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  1. Artikel ; Online: Improved therapeutic index of an acidic pH-selective antibody.

    Lee, Peter S / MacDonald, Katherine G / Massi, Evan / Chew, Pamela V / Bee, Christine / Perkins, Padma / Chau, Bryant / Thudium, Kent / Lohre, Jack / Nandi, Pradyot / Deyanova, Ekaterina G / Barman, Ishita / Gudmundsson, Olafur / Dollinger, Gavin / Sproul, Tim / Engelhardt, John J / Strop, Pavel / Rajpal, Arvind

    mAbs

    2022  Band 14, Heft 1, Seite(n) 2024642

    Abstract: Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which ... ...

    Abstract Although therapeutically efficacious, ipilimumab can exhibit dose-limiting toxicity that prevents maximal efficacious clinical outcomes and can lead to discontinuation of treatment. We hypothesized that an acidic pH-selective ipilimumab (pH Ipi), which preferentially and reversibly targets the acidic tumor microenvironment over the neutral periphery, may have a more favorable therapeutic index. While ipilimumab has pH-independent CTLA-4 affinity, pH Ipi variants have been engineered to have up to 50-fold enhanced affinity to CTLA-4 at pH 6.0 compared to pH 7.4. In hCTLA-4 knock-in mice, these variants have maintained anti-tumor activity and reduced peripheral activation, a surrogate marker for toxicity. pH-sensitive therapeutic antibodies may be a differentiating paradigm and a novel modality for enhanced tumor targeting and improved safety profiles.
    Mesh-Begriff(e) Animals ; Hydrogen-Ion Concentration ; Ipilimumab/therapeutic use ; Mice ; Neoplasms ; Therapeutic Index ; Tumor Microenvironment
    Chemische Substanzen Ipilimumab
    Sprache Englisch
    Erscheinungsdatum 2022-02-23
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 2537838-7
    ISSN 1942-0870 ; 1942-0870
    ISSN (online) 1942-0870
    ISSN 1942-0870
    DOI 10.1080/19420862.2021.2024642
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  2. Artikel ; Online: Fc-Optimized Anti-CCR8 Antibody Depletes Regulatory T Cells in Human Tumor Models.

    Campbell, Joseph R / McDonald, Bryan R / Mesko, Paul B / Siemers, Nathan O / Singh, Priti B / Selby, Mark / Sproul, Tim W / Korman, Alan J / Vlach, Logan M / Houser, Jeff / Sambanthamoorthy, Sharmila / Lu, Kai / Hatcher, Sandra V / Lohre, Jack / Jain, Renu / Lan, Ruth Y

    Cancer research

    2021  Band 81, Heft 11, Seite(n) 2983–2994

    Abstract: ... ...

    Abstract FOXP3
    Mesh-Begriff(e) Animals ; Antibodies, Monoclonal/pharmacology ; Apoptosis ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immune Tolerance/immunology ; Immunoglobulin Fc Fragments/immunology ; Immunotherapy/methods ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Programmed Cell Death 1 Receptor/antagonists & inhibitors ; Programmed Cell Death 1 Receptor/immunology ; Receptors, CCR8/antagonists & inhibitors ; Receptors, CCR8/immunology ; Skin/drug effects ; Skin/immunology ; Skin/metabolism ; Skin/pathology ; T-Lymphocytes, Regulatory/immunology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemische Substanzen Antibodies, Monoclonal ; CCR8 protein, human ; Immunoglobulin Fc Fragments ; Programmed Cell Death 1 Receptor ; Receptors, CCR8
    Sprache Englisch
    Erscheinungsdatum 2021-03-23
    Erscheinungsland United States
    Dokumenttyp Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-20-3585
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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  3. Artikel ; Online: Humanization of a strategic CD3 epitope enables evaluation of clinical T-cell engagers in a fully immunocompetent in vivo model.

    Zorn, Julie A / Wheeler, Matthew L / Barnes, Ralston M / Kaberna, Jim / Morishige, Winse / Harris, Marek / Huang, Richard Y-C / Lohre, Jack / Chang, Yu Ching / Chau, Bryant / Powers, Kathleen / Schindler, Ian / Neradugomma, Naveen / Thomas, Winston / Liao, Xiaoyun / Zhou, Yinhan / West, Sean M / Wang, Feng / Kotapati, Srikanth /
    Chen, Guodong / Yamazoe, Sayumi / Kosenko, Anastasia / Dollinger, Gavin / Sproul, Tim / Rajpal, Arvind / Strop, Pavel

    Scientific reports

    2022  Band 12, Heft 1, Seite(n) 3530

    Abstract: T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft ... ...

    Abstract T-cell engagers (TCEs) are a growing class of biotherapeutics being investigated in the clinic for treatment of a variety of hematological and solid tumor indications. However, preclinical evaluation of TCEs in vivo has been mostly limited to xenograft tumor models in human T-cell reconstituted immunodeficient mice, which have a number of limitations. To explore the efficacy of human TCEs in fully immunocompetent hosts, we developed a knock-in mouse model (hCD3E-epi) in which a 5-residue N-terminal fragment of murine CD3-epsilon was replaced with an 11-residue stretch from the human sequence that encodes for a common epitope recognized by anti-human CD3E antibodies in the clinic. T cells from hCD3E-epi mice underwent normal thymic development and could be efficiently activated upon crosslinking of the T-cell receptor with anti-human CD3E antibodies in vitro. Furthermore, a TCE targeting human CD3E and murine CD20 induced robust T-cell redirected killing of murine CD20-positive B cells in ex vivo hCD3E-epi splenocyte cultures, and also depleted nearly 100% of peripheral B cells for up to 7 days following in vivo administration. These results highlight the utility of this novel mouse model for exploring the efficacy of human TCEs in vivo, and suggest a useful tool for evaluating TCEs in combination with immuno-oncology/non-immuno-oncology agents against heme and solid tumor targets in hosts with a fully intact immune system.
    Mesh-Begriff(e) Animals ; Antibodies, Bispecific ; Antigens, CD20 ; CD3 Complex ; Epitopes ; Humans ; Mice ; Neoplasms ; T-Lymphocytes
    Chemische Substanzen Antibodies, Bispecific ; Antigens, CD20 ; CD3 Complex ; Epitopes
    Sprache Englisch
    Erscheinungsdatum 2022-03-03
    Erscheinungsland England
    Dokumenttyp Journal Article
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-06953-7
    Datenquelle MEDical Literature Analysis and Retrieval System OnLINE

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    Dieser Service ist kostenpflichtig (siehe Lieferbedingungen von subito). Bestellungen, die einen Artikel nebst Supplementary Material umfassen, werden grundsätzlich wie mehrfache Bestellungen bearbeitet. Gebühren fallen in diesen Fällen für jede einzelne Bestellung an.

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