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      NKG2D ligand targeted Bispecific T Cell Engagers lead to robust antitumor activity against diverse human tumors

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          Abstract

          Two new bispecific T cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3ε binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3ε on human T cells. Both BiTEs specifically activated T cells to kill human tumor cell lines. Cytotoxicity by B2-OKT3 but not huNKG2D-OKT3 is blocked by soluble rMICA. The huNKG2D-OKT3 induced greater T cell cytokine production in comparison to B2-OKT3. No T cell pre-treatment was required for IFNγ production upon co-culture of B2-OKT3 or huNKG2D-OKT3 with T cells and target cells. The effector memory T cell compartment was the primary source of IFNγ, and culture of T cells and these BiTEs with plate-bound rMICA showed ligand density dependent production of IFNγ from both CD4 + and CD8 + T cells. There was two-fold more IFNγ produced per CD8 + T cell and five-fold greater percentage of CD8 + T cells producing IFNγ compared to CD4 + T cells. In addition, both BiTEs elicited significant anti-tumor responses against human metastatic melanoma tumor samples using autologous or healthy donor T cells. These data demonstrate the robust anti-tumor activity of these NKG2D ligand binding bispecific proteins and support their further development for clinical use.

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          Author and article information

          Journal
          101132535
          30097
          Mol Cancer Ther
          Mol. Cancer Ther.
          Molecular cancer therapeutics
          1535-7163
          1538-8514
          11 May 2017
          12 May 2017
          July 2017
          01 July 2018
          : 16
          : 7
          : 1335-1346
          Affiliations
          [1 ]Department of Microbiology & Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, NH
          [2 ]Department of Medicine, The Geisel School of Medicine at Dartmouth, Lebanon, NH
          [3 ]The Center for Synthetic Immunity, The Geisel School of Medicine at Dartmouth, Lebanon, NH
          Author notes
          Correspondence to: Charles.L.Sentman@ 123456dartmouth.edu , Department of Microbiology and Immunology, One Medical Center Drive, Lebanon, NH 03756 Phone: 603-653-0611 Fax: 603-650-6223
          [*]

          These authors contributed equally to this study.

          Article
          PMC5531202 PMC5531202 5531202 nihpa874374
          10.1158/1535-7163.MCT-16-0846
          5531202
          28500232
          66719218-561d-4c62-abc1-5d1566c9a7af
          History
          Categories
          Article

          BiTE,immunotherapy,interferon-gamma,MICA,cytotoxicity
          BiTE, immunotherapy, interferon-gamma, MICA, cytotoxicity

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