构

Aronora, Inc.

权益机构-

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-

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结构/序列

Sequence Code 1117836273

关联

2

项与 E WE thrombin(Aronora, Inc.) 相关的临床试验

NCT03963895

/ Completed临床2期

A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of a Single Dose of E-WE Thrombin, Administered During a Regular Hemodialysis Procedure, in Patients With End-Stage Renal Disease on Chronic Hemodialysis

This study evaluates the safety and efficacy of AB002 (E-WE thrombin) in patients with end stage renal disease on chronic hemodialysis. Two dose levels will be evaluated in two cohorts. Within each cohort the patients will be randomized to receive either AB002 (E-WE thrombin) or placebo (at a ratio of 2:1 active: placebo).

开始日期2019-07-03

申办/合作机构

Aronora, Inc.

[+1]

NCT03453060

/ Completed临床1期

A Phase 1, Single Ascending Dose, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of E-WE Thrombin as an Intravenous Bolus in Healthy Adult Subjects

The purpose of this study is to assess the safety, tolerability and pharmacodynamics of a single iv dose of E-WE Thrombin in healthy adult subjects.

开始日期2018-05-30

申办/合作机构

Aronora, Inc.

100 项与 E WE thrombin(Aronora, Inc.) 相关的临床结果

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100 项与 E WE thrombin(Aronora, Inc.) 相关的转化医学

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100 项与 E WE thrombin(Aronora, Inc.) 相关的专利（医药）

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4

项与 E WE thrombin(Aronora, Inc.) 相关的文献（医药）

2023-04-17·Research square

E-WE thrombin, a protein C activator, reduces disease severity and spinal cord inflammation in relapsing-remitting murine experimental autoimmune encephalomyelitis.

作者: Sherman, Larry S ; Verbout, Norah G ; Su, Weiping ; Tucker, Erik I ; Jordan, Kelley ; McCarty, Owen Jt ; Pham, Peter ; Kohs, Tia Cl

ObjectiveRelapses in patients with relapsing-remitting multiple sclerosis (RRMS) are typically treated with high-dose corticosteroids including methylprednisolone. However, high-dose corticosteroids are associated with significant adverse effects, can increase the risk for other morbidities, and often do not impact disease course. Multiple mechanisms are proposed to contribute to acute relapses in RRMS patients, including neuroinflammation, fibrin formation and compromised blood vessel barrier function. The protein C activator, E-WE thrombin is a recombinant therapeutic in clinical development for its antithrombotic and cytoprotective properties, including protection of endothelial cell barrier function. In mice, treatment with E-WE thrombin reduced neuroinflammation and extracellular fibrin formation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). We therefore tested the hypothesis that E-WE thrombin could reduce disease severity in a relapsing-remitting model of EAE.MethodsFemale SJL mice were inoculated with proteolipid protein (PLP) peptide and treated with E-WE thrombin (25 μg/kg; iv) or vehicle at onset of detectable disease. In other experiments, E-WE thrombin was compared to methylprednisolone (100 mg/kg; iv) or the combination of both.ResultsCompared to vehicle, administration of E-WE thrombin significantly improved disease severity of the initial attack and relapse and delayed onset of relapse as effectively as methylprednisolone. Both methylprednisolone and E-WE thrombin reduced demyelination and immune cell recruitment, and the combination of both treatments had an additive effect.ConclusionThe data presented herein demonstrate that E-WE thrombin is protective in mice with relapsing-remitting EAE, a widely used model of MS. Our data indicate that E-WE thrombin is as effective as high-dose methylprednisolone in improving disease score and may exert additional benefit when administered in combination. Taken together, these data suggest that E-WE thrombin may be an effective alternative to high-dose methylprednisolone for managing acute MS attacks.

2020-11-01·Molecular Cancer Therapeutics2区 · 医学

Dual Mechanisms of Novel CD73-Targeted Antibody and Antibody–Drug Conjugate in Inhibiting Lung Tumor Growth and Promoting Antitumor Immune-Effector Function

2区 · 医学

Article

作者: Wang, Xin ; Yu, Ker ; Jin, Rui ; Ren, Zhiqiang ; Ma, Lanping ; Liu, Liang ; Shen, Jingkang ; Xing, Yun ; Cong, Ying ; Zhang, Xuesai ; Meng, Tao ; Pei, Jinpeng

AbstractAlthough tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50<0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors, including the RAS-mutant models [minimum effective dose <1 mg/kg]. Treatment with CD73–ADC triggered a robust intratumoral accumulation of proinflammatory macrophages and activated dendritic cells (DC), which were not observed with naked CD73 antibody or standard chemotherapy. Studies with human PBMC-derived systems confirmed CD73-ADC as fully functional in protecting effector T cells and stimulating DCs thus providing dual benefits in killing CD73-high tumors and improving cancer immunity response. These results warrant clinical investigation of CD73-targeted antibody and ADC for treating advanced lung cancer.

2020-02-27·Blood1区 · 医学

The protein C activator AB002 rapidly interrupts thrombus development in baboons

1区 · 医学

Article

作者: Hinds, Monica T. ; Verbout, Norah G. ; Markway, Brandon D. ; Lorentz, Christina U. ; McCarty, Owen J. T. ; Wood, David C. ; Shatzel, Joseph J. ; Pelc, Leslie A. ; Gruber, András ; Tucker, Erik I. ; Wallisch, Michael ; Di Cera, Enrico

AbstractAlthough thrombin is a key enzyme in the coagulation cascade and is required for both normal hemostasis and pathologic thrombogenesis, it also participates in its own negative feedback via activation of protein C, which downregulates thrombin generation by enzymatically inactivating factors Va and VIIIa. Our group and others have previously shown that thrombin’s procoagulant and anticoagulant activities can be effectively disassociated to varying extents through site-directed mutagenesis. The thrombin mutant W215A/E217A (WE thrombin) has been one of the best characterized constructs with selective activity toward protein C. Although animal studies have demonstrated that WE thrombin acts as an anticoagulant through activated protein C (APC) generation, the observed limited systemic anticoagulation does not fully explain the antithrombotic potency of this or other thrombin mutants. AB002 (E-WE thrombin) is an investigational protein C activator thrombin analog in phase 2 clinical development (clinicaltrials.gov NCT03963895). Here, we demonstrate that this molecule is a potent enzyme that is able to rapidly interrupt arterial-type thrombus propagation at exceedingly low doses (<2 µg/kg, IV), yet without substantial systemic anticoagulation in baboons. We demonstrate that AB002 produces APC on platelet aggregates and competitively inhibits thrombin-activatable fibrinolysis inhibitor (carboxypeptidase B2) activation in vitro, which may contribute to the observed in vivo efficacy. We also describe its safety and activity in a phase 1 first-in-human clinical trial. Together, these results support further clinical evaluation of AB002 as a potentially safe and effective new approach for treating or preventing acute thrombotic and thromboembolic conditions. This trial was registered at www.clinicaltrials.gov as #NCT03453060.

1

项与 E WE thrombin(Aronora, Inc.) 相关的新闻（医药）

2022-02-10

·新浪医药

华东医药与AKSO达成战略合作引进一款双靶点融合蛋白创新药

2月9日，华东医药全资子公司中美华东制药与AKSO Biopharmaceutical宣布达成战略合作。根据协议，中美华东制药将获得后者开发的在研产品AB002（用于实体瘤治疗）在亚太地区（除日本）的独家临床开发及商业化权益，此项合作总金额最高可达7500万美元。AB002是一款靶向PD-L1/L2和IL-15的双靶点融合蛋白，可以通过抑制免疫检查点并激活自然杀伤细胞治疗实体瘤，目前处于临床前开发阶段。 AB002是AKSO公司开发的双靶点融合蛋白，它包括一种可溶性PD-1和一种IL-15激动剂，可以超高的结合亲和力捕获PD-L1和PD-L2，同时将IL-15激动剂靶向传递至肿瘤细胞。新闻稿指出，AB002精准靶向肿瘤细胞的能力不仅避免了全身自然杀伤细胞（NK细胞）的活化，同时延长了IL-15激动剂的半衰期。根据合作协议，华东医药将负责AB002在亚太地区（除日本）的临床开发、注册和商业化，并通过联合研究委员会与AKSO公司共同指导临床试验申请工作。AKSO公司将继续负责AB002在全球其他地区的开发。华东医药将向AKSO公司支付总金额最高不超过7500万美元，包括首付款以及临床开发、注册和销售里程碑付款。此外，AKSO公司还将在未来产品上市后获得约定比例的销售分成。内容来源于网络，如有侵权，请联系删除，谢谢。

创新药合作抗体免疫疗法细胞疗法

100 项与 E WE thrombin(Aronora, Inc.) 相关的药物交易

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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
终末期肾脏病	临床2期	美国	Aronora, Inc.	2019-07-03
血栓形成	临床2期	美国	Aronora, Inc.	2019-07-03

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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


NCT03963895 (ASH2023)	临床2期	急性缺血性卒中	40	AB002 (E-WE thrombin)	醖醖遞繭選觸願願餘鹽(淵選齋獵壓餘構淵廠壓) = 鑰願艱憲遞積構窪製鏇獵膚選糧製構選鹹願築 (淵簾築窪鬱淵觸膚廠鹹 ) 更多	-	2023-12-11
				Saline placebo	醖醖遞繭選觸願願餘鹽(淵選齋獵壓餘構淵廠壓) = 齋願夢鏇夢獵壓網網範獵膚選糧製構選鹹願築 (淵簾築窪鬱淵觸膚廠鹹 ) 更多
NCT03963895 (3949, CTgov)	临床2期	血栓形成 \| 终末期肾脏病	40	AB002 Dose 1 (AB002 (E-WE-thrombin) Dose 1)	觸鑰壓餘壓積鹽膚艱憲(餘簾夢憲夢鑰齋醖鑰獵) = 鬱鬱衊鹽觸繭餘廠願積淵鏇餘糧獵衊選製鏇壓 (願獵獵鏇艱壓選簾膚齋, 遞衊簾齋遞齋餘繭醖衊 ~ 艱選壓膚鑰願齋獵鹽鏇) 更多	-	2022-03-15
				AB002 Dose 2 (AB002 (E-WE-thrombin) Dose 2)	觸鑰壓餘壓積鹽膚艱憲(餘簾夢憲夢鑰齋醖鑰獵) = 鏇願糧築觸廠廠壓願製淵鏇餘糧獵衊選製鏇壓 (願獵獵鏇艱壓選簾膚齋, 壓網壓繭顧壓壓餘獵襯 ~ 積餘範顧襯顧選夢憲鬱) 更多
NCT03453060 (CTgov)	临床1期	血栓形成	21	E-WE Thrombin- Dose 1 (E-WE Thrombin Dose 1)	網願壓築鏇願憲蓋淵願(願艱積淵積醖餘觸淵範) = 膚夢膚製選積衊繭鬱鹽簾蓋範膚艱製鬱醖繭鹽 (窪糧鹽網顧簾鹹膚鬱網, 選獵餘積鑰鬱鏇蓋遞網 ~ 遞醖鏇夢選鏇夢餘網膚) 更多	-	2019-10-29
				E-WE Thrombin- Dose 2 (E-WE Thrombin Dose 2)	網願壓築鏇願憲蓋淵願(願艱積淵積醖餘觸淵範) = 選選窪醖構製選壓積鑰簾蓋範膚艱製鬱醖繭鹽 (窪糧鹽網顧簾鹹膚鬱網, 顧選膚醖選糧醖艱廠艱 ~ 齋窪鬱壓鬱蓋鏇鏇艱遞) 更多