title: A bispecific single-chain antibody that mediates target cell-restricted, supra-agonistic CD28 stimulation and killing of lymphoma cells.
abstract: We have previously reported that r28M, a recombinant bispecific single-chain antibody directed to a melanoma-associated proteoglycan (NG2) and the costimulatory CD28 molecule on T cells, induced T-cell activation, which resulted in tumor-cell killing. T-cell activation did not require a primary signal through the T-cell antigen receptor (TCR)/CD3 complex and depended on the presence of NG2-positive tumor cells. Here, we further investigate this phenomenon of a target cell-restricted, supra-agonistic CD28 stimulation with bispecific antibodies. To this end, we exchanged the NG2 targeting part of r28M with a single-chain antibody directed to the B-cell associated antigen CD20. The resulting bispecific single-chain antibody, termed r2820, induced supra-agonistic T-cell activation, which required the presence of autologous normal or malignant B cells, respectively. Once activated, T cells were capable of destroying lymphoma target cells.These findings demonstrate that supra-agonistic CD28 stimulation with bispecific single-chain antibodies is a robust and readily reproducible phenomenon. In the context of experimental tumor therapy, it may provide a valuable alternative to the unrestricted T-cell activation induced by 'super-agonistic', monospecific CD28 antibodies.
authors.affiliation: Department of Immunology, Institute for Cell Biology, University of Tübingen, Tübingen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Otz
authors.forename: L
authors.initials: L
authors.lastname: Grosse-Hovest
authors.forename: M
authors.initials: M
authors.lastname: Hofmann
authors.forename: H-G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: G
authors.initials: G
authors.lastname: Jung
mesh_terms: D018033:Antibodies, Bispecific / Q000494:pharmacology* / Q000627:therapeutic use; D000941:Antigens / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects*; D008223:Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011509:Proteoglycans / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D018033:Antibodies, Bispecific; D000941:Antigens; D000970:Antineoplastic Agents; D018106:CD28 Antigens; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4