Optimizing eCD4-Ig for eradication and a functional cure

优化 eCD4-Ig 以实现根除和功能性治愈

• 批准号: 9982755
• 负责人: Michael R. Farzan
• 金额: $ 94.1万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-16 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982755
• 关键词: Agonist; Antibodies; Antiviral Agents; Avidity; Binding; Biological Assay; CCR5 gene; CXCR4 gene; Cell physiology; Cells; Clinical Trials; Data; Disease remission; Dose; Drug Kinetics; Foundations; Frequencies; Future; Gene Expression; Glycoproteins; HIV-1; HIV-2; Half-Life; Hepatitis B Therapy; Hepatitis B Virus; Human; IgG1; Immune; In Vitro; Individual; Infection; Intravenous; Macaca; Macaca mulatta; Measures; Mediating; Mediator of activation protein; Mucous Membrane; Natural Killer Cells; Oral; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase II Clinical Trials; Production; Proteins; Proviruses; Regimen; Resistance; Route; SIV; Schedule; Solubility; T-Lymphocyte; TLR7 gene; Testing; Variant; Viral; Viral Genes; Viral Load result; Viral reservoir; Virus; Withdrawal; analog; antibody-dependent cell cytotoxicity; cell killing; design; immunogenicity; improved; in vivo; inhibitor/antagonist; innovation; lymph nodes; neutralizing antibody; nonhuman primate; prevent; simian human immunodeficiency virus; viral rebound; virology

PROJECT SUMMARY One strategy for eradicating the HIV-1 viral reservoir combines a means of activating viral gene expression in latently infected T cells (a ‘kick’) with a way to eliminate these activated cells (a ‘kill’). The TLR7 agonist GS-9620 is a safe, well tolerated latency reversing agent that indirectly induces latently infected T cells to produce virus. Preliminary data indicates that it can partially reduce, or in some cases perhaps completely eliminate, the SIV reservoir in rhesus macaques. eCD4-Ig is an antibody- like entry inhibitor with unmatched breadth and very potent neutralizing and antibody-dependent cell- mediated cytotoxicity (ADCC) activities against HIV-1, HIV-2 and SIV. Moreover, it can protect macaques against from repeated high-dose challenges with two divergent viruses – SIVmac239 and SHIV-AD8. Finally a single dose of an IgG1 form of human eCD4-Ig protein can suppress infection in macaques by 2.5 logs without evidence of viral escape. eCD4-Ig’s potent neutralization and ADCC activities, and its exceptional breadth, suggest that it may uniquely overcome the diversity of the viral reservoir and facilitate the elimination of most reactivated cells. Accordingly, we will test the hypothesis that the effector functions of eCD4-Ig can accelerate reduction of the latent reservoir observed in GS-9620-treated macaques. To do so, we will first optimize the half- life, immunogenicity, neutralization potency, and ADCC activities of eCD4-Ig. We will then optimize the schedule, dosing, and route of administration of GS-9620, and establish the relationship between GS- 9620-induced virus ‘blips’ and reservoir reduction. Finally, we will compare GS-9620, eCD4-Ig, and both therapies combined, for their abilities to reduce the size of the latent reservoir and/or establish a stable state of virologic control. If successful, these studies will lay a foundation for future human clinical trials combining GS-9620 and eCD4-Ig.

项目概要 根除 HIV-1 病毒库的一种策略结合了激活病毒基因的方法 在潜伏感染的 T 细胞中表达（“踢”），并通过某种方式消除这些激活的细胞（“杀死”）。 TLR7 激动剂 GS-9620 是一种安全、耐受性良好的潜伏期逆转剂，可间接诱导潜伏期 初步数据表明，感染T细胞产生的病毒可以部分减少，或者部分减少。 恒河猴中的 SIV 储库可能完全消除，eCD4-Ig 是一种抗体。 像进入抑制剂一样具有无与伦比的广度和非常有效的中和和抗体依赖性细胞- 此外，它还具有针对 HIV-1、HIV-2 和 SIV 的介导细胞毒性（ADCC）活性。 猕猴抵抗两种不同病毒（SIVmac239 和）的反复高剂量挑战 最后，单剂量的 IgG1 形式的人类 eCD4-Ig 蛋白可以抑制感染。 猕猴 2.5 个对数级，没有证据表明 eCD4-Ig 具有有效的中和作用和 ADCC。 活动及其特殊的广度表明它可以独特地克服病毒的多样性 储存库并促进消除大多数重新激活的细胞。 因此，我们将检验 eCD4-Ig 的效应功能可以加速还原的假设 为了做到这一点，我们将首先优化半- 然后我们将优化 eCD4-Ig 的寿命、免疫原性、中和效力和 ADCC 活性。 GS-9620 的时间表、剂量和给药途径，并建立 GS-9620 之间的关系 最后，我们将比较 GS-9620、eCD4-Ig 和 9620 诱导的病毒“斑点”和病毒储存库减少。 这两种疗法结合起来，能够减少潜伏储库的大小和/或建立一个 如果成功的话，这些研究将为未来的人类奠定基础。 GS-9620 和 eCD4-Ig 结合的临床试验。