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: 10327130
• 负责人: James Even Voss
• 金额: $ 88.59万
• 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/10327130
• 关键词: Affect; Affinity; Animal Model; Animals; Antibodies; Antibody Response; Antigen Receptors; Antigens; Autologous; B cell repertoire; B-Cell Antigen Receptor; B-Lymphocytes; Cells; Code; Development; Engineering; Failure; Genes; Genetic; Genome; Goals; HIV; HIV Infections; 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; Receptor Cell; 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; base; 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.

项目摘要/摘要 HIV广泛中和抗体（BNAB）对病毒有效，但不能通过 B细胞抗原受体（BCR）施加的遗传局限性引起的疫苗接种。我们 最近表明，来自野生型小鼠的成熟原代B细胞可以在体内设计以表达 BNAB基因作为功能性抗原受体，可以将这些细胞返回到宿主并接种疫苗 产生耐用的BNAB响应。因为该动物模型不能支持HIV感染，治疗或 这些反应的保护效率尚未评估。这里描述的建议：1）探索 新型B细胞靶向方法旨在改善B细胞在体内的工程和功能。 2） 定义疫苗参数以及可再现启发所需的工程单元的特性 鼠标模型中的耐用BNAB响应； 3）翻译我们成功的“工程B细胞疫苗” （EBCV）使用嵌合HIV/SIV病毒的恒河猴猕猴模型的原型 （Shivs）。在非人类灵长类动物（NHP）中引起的BNABS将测试其预防异源的能力 为了评估EBCV的潜力 充当预防性疫苗或HIV功能治疗。这样的方法可能具有重要的 比其他基因治疗策略的优势，旨在持久地从肌肉或肝细胞中分泌BNAB。 当从修饰的B细胞中引起BNAB响应时，应为：1）能够以A的亲和力成熟 快速发展的病原体； 2）在存在抗原的情况下增加滴度； 3）表示为所有效应器 同种型； 4）免疫系统耐受性，因为它们起源于B细胞； 5）受到公差 如果它们有害，则应使它们表达的细胞表达它们的机制。所有设计的研究 建议支持我们的长期目标，安全，有效且经济可行的“工程” B细胞疫苗会从基因组修饰的B细胞中产生耐用的HIV BNAB反应作为一种策略 用于预防或HIV功能治疗。