Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing

Cancer Cell. 2017 Mar 13;31(3):383-395. doi: 10.1016/j.ccell.2017.02.001. Epub 2017 Mar 2.


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.

Keywords: CD3; FCRL5; FcRH5; T cell; bispecific antibody; multiple myeloma.

MeSH terms

  • Animals
  • Antibodies, Bispecific / therapeutic use*
  • CD3 Complex / immunology*
  • Cytokines / metabolism
  • Epitopes*
  • Humans
  • Immunological Synapses / physiology*
  • Leukocyte Common Antigens / physiology
  • Lymphocyte Activation
  • Macaca fascicularis
  • Mice
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / immunology
  • Multiple Myeloma / pathology
  • Programmed Cell Death 1 Receptor / physiology
  • Receptors, Antigen, T-Cell / physiology
  • Receptors, Fc / analysis
  • Receptors, Fc / immunology*
  • T-Lymphocytes / immunology*


  • Antibodies, Bispecific
  • CD3 Complex
  • Cytokines
  • Epitopes
  • FCRL5 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell
  • Receptors, Fc
  • Leukocyte Common Antigens
  • PTPRC protein, human