[Translation] A multicenter, randomized, blinded outcome, and positive drug-controlled phase III clinical study of recombinant human tissue-type plasminogen kinase derivatives for injection in the treatment of patients with acute ischemic stroke

主要目的：评价注射用重组人组织型纤溶酶原激酶衍生物与阿替普酶治疗发作 4.5 小时内的急性缺血性卒中患者的有效性。次要目的：评价注射用重组人组织型纤溶酶原激酶衍生物与阿替普酶治疗发作 4.5 小时内的急性缺血性卒中患者的安全性。

[Translation]

Primary objective: To evaluate the efficacy of recombinant human tissue-type plasminogen kinase derivatives for injection and alteplase in the treatment of patients with acute ischemic stroke within 4.5 hours of onset. Secondary objective: To evaluate the safety of recombinant human tissue-type plasminogen kinase derivatives for injection and alteplase in the treatment of patients with acute ischemic stroke within 4.5 hours of onset.

Start Date21 Mar 2022

Sponsor / Collaborator

China Resources Angde Biotech Pharma Co., Ltd.

NCT05295173 / CompletedPhase 3

A Phase III, Multicenter, Randomized, Blind Endpoint and Positive Drug Control Study of Recombinant Human Tissue Plasminogen Kinase Derivatives for Injection in the Treatment of Patients With Acute Ischemic Stroke

The purpose of this study is to assess the efficacy and safety of recombinant human tissue plasminogen kinase derivatives for injection and alteplase in the treatment of patients with acute ischemic stroke within 4.5 hours.

Start Date21 Mar 2022

Sponsor / Collaborator

China Resources Angde Biotech Pharma Co., Ltd.

[+1]

CTR20213141 / RecruitingPhase 2

评价注射用重组人组织型纤溶酶原激酶衍生物（瑞通立）治疗成人急性中央型下肢深静脉血栓患者有效性和安全性的多中心、随机、开放II期临床研究

[Translation] A multicenter, randomized, open-label phase II clinical study to evaluate the efficacy and safety of recombinant human tissue plasminogen kinase derivative (Rui Tongli) for injection in the treatment of adult patients with acute central deep vein thrombosis of the lower extremities

主要目的：评价不同剂量瑞通立导管溶栓给药治疗急性中央型下肢深静脉血栓患者的有效性和安全性，探索有效剂量推荐用于III期临床试验；次要目的：探索瑞通立导管溶栓给药治疗急性中央型下肢深静脉血栓患者的药代动力学特征；

[Translation]

Primary purpose: To evaluate the efficacy and safety of different doses of catheter-directed thrombolytic therapy for patients with acute central lower extremity deep vein thrombosis, and to explore the effective dose recommended for Phase III clinical trials; Secondary purpose: To explore the pharmacokinetic characteristics of catheter-directed thrombolytic therapy for patients with acute central lower extremity deep vein thrombosis;

Start Date23 Dec 2021

Sponsor / Collaborator

China Resources Angde Biotech Pharma Co., Ltd.

100 Clinical Results associated with Recombinant human tissue-type plasminogen activator derivative(China Resources Angde Biotech Pharma)

100 Translational Medicine associated with Recombinant human tissue-type plasminogen activator derivative(China Resources Angde Biotech Pharma)

100 Patents (Medical) associated with Recombinant human tissue-type plasminogen activator derivative(China Resources Angde Biotech Pharma)

1,077

Literatures (Medical) associated with Recombinant human tissue-type plasminogen activator derivative(China Resources Angde Biotech Pharma)

01 Sep 2024·Protein Expression and Purification

Heterologous expression, purification and single step efficient refolding of recombinant tissue plasminogen activator (Reteplase) from E. coli

Article

Author: Patel, Amrutlal ; Bhatt, Meha ; Joshi, Chaitanya ; Masi, Haidar Abbas ; Singh, Niraj Kumar

Reteplase (recombinant plasminogen activator, rPA) is a mutant non-glycosylated tissue-type plasminogen activator (tPA) containing 355 amino acids with longer half-life and promising thrombolytic activity than its original counterpart, full length tPA. In this study, we aimed to produce and optimize the purification process of recombinant tissue-type plasminogen activator (tPA) known as Reteplase (rPA). Reteplase cDNA synthesized from total mRNA isolated from human placenta was PCR amplified, cloned into a pET-28a(+) E. coli expression vector and expressed in Rosetta-gami 2 E. coli (Novagen^Ⓡ) host. rPA was expressed as an inclusion body in E. coli and its biological activity was achieved after single step solubilization, purification and refolding. We exploited the strategy of Slow Refolding using Gradual Dialysis (SRGD) in which a refolding buffer containing glutathione oxidized (1 mM GSSG) and glutathione reduced (3 mM GSH) and pH 9.0 was used. Using the SRGD method, we were able to successfully obtain the protein in its active form. We obtained 4.26 mg of active refolded protein from a 50 mL culture that was scaled up in a bioreactor. The purity and homogeneity of rPA was evaluated by SDS-PAGE, Western blotting and mass spectrometry. Circular dichroism spectroscopy was conducted to evaluate the refolding and stability of the refolded rPA in comparison to reference standard rPA. The thrombolytic potential of rPA was assessed by fibrin plate assay and In Vitro clot lysis assay. The presented protocol offers a viable approach for enhancing both the yield and refolding efficiency of reteplase, potentially resulting in an increase in yield.

01 May 2024·Stroke

R-tPA Resistance Is Specific for Platelet-Rich Stroke Thrombi and Can Be Overcome by Targeting Nonfibrin Components

Article

Author: Staessens, Senna ; Vanhoorne, Alexander ; Vanhoorelbeke, Karen ; Desender, Linda ; Vandelanotte, Sarah ; Andersson, Tommy ; Tersteeg, Claudia ; François, Olivier ; De Meyer, Simon F. ; Van Gool, Fréderick ; Vanacker, Peter

BACKGROUND:Resistance to r-tPA (recombinant tissue-type plasminogen activator) is a well-known but poorly understood phenomenon that hampers successful recanalization in patients with acute ischemic stroke. Using clinically relevant thrombi from patients with acute ischemic stroke, we investigated if and how thrombus composition impacts r-tPA-mediated lysis. In addition, we explored strategies to overcome r-tPA resistance.METHODS: Thrombi were split into 2 parts, 1 of which was used for thrombolysis and the other for detailed histological analysis. Thrombolysis was performed in normal human plasma using r-tPA alone, using r-tPA in combination with DNase-1 or using r-tPA in combination with N,N′-diacetyl- l -cystine. Thrombus lysis was calculated as the percentage of residual thrombus weight compared with its initial weight and the degree of lysis was linked to thrombus composition determined via histology. RESULTS: Interestingly, we found that the efficacy of r-tPA-mediated thrombolysis was strongly correlated with the composition of the thrombi. Thrombi containing high amounts of red blood cells and low amounts of DNA and von Willebrand Factor were efficiently degraded by r-tPA, whereas thrombi containing low amounts of red blood cells and higher amounts of DNA and von Willebrand Factor were resistant to r-tPA. Importantly, combination of r-tPA with DNase-1 or N,N′-diacetyl- l -cystine significantly and specifically improved the lysis of these r-tPA-resistant thrombi. CONCLUSIONS: Using patient thrombus material, our results for the first time show that the composition of stroke thrombi largely determines their susceptibility to r-tPA-mediated thrombolysis. Red blood cell-poor thrombi have a specific resistance to r-tPA, which can be overcome by targeting nonfibrin components using DNase-1 or N,N′-diacetyl- l -cystine.

01 Apr 2024·Journal of Thrombosis and Haemostasis

Validation of the time to attain maximal clot amplitude after reaching maximal clot formation velocity parameter as a measure of fibrinolysis using rotational thromboelastometry and its application in the assessment of fibrinolytic resistance in septic patients: a prospective observational study: communication from the ISTH SSC Subcommittee on Fibrinolysis

Article

Author: Scarlatescu, Ecaterina ; Marchenko, Sergey P ; Kim, Paul Y ; Tomescu, Dana R

BACKGROUNDIn sepsis, fibrinolysis resistance correlates with worse outcomes. Practically, rotational thromboelastometry (ROTEM) is used to report residual clot amplitude relative to maximum amplitude at specified times after clot formation clot lysis indices (CLIs). However, healthy individuals can exhibit similar CLIs, thus making it challenging to solely diagnose the low fibrinolytic state. Furthermore, CLI does not include the kinetics of clot formation, which can affect overall fibrinolysis. Therefore, a more nuanced analysis, such as time to attain maximal clot amplitude after reaching maximal clot formation velocity (t-AUCi), is needed to better identify fibrinolysis resistance in sepsis.OBJECTIVESTo evaluate the correlation between the degree of fibrinolytic activation and t-AUCi in healthy or septic individuals.METHODSWhole blood (n = 60) from septic or healthy donors was analyzed using tissue factor-activated (EXTEM) and nonactivated (NATEM) ROTEM assays. Lysis was initiated with tissue-type plasminogen activator, and CLI and t-AUCi were calculated. Standard coagulation tests and plasma fibrinolysis markers (D-dimer, plasmin-α2-antiplasmin complex, plasminogen activator inhibitor type 1, and plasminogen) were also measured.RESULTSt-AUCi values decreased with increasing fibrinolytic activity and correlated positively with CLI for different degrees of clot lysis both in EXTEM and NATEM. t-AUCi cutoff value of 1962.0 seconds in EXTEM predicted low fibrinolytic activity with 81.8% sensitivity and 83.7% specificity. In addition, t-AUCi is not influenced by clot retraction.CONCLUSIONWhole-blood point-of-care ROTEM analyses with t-AUCi offers a more rapid and parametric evaluation of fibrinolytic potential compared with CLI, which can be used for a more rapid and accurate diagnosis of fibrinolysis resistance in sepsis.

100 Deals associated with Recombinant human tissue-type plasminogen activator derivative(China Resources Angde Biotech Pharma)

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Indication	Country/Location	Organization	Date
Myocardial Infarction	CN	China Resources Angde Biotech Pharma Co., Ltd.	30 Sep 2007

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Ischemic Stroke	NDA/BLA	CN	China Resources Angde Biotech Pharma Co., Ltd.	05 Feb 2024
Acute deep vein thrombosis of lower limb	Phase 2	CN	China Resources Angde Biotech Pharma Co., Ltd.	23 Dec 2021
Pulmonary Embolism	Phase 1	-	China Resources Angde Biotech Pharma Co., Ltd.	01 Oct 2019

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