Project

Back to overview

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 182003
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 01.10.2018 - 31.12.2020
Approved amount 700'300.00
Show all

All Disciplines (5)

Discipline
Experimental Cancer Research
Pharmacology, Pharmacy
Immunology, Immunopathology
Cellular Biology, Cytology
Organic Chemistry

Keywords (3)

Encoded Combinatorial Libraries; Vascular Targeting; Antibody-Cytokine Fusion Proteins

Lay Summary (Italian)

Lead
Uno degli scopi principali della ricerca moderna in Oncologia consiste nello sviluppo di farmaci che si localizzino in maniera selettiva nei tumori, risparmiando cosi' i tessuti sani. Gli anticorpi monoclonali sono molecole ideali per la "veicolazione" selettiva di farmaci. In particolare, e' conveniente usare anticorpi che si localizzino attorno ai vasi sanguigni dei tumori, in quanto queste strutture sono facilmente accessibili per farmaci somministrati per via endovenosa.
Lay summary
In questo progetto, pianifichiamo di capitalizzare su due decenni di ricerca del nostro gruppo, finalizzato all'uso di prodotti a base di anticorpi monoclonali, capaci di localizzarsi selettivamente attorno ai vasi sanguigni dei tumori.
Piu' precisamente, perseguiremo quattro obbiettivi principali di ricerca, che si basano sulla veicolazione selettiva nel tumore di citochine o altri farmaci capaci di modulare l'attivita' del sistema immunitario
a) Cercheremo di veicolare, tramite anticorpi monoclonali, l'interleuchina-15, una delle citochine piu' importanti
b) Cercheremo di ridurre la tossicita' di anticorpi fusi a citochine mediante l'uso di inibitori, che blocchino l'attivita' delle citochine in maniera transiente
c) Cercheremo di sviluppare strategie molecolari, mirate a rimpiazzare le citochine con molecule funzionalmente equivalenti (e.g., anticorpi o piccole molecole leganti, capaci di attivare il sistema immunitario)
d) Combineremo proteine di fusione (basate su anticorpi fusi a citochine) con altri farmaci (e.g., anticorpi monoclonali, bispecifici o cellule T ingegnerizzate) 

 
Direct link to Lay Summary Last update: 04.10.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Antibody-mediated delivery of LIGHT to the tumor boosts natural killer cells and delays tumor progression.
M Stringhini, J Mock, V Fontana, P Murer, D Neri (2021), Antibody-mediated delivery of LIGHT to the tumor boosts natural killer cells and delays tumor progression., in mAbs, 13(1), 1868066.
A universal reporter cell line for bioactivity evaluation of engineered cytokine products
Mock Jacqueline, Pellegrino Christian, Neri Dario (2020), A universal reporter cell line for bioactivity evaluation of engineered cytokine products, in Scientific Reports, 10(1), 3234-3234.
A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis
Murer Patrizia, Plüss Louis, Neri Dario (2020), A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis, in mAbs, 12(1), 1714371-1714371.
A Single-Stranded DNA-Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks.
G Bassi, N Favalli, M Vuk, M Catalano, A Martinelli, A Trenner, A Porro, S Yang, CL Tham, M Moroglu, WW Yue, SJ Conway, PK Vogt, AA Sartori, J Scheuermann, D Neri (2020), A Single-Stranded DNA-Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular Assembly of Building Blocks., in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 7(22), 2001970.
An Antibody-Tumor Necrosis Factor Fusion Protein that Synergizes with Oxaliplatin for Treatment of Colorectal Cancer.
D Bajic, K Chester, D Neri (2020), An Antibody-Tumor Necrosis Factor Fusion Protein that Synergizes with Oxaliplatin for Treatment of Colorectal Cancer., in Molecular cancer therapeutics, 19(12), 2554-2563.
An engineered 4-1BBL fusion protein with "activity on demand".
J Mock, M Stringhini, A Villa, M Weller, T Weiss, D Neri (2020), An engineered 4-1BBL fusion protein with "activity on demand"., in Proceedings of the National Academy of Sciences of the United States of America, 117(50), 31780-31788.
Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells.
R Myburgh, JD Kiefer, NF Russkamp, CF Magnani, N Nuñez, A Simonis, S Pfister, CM Wilk, D McHugh, J Friemel, AM Müller, B Becher, C Münz, D Neri, MG Manz (2020), Anti-human CD117 CAR T-cells efficiently eliminate healthy and malignant CD117-expressing hematopoietic cells., in Leukemia, 2688-2703.
Comparative evaluation of DNA-encoded chemical selections performed using DNA in single-stranded or double-stranded format.
G Bassi, N Favalli, S Oehler, A Martinelli, M Catalano, J Scheuermann, D Neri (2020), Comparative evaluation of DNA-encoded chemical selections performed using DNA in single-stranded or double-stranded format., in Biochemical and biophysical research communications, 533(2), 223-229.
Complexation with a Cognate Antibody Fragment Facilitates Affinity Measurements of Fluorescein-Linked Small Molecule Ligands.
M Catalano, S Oehler, L Prati, N Favalli, G Bassi, J Scheuermann, D Neri (2020), Complexation with a Cognate Antibody Fragment Facilitates Affinity Measurements of Fluorescein-Linked Small Molecule Ligands., in Analytical chemistry, 92(15), 10822-10829.
Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels
J Mock, IA Rascon, M Stringhini, M Catalano, D Neri (2020), Engineering murine GITRL for antibody-mediated delivery to tumor-associated blood vessels, in BioRxiv.
Immunocytokines are a promising immunotherapeutic approach against glioblastoma.
T Weiss, E Puca, M Silginer, T Hemmerle, S Pazahr, A Bink, M Weller, D Neri, P Roth (2020), Immunocytokines are a promising immunotherapeutic approach against glioblastoma., in Science translational medicine, 12(564), eabb2311.
Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response of tissue-resident memory T cells against the AH1 rejection antigen.
M Stringhini, P Probst, D Neri (2020), Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response of tissue-resident memory T cells against the AH1 rejection antigen., in European journal of immunology, 50(10), 1591-1597.
Impact of Ligand Size and Conjugation Chemistry on the Performance of Universal Chimeric Antigen Receptor T-Cells for Tumor Killing.
C Pellegrino, N Favalli, M Sandholzer, L Volta, G Bassi, J Millul, S Cazzamalli, M Matasci, A Villa, R Myburgh, MG Manz, D Neri (2020), Impact of Ligand Size and Conjugation Chemistry on the Performance of Universal Chimeric Antigen Receptor T-Cells for Tumor Killing., in Bioconjugate chemistry, 31(7), 1775-1783.
Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library.
M Catalano, M Moroglu, P Balbi, F Mazzieri, J Clayton, KH Andrews, M Bigatti, J Scheuermann, SJ Conway, D Neri (2020), Selective Fragments for the CREBBP Bromodomain Identified from an Encoded Self-assembly Chemical Library., in ChemMedChem, 15(18), 1752-1756.
Special edition on DNA-Encoded chemical libraries.
J Scheuermann, D Neri (2020), Special edition on DNA-Encoded chemical libraries., in Biochemical and biophysical research communications, 533(2), iii-iv.
Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors.
MR Mortensen, J Mock, M Bertolini, M Stringhini, M Catalano, D Neri (2020), Targeting an engineered cytokine with interleukin-2 and interleukin-15 activity to the neovasculature of solid tumors., in Oncotarget, 11, 3972-3983.
The targeted delivery of interleukin-12 to the carcinoembryonic antigen increases the intratumoral density of NK and CD8+ T cell in an immunocompetent mouse model of colorectal cancer.
E Puca, C Schmitt-Koopmann, M Furter, P Murer, P Probst, M Dihr, D Bajic, D Neri (2020), The targeted delivery of interleukin-12 to the carcinoembryonic antigen increases the intratumoral density of NK and CD8+ T cell in an immunocompetent mouse model of colorectal cancer., in Journal of gastrointestinal oncology, 11(4), 803-811.
Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade
Dakhel Sheila, Ongaro Tiziano, Gouyou Baptiste, Matasci Mattia, Villa Alessandra, Neri Dario, Cazzamalli Samuele (2019), Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade, in Oncotarget, 10(62), 6678-6690.
Comparative evaluation of bolus and fractionated administration modalities for two antibody-cytokine fusions in immunocompetent tumor-bearing mice
Puca Emanuele, De Luca Roberto, Seehusen Frauke, Rodriguez Josep Maria Monné, Neri Dario (2019), Comparative evaluation of bolus and fractionated administration modalities for two antibody-cytokine fusions in immunocompetent tumor-bearing mice, in Journal of Controlled Release, *-*.
The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8 + T cell activity and synergizes with immune checkpoint inhibitors
Puca Emanuele, Probst Philipp, Stringhini Marco, Murer Patrizia, Pellegrini Giovanni, Cazzamalli Samuele, Hutmacher Cornelia, Gouyou Baptiste, Wulhfard Sarah, Matasci Mattia, Villa Alessandra, Neri Dario (2019), The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8 + T cell activity and synergizes with immune checkpoint inhibitors, in International Journal of Cancer, ijc.32603-ijc.32603.
Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response against the AH1 tumor rejection antigen
StringhiniMarco, ProbstPhilipp, NeriDario, Immunotherapy of CT26 murine tumors is characterized by an oligoclonal response against the AH1 tumor rejection antigen, in European Journal of Immunology.

Datasets

SNF310030_182003_ResearchData

Author Neri, Dario
Publication date 11.06.2020
Persistent Identifier (PID) https://doi.org/10.3929/ethz-b-000419436
Repository ETHZ Research Collection
Abstract
Auszüge aus Laborjournalen und Daten aus Mausexperimenten der drei Doktorand/innenJacqueline Mock, Emanuele Puca, Marco Stringhini. Alle drei haben für das Projekt 310030_182003 gearbeitet. Aus den Daten gingen mehrere Publikationen hervor (siehe Outputdaten "Wiss. Publikationen"

Associated projects

Number Title Start Funding scheme
163479 Understanding and Exploiting the Molecular Targeting of Tumor Neo-vasculature 01.10.2015 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. The recent introduction of antibodies directed against immune check-point inhibitors is revolutionizing the way patients with metastatic disease are treated. However, although much of the current focus in cancer immunotherapy is on immune check-point blockade, those products are rarely able to induce durable complete responses. Cytokines are modulators of immune activity and some cytokine-based products play an important role in providing complementary anti-cancer opportunities, alone and in combination. Our Laboratory at ETH Zürich has almost 20 years of experience in the development of antibody-cytokine fusions for cancer therapy. In order to accumulate cytokine payloads at the tumor site, the use of antibody “vehicles” specific to targets associated with 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) Nat. Rev. Cancer, 5, 436; Neri & Supuran (2011) Nat. Rev. Drug Discov., 10, 767]. The newly-formed blood vessels in cancer and in other diseases (e.g., endometriosis) 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) Nat. Methods, 2, 291; Schliemann et al. (2010) Blood, 115, 736]. Our group has previously developed vascular targeting antibody-cytokine fusions, which are currently being investigated in Phase I, Phase II and Phase III clinical trials in collaboration with industry.After having fused more than 50 payloads to antibodies of proven tumor-targeting performance, we now know that fusions based on interleukin-2, interleukin-12, interleukin-15 and tumor necrosis factor are particularly attractive for anti-cancer applications. In this Project, we wish to develop novel antibody-cytokine strategies, which further enhance therapeutic activity and selectivity. Specifically, the main goals of the current Project can be summarized as follows:• Improvement of the tumor-homing properties and of therapeutic activity of IL15-based pharmaceuticals: a class of products which (until now) has been difficult to efficiently deliver to neoplastic lesions• Development of kinetically-tuned transient inhibitors of immunocytokine activity, in order to decrease systemic toxicity and maximize activity at the site of disease of cytokine-based therapeutics• Exploration of antibody-cytokine fusions for the potentiation of intact antibodies, bispecific antibodies and CAR-T biopharmaceuticals• Investigations on the possibility to replace cytokine payloads with human antibody fragments or with small organic ligands, isolated from DNA-encoded combinatorial librariesIf the new concepts and products developed in this Project are successful in preclinical models of cancer, this will open immediate clinical and industrial applications.
-