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: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9797160
• 关键词: Antibodies; Antibody Therapy; Antigens; B-Lymphocytes; CD19 gene; CD20 Antigens; Cancerous; Cells; Complex; Diagnosis; Epithelial Cells; Epstein-Barr Virus Infections; Glycoproteins; Goals; Human Herpesvirus 4; Immune system; Immunize; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Vitro; Individual; Infection; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Monoclonal Antibodies; Mus; Opportunistic Infections; Organ; Patients; Peptide antibodies; Peptides; Pharmaceutical Preparations; Prevention; Research; Research Personnel; Risk; Stem cells; Testing; Transplant Recipients; Transplantation; Vaccines; Virus; antibody conjugate; cell killing; combinatorial; graft vs host disease; in vivo; infection risk; innovation; neutralizing antibody; novel; post-transplant; preclinical study; preclinical trial; prevent; prophylactic; side effect; tool

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.

项目总结