Elicitation of HIV Broadly Neutralizing Antibodies from Engineered B cells

从工程化 B 细胞中引发 HIV 广泛中和抗体

• 批准号: 10644025
• 负责人: James Even Voss
• 金额: $ 103.92万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644025
• 关键词: Affect; Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigen Receptors; Antigens; Autologous; B cell repertoire; B-Cell Acute Lymphoblastic Leukemia; B-Cell Antigen Receptor; B-Lymphocytes; Cells; Code; Development; Engineering; Failure; Genes; Genetic; Genome; Goals; HIV; HIV Infections; HIV envelope protein; Hepatocyte; Human; Immune system; Immunization; Immunize; Immunocompetent; Immunoglobulin Constant Region; Immunoglobulins; Infection; Infection prevention; Light; Macaca mulatta; Memory; Modeling; Multi-Drug Resistance; Mus; Muscle Cells; Mutation; Passive Immunization; Patients; Physiological; Prevention strategy; Preventive vaccine; Process; Property; Reproducibility; Research; Research Design; SIV; Structure of germinal center of lymph node; System; Technology; Testing; Translating; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Variant; Viremia; Virus; Virus Diseases; Wild Type Mouse; antibody engineering; antiretroviral therapy; cellular engineering; design; efficacy testing; evaluation/testing; experimental study; gene therapy; genome editing; improved; in vivo; mouse model; neutralizing antibody; nonhuman primate; novel; pathogen; prevent; prophylactic; protective efficacy; prototype; research clinical testing; response; success; vaccination strategy

Project Summary/Abstract HIV broadly neutralizing antibodies (bnAbs) are effective against the virus, but cannot be elicited through vaccination due to genetic limitations imposed by the human repertoire of B cell antigen-receptors (BCRs). We have recently shown that mature primary B cells from wild-type mice can be engineered ex vivo to express bnAb genes as functional antigen receptors, and that these cells can be returned to the host and vaccinated to generate durable bnAb responses. Because this animal model cannot support HIV infection, therapeutic or protective efficacy of these responses have not yet been evaluated. The proposal described here: 1) Explores novel B cell targeting approaches that aim to improve how B cells are engineered and function in vivo; 2) Defines vaccine parameters and the properties of engineered cells required for reproducible elicitation of durable bnAb responses in the mouse model and; 3) Translates our successful ‘Engineered B cell Vaccine’ (EBcV) prototype to the rhesus macaque animal model for efficacy testing using chimeric HIV/SIV viruses (SHIVs). BnAbs elicited in non-human primates (NHP) will be tested for their ability to prevent heterologous tier-2 virus infection, suppress, or maintain suppression of viremia, in order to evaluate the potential for EBcVs to function as prophylactic vaccines or as an HIV functional cure. Such an approach may have significant advantages over other gene therapy strategies that aim to durably secrete bnAbs from muscle or liver cells. When elicited from modified B cells, bnAb responses should be: 1) able to mature in affinity in response to a rapidly evolving pathogen; 2) increase titers in the presence of antigen; 3) be expressed as all effector isotypes; 4) tolerated by the immune system because they originate from B cells and; 5) subject to tolerance mechanisms that should inactivate the cells expressing them if they are harmful. All studies designed in this proposal support our long-term goal, the development of safe, effective and economically feasible ‘Engineered B cell vaccines’ that would generate durable HIV bnAb responses from genome modified B cells as a strategy for prevention or HIV functional cure.

项目概要/摘要 HIV 广泛中和抗体 (bnAb) 对病毒有效，但不能通过 由于人类 B 细胞抗原受体 (BCR) 的遗传限制，我们需要进行疫苗接种。 最近表明，来自野生型小鼠的成熟原代 B 细胞可以通过离体工程改造来表达 bnAb 基因作为功能性抗原受体，并且这些细胞可以返回宿主并与肺炎结合 产生持久的 bnAb 反应，因为这种动物模型不能支持 HIV 感染、治疗或治疗。 这些反应的保护功效尚未得到评估，此处描述的提案：1) 探索。 旨在改善 B 细胞在体内的工程和功能的新型 B 细胞靶向方法 2) 定义疫苗参数和可重复引发所需的工程细胞的特性 小鼠模型中持久的 bnAb 反应；3) 转化我们成功的“工程 B 细胞疫苗” (EBcV) 恒河猴动物模型原型，用于使用嵌合 HIV/SIV 病毒进行功效测试 (SHIV) 在非人类灵长类动物 (NHP) 中引发的 BnAb 将被测试其预防异源性的能力。 2 级病毒感染、抑制或维持对病毒血症的抑制，以评估 EBcV 的潜力 作为预防性疫苗或艾滋病毒功能性治疗，这种方法可能具有重要意义。 与其他旨在从肌肉或肝细胞持久分泌 bnAb 的基因治疗策略相比，该策略具有优势。 当从修饰的 B 细胞中引发时，bnAb 反应应该是：1) 能够在亲和力上成熟，以响应 快速进化的病原体；2) 在抗原存在下增加滴度；3) 表达为所有效应子； 同种型；4) 被免疫系统耐受，因为它们源自 B 细胞；5) 具有耐受性； 如果它们有害，则应使表达它们的细胞失活。 提案支持我们的长期目标，即开发安全、有效且经济可行的“工程化” B 细胞疫苗将通过基因组修饰的 B 细胞产生持久的 HIV bnAb 反应作为一种策略 用于预防或艾滋病毒功能性治疗。