Project

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Understanding and improving the selective molecular targeting of tumor neo-vasculature

Applicant Neri Dario
Number 126988
Funding scheme Project funding (Div. I-III)
Research institution Institut für Pharmazeutische Wissenschaften ETH Zürich
Institution of higher education ETH Zurich - ETHZ
Main discipline Experimental Cancer Research
Start/End 01.10.2009 - 30.09.2012
Approved amount 542'550.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology

Keywords (9)

tumor angiogenesis; human antibodies; protein engineering; biopharmaceuticals; cancer; oncofetal fibronectins; oncofetal tenascins; vascular targeting; immunocytokines

Lay Summary (English)

Lead
Lay summary
Monoclonal antibodies represent the fastest growing sector of pharmaceutical biotechnology and a number of antibody-based biopharmaceuticals have been approved for cancer treatment. However, anti-cancer antibodies currently used for the treatment of solid tumors offer only a modest survival benefit to cancer patients. One avenue towards the development of more potent anti-cancer therapeutics consists in the use of antibody derivatives for the targeted delivery of bioactive molecules (drugs, cytokines, procoagulant factors, photosensitizers, radionuclides, etc.) to the tumor environment. In this context, the targeted delivery of therapeutic agents to newly-formed blood vessels (“vascular targeting”) is particularly attractive, because of the dependence of many different tumors on new blood vessels to sustain growth and invasion, and because of the accessibility of neo-vascular structures for therapeutic agents injected intravenously [Neri & Bicknell (2005) Nature Reviews Cancer, 5, 436-446].Our group has previously developed vascular targeting antibody-cytokine fusion proteins (“immunocytokines”), which are currently being investigated in Phase II clinical trials. Until now, we have mainly work on fully human immunocytokines. Indeed, our vascular targeting antibody derivatives have been found to be non-immunogenic in humans and are exhibiting impressive therapeutic results in patients with metastatic cancer. The encouraging clinical results obtained so far provide a strong motivation to intensify research activities in this area, both by (i) exploring novel cytokines as fusion partners for vascular targeting antibodies and by (ii) investigating the potency and tolerability of these biopharmaceuticals when used as single agents or in combination with other drugs (e.g., cytotoxic agents, full immunoglobulins). In this Project, we aim at generating novel fully murine vascular targeting immunocytokines and at investigating their therapeutic potency and mechanism of action in syngeneic immunocompetent models of cancer. The use of fully murine proteins is essential in order to avoid artifacts and allow a proper functional study in rodent models of cancer. As many of the markers of angiogenesis targeted by the group are extremely well conserved among species and do not allow the generation of good quality antibodies by hybridoma technology, we will generate murine monoclonal antibodies using antibody phage technology. We also plan to expand the range of immunocytokines already investigated (e.g., those based on IL2, IL10, IL12, IL15, IL24, GM-CSF, TNF) with novel fusion proteins, featuring IL7, IL17, IL18 and IL21: potent pro-inflammatory cytokines which have so far not been studied in the context of antibody-based pharmacodelivery applications.We anticipate that the Project will show whether the new immunocytokines display a superior therapeutic performance compared to the ones previously developed by the group, and that mechanistic studies with the new therapeutic agents in immunocompetent rodent models of cancer will shed light on treatment combination modalities, which may offer a curative potential in animal models and, eventually, in the clinical setting.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Sequence determinants of a microtubule tip localization signal (MtLS).
Buey Rubén M, Sen Indrani, Kortt Oliver, Mohan Renu, Gfeller David, Veprintsev Dmitry, Kretzschmar Ines, Scheuermann Jörg, Neri Dario, Zoete Vincent, Michielin Olivier, de Pereda José María, Akhmanova Anna, Volkmer Rudolf, Steinmetz Michel O (2012), Sequence determinants of a microtubule tip localization signal (MtLS)., in The Journal of biological chemistry, 287(34), 28227-42.
The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel.
Pasche Nadine, Wulhfard Sarah, Pretto Francesca, Carugati Elisa, Neri Dario (2012), The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel., in Clinical cancer research : an official journal of the American Association for Cancer Research, 18(15), 4092-103.
Antibody-drug conjugates: basic concepts, examples and future perspectives.
Casi Giulio, Neri Dario (2012), Antibody-drug conjugates: basic concepts, examples and future perspectives., in Journal of controlled release : official journal of the Controlled Release Society, 161(2), 422-8.
Fucose-specific conjugation of hydrazide derivatives to a vascular-targeting monoclonal antibody in IgG format.
Zuberbühler Kathrin, Casi Giulio, Bernardes Gonçalo J L, Neri Dario (2012), Fucose-specific conjugation of hydrazide derivatives to a vascular-targeting monoclonal antibody in IgG format., in Chemical communications (Cambridge, England), 48(56), 7100-2.
Immunocytokines: a novel class of potent armed antibodies.
Pasche Nadine, Neri Dario (2012), Immunocytokines: a novel class of potent armed antibodies., in Drug discovery today, 17(11-12), 583-90.
Radioimmunotherapy with radretumab in patients with relapsed hematologic malignancies.
Erba Paola A, Sollini Martina, Orciuolo Enrico, Traino Claudio, Petrini Mario, Paganelli Giovanni, Bombardieri Emilio, Grana Chiara, Giovannoni Leonardo, Neri Dario, Menssen Hans D, Mariani Giuliano (2012), Radioimmunotherapy with radretumab in patients with relapsed hematologic malignancies., in Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 53(6), 922-7.
Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library.
Leimbacher Markus, Zhang Yixin, Mannocci Luca, Stravs Michael, Geppert Tim, Scheuermann Jörg, Schneider Gisbert, Neri Dario (2012), Discovery of small-molecule interleukin-2 inhibitors from a DNA-encoded chemical library., in Chemistry (Weinheim an der Bergstrasse, Germany), 18(25), 7729-37.
Site-specific traceless coupling of potent cytotoxic drugs to recombinant antibodies for pharmacodelivery.
Casi Giulio, Huguenin-Dezot Nicolas, Zuberbühler Kathrin, Scheuermann Jörg, Neri Dario (2012), Site-specific traceless coupling of potent cytotoxic drugs to recombinant antibodies for pharmacodelivery., in Journal of the American Chemical Society, 134(13), 5887-92.
Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts.
Moschetta Michele, Pretto Francesca, Berndt Alexander, Galler Kerstin, Richter Petra, Bassi Andrea, Oliva Paolo, Micotti Edoardo, Valbusa Giovanni, Schwager Kathrin, Kaspar Manuela, Trachsel Eveline, Kosmehl Hartwig, Bani Maria Rosa, Neri Dario, Giavazzi Raffaella (2012), Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts., in Cancer research, 72(7), 1814-24.
Chronic cardiac allograft rejection: critical role of ED-A(+) fibronectin and implications for targeted therapy strategies.
Franz Marcus, Neri Dario, Berndt Alexander (2012), Chronic cardiac allograft rejection: critical role of ED-A(+) fibronectin and implications for targeted therapy strategies., in The Journal of pathology, 226(4), 557-61.
The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate.
Pasche Nadine, Frey Katharina, Neri Dario (2012), The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate., in Angiogenesis, 15(1), 165-9.
The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate.
Pasche Nadine, Frey Katharina, Neri Dario (2012), The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate., in Angiogenesis, 15(1), 165-9.
Selection and characterization of human antibody fragments specific for psoriasin - a cancer associated protein.
Cyranka-Czaja Anna, Wulhfard Sarah, Neri Dario, Otlewski Jacek (2012), Selection and characterization of human antibody fragments specific for psoriasin - a cancer associated protein., in Biochemical and biophysical research communications, 419(2), 250-5.
Differential vascular expression and regulation of oncofetal tenascin-C and fibronectin variants in renal cell carcinoma (RCC): implications for an individualized angiogenesis-related targeted drug delivery.
Galler Kerstin, Junker Kerstin, Franz Marcus, Hentschel Julia, Richter Petra, Gajda Mieczyslaw, Göhlert Angela, von Eggeling Ferdinand, Heller Regine, Giavazzi Raffaella, Neri Dario, Kosmehl Hartwig, Wunderlich Heiko, Berndt Alexander (2012), Differential vascular expression and regulation of oncofetal tenascin-C and fibronectin variants in renal cell carcinoma (RCC): implications for an individualized angiogenesis-related targeted drug delivery., in Histochemistry and cell biology, 137(2), 195-204.
A traceless vascular-targeting antibody-drug conjugate for cancer therapy.
Bernardes Gonçalo J L, Casi Giulio, Trüssel Sabrina, Hartmann Isabelle, Schwager Kathrin, Scheuermann Jörg, Neri Dario (2012), A traceless vascular-targeting antibody-drug conjugate for cancer therapy., in Angewandte Chemie (International ed. in English), 51(4), 941-4.
A traceless vascular-targeting antibody-drug conjugate for cancer therapy.
Bernardes Gonçalo J L, Casi Giulio, Trüssel Sabrina, Hartmann Isabelle, Schwager Kathrin, Scheuermann Jörg, Neri Dario (2012), A traceless vascular-targeting antibody-drug conjugate for cancer therapy., in Angewandte Chemie (International ed. in English), 51(4), 941-4.
20 years of DNA-encoded chemical libraries.
Mannocci Luca, Leimbacher Markus, Wichert Moreno, Scheuermann Jörg, Neri Dario (2011), 20 years of DNA-encoded chemical libraries., in Chemical communications (Cambridge, England), 47(48), 12747-53.
Antibody-radionuclide conjugates for cancer therapy: historical considerations and new trends.
Steiner Martina, Neri Dario (2011), Antibody-radionuclide conjugates for cancer therapy: historical considerations and new trends., in Clinical cancer research : an official journal of the American Association for Cancer Research, 17(20), 6406-16.
Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions.
Frey Katharina, Fiechter Michael, Schwager Kathrin, Belloni Benedetta, Barysch Marjam J, Neri Dario, Dummer Reinhard (2011), Different patterns of fibronectin and tenascin-C splice variants expression in primary and metastatic melanoma lesions., in Experimental dermatology, 20(8), 685-8.
Proteomic identification of vanin-1 as a marker of kidney damage in a rat model of type 1 diabetic nephropathy.
Fugmann Tim, Borgia Beatrice, Révész Csaba, Godó Mária, Forsblom Carol, Hamar Peter, Holthöfer Harry, Neri Dario, Roesli Christoph (2011), Proteomic identification of vanin-1 as a marker of kidney damage in a rat model of type 1 diabetic nephropathy., in Kidney international, 80(3), 272-81.
Cloning and characterization of novel tumor-targeting immunocytokines based on murine IL7.
Pasche Nadine, Woytschak Janine, Wulhfard Sarah, Villa Alessandra, Frey Katharina, Neri Dario (2011), Cloning and characterization of novel tumor-targeting immunocytokines based on murine IL7., in Journal of biotechnology, 154(1), 84-92.
A comparative immunofluorescence analysis of three clinical-stage antibodies in head and neck cancer.
Schwager Kathrin, Villa Alessandra, Rösli Christoph, Neri Dario, Rösli-Khabas Maria, Moser Gerhard (2011), A comparative immunofluorescence analysis of three clinical-stage antibodies in head and neck cancer., in Head & neck oncology, 3( .), .- ..
A novel synthetic naïve human antibody library allows the isolation of antibodies against a new epitope of oncofetal fibronectin.
Villa Alessandra, Lovato Valeria, Bujak Emil, Wulhfard Sarah, Pasche Nadine, Neri Dario (2011), A novel synthetic naïve human antibody library allows the isolation of antibodies against a new epitope of oncofetal fibronectin., in mAbs, 3(3), 264-72.
Antibody-based targeting of interferon-alpha to the tumor neovasculature: a critical evaluation.
Frey Katharina, Zivanovic Andjelija, Schwager Kathrin, Neri Dario (2011), Antibody-based targeting of interferon-alpha to the tumor neovasculature: a critical evaluation., in Integrative biology : quantitative biosciences from nano to macro, 3(4), 468-78.
Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds.
Buller Fabian, Steiner Martina, Frey Katharina, Mircsof Dennis, Scheuermann Jorg, Kalisch Markus, Buhlmann Peter, Supuran Claudiu T, Neri Dario (2011), Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds., in ACS chemical biology, 6(4), 336-44.
The accessible cerebral vascular proteome in a mouse model of cerebral β-amyloidosis.
Roesli Christoph, Fugmann Tim, Borgia Beatrice, Schliemann Christoph, Neri Dario, Jucker Mathias (2011), The accessible cerebral vascular proteome in a mouse model of cerebral β-amyloidosis., in Journal of proteomics, 74(4), 539-46.
A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels.
Palumbo A, Hauler F, Dziunycz P, Schwager K, Soltermann A, Pretto F, Alonso C, Hofbauer G F, Boyle R W, Neri D (2011), A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels., in British journal of cancer, 104(7), 1106-15.
Comparative in vivo analysis of the atherosclerotic plaque targeting properties of eight human monoclonal antibodies.
Fiechter Michael, Frey Katharina, Fugmann Tim, Kaufmann Philipp A, Neri Dario (2011), Comparative in vivo analysis of the atherosclerotic plaque targeting properties of eight human monoclonal antibodies., in Atherosclerosis, 214(2), 325-30.
In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography.
Mumprecht Viviane, Honer Michael, Vigl Benjamin, Proulx Steven T, Trachsel Eveline, Kaspar Manuela, Banziger-Tobler Nadja E, Schibli Roger, Neri Dario, Detmar Michael (2010), In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography., in Cancer research, 70(21), 8842-51.
Isolation of potent and specific trypsin inhibitors from a DNA-encoded chemical library.
Mannocci Luca, Melkko Samu, Buller Fabian, Molnàr Ilona, Bianké Jean-Paul Gapian, Dumelin Christoph E, Scheuermann Jörg, Neri Dario (2010), Isolation of potent and specific trypsin inhibitors from a DNA-encoded chemical library., in Bioconjugate chemistry, 21(10), 1836-41.
A critical evaluation of the tumor-targeting properties of bispecific antibodies based on quantitative biodistribution data.
Hemmerle Teresa, Wulhfard Sarah, Neri Dario, A critical evaluation of the tumor-targeting properties of bispecific antibodies based on quantitative biodistribution data., in Protein engineering, design & selection : PEDS.
A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma.
Eigentler Thomas K, Weide Benjamin, de Braud Filippo, Spitaleri Gianluca, Romanini Antonella, Pflugfelder Annette, Gonzales-Inglesias Reinerio, Tasciotti Annaelisa, Giovannoni Leonardo, Schwager Kathrin, Lovato Valeria, Kaspar Manuela, Trachsel Eveline, Mennsen Hans D, Neri Dario, Garbe Claus, A dose-escalation and signal-generating study of the immunocytokine L19-IL2 in combination with dacarbazine for the therapy of patients with metastatic melanoma., in Clinical cancer research : an official journal of the American Association for Cancer Research.
Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site.
List Thomas, Neri Dario, Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site., in mAbs, 4(6).
Interfering with pH regulation in tumours as a therapeutic strategy.
Neri Dario, Supuran Claudiu T, Interfering with pH regulation in tumours as a therapeutic strategy., in Nature reviews. Drug discovery, 10(10), 767-77.
Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma.
Papadia Francesco, Basso Valeria, Patuzzo Roberto, Maurichi Andrea, Di Florio Annabella, Zardi Luciano, Ventura Elisa, González-Iglesias Reinerio, Lovato Valeria, Giovannoni Leonardo, Tasciotti Annaelisa, Neri Dario, Santinami Mario, Menssen Hans D, De Cian Franco, Isolated limb perfusion with the tumor-targeting human monoclonal antibody-cytokine fusion protein L19-TNF plus melphalan and mild hyperthermia in patients with locally advanced extremity melanoma., in Journal of surgical oncology.
The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model.
Schwager Kathrin, Bootz Frank, Imesch Patrick, Kaspar Manuela, Trachsel Eveline, Neri Dario, The antibody-mediated targeted delivery of interleukin-10 inhibits endometriosis in a syngeneic mouse model., in Human reproduction (Oxford, England), 26(9), 2344-52.
The Immunocytokine L19-IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF.
Schwager Kathrin, Hemmerle Teresa, Aebischer David, Neri Dario, The Immunocytokine L19-IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF., in The Journal of investigative dermatology.
The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate.
Pasche Nadine, Frey Katharina, Neri Dario, The targeted delivery of IL17 to the mouse tumor neo-vasculature enhances angiogenesis but does not reduce tumor growth rate., in Angiogenesis.

Scientific events



Self-organised

Title Date Place
3rd International Conference on DNA-Encoded Chemical Libraries 20.08.2012 ETH Zürich

Awards

Title Year
Prix Mentzer 2011

Associated projects

Number Title Start Funding scheme
144091 Understanding and exploiting the molecular targeting of tumor neo-vasculature 01.10.2012 Project funding (Div. I-III)
105919 Understanding and improving the selective molecular targeting of neovasculature 01.10.2004 Project funding (Div. I-III)
144091 Understanding and exploiting the molecular targeting of tumor neo-vasculature 01.10.2012 Project funding (Div. I-III)

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