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

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

Cancer Cell
Published Online: March 02, 2017

Ji Li, Nicola J. Stagg, Jennifer Johnston, Michael J. Harris, Sam A. Menzies, Danielle DiCara, Vanessa Clark, Maria Hristopoulos, Ryan Cook, Dionysos Slaga, Rin Nakamura, Luke McCarty, Siddharth Sukumaran, Elizabeth Luis, Zhengmao Ye, Thomas D. Wu, Teiko Sumiyoshi, Dimitry Danilenko, Genee Y. Lee, Klara Totpal, Diego Ellerman, Isidro Hötzel, John R. James, Teemu T. Junttila.

Abstract

Highlights

  • Prevalence of FcRH5 expression in multiple myeloma is 100%
  • Anti-FcRH5/CD3 TDB redirects T cells to kill myeloma cells
  • Target clustering and CD45 exclusion activate T cells
  • Anti-FcRH5/CD3 TDB is a highly efficacious immunotherapy for myeloma

Summary

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.

Significance

Our study describes how CD3-bispecific antibody “triggers” intracellular T cell signaling and shows that the dimensions of the target molecule and epitope location play a key role in the efficiency of the synapse formation and subsequent T cell activation. These findings are important for future design of T cell-recruiting therapies. Using this information we developed and preclinically validated an anti-FcRH5/CD3 TDB as an immunotherapy for multiple myeloma. The anti-FcRH5/CD3 TDB is highly efficacious in the killing of myeloma cells and depletes bone marrow plasma cells in primates.

Introduction

Multiple myeloma (MM) is an incurable malignancy of plasma cells characterized by dysregulated growth of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulins that ultimately lead to clinical manifestations including skeletal lesions, renal failure, anemia, and hypercalcemia. Currently the backbone of MM treatment involves combinations of proteasome inhibitors (PIs), immunomodulators, and corticosteroids, with bone marrow transplantation as an additional option for eligible patients. Newer agents are being developed for the treatment of MM, including the monoclonal antibodies targeting CD38 (daratumomab) and SLAMF7 (elotuzumab). Nevertheless, despite progressive improvements in myeloma treatment, the mortality rate remains high and median survival remains less than 5 years (http://seer.cancer.gov/).

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