title: A Novel Carcinoembryonic Antigen T-Cell Bispecific Antibody (CEA TCB) for the Treatment of Solid Tumors.
abstract: CEA TCB is a novel IgG-based T-cell bispecific (TCB) antibody for the treatment of CEA-expressing solid tumors currently in phase I clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA- and CD3e-binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB.
  
  
  
  CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human peripheral blood mononuclear cells.
  
  
  
  Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunologic synapses, T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA-binding sites/cell, which allows distinguishing between high- and low-CEA-expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells, and converts PD-L1 negative into PD-L1-positive tumors.
  
  
  
  CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment. Clin Cancer Res; 22(13); 3286-97. ©2016 AACR.
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland. marina.bacac@roche.com Pablo.umana@roche.com.
authors: Marina
authors: M
authors: Bacac
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Tanja
authors: T
authors: Fauti
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Johannes
authors: J
authors: Sam
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Sara
authors: S
authors: Colombetti
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Tina
authors: T
authors: Weinzierl
authors: Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Djamila
authors: D
authors: Ouaret
authors: Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
authors: Walter
authors: W
authors: Bodmer
authors: Animal Imaging Center, Institute for Biomedical Engineering, ETH and University of Zurich, Zurich, Switzerland.
authors: Steffi
authors: S
authors: Lehmann
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Thomas
authors: T
authors: Hofer
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Ralf J
authors: RJ
authors: Hosse
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Ekkehard
authors: E
authors: Moessner
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Oliver
authors: O
authors: Ast
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Peter
authors: P
authors: Bruenker
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Sandra
authors: S
authors: Grau-Richards
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Teilo
authors: T
authors: Schaller
authors: Roche Diagnostics GmbH, Penzberg, Germany.
authors: Annette
authors: A
authors: Seidl
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Christian
authors: C
authors: Gerdes
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Mario
authors: M
authors: Perro
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Valeria
authors: V
authors: Nicolini
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Nathalie
authors: N
authors: Steinhoff
authors: Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland.
authors: Sherri
authors: S
authors: Dudal
authors: Global Technical Development Project Management, F. Hoffmann-La Roche AG, Basel, Switzerland.
authors: Sebastian
authors: S
authors: Neumann
authors: Large Molecule Research, Roche Innovation Center Penzberg, Germany.
authors: Thomas
authors: T
authors: von Hirschheydt
authors: Large Molecule Research, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Christiane
authors: C
authors: Jaeger
authors: Translational Medicine, Roche Innovation Center Zurich, Zurich, Switzerland.
authors: Jose
authors: J
authors: Saro
authors: Translational Medicine, Roche Innovation Center Zurich, Zurich, Switzerland.
authors: Vaios
authors: V
authors: Karanikas
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland.
authors: Christian
authors: C
authors: Klein
authors: Oncology Discovery, Roche Innovation Center Zurich, Roche Pharmaceutical Research and Early Development, pRED, Zurich, Switzerland. marina.bacac@roche.com Pablo.umana@roche.com.
authors: Pablo
authors: P
authors: Umaña
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology*; D001665:Binding Sites / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000628:therapy*; D011961:Receptors, Fc / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D017252:CD3 Complex; C115335:CD3E protein, human; D002272:Carcinoembryonic Antigen; D011961:Receptors, Fc