tTF-NGR(University of Münster)(tTF-NGR(University of Münster)) - 药物靶点：APN_在研适应症：淋巴瘤_专利_临床

概要

基本信息

药物类型

融合蛋白

别名

tTF-NGR (University of Muenster)

靶点

APN

作用方式

抑制剂

作用机制

APN抑制剂(氨肽酶N抑制剂)

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病

在研适应症

淋巴瘤

非在研适应症-

原研机构

University of Münster

在研机构

University of Münster

非在研机构-

权益机构-

最高研发阶段临床1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 10239296

关联

1

项与 tTF-NGR(University of Münster) 相关的临床试验

NCT02902237

/ Completed临床1期IIT

Phase I Study of tTF-NGR in Patients With Recurrent or Refractory Malignant Tumors and Lymphomas Beyond All Standard Treatments

In this phase I clinical trial cancer patients suffering from solid tumors or lymphomas, recurring after and/or refractory against standard treatment are treated intravenously (iv) with increasing doses of tTF-NGR(tTF= truncated tissue factor; NGR=Asn-Gly-Arg). The objectives of this trial are to evaluate the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of intravenously (iv) infused daily applications of tTF-NGR for 5 days every 3 weeks in patients with cancer, who had obtained all standard treatment known for their disease entity prior to entry on study. Further objectives are to determine the perfusion and vascular volume fraction of measurable tumor lesions versus normal reference tissue before and after tTF-NGR application by MRI as a biological surrogate parameter for biological activity of the investigational medicinal product (IMP), tTF-NGR, and to obtain pharmacokinetic data.

开始日期2017-03-01

申办/合作机构

Universitätsklinikum Münster

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100 项与 tTF-NGR(University of Münster) 相关的临床结果

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100 项与 tTF-NGR(University of Münster) 相关的转化医学

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100 项与 tTF-NGR(University of Münster) 相关的专利（医药）

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12

项与 tTF-NGR(University of Münster) 相关的文献（医药）

2016-12-13·Oncotarget

Combinatorial effects of doxorubicin and retargeted tissue factor by intratumoral entrapment of doxorubicin and proapoptotic increase of tumor vascular infarction

Article

作者: Schmidt, Lars Henning ; Brand, Caroline ; Mesters, Rolf M. ; Stucke-Ring, Janine ; Kessler, Torsten ; Harrach, Saliha ; Hintelmann, Heike ; Müller-Tidow, Carsten ; Lenz, Georg ; Mantke, Verena ; Höltke, Carsten ; Berdel, Wolfgang E. ; Wünsch, Bernhard ; Hartmann, Wolfgang ; Wardelmann, Eva ; Schwöppe, Christian ; Schliemann, Christoph ; Ronnacker, Julian

Truncated tissue factor (tTF), retargeted to tumor vasculature by GNGRAHA peptide (tTF-NGR), and doxorubicin have therapeutic activity against a variety of tumors. We report on combination experiments of both drugs using different schedules. We have tested fluorescence- and HPLC-based intratumoral pharmacokinetics of doxorubicin, flow cytometry for cellular phosphatidylserine (PS) expression, and tumor xenograft studies for showing in vivo apoptosis, proliferation decrease, and tumor shrinkage upon combination therapy with doxorubicin and induced tumor vascular infarction. tTF-NGR given before doxorubicin inhibits the uptake of the drug into human fibrosarcoma xenografts in vivo. Reverse sequence does not influence the uptake of doxorubicin into tumor, but significantly inhibits the late wash-out phase, thus entrapping doxorubicin in tumor tissue by vascular occlusion. Incubation of endothelial and tumor cells with doxorubicin in vitro increases PS concentrations in the outer layer of the cell membrane as a sign of early apoptosis. Cells expressing increased PS concentrations show comparatively higher procoagulatory efficacy on the basis of equimolar tTF-NGR present in the Factor X assay. Experiments using human M21 melanoma and HT1080 fibrosarcoma xenografts in athymic nude mice indeed show a combinatorial tumor growth inhibition applying doxorubicin and tTF-NGR in sequence over single drug treatment. Combination of cytotoxic drugs such as doxorubicin with tTF-NGR-induced tumor vessel infarction can improve pharmacodynamics of the drugs by new mechanisms, entrapping a cytotoxic molecule inside tumor tissue and reciprocally improving procoagulatory activity of tTF-NGR in the tumor vasculature via apoptosis induction in tumor endothelial and tumor cells.

2014-01-01·Angiogenesis1区 · 医学

Non-invasive monitoring of tumor-vessel infarction by retargeted truncated tissue factor tTF–NGR using multi-modal imaging

1区 · 医学

Article

作者: Christian Schwöppe ; Janine Ring ; Jörg Stypmann ; Christoph Schliemann ; Richard Holtmeier ; Christoph Bremer ; Michael Claesener ; Michael Schäfers ; Caroline Zerbst ; Wolfgang E. Berdel ; Walter Heindel ; Sven Hermann ; Rolf M. Mesters ; Thorsten Persigehl

The fusion protein tTF-NGR consists of the extracellular domain of the thrombogenic human tissue factor (truncated tissue factor, tTF) and the peptide GNGRAHA (NGR), a ligand of the surface protein CD13 (aminopeptidase N), upregulated on endothelial cells of tumor vessels. tTF-NGR preferentially activates blood coagulation within tumor vasculature, resulting in tumor vessel infarction and subsequent tumor growth retardation/regression. The anti-vascular mechanism of the tTF-NGR therapy approach was verified by quantifying the reduced tumor blood-perfusion with contrast-enhanced ultrasound, the reduced relative tumor blood volume by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging, and by in vivo-evaluation of hemorrhagic bleeding with fluorescent biomarkers (AngioSense(680)) in fluorescence reflectance imaging. The accumulation of tTF-NGR within the tumor was proven by visualizing the distribution of the iodine-123-labelled protein by single-photon emission computed tomography. Use of these multi-modal vascular and molecular imaging tools helped to assess the therapeutic effect even at real time and to detect non-responding tumors directly after the first tTF-NGR treatment. This emphasizes the importance of imaging within clinical studies with tTF-NGR. The imaging techniques as used here have applicability within a wider scope of therapeutic regimes interfering with tumor vasculature. Some even are useful to obtain predictive biosignals in personalized cancer treatment.

2013-03-28·Journal of Medicinal Chemistry1区 · 医学

Anticancer Therapy by Tumor Vessel Infarction with Polyethylene Glycol Conjugated Retargeted Tissue Factor

1区 · 医学

Article

作者: Schliemann, Christoph ; Zerbst, Caroline ; Schwöppe, Christian ; Liersch, Ruediger ; Stypmann, Jörg ; Lücke, Martin ; König, Simone ; Holtmeier, Richard ; Dreiling, Alena ; Kessler, Torsten ; Höltke, Carsten ; Mesters, Rolf M. ; Müller-Tidow, Carsten ; Fröhlich, Max ; Overkamp, Laura ; Berdel, Wolfgang E.

tTF-NGR consists of the extracellular domain of tissue factor and the peptide GNGRAHA, a ligand of the surface protein aminopeptidase N and of integrin αvβ3. Both surface proteins are upregulated on endothelial cells of tumor vessels. tTF-NGR shows antitumor activity in xenografts and inhibition of tumor blood flow in cancer patients. We performed random TMS(PEG)12 PEGylation of tTF-NGR to improve the antitumor profile of the molecule. PEGylation resulted in an approximately 2-log step decreased procoagulatory activity of the molecule. Pharmacokinetic studies in mice showed a more than 1-log step higher mean area under the curve. Comparison of the LD10 values for both compounds and their lowest effective antitumor dose against human tumor xenografts showed an improved therapeutic range (active/toxic dose in mg/kg body weight) of 1/5 mg/kg for tTF-NGR and 3/>160 mg/kg for TMS(PEG)12 tTF-NGR. Results demonstrate that PEGylation can significantly improve the therapeutic range of tTF-NGR.

100 项与 tTF-NGR(University of Münster) 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
淋巴瘤	临床1期	-	University of Münster	-
肿瘤	临床前	德国	University of Münster	2008-03-01

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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


NCT02902237 (CTgov)	临床1期	恶性实体肿瘤 \| 淋巴瘤	24	tTF-NGR	(壓製觸構獵蓋糧繭壓繭) = 襯夢積壓醖簾廠製鬱選齋願築夢膚構衊憲糧獵 (窪築齋窪觸衊壓壓壓壓, 繭淵憲築壓壓選鑰構齋 ~ 壓憲願鹽鏇蓋鹽築蓋糧) 更多	-	2020-12-08
NCT02902237 (ESMO2020)	临床1期	肿瘤	17	tTF-NGR	繭鏇壓範醖窪積壓願構(鏇齋憲餘齋網繭艱夢積) = Isolated Troponin T hs elevation occurred as DLT and was interpreted as sensitive early sign for myocardial cell hypoxia, valuable for prevention of clinically relevant side effects. 觸壓願餘艱膚廠製選顧 (獵鹽簾願顧壓築醖夢選 ) 更多	-	2020-09-17
NCT02902237 (Pubmed \| Cancers (Basel)) 人工标引	临床1期	肿瘤	17	tTF-NGR	(築顧鹽獵襯願窪築顧選) = solated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae 構獵鹹襯鏇醖觸鑰網膚 (壓齋網衊鏇獵廠憲範憲 ) 更多	积极	2020-06-07