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Understanding and exploiting the molecular targeting of tumor neo-vasculature

English title Understanding and exploiting the molecular targeting of tumor neo-vasculature
Applicant Neri Dario
Number 144091
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 01.10.2012 - 30.09.2015
Approved amount 590'525.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Cellular Biology, Cytology

Keywords (9)

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

Lay Summary (English)

Lead
Lay summary

Antibodies represent the largest and fastest growing class of pharmaceutical biotechnology products. These proteins can be used to deliver bioactive molecules (drugs, cytokines, photosensitizers, radionuclides, etc.) to the tumor environment, thus sparing normal tissues. The targeting of tumor blood vessels (and more specifically of modified sub-endothelial extracellular matrix components) using armed antibodies is particularly attractive , because of the accessibility of these structures in vivo and because targets have been identified, which are shared by many different types of malignancies.

In this Project, we will:

1) Use "armed" forms of vascular targeting antibodies for the implementation of pharmacodelivery therapeutic strategies in acute myeloid leukemia (AML). We have recently discovered that subcutaneous AML lesions and diseased bone marrow abundantly express vascular tumor markers, such as splice isoforms of fibronectin or tenascin-C, which can be efficiently reached with antibodies.

2) Use combinations of tumor targeting antibody-cytokine fusion proteins and evaluate their therapeutic efficacy in mouse models of cancer

3) Use the newly-developed technology of "DNA-Encoded Chemical Libraries" to see whether we can isolate small organic molecules specific to vascular tumor markers, which may by-pass antibodies for in vivo tumor targeting applications

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease.
Bootz Franziska, Schmid Anja Sophie, Neri Dario (2015), Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease., in Inflammatory bowel diseases, 21(8), 1908-17.
Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates
Gebleux R., Wulhfard S., Casi G., Neri D. (2015), Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates, in Molecular Cancer Therapeutics, 14(11), 2606-2612.
Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation.
Wichert Moreno, Krall Nikolaus, Decurtins Willy, Franzini Raphael M, Pretto Francesca, Schneider Petra, Neri Dario, Scheuermann Jörg (2015), Dual-display of small molecules enables the discovery of ligand pairs and facilitates affinity maturation., in Nature chemistry, 7(3), 241-9.
Dual-pharmacophore DNA-encoded chemical libraries.
Scheuermann Jörg, Neri Dario (2015), Dual-pharmacophore DNA-encoded chemical libraries., in Current opinion in chemical biology, 26, 99-103.
Generation and tumor recognition properties of two human monoclonal antibodies specific to cell surface anionic phospholipids.
Bujak Emil, Pretto Francesca, Neri Dario (2015), Generation and tumor recognition properties of two human monoclonal antibodies specific to cell surface anionic phospholipids., in Investigational new drugs, 33(4), 791-800.
Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies.
Venetz Dario, Hess Christian, Lin Chia-wei, Aebi Markus, Neri Dario (2015), Glycosylation profiles determine extravasation and disease-targeting properties of armed antibodies., in Proceedings of the National Academy of Sciences of the United States of America, 112(7), 2000-5.
Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins
Franzini Raphael M., Nauer Angela, Scheuermann Jörg, Neri Dario (2015), Interrogating target-specificity by parallel screening of a DNA-encoded chemical library against closely related proteins, in Chem. Commun., 51(38), 8014-8016.
Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library.
Samain Florent, Ekblad Torun, Mikutis Gediminas, Zhong Nan, Zimmermann Mauro, Nauer Angela, Bajic Davor, Decurtins Willy, Scheuermann Jörg, Brown Peter J, Hall Jonathan, Gräslund Susanne, Schüler Herwig, Neri Dario, Franzini Raphael M (2015), Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library., in Journal of medicinal chemistry, 58(12), 5143-9.
The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity.
Hess Christian, Neri Dario (2015), The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity., in Cancer immunology, immunotherapy : CII, 64(5), 635-44.
Therapeutic efficacy of the F8-IL2 immunocytokine in a metastatic mouse model of lung adenocarcinoma.
Wieckowski Sébastien, Hemmerle Teresa, Prince Spasenja Savic, Schlienger Béatrice Dolder, Hillinger Sven, Neri Dario, Zippelius Alfred (2015), Therapeutic efficacy of the F8-IL2 immunocytokine in a metastatic mouse model of lung adenocarcinoma., in Lung cancer (Amsterdam, Netherlands), 88(1), 9-15.
A bivalent small molecule-drug conjugate directed against carbonic anhydrase IX can elicit complete tumour regression in mice
Krall N., Pretto F., Neri D. (2014), A bivalent small molecule-drug conjugate directed against carbonic anhydrase IX can elicit complete tumour regression in mice, in CHEMICAL SCIENCE, 5(9), 3640-3644.
A Chemically Defined Trifunctional Antibody-Cytokine-Drug Conjugate with Potent Antitumor Activity
List Thomas, Casi Giulio, Neri Dario (2014), A Chemically Defined Trifunctional Antibody-Cytokine-Drug Conjugate with Potent Antitumor Activity, in MOLECULAR CANCER THERAPEUTICS, 13(11), 2641-2652.
A comprehensive surface proteome analysis of myeloid leukemia cell lines for therapeutic antibody development
Strassberger Verena, Gutbrodt Katrin L., Krall Nikolaus, Roesli Christoph, Takizawa Hitoshi, Manz Markus G., Fugmann Tim, Neri Dario (2014), A comprehensive surface proteome analysis of myeloid leukemia cell lines for therapeutic antibody development, in JOURNAL OF PROTEOMICS, 99, 138-151.
A Fibrin-Specific Monoclonal Antibody from a Designed Phage Display Library Inhibits Clot Formation and Localizes to Tumors In Vivo
Putelli Alessia, Kiefer Jonathan D., Zadory Matthias, Matasci Mattia, Neri Dario (2014), A Fibrin-Specific Monoclonal Antibody from a Designed Phage Display Library Inhibits Clot Formation and Localizes to Tumors In Vivo, in JOURNAL OF MOLECULAR BIOLOGY, 426(21), 3606-3618.
A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors
Krall Nikolaus, Pretto Francesca, Decurtins Willy, Bernardes Gonçalo J L, Bernardes Gonçalo J L, Bernardes Gonçalo J L, Supuran Claudiu T., Neri Dario (2014), A small-molecule drug conjugate for the treatment of carbonic anhydrase IX expressing tumors, in Angewandte Chemie - International Edition, 53(16), 4231-4235.
Antibody-Based Delivery of IL2 and Cytotoxics Eradicates Tumors in Immunocompetent Mice
Gutbrodt Katrin L., Casi Giulio, Neri Dario (2014), Antibody-Based Delivery of IL2 and Cytotoxics Eradicates Tumors in Immunocompetent Mice, in MOLECULAR CANCER THERAPEUTICS, 13(7), 1772-1776.
Antibody-based delivery of IL4 to the neovasculature cures mice with arthritis
Hemmerle Teresa, Doll Fabia, Neri Dario (2014), Antibody-based delivery of IL4 to the neovasculature cures mice with arthritis, in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 111(33), 12008-12012.
Antibody-mediated delivery of interleukin 4 to the neo-vasculature reduces chronic skin inflammation
Hemmerle Teresa, Zgraggen Silvana, Matasci Mattia, Halin Cornelia, Detmar Michael, Neri Dario (2014), Antibody-mediated delivery of interleukin 4 to the neo-vasculature reduces chronic skin inflammation, in JOURNAL OF DERMATOLOGICAL SCIENCE, 76(2), 96-103.
Curative properties of noninternalizing antibody-drug conjugates based on maytansinoids
Perrino Elena, Steiner Martina, Krall Nikolaus, Bernardes Gonçalo J L, Bernardes Gonçalo J L, Bernardes Gonçalo J L, Pretto Francesca, Casi Giulio, Neri Dario (2014), Curative properties of noninternalizing antibody-drug conjugates based on maytansinoids, in Cancer Research, 74(9), 2569-2578.
DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries
Franzini Raphael M., Neri Dario, Scheuermann Jörg (2014), DNA-Encoded Chemical Libraries: Advancing beyond Conventional Small-Molecule Libraries, in Acc. Chem. Res., 47(4), 1247-1255.
Evaluation of antibody-chemokine fusion proteins for tumor-targeting applications
Hess Christian, Neri Dario (2014), Evaluation of antibody-chemokine fusion proteins for tumor-targeting applications, in EXPERIMENTAL BIOLOGY AND MEDICINE, 239(7), 842-852.
From target discovery to clinical trials with armed antibody products
Elia Giuliano, Fugmann Tim, Neri Dario (2014), From target discovery to clinical trials with armed antibody products, in JOURNAL OF PROTEOMICS, 107, 50-55.
Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues
Bujak Emil, Pretto Francesca, Ritz Data, Gualandi Laura, Wulhfard Sarah, Neri Dario (2014), Monoclonal antibodies to murine thrombospondin-1 and thrombospondin-2 reveal differential expression patterns in cancer and low antigen expression in normal tissues, in EXPERIMENTAL CELL RESEARCH, 327(1), 135-145.
Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy
Pretto Francesca, Elia Giuliano, Castioni Nadia, Neri Dario (2014), Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy, in CANCER IMMUNOLOGY IMMUNOTHERAPY, 63(9), 901-910.
Systematic Evaluation and Optimization of Modification Reactions of Oligonucleotides with Amines and Carboxylic Acids for the Synthesis of DNA-Encoded Chemical Libraries
Franzini Raphael M., Samain Florent, Abd Elrahman Maaly, Mikutis Gediminas, Nauer Angela, Zimmermann Mauro, Scheuermann Joerg, Hall Jonathan, Neri Dario (2014), Systematic Evaluation and Optimization of Modification Reactions of Oligonucleotides with Amines and Carboxylic Acids for the Synthesis of DNA-Encoded Chemical Libraries, in BIOCONJUGATE CHEMISTRY, 25(8), 1453-1461.
The antibody-based targeted delivery of interleukin-4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancerIL4- and IL12-based immunocytokines
Hemmerle Teresa, Neri Dario (2014), The antibody-based targeted delivery of interleukin-4 and 12 to the tumor neovasculature eradicates tumors in three mouse models of cancerIL4- and IL12-based immunocytokines, in International Journal of Cancer, 134(2), 467-477.
The Dose-Dependent Tumor Targeting of Antibody-IFN gamma Fusion Proteins Reveals an Unexpected Receptor-Trapping Mechanism In Vivo
Hemmerle Teresa, Neri Dario (2014), The Dose-Dependent Tumor Targeting of Antibody-IFN gamma Fusion Proteins Reveals an Unexpected Receptor-Trapping Mechanism In Vivo, in CANCER IMMUNOLOGY RESEARCH, 2(6), 559-567.
Tumor targeting properties of antibody fusion proteins based on different members of the murine tumor necrosis superfamily
Hemmerle Teresa, Hess Christian, Venetz Dario, Neri Dario (2014), Tumor targeting properties of antibody fusion proteins based on different members of the murine tumor necrosis superfamily, in JOURNAL OF BIOTECHNOLOGY, 172, 73-76.
A human monoclonal antibody specific to placental alkaline phosphatase, a marker of ovarian cancer
Ravenni Niccolo, Weber Marcel, Neri Dario (2013), A human monoclonal antibody specific to placental alkaline phosphatase, a marker of ovarian cancer, in mAbs, 6(1), 86-94.
Antibody-based delivery of interleukin-2 to neovasculature has potent activity against acute myeloid leukemia
Gutbrodt Katrin L., Schliemann Christoph, Giovannoni Leonardo, Frey Katharina, Pabst Thomas, Klapper Wolfram, Berdel Wolfgang E., Neri Dario (2013), Antibody-based delivery of interleukin-2 to neovasculature has potent activity against acute myeloid leukemia, in Science Translational Medicine, 5(201), 201ra118.
Murine analogues of etanercept and of F8-IL10 inhibit the progression of collagen-induced arthritis in the mouse
Doll Fabia, Schwager Kathrin, Hemmerle Teresa, Neri Dario (2013), Murine analogues of etanercept and of F8-IL10 inhibit the progression of collagen-induced arthritis in the mouse, in Arthritis Research and Therapy, 15(5), R138.
Pharmacotherapy of metastatic melanoma: Emerging trends and opportunities for a cure
Pretto Francesca, Neri Dario (2013), Pharmacotherapy of metastatic melanoma: Emerging trends and opportunities for a cure, in Pharmacology and Therapeutics, 139(3), 405-411.
Site-specific chemical modification of antibody fragments using traceless cleavable linkers
Bernardes Goncalo J. L., Steiner Martina, Hartmann Isabelle, Neri Dario, Casi Giulio (2013), Site-specific chemical modification of antibody fragments using traceless cleavable linkers, in NATURE PROTOCOLS, 8(11), 2079-2089.
Spacer length shapes drug release and therapeutic efficacy of traceless disulfide-linked ADCs targeting the tumor neovasculature
Steiner Martina, Hartmann Isabelle, Perrino Elena, Casi Giulio, Brighton Samatanga, Brighton Samatanga, Jelesarov Ilian, Bernardes Gonçalo J L, Neri Dario (2013), Spacer length shapes drug release and therapeutic efficacy of traceless disulfide-linked ADCs targeting the tumor neovasculature, in Chemical Science, 4(1), 297-302.
The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity
Hemmerle T., Probst P., Giovannoni L., Green A. J., Meyer T., Neri D. (2013), The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity, in British Journal of Cancer, 109(5), 1206-1213.
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 (2013), The Immunocytokine L19-IL2 Eradicates Cancer When Used in Combination with CTLA-4 Blockade or with L19-TNF, in JOURNAL OF INVESTIGATIVE DERMATOLOGY, 133(3), 751-758.
Tumor-targeting properties of novel immunocytokines based on murine IL1β and IL6
Hess Christian, Neri Dario (2013), Tumor-targeting properties of novel immunocytokines based on murine IL1β and IL6, in Protein Engineering, Design and Selection, 27(6), 207-213.

Awards

Title Year
MTTC Award Deutsches Council der Fortbildungsinitiative Molecular Targeted Therapy of Cancer. Prämierte Leistung: “Antibody-based delivery of interleukin-2 to neovasculature has potent activity against Acute Myeloid Leukemia” 2014
Phoenix Award 2014 in Clinical Pharmacology, Vienna (Austria) 2014

Associated projects

Number Title Start Funding scheme
126988 Understanding and improving the selective molecular targeting of tumor neo-vasculature 01.10.2009 Project funding (Div. I-III)
163479 Understanding and Exploiting the Molecular Targeting of Tumor Neo-vasculature 01.10.2015 Project funding (Div. I-III)
163479 Understanding and Exploiting the Molecular Targeting of Tumor Neo-vasculature 01.10.2015 Project funding (Div. I-III)
126988 Understanding and improving the selective molecular targeting of tumor neo-vasculature 01.10.2009 Project funding (Div. I-III)

Abstract

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 (“armed antibodies”) for the targeted delivery of bioactive molecules (drugs, cytokines, procoagulant factors, photosensitizers, radionuclides, etc.) to the tumor environment. In this context, the selective 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 Rev. Cancer, 5, 436; Neri & Supuran (2011) Nature Rev. Drug Discov., 10, 767].The newly-formed blood vessels in cancer and in other diseases (e.g., endometriosis, arthritis, atherosclerosis, psoriasis, as well as in certain blinding ocular disorders) are different at the molecular level, compared to normal blood vessels. Markers of angiogenesis can be discovered by the perfusion-based chemical modification (i.e., biotinylation) of blood vessels, followed by a mass-spectrometric analysis of biotinylated proteins [Rybak et al. (2005) Nature Methods, 2, 291; Schliemann et al. (2010) Blood, 115, 736]. Our group has previously developed vascular targeting armed antibodies (i.e., antibody-cytokine fusions and radiolabeled antibodies), which are currently being investigated in Phase I and Phase II clinical trials in collaboration with industrial partners [Sauer et al. (2009) Blood, 113, 2265; Eigentler et al. (2011) Clin. Cancer Res., 17, 7732].In this Project, we aim at improving and exploiting the molecular targeting of neo-vasculature, on the basis of the following strategies:1) Vascular targeting beyond solid tumors and lymphomasWe have initially worked on vascular targeting applications for solid tumors [Neri et al. (1997) Nature Biotech., 15, 1271] and we have discovered only later that also certain hematological malignancies (i.e., lymphomas and CLL) express markers of angiogenesis suitable for in vivo pharmacodelivery applications [Sauer et al. (2009) Blood, 113, 2265; Schliemann et al. (2009) Blood, 113, 2275; Schliemann et al. (2010) Blood, 115, 736]. We have recently discovered that also the bone marrow of patients with certain types of leukemia (e.g., AML) exhibits a vascular proliferation with expression of markers of angiogenesis which can be targeted by antibodies. Initial studies (which we plan to continue in this Project) have revealed that the targeting of AML in animal models with antibody-cytokine fusions (“immunocytokines”) eradicates the disease, which cannot be cured by chemotherapy alone.2) Combination of immunocytokines Among the four major classes of payloads which can be used to generate anti-cancer “armed” antibodies: (i) drugs with cleavable linkers; (ii) cytokines; (iii) radionuclides; (iv) bispecific antibodies, we have so far obtained the best therapeutic results with antibody-cytokine fusion proteins (immunocytokines). We have recently observed that combination therapy based on immunocytokines can lead to complete eradication of tumors, which cannot be cured by high-dose chemotherapy. We plan to study, in a systematic fashion, which combinations lead to cures and whether mice are vaccinated against subsequent challenges with tumor cells.3) By-passing antibodies for vascular targeting applications We are accumulating evidence that solid tumors can be efficiently targeted in vivo using small organic ligands, which diffuse more rapidly and homogenously into the tumor mass compared to monoclonal antibodies. We now intend to use innovative chemical methodologies to generate organic ligands specific to markers of angiogenesis and to test their targeting performance in vivo. We anticipate that the Project will not only generate innovative anti-cancer agents with a potential clinical applicability, but also provide information about chemical and biological factors, which influence the molecular targeting of pathological angiogenesis in vivo.
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