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- Title
Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs).
- Authors
Hambach, Julia; Riecken, Kristoffer; Cichutek, Sophia; Schütze, Kerstin; Albrecht, Birte; Petry, Katharina; Röckendorf, Jana Larissa; Baum, Natalie; Kröger, Nicolaus; Hansen, Timon; Schuch, Gunter; Haag, Friedrich; Adam, Gerhard; Fehse, Boris; Bannas, Peter; Koch-Nolte, Friedrich
- 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.
- Subjects
CHIMERIC antigen receptors; MULTIPLE myeloma; CD19 antigen; CHIMERIC proteins; LYMPHOMAS; RECOMBINANT proteins; LUCIFERASES; T cell receptors
- Publication
Cells (2073-4409), 2020, Vol 9, Issue 2, p321
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells9020321