Delving into the Latest Updates on tTF-NGR(University of Münster) with Synapse

Overview

Basic Info

Drug Type

Fusion protein

Synonyms

tTF-NGR (University of Muenster)

Target

APN

Action

inhibitors

Mechanism

APN inhibitors(Aminopeptidase N inhibitors)

Therapeutic Areas

NeoplasmsImmune System DiseasesHemic and Lymphatic Diseases

Active Indication

Lymphoma

Inactive Indication-

Originator Organization

University of Münster

Active Organization

University of Münster

Inactive Organization-

License Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Structure/Sequence

Sequence Code 10239296

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.

Start Date01 Mar 2017

Sponsor / Collaborator

Universitätsklinikum Münster

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100 Clinical Results associated with tTF-NGR(University of Münster)

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100 Translational Medicine associated with tTF-NGR(University of Münster)

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100 Patents (Medical) associated with tTF-NGR(University of Münster)

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12

Literatures (Medical) associated with tTF-NGR(University of Münster)

13 Dec 2016·Oncotarget

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

Article

Author: 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.

01 Jan 2014·AngiogenesisQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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.

28 Mar 2013·Journal of Medicinal ChemistryQ1 · MEDICINE

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

Q1 · MEDICINE

Article

Author: 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 Deals associated with tTF-NGR(University of Münster)

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Lymphoma	Phase 1	-	University of Münster	-
Neoplasms	Preclinical	Germany	University of Münster	01 Mar 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02902237 (CTgov)	Phase 1	Malignant Solid Neoplasm \| Lymphoma	24	tTF-NGR	(zxzjkjxpab) = phsfxdhlov wjubcjxrdw (ezzvfjpnnr, jdxnccwilo - cwitkhxogo) View more	-	08 Dec 2020
NCT02902237 (ESMO2020)	Phase 1	Neoplasms	17	tTF-NGR	ssbhocgxmn(owgpgutskj) = 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. vclosynlaf (nzuzqfslfc ) View more	-	17 Sep 2020
NCT02902237 (Pubmed \| Cancers (Basel)) Manual	Phase 1	Neoplasms	17	tTF-NGR	(tanykzqlvx) = solated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae amymtcduen (emiqzlxtch ) View more	Positive	07 Jun 2020

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Biosimilar

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