title: Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing.
abstract: The anti-FcRH5/CD3 T cell-dependent bispecific antibody (TDB) targets the B cell lineage marker FcRH5 expressed in multiple myeloma (MM) tumor cells. We demonstrate that TDBs trigger T cell receptor activation by inducing target clustering and exclusion of CD45 phosphatase from the synapse. The dimensions of the target molecule play a key role in the efficiency of the synapse formation. The anti-FcRH5/CD3 TDB kills human plasma cells and patient-derived myeloma cells at picomolar concentrations and results in complete depletion of B cells and bone marrow plasma cells in cynomolgus monkeys. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD-1/PD-L1 signaling, in the treatment of MM and other B cell malignancies.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Stagg
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johnston
authors.affiliation: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-LMB, Cambridge, CB2 0QH, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Harris
authors.affiliation: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-LMB, Cambridge, CB2 0QH, UK.
authors.forename: Sam A
authors.initials: SA
authors.lastname: Menzies
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Danielle
authors.initials: D
authors.lastname: DiCara
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Clark
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Hristopoulos
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Cook
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Dionysos
authors.initials: D
authors.lastname: Slaga
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Rin
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Luke
authors.initials: L
authors.lastname: McCarty
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Siddharth
authors.initials: S
authors.lastname: Sukumaran
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Zhengmao
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Teiko
authors.initials: T
authors.lastname: Sumiyoshi
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Dimitry
authors.initials: D
authors.lastname: Danilenko
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Genee Y
authors.initials: GY
authors.lastname: Lee
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Klara
authors.initials: K
authors.lastname: Totpal
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Diego
authors.initials: D
authors.lastname: Ellerman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
authors.forename: Isidro
authors.initials: I
authors.lastname: Hötzel
authors.affiliation: Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-LMB, Cambridge, CB2 0QH, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: James
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA. Electronic address: junttila.teemu@gene.com.
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Junttila
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D000939:Epitopes; D006801:Humans; D054992:Immunological Synapses / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000502:physiology; D008213:Lymphocyte Activation; D008252:Macaca fascicularis; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D011961:Receptors, Fc / Q000032:analysis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D018033:Antibodies, Bispecific; D017252:CD3 Complex; D016207:Cytokines; D000939:Epitopes; C432367:FCRL5 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011948:Receptors, Antigen, T-Cell; D011961:Receptors, Fc; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human
keywords: CD3; FCRL5; FcRH5; T cell; bispecific antibody; multiple myeloma