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.
Ji Li  1 ,  Nicola J Stagg  1 ,  Jennifer Johnston  1 ,  Michael J Harris  2 ,  Sam A Menzies  2 ,  Danielle DiCara  1 ,  Vanessa Clark  1 ,  Maria Hristopoulos  1 ,  Ryan Cook  1 ,  Dionysos Slaga  1 ,  Rin Nakamura  1 ,  Luke McCarty  1 ,  Siddharth Sukumaran  1 ,  Elizabeth Luis  1 ,  Zhengmao Ye  1 ,  Thomas D Wu  1 ,  Teiko Sumiyoshi  1 ,  Dimitry Danilenko  1 ,  Genee Y Lee  1 ,  Klara Totpal  1 ,  Diego Ellerman  1 ,  Isidro Hötzel  1 ,  John R James  2 ,  Teemu T Junttila  3
Affiliations
  • 1. Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA.
  • 2. Molecular Immunity Unit, Department of Medicine, University of Cambridge, MRC-LMB, Cambridge, CB2 0QH, UK.
  • 3. Genentech, Inc., 1 DNA Way, South San Francisco, San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 28262555 DOI: 10.1016/j.ccell.2017.02.001
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.

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