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  1. Article ; Online: Design and Characterization of Novel Antibody-Cytokine Fusion Proteins Based on Interleukin-21.

    Di Nitto, Cesare / Neri, Dario / Weiss, Tobias / Weller, Michael / De Luca, Roberto

    Antibodies (Basel, Switzerland)

    2022  Volume 11, Issue 1

    Abstract: Interleukin-21 (IL21) is a pleiotropic cytokine involved in the modulation of both innate and adaptive immunity. IL21 is mainly secreted by natural killer (NK) and activated CD4+ T-cells. The biology of this cytokine can be associated to proinflammatory ... ...

    Abstract Interleukin-21 (IL21) is a pleiotropic cytokine involved in the modulation of both innate and adaptive immunity. IL21 is mainly secreted by natural killer (NK) and activated CD4+ T-cells. The biology of this cytokine can be associated to proinflammatory responses reflecting its potent stimulatory activity of NK and CD8+ T-cells. Here we describe four formats of novel IL21-based antibody-cytokine fusion proteins, targeting the extra domain A (EDA) of fibronectin and explore their potential for cancer treatment. The fusion proteins were designed, expressed, and characterized. F8 in single-chain diabody (scDb) format fused to IL21 at its C-terminus exhibited a promising profile in size exclusion chromatography (SEC) and SDS-PAGE. The lead candidate was further characterized in vitro. A cell-based activity assay on murine cytotoxic T-cells showed that human IL21, compared to murine IL21 partially cross-reacted with the murine receptor. The prototype was able to recognize EDA as demonstrated by immunofluorescence analysis on tumor sections. In an in vivo quantitative biodistribution experiment, F8(scDb)-murine IL21 did not preferentially accumulate at the site of disease after intravenous injection, suggesting that additional protein engineering would be required to improve the tumor-homing properties of IL21-based product.
    Language English
    Publishing date 2022-03-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661514-9
    ISSN 2073-4468 ; 2073-4468
    ISSN (online) 2073-4468
    ISSN 2073-4468
    DOI 10.3390/antib11010019
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: An Antibody Targeting Fibroblast Activation Protein Simultaneously Fused to Interleukin-2 and Tumor Necrosis Factor Selectively Localizes to Neoplastic Lesions.

    Prodi, Eleonora / Comacchio, Claudia / Gilardoni, Ettore / Di Nitto, Cesare / Puca, Emanuele / Neri, Dario / De Luca, Roberto

    Antibodies (Basel, Switzerland)

    2023  Volume 12, Issue 2

    Abstract: The delivery of specific cytokine payloads to a neoplastic environment employing antibodies able to selectively accumulate at the tumor site represents an attractive strategy to stimulate an immune response to cancer. Whilst conventional antibody- ... ...

    Abstract The delivery of specific cytokine payloads to a neoplastic environment employing antibodies able to selectively accumulate at the tumor site represents an attractive strategy to stimulate an immune response to cancer. Whilst conventional antibody-cytokine fusions based on a single payload have shown potent anticancer activity, the concomitant delivery of two cytokine payloads may further improve the therapeutic outcome as the immune system typically adopts multiple signals to reinforce an antitumor strategy. We here describe a potency-matched dual-cytokine antibody fusion protein containing a tumor-targeting antibody fragment specific to human fibroblast activation protein (FAP), simultaneously linked to both interleukin-2 (IL2) and a tumor necrosis factor (TNF) mutant. The resulting fusion protein, termed IL2-7NP2-TNF
    Language English
    Publishing date 2023-04-14
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661514-9
    ISSN 2073-4468 ; 2073-4468
    ISSN (online) 2073-4468
    ISSN 2073-4468
    DOI 10.3390/antib12020029
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A Comparative Analysis of Fibroblast Activation Protein-Targeted Small Molecule-Drug, Antibody-Drug, and Peptide-Drug Conjugates.

    Zana, Aureliano / Puig-Moreno, Claudia / Bocci, Matilde / Gilardoni, Ettore / Di Nitto, Cesare / Principi, Lucrezia / Ravazza, Domenico / Rotta, Giulia / Prodi, Eleonora / De Luca, Roberto / Neri, Dario / Cazzamalli, Samuele

    Bioconjugate chemistry

    2023  Volume 34, Issue 7, Page(s) 1205–1211

    Abstract: We present the ... ...

    Abstract We present the first
    MeSH term(s) Humans ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Fibroblasts ; Immunoconjugates ; Neoplasms ; Oligopeptides ; Peptides ; Xenograft Model Antitumor Assays
    Chemical Substances Antineoplastic Agents ; Immunoconjugates ; Oligopeptides ; Peptides
    Language English
    Publishing date 2023-07-03
    Publishing country United States
    Document type Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1024041-x
    ISSN 1520-4812 ; 1043-1802
    ISSN (online) 1520-4812
    ISSN 1043-1802
    DOI 10.1021/acs.bioconjchem.3c00244
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 3400: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: An Engineered IFNγ-Antibody Fusion Protein with Improved Tumor-Homing Properties.

    Di Nitto, Cesare / Gilardoni, Ettore / Mock, Jacqueline / Nadal, Lisa / Weiss, Tobias / Weller, Michael / Seehusen, Frauke / Libbra, Chiara / Puca, Emanuele / Neri, Dario / De Luca, Roberto

    Pharmaceutics

    2023  Volume 15, Issue 2

    Abstract: Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune ... ...

    Abstract Interferon-gamma (IFNγ) is one of the central cytokines produced by the innate and adaptive immune systems. IFNγ directly favors tumor growth control by enhancing the immunogenicity of tumor cells, induces IP-10 secretion facilitating (CXCR3+) immune cell infiltration, and can prime macrophages to an M1-like phenotype inducing proinflammatory cytokine release. We had previously reported that the targeted delivery of IFNγ to neoplastic lesions may be limited by the trapping of IFNγ-based products by cognate receptors found in different organs. Here we describe a novel fusion protein consisting of the L19 antibody, specific to the alternatively spliced extra-domain B of fibronectin (EDB), fused to a variant of IFNγ with reduced affinity to its cognate receptor. The product (named L19-IFNγ KRG) selectively localized to tumors in mice, showed favorable pharmacokinetic profiles in monkeys and regained biological activity upon antigen binding. The fusion protein was investigated in two murine models of cancer, both as monotherapy and in combination with therapeutic modalities which are frequently used for cancer therapy. L19-IFNγ KRG induced tumor growth retardation and increased the intratumoral concentration of T cells and NK cells in combination with anti-PD-1.
    Language English
    Publishing date 2023-01-22
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527217-2
    ISSN 1999-4923
    ISSN 1999-4923
    DOI 10.3390/pharmaceutics15020377
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Intracellular label-free detection of mesenchymal stem cell metabolism within a perivascular niche-on-a-chip.

    Perottoni, Simone / Neto, Nuno G B / Di Nitto, Cesare / Dmitriev, Ruslan I / Raimondi, Manuela Teresa / Monaghan, Michael G

    Lab on a chip

    2021  Volume 21, Issue 7, Page(s) 1395–1408

    Abstract: The stem cell niche at the perivascular space in human tissue plays a pivotal role in dictating the overall fate of stem cells within it. Mesenchymal stem cells (MSCs) in particular, experience influential microenvironmental conditions, which induce ... ...

    Abstract The stem cell niche at the perivascular space in human tissue plays a pivotal role in dictating the overall fate of stem cells within it. Mesenchymal stem cells (MSCs) in particular, experience influential microenvironmental conditions, which induce specific metabolic profiles that affect processes of cell differentiation and dysregulation of the immunomodulatory function. Reports focusing specifically on the metabolic status of MSCs under the effect of pathophysiological stimuli - in terms of flow velocities, shear stresses or oxygen tension - do not model heterogeneous gradients, highlighting the need for more advanced models reproducing the metabolic niche. Organ-on-a-chip technology offers the most advanced tools for stem cell niche modelling thus allowing for controlled dynamic culture conditions while profiling tuneable oxygen tension gradients. However, current systems for live cell detection of metabolic activity inside microfluidic devices require the integration of microsensors. The presence of such microsensors poses the potential to alter microfluidics and their resolution does not enable intracellular measurements but rather a global representation concerning cellular metabolism. Here, we present a metabolic toolbox coupling a miniaturised in vitro system for human-MSCs dynamic culture, which mimics microenvironmental conditions of the perivascular niche, with high-resolution imaging of cell metabolism. Using fluorescence lifetime imaging microscopy (FLIM) we monitor the spatial metabolic machinery and correlate it with experimentally validated intracellular oxygen concentration after designing the oxygen tension decay along the fluidic chamber by in silico models prediction. Our platform allows the metabolic regulation of MSCs, mimicking the physiological niche in space and time, and its real-time monitoring representing a functional tool for modelling perivascular niches, relevant diseases and metabolic-related uptake of pharmaceuticals.
    MeSH term(s) Cell Differentiation ; Humans ; Lab-On-A-Chip Devices ; Mesenchymal Stem Cells ; Stem Cell Niche ; Stem Cells
    Language English
    Publishing date 2021-02-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2056646-3
    ISSN 1473-0189 ; 1473-0197
    ISSN (online) 1473-0189
    ISSN 1473-0197
    DOI 10.1039/d0lc01034k
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma.

    Look, Thomas / Puca, Emanuele / Bühler, Marcel / Kirschenbaum, Daniel / De Luca, Roberto / Stucchi, Riccardo / Ravazza, Domenico / Di Nitto, Cesare / Roth, Patrick / Katzenelenbogen, Yonatan / Weiner, Assaf / Rindlisbacher, Lukas / Becher, Burkhard / Amit, Ido / Weller, Michael / Neri, Dario / Hemmerle, Teresa / Weiss, Tobias

    Science translational medicine

    2023  Volume 15, Issue 697, Page(s) eadf2281

    Abstract: Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively ... ...

    Abstract Glioblastoma is the most aggressive primary brain tumor with an unmet need for more effective therapies. Here, we investigated combination therapies based on L19TNF, an antibody-cytokine fusion protein based on tumor necrosis factor that selectively localizes to cancer neovasculature. Using immunocompetent orthotopic glioma mouse models, we identified strong anti-glioma activity of L19TNF in combination with the alkylating agent CCNU, which cured the majority of tumor-bearing mice, whereas monotherapies only had limited efficacy. In situ and ex vivo immunophenotypic and molecular profiling in the mouse models revealed that L19TNF and CCNU induced tumor DNA damage and treatment-associated tumor necrosis. In addition, this combination also up-regulated tumor endothelial cell adhesion molecules, promoted the infiltration of immune cells into the tumor, induced immunostimulatory pathways, and decreased immunosuppression pathways. MHC immunopeptidomics demonstrated that L19TNF and CCNU increased antigen presentation on MHC class I molecules. The antitumor activity was T cell dependent and completely abrogated in immunodeficient mouse models. On the basis of these encouraging results, we translated this treatment combination to patients with glioblastoma. The clinical translation is ongoing but already shows objective responses in three of five patients in the first recurrent glioblastoma patient cohort treated with L19TNF in combination with CCNU (NCT04573192).
    MeSH term(s) Animals ; Mice ; Glioblastoma/drug therapy ; T-Lymphocytes ; Neoplasm Recurrence, Local ; Tumor Necrosis Factor-alpha ; Disease Models, Animal ; Lomustine
    Chemical Substances Tumor Necrosis Factor-alpha ; Lomustine (7BRF0Z81KG)
    Language English
    Publishing date 2023-05-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.adf2281
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6941: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  7. Article ; Online: Generation and

    Nadal, Lisa / Peissert, Frederik / Elsayed, Abdullah / Weiss, Tobias / Look, Thomas / Weller, Michael / Piro, Geny / Carbone, Carmine / Tortora, Giampaolo / Matasci, Mattia / Favalli, Nicholas / Corbellari, Riccardo / Di Nitto, Cesare / Prodi, Eleonora / Libbra, Chiara / Galeazzi, Simone / Carotenuto, Claudiopietro / Halin, Cornelia / Puca, Emanuele /
    Neri, Dario / De Luca, Roberto

    Journal for immunotherapy of cancer

    2022  Volume 10, Issue 9

    Abstract: Background: In this study, we describe the generation of a fully human monoclonal antibody (named '7NP2') targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.: Methods! ...

    Abstract Background: In this study, we describe the generation of a fully human monoclonal antibody (named '7NP2') targeting human fibroblast activation protein (FAP), an antigen expressed in the microenvironment of different types of solid neoplasms.
    Methods: 7NP2 was isolated from a synthetic antibody phage display library and was improved by one round of mutagenesis-based affinity maturation. The tumor recognition properties of the antibody were validated by immunofluorescence procedures performed on cancer biopsies from human patients. A fusion protein consisting of the 7NP2 antibody linked to interleukin (IL)-12 was generated and the anticancer activity of the murine surrogate product (named mIL12-7NP2) was evaluated in mouse models. Furthermore, the safety of the fully human product (named IL12-7NP2) was evaluated in
    Results: Biodistribution analysis in tumor-bearing mice confirmed the ability of the product to selectively localize to solid tumors while sparing healthy organs. Encouraged by these results, therapy studies were conducted
    Conclusions: The results obtained in this work provided a rationale for future clinical translation activities using IL12-7NP2.
    MeSH term(s) Animals ; Antibodies, Monoclonal/pharmacology ; Antibodies, Monoclonal/therapeutic use ; Humans ; Interleukin-12/metabolism ; Mice ; Neoplasms/drug therapy ; Tissue Distribution ; Tumor Microenvironment
    Chemical Substances Antibodies, Monoclonal ; Interleukin-12 (187348-17-0)
    Language English
    Publishing date 2022-09-14
    Publishing country England
    Document type Journal Article
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-005282
    Database MEDical Literature Analysis and Retrieval System OnLINE

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