NKG2D Ligand-Targeted Bispecific T-Cell Engagers Lead to Robust Antitumor Activity against Diverse Human Tumors

Molecular Cancer Therapeutics
Claire GodbersenCharles L Sentman

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 with B2-OKT3. No T-cell pretreatment was required for IFNγ production upon coculture 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 2-fold more IFNγ produced per CD8+ T cell and 5-fold greater percentage of CD8+ T cells producing IFNγ compared with CD4+ T...Continue Reading

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Citations

Apr 17, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Claire Godbersen-PalmerCharles L Sentman
Feb 27, 2020·Journal of Immunotoxicology·Cris KamperschroerOliver Thomas
Sep 27, 2018·Frontiers in Immunology·Dominik Schmiedel, Ofer Mandelboim
Mar 31, 2018·Science·Adelheid Cerwenka, Lewis L Lanier
Apr 27, 2019·Clinical Lymphoma, Myeloma & Leukemia·Irene GhobrialSagar Lonial
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May 5, 2021·Journal of Hematology & Oncology·Zheng TianXin Wang
May 4, 2021·Frontiers in Immunology·Ilona HagelsteinClemens Hinterleitner

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