title: Dual-targeting triplebody 33-3-19 mediates selective lysis of biphenotypic CD19+ CD33+ leukemia cells.
abstract: Simultaneous targeting of multiple tumor-associated antigens (TAAs) in cancer immunotherapy is presumed to enhance tumor cell selectivity and to reduce immune escape.The combination of B lymphoid marker CD19 and myeloid marker CD33 is exclusively present on biphenotypic B/myeloid leukemia cells. Triplebody 33-3-19 binds specifically to both of these TAAs and activates T cells as immune effectors. Thereby it induces specific lysis of established myeloid (MOLM13, THP-1) and B-lymphoid cell lines (BV173, SEM, Raji, ARH77) as well as of primary patient cells. EC50 values range from 3 pM to 2.4 nM. In accordance with our hypothesis, 33-3-19 is able to induce preferential lysis of double- rather than single-positive leukemia cells in a target cell mixture: CD19/CD33 double-positive BV173 cells were eliminated to a significantly greater extent than CD19 single-positive SEM cells (36.6% vs. 20.9% in 3 hours, p = 0.0048) in the presence of both cell lines. In contrast, equivalent elimination efficiencies were observed for both cell lines, when control triplebody 19-3-19 or a mixture of the bispecific single chain variable fragments 19-3 and 33-3 were used. This result highlights the potential of dual-targeting agents for efficient and selective immune-intervention in leukemia patients.
authors.affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Hematology/Oncology, Munich, Germany.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Roskopf
authors.affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Hematology/Oncology, Munich, Germany.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Braciak
authors.affiliation: Ludwig-Maximilians-Universität München, Department of Biochemistry and Gene Center, Munich, Germany.
authors.forename: Nadja C
authors.initials: NC
authors.lastname: Fenn
authors.affiliation: Center for Integrated Protein Science (CIPSM) and Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Division of Clinical Pharmacology, Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kobold
authors.affiliation: Friedrich-Alexander-University Erlangen-Nuremberg, Department of Biology, Erlangen, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Fey
authors.affiliation: Ludwig-Maximilians-Universität München, Department of Biochemistry and Gene Center, Munich, Germany.
authors.forename: Karl-Peter
authors.initials: KP
authors.lastname: Hopfner
authors.affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Hematology/Oncology, Munich, Germany.
authors.forename: Fuat S
authors.initials: FS
authors.lastname: Oduncu
mesh_terms: D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000187:drug effects / Q000276:immunology; D000951:Antigens, Neoplasm / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015456:Leukemia, Biphenotypic, Acute; D063268:Sialic Acid Binding Ig-like Lectin 3 / Q000276:immunology; D057127:Single-Chain Antibodies / Q000494:pharmacology*
chemical_list: D018941:Antigens, CD19; D015214:Antigens, Differentiation, Myelomonocytic; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; C000604811:CD19 molecule, human; C571163:CD33 protein, human; D063268:Sialic Acid Binding Ig-like Lectin 3; D057127:Single-Chain Antibodies
keywords: dual-targeting triplebody; immunotherapy; leukemia; mixed phenotype acute leukemia (MPAL); selectivity