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.

Public Health Relevance

Patients receiving transplants must take immunosuppressive drugs to prevent organ/stem cell rejection; however, these drugs put them at risk of infection with or reactivation of Epstein-Barr virus (EBV), which is associated with post-transplant lymphoproliferative diseases (PTLD) and other cancers. Therefore, we propose to develop two new potential treatments: an antibody that will target EBV to block infection, and a specialized antibody that will target EBV-infected cells and kill them. If successful, the proposed research will yield innovative treatments that can prevent and treat EBV infections and EBV-associated PTLDs and cancers in transplant patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21CA232275-01S1
Application #
9976115
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Schwartz, Elena Ivan
Project Start
2018-07-01
Project End
2020-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010