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  1. AU="Dadas, Osman"
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  1. Article ; Online: Delivering co-stimulatory tumor necrosis factor receptor agonism for cancer immunotherapy: past, current and future perspectives.

    Dadas, Osman / Ertay, Ayse / Cragg, Mark S

    Frontiers in immunology

    2023  Volume 14, Page(s) 1147467

    Abstract: The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is ... ...

    Abstract The tumor necrosis factor superfamily (TNFSF) and their receptors (TNFRSF) are important regulators of the immune system, mediating proliferation, survival, differentiation, and function of immune cells. As a result, their targeting for immunotherapy is attractive, although to date, under-exploited. In this review we discuss the importance of co-stimulatory members of the TNFRSF in optimal immune response generation, the rationale behind targeting these receptors for immunotherapy, the success of targeting them in pre-clinical studies and the challenges in translating this success into the clinic. The efficacy and limitations of the currently available agents are discussed alongside the development of next generation immunostimulatory agents designed to overcome current issues, and capitalize on this receptor class to deliver potent, durable and safe drugs for patients.
    MeSH term(s) Humans ; Neoplasms ; Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha ; Immune System/pathology ; Immunotherapy
    Chemical Substances Receptors, Tumor Necrosis Factor ; Tumor Necrosis Factor-alpha
    Language English
    Publishing date 2023-04-25
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1147467
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Protective low-avidity anti-tumour CD8+ T cells are selectively attenuated by regulatory T cells.

    Sugiyarto, Gessa / Prossor, David / Dadas, Osman / Arcia-Anaya, E David / Elliott, Tim / James, Edward

    Immunotherapy advances

    2020  Volume 1, Issue 1, Page(s) ltaa001

    Abstract: Objectives: Regulatory T cells (Treg) play a major role in the suppression of protective anti-tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, Tregs differentially suppress responses to two characterised CD8+ T epitopes, ...

    Abstract Objectives: Regulatory T cells (Treg) play a major role in the suppression of protective anti-tumour T cell responses. In the CT26 BALB/c murine model of colorectal carcinoma, Tregs differentially suppress responses to two characterised CD8+ T epitopes, AH1 and GSW11, which results in an absence of detectable IFN-γ-producing GSW11-specific T cells in the spleen and lymph nodes of tumour challenged mice. Activation of GSW11-specific T cells correlates with protection against tumour progression. We wanted to examine the presence of non-functional GSW11-specific T cells in Treg replete and depleted mice, assess their phenotype and their affinity compared to AH1-specific T cells.
    Methods: We used peptide-specific tetramers to identify tumour-specific CD8+ T cells and assessed the cell surface expression of markers associated with exhaustion (PD-1, Tim3 and Lag-3) and their function by IFN-g production using flow cytometry. We also assessed the T cell receptor (TcR) clonality of tumour-specific T cells. Tetramer competition assays were performed to determine the relative affinity of identified TcR.
    Results: Here, we show that GSW11-specific T cells are in fact induced in Treg-replete, CT26-bearing mice, where they make up the majority of tumour-infiltrating CD8+ lymphocytes, but exhibit an 'exhausted' phenotype. This dysfunctional phenotype is induced early in the anti-tumour response in tumours. Depletion of Tregs prior to tumour challenge correlates with an altered T cell receptor (TcR) repertoire. Moreover, the avidity of GSW11-specific TcRs that expanded in the absence of Tregs was significantly lower compared with TcRs of CD8+populations that were diminished in protective anti-tumour responses.
    Conclusion: Our results indicate that Tregs suppress the induction of protective anti-tumour T cell responses and may signify that low-avidity T cells play an important role in this protection.
    Language English
    Publishing date 2020-11-25
    Publishing country England
    Document type Journal Article
    ISSN 2732-4303
    ISSN (online) 2732-4303
    DOI 10.1093/immadv/ltaa001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Fcγ receptor binding is required for maximal immunostimulation by CD70-Fc.

    Dadas, Osman / Allen, Joel D / Buchan, Sarah L / Kim, Jinny / Chan, H T Claude / Mockridge, C Ian / Duriez, Patrick J / Rogel, Anne / Crispin, Max / Al-Shamkhani, Aymen

    Frontiers in immunology

    2023  Volume 14, Page(s) 1252274

    Abstract: Introduction: T cell expressed CD27 provides costimulation upon binding to inducible membrane expressed trimeric CD70 and is required for protective CD8 T cell responses. CD27 agonists could therefore be used to bolster cellular vaccines and anti-tumour ...

    Abstract Introduction: T cell expressed CD27 provides costimulation upon binding to inducible membrane expressed trimeric CD70 and is required for protective CD8 T cell responses. CD27 agonists could therefore be used to bolster cellular vaccines and anti-tumour immune responses. To date, clinical development of CD27 agonists has focussed on anti-CD27 antibodies with little attention given to alternative approaches.
    Methods: Here, we describe the generation and activity of soluble variants of CD70 that form either trimeric (t) or dimer-of-trimer proteins and conduct side-by-side comparisons with an agonist anti-CD27 antibody. To generate a dimer-of-trimer protein (dt), we fused three extracellular domains of CD70 to the Fc domain of mouse IgG1 in a 'string of beads' configuration (dtCD70-Fc).
    Results: Whereas tCD70 failed to costimulate CD8 T cells, both dtCD70-Fc and an agonist anti-CD27 antibody were capable of enhancing T cell proliferation
    Discussion: These data reveal that TNFRSF ligands can be generated with a tunable activity profile and suggest that this class of immune agonists could have broad applications in immunotherapy.
    MeSH term(s) Animals ; Mice ; Receptors, IgG ; CD27 Ligand/metabolism ; Tumor Necrosis Factor Receptor Superfamily, Member 7/metabolism ; Immunization ; Vaccines
    Chemical Substances Receptors, IgG ; CD27 Ligand ; Tumor Necrosis Factor Receptor Superfamily, Member 7 ; Vaccines
    Language English
    Publishing date 2023-10-27
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2023.1252274
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Agonistic CD27 antibody potency is determined by epitope-dependent receptor clustering augmented through Fc-engineering.

    Heckel, Franziska / Turaj, Anna H / Fisher, Hayden / Chan, H T Claude / Marshall, Michael J E / Dadas, Osman / Penfold, Christine A / Inzhelevskaya, Tatyana / Mockridge, C Ian / Alvarado, Diego / Tews, Ivo / Keler, Tibor / Beers, Stephen A / Cragg, Mark S / Lim, Sean H

    Communications biology

    2022  Volume 5, Issue 1, Page(s) 229

    Abstract: Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel ... ...

    Abstract Agonistic CD27 monoclonal antibodies (mAb) have demonstrated impressive anti-tumour efficacy in multiple preclinical models but modest clinical responses. This might reflect current reagents delivering suboptimal CD27 agonism. Here, using a novel panel of CD27 mAb including a clinical candidate, we investigate the determinants of CD27 mAb agonism. Epitope mapping and in silico docking analysis show that mAb binding to membrane-distal and external-facing residues are stronger agonists. However, poor epitope-dependent agonism could partially be overcome by Fc-engineering, using mAb isotypes that promote receptor clustering, such as human immunoglobulin G1 (hIgG1, h1) with enhanced affinity to Fc gamma receptor (FcγR) IIb, or hIgG2 (h2). This study provides the critical knowledge required for the development of agonistic CD27 mAb that are potentially more clinically efficacious.
    MeSH term(s) Antibodies, Monoclonal/chemistry ; Antineoplastic Agents, Immunological/therapeutic use ; Cluster Analysis ; Epitopes ; Humans ; Neoplasms/metabolism
    Chemical Substances Antibodies, Monoclonal ; Antineoplastic Agents, Immunological ; Epitopes
    Language English
    Publishing date 2022-03-14
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2399-3642
    ISSN (online) 2399-3642
    DOI 10.1038/s42003-022-03182-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Complex Interplay between Epitope Specificity and Isotype Dictates the Biological Activity of Anti-human CD40 Antibodies.

    Yu, Xiaojie / Chan, H T Claude / Orr, Christian M / Dadas, Osman / Booth, Steven G / Dahal, Lekh N / Penfold, Christine A / O'Brien, Lyn / Mockridge, C Ian / French, Ruth R / Duriez, Patrick / Douglas, Leon R / Pearson, Arwen R / Cragg, Mark S / Tews, Ivo / Glennie, Martin J / White, Ann L

    Cancer cell

    2018  Volume 33, Issue 4, Page(s) 664–675.e4

    Abstract: Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine ... ...

    Abstract Anti-CD40 monoclonal antibodies (mAbs) that promote or inhibit receptor function hold promise as therapeutics for cancer and autoimmunity. Rules governing their diverse range of functions, however, are lacking. Here we determined characteristics of nine hCD40 mAbs engaging epitopes throughout the CD40 extracellular region expressed as varying isotypes. All mAb formats were strong agonists when hyper-crosslinked; however, only those binding the membrane-distal cysteine-rich domain 1 (CRD1) retained agonistic activity with physiological Fc gamma receptor crosslinking or as human immunoglobulin G2 isotype; agonistic activity decreased as epitopes drew closer to the membrane. In addition, all CRD2-4 binding mAbs blocked CD40 ligand interaction and were potent antagonists. Thus, the membrane distal CRD1 provides a region of choice for selecting CD40 agonists while CRD2-4 provides antagonistic epitopes.
    MeSH term(s) Antibodies, Monoclonal/chemistry ; Antibodies, Monoclonal/pharmacology ; Antibody Specificity ; CD40 Antigens/agonists ; CD40 Antigens/chemistry ; CD40 Antigens/metabolism ; CD40 Ligand/metabolism ; Cross-Linking Reagents ; Epitopes/chemistry ; Humans ; Models, Molecular ; Protein Binding/drug effects
    Chemical Substances Antibodies, Monoclonal ; CD40 Antigens ; Cross-Linking Reagents ; Epitopes ; CD40 Ligand (147205-72-9)
    Language English
    Publishing date 2018-03-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2018.02.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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