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是一种将前两个结构域与抗体Fc进行有效和异常广泛的融合 结构域和一个短的酪氨酸硫化的辅受体模拟肽。在恒河猴中，腺相关 甲型肝炎病毒(AAV)表达的eCD4-Ig介导了对SHV-Ig持续且非常有效的长期保护- AD8和SIVmac239。ECD4-Ig还具有使其特别有用的特性，用于建立 在恒河猴和人类身上的功能性治疗。这些包括它的效力、广度、难度-- -逃逸，AAV表达时免疫原性低，AAV表达一致，强大的内在 ADCC活性，并与血清抗体协同介导ADCC。这些特性允许eCD4- 免疫球蛋白绕过与使用AAV表达的抗体相关的两个主要问题 功能性治疗，即免疫清除和病毒逃逸。 在即将到来的获奖期，我们将改进允许AAV中介交付的技术 通过优化其作为AAV转基因的表达，通过消除残留的抗体应答 AAV递送的eCD4-Ig，并通过评估eCD4-Ig Fc结构域在抗eCD4-Ig抗体中的作用 应对并控制已确定的SIVmac239感染。这些努力将开发出 可应用于许多实验室正在进行的预防新感染的努力，提供长期的 作为联合抗逆转录病毒疗法的替代品，并减少病毒库的规模。 相关性(请参阅说明)： ECD4-Ig是一种有效且特别广泛的HIV-1和SIV进入抑制剂，当由 AAV载体，为恒河猴提供强大的长期保护，使其免受新的感染 在缺乏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递送的eCD4-Ig的这些特性。