Therapeutic Use of an Enhanced Form of CD4-Ig

增强形式的 CD4-Ig 的治疗用途

• 批准号: 9970576
• 负责人: Michael R. Farzan
• 金额: $ 92.43万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-04 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9970576
• 关键词: Antibodies; Antibody Response; Award; Collaborations; Dependovirus; Fc domain; HIV-1; Human; Infection; Instruction; Laboratories; Macaca mulatta; Mediating; Property; Residual state; Role; SIV; Serum; Technology; Therapeutic Uses; Transgenes; Viral; Viral reservoir; Virus Replication; adeno-associated viral vector; antiretroviral therapy; immune clearance; immunogenicity; improved; inhibitor/antagonist; peptidomimetics; prevent; simian human immunodeficiency virus; tyrosine O-sulfate

eCD4-Ig is a potent and exceptionally broad fusion of the first two domains of CD4 to an antibody Fc domain and a short tyrosine-sulfated coreceptor-mimetic peptide. In rhesus macaques, adeno-associated virus (AAV)-expressed eCD4-Ig mediates consistent and very effective long-term protection against SHIV- AD8 and SIVmac239. eCD4-Ig also has properties that make it especially useful for establishing a functional cure in rhesus macaques and perhaps in humans. These include its potency, breadth, difficulty- of-escape, low immunogenicity when expressed by AAV, consistent expression by AAV, potent intrinsic ADCC activity, and collaboration with serum antibodies to mediate ADCC. These properties allow eCD4- Ig to circumvent two major problems associated with using AAV-expressed antibodies to establish functional cures, namely immune clearance and viral escape. In the forthcoming award period, we will improve the technologies allowing AAV-mediated delivery of eCD4-Ig by optimizing its expression as an AAV transgene, by eliminating residual antibody responses to AAV-delivered eCD4-Ig, and by assessing the role of the eCD4-Ig Fc domain in anti-eCD4-Ig antibody responses and in control an established SIVmac239 infection. These efforts will develop technologies that can be applied to the ongoing efforts by many laboratories to prevent new infections, to provide long- acting alternatives to combined antiretroviral therapies, and to reduce the scale of the viral reservoir. RELEVANCE (See instructions): eCD4-Ig is a potent and exceptionally broad HIV-1 and SIV entry inhibitor that, when delivered by an AAV vector, provides rhesus macaques robust long-term protection from new infections, and by itself suppresses viral replication in the absence of anti-retroviral therapies. Here we seek to optimize and better understand these properties of AAV-delivered eCD4-Ig.

eCD4-Ig 是 CD4 前两个结构域与抗体 Fc 的有效且异常广泛的融合 结构域和短的酪氨酸硫酸化辅助受体模拟肽。在恒河猴中，腺相关 病毒 (AAV) 表达的 eCD4-Ig 介导针对 SHIV 的一致且非常有效的长期保护- AD8 和 SIVmac239。 eCD4-Ig 还具有使其特别适用于建立 恒河猴甚至人类的功能性治愈。这些包括它的效力、广度、难度—— 逃逸，AAV 表达时免疫原性低，AAV 一致表达，强内在 ADCC 活性，以及​​与血清抗体协作介导 ADCC。这些特性使得 eCD4- Ig 可以规避与使用 AAV 表达的抗体建立相关的两个主要问题 功能性治疗，即免疫清除和病毒逃逸。 在即将到来的奖励期内，我们将改进允许 AAV 介导的交付的技术 eCD4-Ig 通过优化其作为 AAV 转基因的表达、消除残留抗体反应 AAV 递送 eCD4-Ig，并通过评估 eCD4-Ig Fc 结构域在抗 eCD4-Ig 抗体中的作用 反应并控制已确定的 SIVmac239 感染。这些努力将开发出能够 可应用于许多实验室正在进行的预防新感染的努力，以提供长期的 联合抗逆转录病毒疗法的替代方案，并减少病毒库的规模。 相关性（参见说明）： eCD4-Ig 是一种有效且极其广泛的 HIV-1 和 SIV 进入抑制剂，当通过 AAV 载体可为恒河猴提供强大的长期保护，使其免受新感染 在没有抗逆转录病毒治疗的情况下抑制病毒复制。在这里我们寻求优化和 更好地了解 AAV 传递的 eCD4-Ig 的这些特性。