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  1. Article ; 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  Volume 14, Issue 1, Page(s) 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 term(s) Animals ; Hydrogen-Ion Concentration ; Ipilimumab/therapeutic use ; Mice ; Neoplasms ; Therapeutic Index ; Tumor Microenvironment
    Chemical Substances Ipilimumab
    Language English
    Publishing date 2022-02-23
    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 10.1080/19420862.2021.2024642
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; 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  Volume 81, Issue 11, Page(s) 2983–2994

    Abstract: ... ...

    Abstract FOXP3
    MeSH term(s) 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
    Chemical Substances Antibodies, Monoclonal ; CCR8 protein, human ; Immunoglobulin Fc Fragments ; Programmed Cell Death 1 Receptor ; Receptors, CCR8
    Language English
    Publishing date 2021-03-23
    Publishing country United States
    Document type 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uh III Zs.135/5: Show issues Location:
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    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; 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  Volume 12, Issue 1, Page(s) 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 term(s) Animals ; Antibodies, Bispecific ; Antigens, CD20 ; CD3 Complex ; Epitopes ; Humans ; Mice ; Neoplasms ; T-Lymphocytes
    Chemical Substances Antibodies, Bispecific ; Antigens, CD20 ; CD3 Complex ; Epitopes
    Language English
    Publishing date 2022-03-03
    Publishing country England
    Document type 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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