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Article

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

1
Institute of Immunology, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany
2
Department of Diagnostic and Interventional Radiology and Nuclear Medicine, UKE, 20246 Hamburg, Germany
3
Research Department Cell and Gene Therapy, UKE, 20246 Hamburg, Germany
4
Department of Stem Cell Transplantation, UKE, 20246 Hamburg, Germany
5
Hematological-Oncology Center Altona, 22767 Hamburg, Germany
*
Authors to whom correspondence should be addressed.
Cells 2020, 9(2), 321; https://doi.org/10.3390/cells9020321
Received: 28 November 2019 / Revised: 14 January 2020 / Accepted: 22 January 2020 / Published: 29 January 2020
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. View Full-Text
Keywords: CD38; nanobody; chimeric antigen receptor; NK-92 cells; cellular cytotoxicity assays; luciferase; heavy chain antibody; multiple myeloma CD38; nanobody; chimeric antigen receptor; NK-92 cells; cellular cytotoxicity assays; luciferase; heavy chain antibody; multiple myeloma
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MDPI and ACS Style

Hambach, J.; Riecken, K.; Cichutek, S.; Schütze, K.; Albrecht, B.; Petry, K.; Röckendorf, J.L.; Baum, N.; Kröger, N.; Hansen, T.; Schuch, G.; Haag, F.; Adam, G.; Fehse, B.; Bannas, P.; Koch-Nolte, F. Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs). Cells 2020, 9, 321. https://doi.org/10.3390/cells9020321

AMA Style

Hambach J, Riecken K, Cichutek S, Schütze K, Albrecht B, Petry K, Röckendorf JL, Baum N, Kröger N, Hansen T, Schuch G, Haag F, Adam G, Fehse B, Bannas P, Koch-Nolte F. Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs). Cells. 2020; 9(2):321. https://doi.org/10.3390/cells9020321

Chicago/Turabian Style

Hambach, Julia, Kristoffer Riecken, Sophia Cichutek, Kerstin Schütze, Birte Albrecht, Katharina Petry, Jana Larissa Röckendorf, Natalie Baum, Nicolaus Kröger, Timon Hansen, Gunter Schuch, Friedrich Haag, Gerhard Adam, Boris Fehse, Peter Bannas, and Friedrich Koch-Nolte. 2020. "Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs)" Cells 9, no. 2: 321. https://doi.org/10.3390/cells9020321

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