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Characterization of Epstein-Barr virus monoclonal antibodies as tools for diagnosing and prevention of EBV infection in transplant settings

Characterization of Epstein-Barr virus monoclonal antibodies as tools for diagnosing and prevention of EBV infection in transplant settings
EB 病毒单克隆抗体作为移植环境中诊断和预防 EBV 感染工具的表征
批准号:
9797160
负责人:
Javier Gordon Ogembo
金额:
$6.65万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-07-01 至 2021-06-30

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英文摘要
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.
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