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

• Published in: Cancer cell Vol. 31; no. 3; pp. 383 - 395
• Main Authors: Li, Ji, Stagg, Nicola J., Johnston, Jennifer, Harris, Michael J., Menzies, Sam A., DiCara, Danielle, Clark, Vanessa, Hristopoulos, Maria, Cook, Ryan, Slaga, Dionysos, Nakamura, Rin, McCarty, Luke, Sukumaran, Siddharth, Luis, Elizabeth, Ye, Zhengmao, Wu, Thomas D., Sumiyoshi, Teiko, Danilenko, Dimitry, Lee, Genee Y., Totpal, Klara, Ellerman, Diego, Hötzel, Isidro, James, John R., Junttila, Teemu T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.03.2017; Cell Press
• Subjects: Animals; Antibodies, Bispecific - therapeutic use; bispecific antibody; CD3; CD3 Complex - immunology; Cytokines - secretion; Epitopes; FcRH5; FCRL5; Humans; Immunological Synapses - physiology; Leukocyte Common Antigens - physiology; Lymphocyte Activation; Macaca fascicularis; Mice; multiple myeloma; 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 cell; T-Lymphocytes - immunology; bispecific antibody; multiple myeloma; FcRH5; CD3; FCRL5; T cell
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.02.001

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. •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 Li et al. report that the size and epitope location of the target play a key role in the efficiency of T cell activation induced by T cell-dependent bispecific antibodies (TDBs). They develop a TDB targeting FcRH5 expressed in all multiple myeloma tumor cells and show its potential in treating this disease.