title: T cell-recruiting triplebody 19-3-19 mediates serial lysis of malignant B-lymphoid cells by a single T cell.
abstract: Triplebody 19-3-19, an antibody-derived protein, carries three single chain fragment variable domains in tandem in a single polypeptide chain. 19-3-19 binds CD19-bearing lymphoid cells via its two distal domains and primary T cells via its CD3-targeting central domain in an antigen-specific manner. Here, malignant B-lymphoid cell lines and primary cells from patients with B cell malignancies were used as targets in cytotoxicity tests with pre-stimulated allogeneic T cells as effectors. 19-3-19 mediated up to 95 % specific lysis of CD19-positive tumor cells and, at picomolar EC₅₀ doses, had similar cytolytic potency as the clinically successful agent Blinatumomab. 19-3-19 activated resting T cells from healthy unrelated donors and mediated specific lysis of both autologous and allogeneic CD19-positive cells. 19-3-19 led to the elimination of 70 % of CD19-positive target cells even with resting T cells as effectors at an effector-to-target cell ratio of 1 : 10. The molecule is therefore capable of mediating serial lysis of target cells by a single T cell. These results highlight that central domains capable of engaging different immune effectors can be incorporated into the triplebody format to provide more individualized therapy tailored to a patient's specific immune status.
authors.affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Haematology/Oncology, Munich, Germany.
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Roskopf
authors.affiliation: Ludwig-Maximilians-Universität München, Department of Biochemistry/Gene Center, Munich, Germany.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Schiller
authors.affiliation: Klinikum der Universität München, Medizinische Klinik und Poliklinik IV, Haematology/Oncology, Munich, Germany.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Braciak
authors.affiliation: 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-Universität Erlangen-Nürnberg, Department of Biology, Erlangen, Germany.
authors.forename: Ingo A
authors.initials: IA
authors.lastname: Schubert
authors.affiliation: Friedrich-Alexander-Universität Erlangen-Nürnberg, Department of Biology, Erlangen, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Fey
authors.affiliation: Ludwig-Maximilians-Universität München, Department of Biochemistry/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, Haematology/Oncology, Munich, Germany.
authors.forename: Fuat S
authors.initials: FS
authors.lastname: Oduncu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000920:Antibody-Dependent Cell Cytotoxicity; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D057127:Single-Chain Antibodies