title: Novel humanized and highly efficient bispecific antibodies mediate killing of prostate stem cell antigen-expressing tumor cells by CD8+ and CD4+ T cells.
abstract: Prostate cancer is the most common noncutaneous malignancy in men. The prostate stem cell Ag (PSCA) is a promising target for immunotherapy of advanced disease. Based on a novel mAb directed to PSCA, we established and compared a series of murine and humanized anti-CD3-anti-PSCA single-chain bispecific Abs. Their capability to redirect T cells for killing of tumor cells was analyzed. During these studies, we identified a novel bispecific humanized Ab that efficiently retargets T cells to tumor cells in a strictly Ag-dependent manner and at femtomolar concentrations. T cell activation, cytokine release, and lysis of target cells depend on a cross-linkage of redirected T cells with tumor cells, whereas binding of the anti-CD3 domain alone does not lead to an activation or cytokine release. Interestingly, both CD8+ and CD4+ T cells are activated in parallel and can efficiently mediate the lysis of tumor cells. However, the onset of killing via CD4+ T cells is delayed. Furthermore, redirecting T cells via the novel humanized bispecific Abs results in a delay of tumor growth in xenografted nude mice.
authors.affiliation: Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Feldmann
authors.forename: Claudia
authors.initials: C
authors.lastname: Arndt
authors.forename: Katrin
authors.initials: K
authors.lastname: Töpfer
authors.forename: Slava
authors.initials: S
authors.lastname: Stamova
authors.forename: Franziska
authors.initials: F
authors.lastname: Krone
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.forename: Stefanie
authors.initials: S
authors.lastname: Koristka
authors.forename: Irene
authors.initials: I
authors.lastname: Michalk
authors.forename: Dirk
authors.initials: D
authors.lastname: Lindemann
authors.forename: Marc
authors.initials: M
authors.lastname: Schmitz
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Michael
authors.initials: M
authors.lastname: Bachmann
mesh_terms: D018033:Antibodies, Bispecific / Q000502:physiology*; D061067:Antibodies, Monoclonal, Humanized / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016923:Cell Death / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000276:immunology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D013234:Stem Cells / Q000276:immunology* / Q000473:pathology; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human