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  1. Article ; Online: Epitope mapping of monoclonal antibodies: a comprehensive comparison of different technologies.

    Dang, Xibei / Guelen, Lars / Lutje Hulsik, David / Ermakov, Grigori / Hsieh, Edward J / Kreijtz, Joost / Stammen-Vogelzangs, Judith / Lodewijks, Imke / Bertens, Astrid / Bramer, Arne / Guadagnoli, Marco / Nazabal, Alexis / van Elsas, Andrea / Fischmann, Thierry / Juan, Veronica / Beebe, Amy / Beaumont, Maribel / van Eenennaam, Hans

    mAbs

    2023  Volume 15, Issue 1, Page(s) 2285285

    Abstract: Monoclonal antibodies have become an important class of therapeutics in the last 30 years. Because the mechanism of action of therapeutic antibodies is intimately linked to their binding epitopes, identification of the epitope of an antibody to the ... ...

    Abstract Monoclonal antibodies have become an important class of therapeutics in the last 30 years. Because the mechanism of action of therapeutic antibodies is intimately linked to their binding epitopes, identification of the epitope of an antibody to the antigen plays a central role during antibody drug development. The gold standard of epitope mapping, X-ray crystallography, requires a high degree of proficiency with no guarantee of success. Here, we evaluated six widely used alternative methods for epitope identification (peptide array, alanine scan, domain exchange, hydrogen-deuterium exchange, chemical cross-linking, and hydroxyl radical footprinting) in five antibody-antigen combinations (pembrolizumab+PD1, nivolumab+PD1, ipilimumab+CTLA4, tremelimumab+CTLA4, and MK-5890+CD27). The advantages and disadvantages of each technique are demonstrated by our data and practical advice on when and how to apply specific epitope mapping techniques during the drug development process is provided. Our results suggest chemical cross-linking most accurately identifies the epitope as defined by crystallography.
    MeSH term(s) Epitope Mapping/methods ; Antibodies, Monoclonal/chemistry ; CTLA-4 Antigen ; Epitopes ; Antigens
    Chemical Substances Antibodies, Monoclonal ; CTLA-4 Antigen ; Epitopes ; Antigens
    Language English
    Publishing date 2023-11-27
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2537838-7
    ISSN 1942-0870 ; 1942-0870
    ISSN (online) 1942-0870
    ISSN 1942-0870
    DOI 10.1080/19420862.2023.2285285
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Preclinical characterization and clinical translation of pharmacodynamic markers for MK-5890: a human CD27 activating antibody for cancer immunotherapy.

    Guelen, Lars / Fischmann, Thierry O / Wong, Jerelyn / Mauze, Smita / Guadagnoli, Marco / Bąbała, Nikolina / Wagenaars, Jozef / Juan, Veronica / Rosen, David / Prosise, Winnie / Habraken, Maurice / Lodewijks, Imke / Gu, Danling / Stammen-Vogelzangs, Judith / Yu, Ying / Baker, Jeanne / Lutje Hulsik, David / Driessen-Engels, Lilian / Malashock, Dan /
    Kreijtz, Joost / Bertens, Astrid / de Vries, Evert / Bovens, Astrid / Bramer, Arne / Zhang, Yiwei / Wnek, Richard / Troth, Sean / Chartash, Elliot / Dobrenkov, Konstantin / Sadekova, Svetlana / van Elsas, Andrea / Cheung, Jason K / Fayadat-Dilman, Laurence / Borst, Jannie / Beebe, Amy M / Van Eenennaam, Hans

    Journal for immunotherapy of cancer

    2022  Volume 10, Issue 9

    Abstract: Background: Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of ... ...

    Abstract Background: Immune checkpoint inhibitors (ICI) have radically changed cancer therapy, but most patients with cancer are unresponsive or relapse after treatment. MK-5890 is a CD27 agonist antibody intended to complement ICI therapy. CD27 is a member of the tumor necrosis factor receptor superfamily that plays a critical role in promoting responses of T cells, B cells and NK cells.
    Methods: Anti-CD27 antibodies were generated and selected for agonist activity using NF-кB luciferase reporter assays. Antibodies were humanized and characterized for agonism using in vitro T-cell proliferation assays. The epitope recognized on CD27 by MK-5890 was established by X-ray crystallography. Anti-tumor activity was evaluated in a human CD27 knock-in mouse. Preclinical safety was tested in rhesus monkeys. Pharmacodynamic properties were examined in mouse, rhesus monkeys and a phase 1 dose escalation clinical study in patients with cancer.
    Results: Humanized anti-CD27 antibody MK-5890 (hIgG1) was shown to bind human CD27 on the cell surface with sub-nanomolar potency and to partially block binding to its ligand, CD70. Crystallization studies revealed that MK-5890 binds to a unique epitope in the cysteine-rich domain 1 (CRD1). MK-5890 activated CD27 expressed on 293T NF-κB luciferase reporter cells and, conditional on CD3 stimulation, in purified CD8+ T cells without the requirement of crosslinking. Functional Fc-receptor interaction was required to activate CD8+ T cells in an ex vivo tumor explant system and to induce antitumor efficacy in syngeneic murine subcutaneous tumor models. MK-5890 had monotherapy efficacy in these models and enhanced efficacy of PD-1 blockade. MK-5890 reduced in an isotype-dependent and dose-dependent manner circulating, but not tumor-infiltrating T-cell numbers in these mouse models. In rhesus monkey and human patients, reduction in circulating T cells was transient and less pronounced than in mouse. MK-5890 induced transient elevation of chemokines MCP-1, MIP-1α, and MIP-1β in the serum of mice, rhesus monkeys and patients with cancer. MK-5890 was well tolerated in rhesus monkeys and systemic exposure to MK-5890 was associated with CD27 occupancy at all doses.
    Conclusions: MK-5890 is a novel CD27 agonistic antibody with the potential to complement the activity of PD-1 checkpoint inhibition in cancer immunotherapy and is currently undergoing clinical evaluation.
    MeSH term(s) Animals ; Antibodies, Monoclonal/therapeutic use ; Cell Count ; Epitopes ; Humans ; Immunotherapy ; Macaca mulatta ; Mice ; Neoplasms/drug therapy ; Programmed Cell Death 1 Receptor ; Tumor Necrosis Factor Receptor Superfamily, Member 7
    Chemical Substances Antibodies, Monoclonal ; Epitopes ; Programmed Cell Death 1 Receptor ; Tumor Necrosis Factor Receptor Superfamily, Member 7
    Language English
    Publishing date 2022-09-13
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-005049
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: BYON4228 is a pan-allelic antagonistic SIRPα antibody that potentiates destruction of antibody-opsonized tumor cells and lacks binding to SIRPγ on T cells.

    van Helden, Mary J / Zwarthoff, Seline A / Arends, Roel J / Reinieren-Beeren, Inge M J / Paradé, Marc C B C / Driessen-Engels, Lilian / de Laat-Arts, Karin / Damming, Désirée / Santegoeds-Lenssen, Ellen W H / van Kuppeveld, Daphne W J / Lodewijks, Imke / Olsman, Hugo / Matlung, Hanke L / Franke, Katka / Mattaar-Hepp, Ellen / Stokman, Marloes E M / de Wit, Benny / Glaudemans, Dirk H R F / van Wijk, Daniëlle E J W /
    Joosten-Stoffels, Lonnie / Schouten, Jan / Boersema, Paul J / van der Vleuten, Monique / Sanderink, Jorien W H / Kappers, Wendela A / van den Dobbelsteen, Diels / Timmers, Marco / Ubink, Ruud / Rouwendal, Gerard J A / Verheijden, Gijs / van der Lee, Miranda M C / Dokter, Wim H A / van den Berg, Timo K

    Journal for immunotherapy of cancer

    2023  Volume 11, Issue 4

    Abstract: Background: Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, ...

    Abstract Background: Preclinical studies have firmly established the CD47-signal-regulatory protein (SIRP)α axis as a myeloid immune checkpoint in cancer, and this is corroborated by available evidence from the first clinical studies with CD47 blockers. However, CD47 is ubiquitously expressed and mediates functional interactions with other ligands as well, and therefore targeting of the primarily myeloid cell-restricted inhibitory immunoreceptor SIRPα may represent a better strategy.
    Method: We generated BYON4228, a novel SIRPα-directed antibody. An extensive preclinical characterization was performed, including direct comparisons to previously reported anti-SIRPα antibodies.
    Results: BYON4228 is an antibody directed against SIRPα that recognizes both allelic variants of SIRPα in the human population, thereby maximizing its potential clinical applicability. Notably, BYON4228 does not recognize the closely related T-cell expressed SIRPγ that mediates interactions with CD47 as well, which are known to be instrumental in T-cell extravasation and activation. BYON4228 binds to the N-terminal Ig-like domain of SIRPα and its epitope largely overlaps with the CD47-binding site. BYON4228 blocks binding of CD47 to SIRPα and inhibits signaling through the CD47-SIRPα axis. Functional studies show that BYON4228 potentiates macrophage-mediated and neutrophil-mediated killing of hematologic and solid cancer cells in vitro in the presence of a variety of tumor-targeting antibodies, including trastuzumab, rituximab, daratumumab and cetuximab. The silenced Fc region of BYON4228 precludes immune cell-mediated elimination of SIRPα-positive myeloid cells, implying anticipated preservation of myeloid immune effector cells in patients. The unique profile of BYON4228 clearly distinguishes it from previously reported antibodies representative of agents in clinical development, which either lack recognition of one of the two SIRPα polymorphic variants (HEFLB), or cross-react with SIRPγ and inhibit CD47-SIRPγ interactions (SIRPAB-11-K322A, 1H9), and/or have functional Fc regions thereby displaying myeloid cell depletion activity (SIRPAB-11-K322A). In vivo, BYON4228 increases the antitumor activity of rituximab in a B-cell Raji xenograft model in human SIRPα
    Conclusions: Collectively, this defines BYON4228 as a preclinically highly differentiating pan-allelic SIRPα antibody without T-cell SIRPγ recognition that promotes the destruction of antibody-opsonized cancer cells. Clinical studies are planned to start in 2023.
    MeSH term(s) Mice ; Animals ; Humans ; CD47 Antigen ; T-Lymphocytes/metabolism ; Rituximab ; Macrophages ; Neoplasms/drug therapy ; Antibodies, Neoplasm
    Chemical Substances CD47 Antigen ; Rituximab (4F4X42SYQ6) ; Antibodies, Neoplasm
    Language English
    Publishing date 2023-04-19
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2719863-7
    ISSN 2051-1426 ; 2051-1426
    ISSN (online) 2051-1426
    ISSN 2051-1426
    DOI 10.1136/jitc-2022-006567
    Database MEDical Literature Analysis and Retrieval System OnLINE

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