title: MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer.
abstract: Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMA-expressing tumor cells by MOR209/ES414 triggered potent target-dependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID γ (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. ©2016 AACR.
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Hernandez-Hoyos
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Toddy
authors.initials: T
authors.lastname: Sewell
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Robert
authors.initials: R
authors.lastname: Bader
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Bannink
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Chenault
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Mollie
authors.initials: M
authors.lastname: Daugherty
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Maria
authors.initials: M
authors.lastname: Dasovich
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Hang
authors.initials: H
authors.lastname: Fang
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Gottschalk
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: John
authors.initials: J
authors.lastname: Kumer
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Miller
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Padma
authors.initials: P
authors.lastname: Ravikumar
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wiens
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Algate
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: David
authors.initials: D
authors.lastname: Bienvenue
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: McMahan
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Sateesh K
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: Emergent BioSolutions, Seattle, Washington.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Gross
authors.affiliation: Emergent BioSolutions, Seattle, Washington. jblankenship@ebsi.com.
authors.forename: John W
authors.initials: JW
authors.lastname: Blankenship
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000954:Antigens, Surface; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D015195:Drug Design; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015202:Protein Engineering; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D017252:CD3 Complex; D057127:Single-Chain Antibodies; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II