PROJECT SUMMARY
The use of immunosuppressive drugs to prevent stem cell/organ rejection post-transplant imposes several
serious side effects, including increased risk of opportunistic infections or reactivation of viruses such as
Epstein-Barr virus (EBV). Infection with EBV is associated with numerous post-transplant lymphoproliferative
diseases (PTLDs) and other lymphomas. A variety of non-standardized, non-specific treatments are used to
treat EBV+ PTLD cases, such as reduction of immunosuppression or treatment with antibodies against the B
cell antigen CD20. However, these treatments have considerable limitations, such as increased risk of graft-
versus-host disease or weakened immune system, due to indiscriminate targeting of B cells, cancerous or
healthy. Thus, there is an urgent need for a novel EBV-specific immunotherapy that neutralizes EBV infection
and targets EBV+ cells to treat EBV-related PTLDs and other lymphomas. EBV uses multiple envelope
glycoproteins (gps) to infect host cells, including the major immunodominant gp350 and the gH/gL complex
that facilitate entry into B cells and epithelial cells, respectively. Our pre-clinical studies in mice showed that
sera from mice immunized with both gp350 and gH/gL vaccines prevented EBV infection better than individual
immunogens. Furthermore, mAbs against gp350 (72A1) and anti-gH/gL (E1D1) block in vitro EBV infection of
both B cells and epithelial cells. In addition, other researchers have developed drugs and peptides (e.g., L2P4)
that specifically target EBV+ cells in vitro and in vivo. To overcome the existing challenges facing treatment of
EBV+ PTLDs and other lymphomas, we propose to develop and combine two lines of treatment: (1) anti-
gp350-gH/gL, a humanized bispecific neutralizing antibody against EBV glycoproteins gp350 and gL/gH
complex for use as a prophylactic agent to prevent EBV infection; and (2) anti-CD19–P4, a novel antibody-
peptide conjugate (APC) comprised of anti-CD19 (B cell antigen) antibody conjugated to P4 peptide for use as
an immunotherapeutic agent to treat EBV+ PTLDs and other lymphomas. Following the successful completion
of this proposal, our long-term goal is to test combinatorial use of the bispecific nAb and APC in pre-clinical
trials as an innovative immunotherapeutic treatment against EBV-associated PTLDs and lymphomas for
immunocompromised patients.