Anti-FcRH5/CD3 T Cell Dependent Bispecific Antibody (TDB) for the Treatment of Multiple Myeloma

Bispecific antibodies that retarget cytotoxic T cell activity to kill cancer cells are currently under clinical evaluation. However, the molecular mechanism for how CD3-bispecific antibodies 9trigger9 intracellular T cell signaling is not known. We demonstrate that bispecific antibodies invoke an equivalent biophysical mechanism of TCR triggering as that observed for the TCR/pMHC interaction, including 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. However, we demonstrate that rational epitope selection can overcome the spatial inhibition caused by target molecules with a large extracellular domain and result in efficient synapse formation and highly potent T cell triggering. With this insight, we developed a novel T-cell dependent bispecific (TDB) antibody, anti-FcRH5/CD3 TDB, targeting the B cell lineage marker FcRH5 for multiple myeloma. Anti-FcRH5/CD3 TDB demonstrated cytotoxicity against human plasma cells and patient derived myeloma tumor cells at picomolar doses. Very low target expression level is sufficient to induce anti-FcRH5/CD3 TDB mediated killing, indicating broad activity in multiple myeloma where the prevalence of FcRH5 expression is 100%. In primates, anti-FcRH5/CD3 treatment resulted in complete depletion of tissue B cells and bone marrow plasma cells. Anti-FcRH5/CD3 TDB induces immunosuppressive feedback signaling, including PD1 up-regulation, which can be overcome by PD-L1 antibodies. These data demonstrate the potential for the anti-FcRH5/CD3 TDB, alone or in combination with inhibition of PD1/PDL1 signaling in the treatment of multiple myeloma and other B-cell malignancies. Disclosures Li: Genentech: Employment. Stagg: Genentech: Employment. Johnston: Genentech: Employment. DiCara: Genentech: Employment. Clark: Genentech: Employment. Cook: Genentech: Employment. Slaga: Genentech: Employment. Nakamura: Genentech: Employment. Luke: Genentech: Employment. Sukumaran: Genentech: Employment. Luis: Genentech: Employment. Ye: Genentech: Employment. Sumiyoshi: Genentech: Employment. Danilenko: Genentech: Employment. Lee: Genentech: Employment. Totpal: Genentech: Employment. Ellerman: Genentech: Employment. Hotzel: Genentech: Employment. Junttila: Genentech: Employment.