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

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

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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