CD20 bispecific T-cell engager depletes B-cell progenitors preventing EBV-associated lymphomagenesis in humanized mice

Abstract Epstein-Barr virus (EBV) infection is associated with ∼1.5% of human tumors, including B-cell lymphoproliferative diseases (LPDs). A common approach to treating EBV-associated LPDs is targeting infected tumor cells with a CD20 monoclonal antibody, such as rituximab, although this often fails to prevent relapses and refractory disease. In this study, we show using a preclinical humanized mouse model the superior efficacy of a CD3×CD20 bispecific T-cell engager in preventing systemic virus spread and EBV-associated tumor formation, compared with rituximab treatment. This increased efficacy is associated with a deep depletion of human precursor B cells in the bone marrow. Progenitor B cells are permissive to infection with EBV in vitro and correlate with EBV persistence during B-cell depletion therapy, also in vivo. Thus, deep depletion of B cells, including bone marrow progenitors, might target EBV-associated LPDs more efficiently. Infected progenitors should be considered an EBV reservoir from which associated pathologies could relapse.