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.

项目概要 使用免疫抑制药物来防止移植后干细胞/器官排斥会带来一些影响 严重的副作用，包括机会性感染或病毒重新激活的风险增加，例如 爱泼斯坦-巴尔病毒 (EBV)。 EBV 感染与许多移植后淋巴细胞增殖有关 疾病（PTLD）和其他淋巴瘤。各种非标准化、非特异性的治疗方法被用来 治疗 EBV+ PTLD 病例，例如减少免疫抑制或使用抗 B 病毒抗体治疗 细胞抗原CD20。然而，这些治疗有相当大的局限性，例如移植物风险增加。 由于不加区别地针对 B 细胞、癌性或 健康。因此，迫切需要一种新的 EBV 特异性免疫疗法来中和 EBV 感染 并靶向 EBV+ 细胞来治疗 EBV 相关的 PTLD 和其他淋巴瘤。 EBV 使用多个信封 糖蛋白 (gps) 感染宿主细胞，包括主要的免疫显性 gp350 和 gH/gL 复合物 分别促进进入 B 细胞和上皮细胞。我们对小鼠的临床前研究表明 接种 gp350 和 gH/gL 疫苗的小鼠血清比个体小鼠更好地预防 EBV 感染 免疫原。此外，针对 gp350 (72A1) 和抗 gH/gL (E1D1) 的单克隆抗体可阻断体外 EBV 感染 B细胞和上皮细胞。此外，其他研究人员还开发了药物和肽（例如L2P4） 在体外和体内特异性靶向 EBV+ 细胞。克服现有治疗面临的挑战 EBV+ PTLD 和其他淋巴瘤，我们建议开发并结合两种治疗方案：（1）抗 gp350-gH/gL，一种针对 EBV 糖蛋白 gp350 和 gL/gH 的人源化双特异性中和抗体 用作预防剂以预防 EBV 感染的复合物； (2)抗CD19-P4，一种新型抗体- 肽缀合物 (APC) 由与 P4 肽缀合的抗 CD19（B 细胞抗原）抗体组成，用作 一种治疗 EBV+ PTLD 和其他淋巴瘤的免疫治疗剂。顺利完成后 根据该提案，我们的长期目标是测试双特异性 nAb 和 APC 在临床前的组合使用 作为针对 EB 病毒相关 PTLD 和淋巴瘤的创新免疫疗法的试验 免疫功能低下的患者。