title: Regression of human prostate cancer xenografts in mice by AMG 212/BAY2010112, a novel PSMA/CD3-Bispecific BiTE antibody cross-reactive with non-human primate antigens.
abstract: For treatment of patients with prostate cancer (PCa), we developed a novel T cell-engaging (BiTE) antibody designated AMG 212 or BAY2010112 that is bispecific for prostate-specific membrane antigen (PSMA) and the CD3 epsilon subunit of the T cell receptor complex. AMG 212/BAY2010112 induced target cell-dependent activation and cytokine release of T cells, and efficiently redirected T cells for lysis of target cells. In addition to Chinese hamster ovary cells stably expressing human or cynomolgus monkey PSMA, T cells redirected by AMG 212/BAY2010112 also lysed human PCa cell lines VCaP, 22Rv1, MDA PCa 2b, C4-2, PC-3-huPSMA, and LnCaP at half maximal BiTE concentrations between 0.1 and 4 ng/mL (1.8-72 pmol/L). No lysis of PSMA-negative human PCa cell lines PC-3 and DU145 was observed. The subcutaneous (s.c.) formation of tumors from PC-3-huPSMA cells in NOD/SCID mice was significantly prevented by once daily intravenous (i.v.) injection of AMG 212/BAY2010112 at a dose level as low as 0.005 mg/kg/d. Rapid tumor shrinkage with complete remissions were observed in NOD/SCID mice bearing established s.c. 22Rv1 xenografts after repeated daily treatment with AMG 212/BAY2010112 by either the i.v. or s.c. route. Of note, 22Rv1 tumors were grown in the absence of human T cells followed by intraperitoneal injection of T cells 3 days before BiTE treatment. No effects on tumor growth were observed in the absence of human T cells or AMG 212/BAY2010112. On the basis of these preclinical results, AMG 212/BAY2010112 appears as a promising new BiTE antibody for the treatment of patients with PSMA-expressing PCa.
authors.affiliation: Baeuerle, Amgen Research GmbH, Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Friedrich
authors.forename: Tobias
authors.initials: T
authors.lastname: Raum
authors.forename: Ralf
authors.initials: R
authors.lastname: Lutterbuese
authors.forename: Markus
authors.initials: M
authors.lastname: Voelkel
authors.forename: Petra
authors.initials: P
authors.lastname: Deegen
authors.forename: Doris
authors.initials: D
authors.lastname: Rau
authors.forename: Roman
authors.initials: R
authors.lastname: Kischel
authors.forename: Patrick
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Christian
authors.initials: C
authors.lastname: Brandl
authors.forename: Joachim
authors.initials: J
authors.lastname: Schuhmacher
authors.forename: Peter
authors.initials: P
authors.lastname: Mueller
authors.forename: Ricarda
authors.initials: R
authors.lastname: Finnern
authors.forename: Melanie
authors.initials: M
authors.lastname: Fuergut
authors.forename: Dieter
authors.initials: D
authors.lastname: Zopf
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Slootstra
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Baeuerle
authors.forename: Benno
authors.initials: B
authors.lastname: Rattel
authors.forename: Peter
authors.initials: P
authors.lastname: Kufer
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000954:Antigens, Surface / Q000276:immunology*; D017252:CD3 Complex / Q000235:genetics / Q000276:immunology*; D016466:CHO Cells; D006224:Cricetinae; D003429:Cross Reactions; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D000882:Haplorhini; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000954:Antigens, Surface; D017252:CD3 Complex; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II