Targeting Human Cytomegalovirus-Infected Cells by Redirecting T Cells Using an Anti-CD3/Anti-gB Bispecific Antibody [PublishAheadOfPrint]

Host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency although not sufficient to clear the virus. T cells are primarily responsible for control of the viral reactivation. When host immune system is compromised, as in transplant recipients with immunosuppression, HCMV reactivation and progressive infection can cause serious morbidity and mortality. Adoptive T cell therapy is effective for control of HCMV infection in transplant recipients. However, it is a highly personalized therapeutic regimen, and difficult to implement in routine clinical practice. In this study, we explored a bispecific antibody strategy to direct non-HCMV-specific T cells to recognize and exert effector functions against HCMV-infected cells. Using a knobs-into-holes strategy, we constructed a bispecific antibody with one arm specific to CD3, which can trigger T cell activation, and the other specific to HCMV glycoprotein B (gB), which recognizes and marks the cells with HCMV infection based on their surface expression of viral gB. We showed that this bispecific antibody was able to redirect T cells with specificity to HCMV-infected cells in vitro. In the presence of HCMV infection, the engineered antibody was able to activate T cells with no HCMV-specificity for cytokine production, proliferation and expression of phenotype markers unique of T cell activation. The results suggested the potential of the engineered bispecific antibodies such as the construct described here as a prophylactic or therapeutic agent against HCMV reactivation and infection.

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