Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs)

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Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs). / Hambach, Julia; Riecken, Kristoffer; Cichutek, Sophia (Autor/-in intern machen); Schütze, Kerstin; Albrecht, Birte; Petry, Katharina; Röckendorf, Jana Larissa (Autor/-in intern machen); Baum, Natalie; Kröger, Nicolaus; Hansen, Timon; Schuch, Gunter; Haag, Friedrich; Adam, Gerhard; Fehse, Boris; Bannas, Peter; Koch-Nolte, Friedrich.

in: CELLS-BASEL, Jahrgang 9, Nr. 2, 29.01.2020.

Publikationen: SCORING: Beitrag in Fachzeitschrift/ZeitungSCORING: ZeitschriftenaufsätzeForschungBegutachtung

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@article{2d523ee3a1e9475d9b9792e884a9739e,
title = "Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs)",
abstract = "The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematological malignancies. We recently generated CD38-specific nanobodies, single immunoglobulin variable domains derived from heavy-chain antibodies naturally occurring in llamas. Nanobodies exhibit high solubility and stability, allowing easy reformatting into recombinant fusion proteins. Here we explore the utility of CD38-specific nanobodies as ligands for nanobody-based chimeric antigen receptors (Nb-CARs). We cloned retroviral expression vectors for CD38-specific Nb-CARs. The human natural killer cell line NK-92 was transduced to stably express these Nb-CARs. As target cells we used CD38-expressing as well as CRISPR/Cas9-generated CD38-deficient tumor cell lines (CA-46, LP-1, and Daudi) transduced with firefly luciferase. With these effector and target cells we established luminescence and flow-cytometry CAR-dependent cellular cytotoxicity assays (CARDCCs). Finally, the cytotoxic efficacy of Nb-CAR NK-92 cells was tested on primary patient-derived CD38-expressing multiple myeloma cells. NK-92 cells expressing CD38-specific Nb-CARs specifically lysed CD38-expressing but not CD38-deficient tumor cell lines. Moreover, the Nb-CAR-NK cells effectively depleted CD38-expressing multiple myeloma cells in primary human bone marrow samples. Our results demonstrate efficacy of Nb-CARs in vitro. The potential clinical efficacy of Nb-CARs in vivo remains to be evaluated.",
author = "Julia Hambach and Kristoffer Riecken and Sophia Cichutek and Kerstin Sch{\"u}tze and Birte Albrecht and Katharina Petry and R{\"o}ckendorf, {Jana Larissa} and Natalie Baum and Nicolaus Kr{\"o}ger and Timon Hansen and Gunter Schuch and Friedrich Haag and Gerhard Adam and Boris Fehse and Peter Bannas and Friedrich Koch-Nolte",
year = "2020",
month = "1",
day = "29",
doi = "10.3390/cells9020321",
language = "English",
volume = "9",
journal = "CELLS-BASEL",
issn = "2073-4409",
number = "2",

}

RIS

TY - JOUR

T1 - Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs)

AU - Hambach, Julia

AU - Riecken, Kristoffer

AU - Schütze, Kerstin

AU - Albrecht, Birte

AU - Petry, Katharina

AU - Baum, Natalie

AU - Kröger, Nicolaus

AU - Hansen, Timon

AU - Schuch, Gunter

AU - Haag, Friedrich

AU - Adam, Gerhard

AU - Fehse, Boris

AU - Bannas, Peter

AU - Koch-Nolte, Friedrich

A2 - Cichutek, Sophia

A2 - Röckendorf, Jana Larissa

PY - 2020/1/29

Y1 - 2020/1/29

N2 - The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematological malignancies. We recently generated CD38-specific nanobodies, single immunoglobulin variable domains derived from heavy-chain antibodies naturally occurring in llamas. Nanobodies exhibit high solubility and stability, allowing easy reformatting into recombinant fusion proteins. Here we explore the utility of CD38-specific nanobodies as ligands for nanobody-based chimeric antigen receptors (Nb-CARs). We cloned retroviral expression vectors for CD38-specific Nb-CARs. The human natural killer cell line NK-92 was transduced to stably express these Nb-CARs. As target cells we used CD38-expressing as well as CRISPR/Cas9-generated CD38-deficient tumor cell lines (CA-46, LP-1, and Daudi) transduced with firefly luciferase. With these effector and target cells we established luminescence and flow-cytometry CAR-dependent cellular cytotoxicity assays (CARDCCs). Finally, the cytotoxic efficacy of Nb-CAR NK-92 cells was tested on primary patient-derived CD38-expressing multiple myeloma cells. NK-92 cells expressing CD38-specific Nb-CARs specifically lysed CD38-expressing but not CD38-deficient tumor cell lines. Moreover, the Nb-CAR-NK cells effectively depleted CD38-expressing multiple myeloma cells in primary human bone marrow samples. Our results demonstrate efficacy of Nb-CARs in vitro. The potential clinical efficacy of Nb-CARs in vivo remains to be evaluated.

AB - The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematological malignancies. We recently generated CD38-specific nanobodies, single immunoglobulin variable domains derived from heavy-chain antibodies naturally occurring in llamas. Nanobodies exhibit high solubility and stability, allowing easy reformatting into recombinant fusion proteins. Here we explore the utility of CD38-specific nanobodies as ligands for nanobody-based chimeric antigen receptors (Nb-CARs). We cloned retroviral expression vectors for CD38-specific Nb-CARs. The human natural killer cell line NK-92 was transduced to stably express these Nb-CARs. As target cells we used CD38-expressing as well as CRISPR/Cas9-generated CD38-deficient tumor cell lines (CA-46, LP-1, and Daudi) transduced with firefly luciferase. With these effector and target cells we established luminescence and flow-cytometry CAR-dependent cellular cytotoxicity assays (CARDCCs). Finally, the cytotoxic efficacy of Nb-CAR NK-92 cells was tested on primary patient-derived CD38-expressing multiple myeloma cells. NK-92 cells expressing CD38-specific Nb-CARs specifically lysed CD38-expressing but not CD38-deficient tumor cell lines. Moreover, the Nb-CAR-NK cells effectively depleted CD38-expressing multiple myeloma cells in primary human bone marrow samples. Our results demonstrate efficacy of Nb-CARs in vitro. The potential clinical efficacy of Nb-CARs in vivo remains to be evaluated.

U2 - 10.3390/cells9020321

DO - 10.3390/cells9020321

M3 - SCORING: Journal articles

C2 - 32013131

VL - 9

JO - CELLS-BASEL

JF - CELLS-BASEL

SN - 2073-4409

IS - 2

ER -