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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) cells Article Targeting CD38-Expressing Multiple Myeloma and Burkitt Lymphoma Cells In Vitro with Nanobody-Based Chimeric Antigen Receptors (Nb-CARs) Julia Hambach 1,2, Kristoffer Riecken 3,4 , Sophia Cichutek 3,4, Kerstin Schütze 1,2, Birte Albrecht 1,2, Katharina Petry 1,2, Jana Larissa Röckendorf 1,2, Natalie Baum 1,2, Nicolaus Kröger 4, Timon Hansen 5, Gunter Schuch 5, Friedrich Haag 1, Gerhard Adam 2, Boris Fehse 3,4,* , Peter Bannas 2,* and Friedrich Koch-Nolte 1,* 1 Institute of Immunology, University Medical Center Hamburg-Eppendorf (UKE), 20246 Hamburg, Germany; [email protected] (J.H.); [email protected] (K.S.); [email protected] (B.A.); [email protected] (K.P.); [email protected] (J.L.R.); [email protected] (N.B.); [email protected] (F.H.) 2 Department of Diagnostic and Interventional Radiology and Nuclear Medicine, UKE, 20246 Hamburg, Germany; [email protected] 3 Research Department Cell and Gene Therapy, UKE, 20246 Hamburg, Germany; [email protected] (K.R.); [email protected] (S.C.) 4 Department of Stem Cell Transplantation, UKE, 20246 Hamburg, Germany; [email protected] 5 Hematological-Oncology Center Altona, 22767 Hamburg, Germany; [email protected] (T.H.); [email protected] (G.S.) * Correspondence: [email protected] (B.F.); [email protected] (P.B.); [email protected] (F.K.-N.) Received: 28 November 2019; Accepted: 22 January 2020; Published: 29 January 2020 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. Keywords: CD38; nanobody; chimeric antigen receptor; NK-92 cells; cellular cytotoxicity assays; luciferase; heavy chain antibody; multiple myeloma Cells 2020, 9, 321; doi:10.3390/cells9020321 www.mdpi.com/journal/cells Cells 2020, 9, 321 2 of 14 1. Introduction The NAD-hydrolyzing ecto-enzyme CD38 is overexpressed by multiple myeloma and other hematologicalCells 2019, 8, x malignancies [1–3]. CD38 has emerged as a promising target for therapy with cytotoxic2 of 13 antibodies. Three monoclonal antibodies have recently entered the clinic (daratumumab, isatuximab, antibodies. Three monoclonal antibodies have recently entered the clinic (daratumumab, isatuximab, and MOR202) for treatment of multiple myeloma (Figure1a) [4–6]. and MOR202) for treatment of multiple myeloma (Figure 1a) [4–6]. FigureFigure 1. Comparison 1. Comparison of of conventional conventional and and nanobody-based nanobody-based chimeric antigen antigen receptors. receptors. (a ()a Schematic) Schematic diagramsdiagrams of aof conventional a conventional antibody antibody (Ab), (Ab), a chimeric a chimeric antibody, antibody, a single a single chain chain variable variable fragment fragment (scFv), and(scFv), conventional and conventional scFv-based scFv-based chimeric antigenchimeric receptor antigen receptor (CAR). Examples (CAR). Examples of conventional of conventional and chimeric and CD38-specificchimeric CD38-specific Abs include Abs daratumumab include daratumumab and MOR202 and (conventionalMOR202 (conventional Abs) and Abs) isatuximab and isatuximab (chimeric Ab).(chimeric (b) Schematic Ab). (b diagrams) Schematic of diagrams a camelid of heavy a camelid chain heavy antibody chain (hcAb),antibody a (hcAb), chimeric a chimeric hcAb, a nanobodyhcAb, a (Nb)nanobody and a Nb-based (Nb) and chimeric a Nb-based antigen chimeric receptor antigen (Nb-CAR). receptor (Nb-CAR). TheThe variable variable domains domains of of conventional conventional antibodies antibodies (VH(VH and VL) VL) interact interact via via hydrophobic hydrophobic patches patches (indicated(indicated in black)in black) that that help help to to correctly correctly align align the the twotwo domainsdomains for for target target binding. binding. The The hydrophobic hydrophobic naturenature of thisof this interaction interaction and and its its relatively relatively lowlow aaffinity,ffinity, however,however, render render scFvs scFvs unstable unstable and and sticky sticky (Figure(Figure1a). 1a). Nanobodies Nanobodies are are single single variable variable immunoglobulin immunoglobulin domainsdomains derived derived from from heavy heavy chain chain antibodiesantibodies (hcAbs) (hcAbs) that that naturally naturally occur occur in in llamas, llamas, dromedaries,dromedaries, and and other other camelids camelids (Figure (Figure 1b)1b) [7,8]. [ 7, 8]. The mutation(s) that led to deletion of the CH1 domain in heavy chain antibodies must have occurred The mutation(s) that led to deletion of the CH1 domain in heavy chain antibodies must have occurred >50 million years ago, i.e., in a common ancestor of today’s extant camelids (dromedary, camel, >50 million years ago, i.e., in a common ancestor of today’s extant camelids (dromedary, camel, alpaca, alpaca, llama) [9]. The cluster of V genes in the IgH locus of extant camelids encodes both, highly llama) [9]. The cluster of V genes in the IgH locus of extant camelids encodes both, highly soluble soluble (VHH) and less soluble (VH) domains. The former occur in the vast majority of camelid (VHH)hcAbs, and the less latter soluble in camelid (VH) domains.conventional The Abs former akin to occur those in of the mice vast and majority men [9]. of Camelid camelid VHH hcAbs, thedomains latter in camelidapparently conventional have been shaped Abs akin by toevolution those of for mice high and solubility men [9 ].and Camelid stability VHH as a domainssingle apparentlydomain. haveThis renders been shaped nanobodies by evolution particularly for highsuited solubility for reformatting and stability in a LEGO-block as a single domain.like fashion This rendersinto fusion nanobodies proteins, particularly including dimers suited or for multimers reformatting of nanobodies, in a LEGO-block chimeric llama/human like fashion Nb-hcAbs, into fusion proteins,biparatopic including hcAbs, dimers and orNb-based multimers CARs of nanobodies,(Nb-CARs) [10,11]. chimeric Dimerization llama/human and Nb-hcAbs, multimerization biparatopic of hcAbs,nanobodies and Nb-based has been CARs used (Nb-CARs)to increase the [10 binding,11]. Dimerization strength and andthe specificity multimerization of the constructs of nanobodies [10,11]. has been usedFrom to increaseimmunized the llamas, binding we strength previously and theisolated specificity a panel of of the CD38-specific constructs [ 10nanobodies,11]. [12,13]. WeFrom have immunized shown that llamas, these nanobodies we previously can isolatedbe used ato panel construct of CD38-specific Nb-hcAbs, some nanobodies of which [12 exhibit,13]. We havemore shown potent that antibody-dependent these nanobodies can cellular be used cytotoxicity to construct (ADCC) Nb-hcAbs, than somedaratumumab of which exhibit(Figure more2) potent[10,14,15]. antibody-dependent cellular cytotoxicity (ADCC) than daratumumab (Figure2)[10,14,15]. Cells 2020, 9, 321 3 of 14 Cells 2019, 8, x 3 of 13 FigureFigure 2. Antibody- 2. Antibody- and CAR-dependentand CAR-dependent cellular cellular cytotoxicity. cytotoxicity. Schematic Schematic diagrams diagrams of antibody-dependent of antibody- cellulardependent cytotoxicity cellular (ADCC, cytotoxicity left) and (ADCC, chimeric left) antigen-receptor and chimeric dependent antigen-receptor cellular cytotoxicitydependent (CARDCC,cellular right)cytotoxicity mediated (CARDCC, by CD38-specific right) mediated hcAbs and by Nb-CARs, CD38-specific respectively. hcAbs and ADCC Nb-CARs, and CARDCC respectively. are mediatedADCC by perforins,and CARDCC pore-forming are mediated cytolytic by perforins, proteins pore-forming released from cytolytic activated proteins NK released cells. Perforins from activated are depicted NK herecells. schematically Perforins are as depicted yellow bubbles. here schematically as yellow bubbles. TheThe aim aim of of the the current current study study was was to to explore explore thethe utility of CD38-specific CD38-specific nanobodies nanobodies as asligands ligands forfor Nb-CARs. Nb-CARs. To To this this end, end, we we stably stably transduced transduced the human natural natural killer killer cell cell line line NK-92 NK-92 [16] [16 with] with CD38-specific and control Nb-CARs. We chose NK-92 cells as effector cells rather than T cells because CD38-specific
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