Therapeutic Use of an Enhanced Form of CD4-Ig

增强形式的 CD4-Ig 的治疗用途

• 批准号: 9061301
• 负责人: Michael R. Farzan
• 金额: $ 92.92万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9061301
• 关键词: Adverse event; Animals; Anti-Retroviral Agents; Antibodies; Benefits and Risks; Binding; Binding Sites; CCR5 gene; Data; Dependovirus; Dose; Drug Kinetics; Enzymes; Equilibrium; Fc domain; Foundations; Gene Transduction Agent; Glycoproteins; Goals; HIV-1; HIV-2; Human; IgG1; IgG2; In Vitro; Individual; Infection; Intravenous; Macaca; Macaca mulatta; Mediating; Medicine; Modification; Persons; Property; Prophylactic treatment; Proteins; Regimen; Regulation; Regulatory Element; Resistance; Risk; SIV; Safety; Site; System; Testing; Therapeutic; Therapeutic Uses; Time; Transgenes; Vaccines; Vagina; Variant; Viral; Virus; Work; adeno-associated viral vector; base; env Glycoproteins; high risk; immunogenic; improved; in vivo; inhibitor/antagonist; insight; mimetics; neutralizing antibody; non-compliance; protein-tyrosine sulfotransferase 2; public health relevance; receptor binding; rectal; simian human immunodeficiency virus; therapeutic protein; transmission process; vaccine safety; vector

 DESCRIPTION (provided by applicant): We have developed and characterized eCD4-Ig, an exceptionally broad and potent HIV-1 entry inhibitor. eCD4-Ig is a fusion of CD4-Ig - a safe but ineffective therapeutic - with a short CCR5- mimetic sulfopeptide. eCD4-Ig is qualitatively different from CD4-Ig or broadly neutralizing antibodies (bNAbs) because it avidly binds two highly conserved and functionally important receptor-binding regions of the HIV-1 envelope glycoprotein, and only those sites. As a consequence, eCD4-Ig, but not CD4-Ig or bNAbs, neutralized 100% of isolates tested, including both R5- and X4-isolates, and two large panels of antibody-resistant HIV-1, HIV-2 and SIV isolates, all with IC50s < 1.2 µg/ml and IC80s less < 5.2 µg/ml. Moreover, in unpublished data, we show that eCD4-Ig is much harder to escape than CD4-Ig or a well characterized CD4-binding site bNAb, and in fact we have yet to identify isolates fully resistant to eCD4-Ig. Most importantly, and again in contrast to bNAbs, eCD4-Ig could provide long- term protection in vivo. When four rhesus macaques were inoculated intramuscularly with an adeno- associated virus (AAV) vector expressing a rhesus form of eCD4-Ig, these macaques were protected from six infectious and escalating challenges with SHIV-AD8. The last of these challenges, also unpublished, were 8- and 16-times the 50% animal infectious dose of SHIV-AD8, and were administered more than one year after inoculation. Here our primary goal is to understand the strengths and limitations of passively administered and AAV-delivered eCD4-Ig as potential alternatives to current antiretroviral regimens. These studies will also help to understand the risks and improve the safety of AAV-eCD4-Ig, perhaps facilitating its use as an alternative vaccine.

 描述（由适用提供）：我们已经开发并表征了ECD4-Ig，这是一种异常广泛且潜在的HIV-1进入抑制剂。 ECD4-Ig是CD4-Ig的融合 - 一种安全但无效的治疗 - 与CCR5-模拟硫化物的短相。 ECD4-Ig在质量上与CD4-Ig或广泛中和抗体（BNAB）有不同的不同，因为它与HIV-1 Invelope糖蛋白的两个高度保守且在功能上重要的受体结合区域和仅这些位点结合。结果，ECD4-Ig，而不是CD4-Ig或BNAB，中和100％测试的分离株，包括R5-和X4-溶质，以及两个大型抗体抗体抗体抗体HIV-1，HIV-1和SIV酸盐，所有这些分离株，均使用IC50s <1.2 µg/ml和IC80S <5.2 µg/ml。此外，在未发表的数据中，我们表明ECD4-Ig比CD4-ig或表征良好的CD4结合位点BNAB更难逃脱，实际上，我们尚未确定对ECD4-Ig完全抗性的分离物。最重要的是，与BNAB相比，ECD4-Ig可以在体内提供长期保护。当将四个恒河猕猴与腺相关病毒（AAV）载体（表达ECD4-ig的恒河猴形式）接种时，这些猕猴被保护免受六个感染性且在Shiv-AD8的越来越升级的挑战。这些挑战中的最后一个挑战也未发表，是50％和16倍的动物感染剂量的Shiv-AD8，并在接种后一年以上进行了管理。在这里，我们的主要目标是理解被动施用和大量递送的ECD4-Ig的优势和局限性，作为当前抗逆转录病毒治疗方案的潜在替代方法。这些研究还将有助于了解风险并提高AAV-ECD4-Ig的安全性，从而有助于其用作替代疫苗。