NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells

Matteo, P. Di; Hackl, Christina; Jedeszko, Christopher; Valentinis, Barbara; Bordignon, Claudio; Traversari, Catia; Kerbel, Robert S.; Gp, Rizzardi

doi:10.1038/bjc.2013.347

Cited by 16 publications

(10 citation statements)

References 45 publications

(98 reference statements)

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“…Preparation and characterization of NGR-mTNF was previously described. 25 NGR-mTNF was administered intraperitoneally (i.p.) at 5 pg/gr per mouse once or three times a week.…”

Section: Methodsmentioning

confidence: 99%

“…Since it has been demonstrated that NGR-mTNF induces apoptosis of tumor and endothelial cells in vivo, 25 we evaluated the number of apoptotic cells in angiogenic islets after the last treatment, by immunofluorescence microscopy with anti-cleaved-caspase3 mAb. 25 As expected, we observed a significant increase of apoptotic cells (Fig. S1).…”

Section: Ngr-mtnf Treatment Controls the Development Of Angiogenic Ismentioning

confidence: 99%

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The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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NGR-TNF is a vascular targeting agent in advanced clinical development, coupling tumor necrosis factor-a (TNF) with the CNGRCG peptide, which targets a CD13 isoform specifically expressed by angiogenic vessels. Antitumor efficacy of NGR-TNF has been described in different transplantation tumor models. Nevertheless, the mechanism underlying its activity is not fully understood. In the wild type and in the immunodeficient (RAG ¡/¡ ) RIP1-Tag2 models of multistage pancreatic carcinogenesis, we demonstrate that CD13 is highly expressed on endothelial cells of hyperplastic and angiogenic islets, whereas its expression is down regulated in tumors where it partially colocalize with pericytes. In vivo CNGRCG peptides coupled to fluorescent nanoparticles (quantum dots) bind to CD13 and colocalize with anti-CD31, in pancreatic islets. At early stage, low doses of NGR-murine (m)TNF have a direct cytotoxic effect inducing endothelial cell apoptosis, reducing vessel density and eventually inhibiting the development of angiogenic islets. At a later stage, NGRmTNF is able to reduce tumor growth inducing vascular normalization, exclusively when treatment is carried out in the immunocompetent mice. Interestingly, NGR-mTNF-treated tumors from these mice are characterized by CD8 C T cell infiltration. At molecular level, overexpression of genes involved in vessels normalization was detected only in NGRmTNF-treated tumors from immunocompetent mice.These findings identified a new mechanism of action of NGR-mTNF, providing support for the development of new therapeutic strategies combining chemotherapy or active/adoptive immunotherapies to low dose NGR-TNF treatment.

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“…Preparation and characterization of NGR-mTNF was previously described. 25 NGR-mTNF was administered intraperitoneally (i.p.) at 5 pg/gr per mouse once or three times a week.…”

Section: Methodsmentioning

confidence: 99%

Section: Ngr-mtnf Treatment Controls the Development Of Angiogenic Ismentioning

confidence: 99%

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

et al. 2015

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“…Glufosfamide has also proved effective against soft-tissue sarcomas, for which it progressed into Phase II trials (NCT00441467) 174,175 ; however, its development for this indication seems to have been halted. The NGR (Asn-Gly-Arg) peptide ligand which targets aminopeptidase N (a cell surface receptor that is overexpressed in many cancers), is also undergoing evaluation as a conjugate with tumour necrosis factor-α for treatment of solid tumours (NCT00483093) 176,177 . Low-density lipoprotein receptor-related protein 1 (LRP1), a cell surface receptor that is involved in cancer metastasis, has been successfully targeted by a small-molecule drug conjugate that consists of three molecules of paclitaxel linked to the homing peptide, angiopep 2 (REF.…”

Section: Mip-1072mentioning

confidence: 99%

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Srinivasarao

Galliford

Low

2015

Nat Rev Drug Discov

564

502

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Most cancer drugs are designed to interfere with one or more events in cell proliferation or survival. As healthy cells may also need to proliferate and avoid apoptosis, anticancer agents can be toxic to such cells. To minimize these toxicities, strategies have been developed wherein the therapeutic agent is targeted to tumour cells through conjugation to a tumour-cell-specific small-molecule ligand, thereby reducing delivery to normal cells and the associated collateral toxicity. This Review describes the major principles in the design of ligand-targeted drugs and provides an overview of ligand-drug conjugates and ligand-imaging-agent conjugates that are currently in development.

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“…Both these immunocytokines are being investigated and show promising antitumour and antiangiogenic activity in advanced melanoma. As an antitumour agent, TNF has major toxicity in the endothelial cells of the tumour-associated vasculature and increases the antitumour immune response 109 110. A prospective, uncontrolled multicentre phase II trial in Italy (EudraCT #2012-001991-13) is testing the efficacy and safety of an intratumorally administered combination of L19-IL2 plus L19-TNF in patients with advanced metastatic melanoma.…”

Section: The Current State Of Antiangiogenic Therapies In Melanomamentioning

confidence: 99%

“…A prospective, uncontrolled multicentre phase II trial in Italy (EudraCT #2012-001991-13) is testing the efficacy and safety of an intratumorally administered combination of L19-IL2 plus L19-TNF in patients with advanced metastatic melanoma. The study is ongoing, and its results are not yet available 110. Another vasculature-targeting agent being investigated in melanoma is NGR-TNF, which is generated by the fusion of the CNGRCG peptide to the N-terminal domain of human TNF 111.…”

Section: The Current State Of Antiangiogenic Therapies In Melanomamentioning

confidence: 99%

Angiogenesis in melanoma: an update with a focus on current targeted therapies

2016

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Angiogenesis plays a crucial role in melanoma metastasis and progression. In recent years, numerous studies have investigated the prognostic and clinical significance of this phenomenon, and the development of molecular techniques has enabled us to achieve a better understanding of angiogenesis in melanoma. Herein, we review the current state of knowledge regarding angiogenesis in melanoma, including the pathophysiological, histological and immunohistochemical aspects of this phenomenon. We also review the molecular pathways involved in angiogenesis and the interplay between different components that might be manipulated in the future development of efficient targeted therapies. Recently developed targeted antiangiogenic therapies in clinical trials and included in the treatment of advanced-stage melanoma are also reviewed.

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NGR-TNF, a novel vascular-targeting agent, does not induce cytokine recruitment of proangiogenic bone marrow-derived cells

Cited by 16 publications

References 45 publications

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

The tumor vessel targeting agent NGR-TNF controls the different stages of the tumorigenic process in transgenic mice by distinct mechanisms

Principles in the design of ligand-targeted cancer therapeutics and imaging agents

Angiogenesis in melanoma: an update with a focus on current targeted therapies

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