Membrane-Proximal Epitope Facilitates Efficient T Cell Synapse Formation by Anti-FcRH5/CD3 and Is a Requirement for Myeloma Cell Killing
Menée in vitro et à l'aide d'une xénogreffe sur un modèle murin, cette étude met en évidence l'intérêt d'un anticorps anti-FcRH5/CD3, en combinaison ou non avec l'inhibition de la voie de signalisation PD-1/PD-L1, pour traiter un myélome multiple ou d'autres cancers hématologiques liés aux lymphocytes B
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 signaling, in the treatment of MM and other B cell malignancies.