An injectable hydrogel platform for sustained release of eCD4-Ig

项目摘要 联合抗逆转录病毒治疗（cART）和暴露前预防（PrEP）是主要的治疗方法。 这是消除艾滋病和预防新的HIV-1感染的努力中的里程碑。尽管如此， 局限性。例如，终生使用两种或三种化合物递送到几乎每个细胞， 体内的组织可能会带来不希望的、难以预料的副作用。访问和 遵守情况也仍然令人关切，特别是尚未接触到的受感染者 我们的医疗基础设施。同样，PrEP需要访问和有意识的努力， 潜在的传输事件，对于最难到达的人来说并不总是现实的 国内外的人口统计。在这里，我们将开发一种方法，提供强大的预防和 单次注射后可能会有效抑制病毒六个月或更长时间。具体来说，我们将 优化eCD 4-IG，一种非常广泛和有效的抗体样分子，用于其在注射剂中的递送 水凝胶，我们将优化这种水凝胶用于递送eCD 4-IG。eCD 4-IG提供高效的 保护恒河猴免受SHIV-AD 8和SIVmac 239的高剂量攻击。它还 具有抑制已建立的SHIV-AD 8感染的广度和效力。这种广度似乎 足以抑制个体和群体中病毒的广泛多样性。同样重要的是， HIV-1还没有开发出容易从eCD 4-IG中逃逸的途径，因为它已经从中和中逃逸了。 抗体的因此，它是安全、有效和持续的水凝胶递送系统的理想有效载荷。 正如我们所展示的，这些水凝胶具有良好的耐受性，无免疫原性，易于制造， 可交付的高规格需求。重要的是，它们及其有效载荷可以立即撤回， 以防出现不良事件。建模表明，它们可以维持eCD 4-IG浓度， 提供有效的预防措施超过六个月。我们将在人类FcRn中测试这种可能性- 在转基因小鼠和恒河猴中，并证实我们最好的eCD 4-IG/水凝胶制剂可以 替代PrEP和/或cART。

PROJECT SUMMARY Combined anti-retroviral therapy (cART) and pre-exposure prophylaxis (PrEP) represent major milestones in the effort to eliminate AIDS and prevent new HIV-1 infections. They nonetheless have limitations. For example, a life-time use of two or three compounds delivered to most every cell and tissue in the body will likely come with undesirable, difficult-to-anticipate side effects. Access and compliance also remain concerns, especially among infected persons who have not yet been reached by our healthcare infrastructures. Similarly, PrEP requires both access and a conscious effort before a potential transmission event, something that is not always realistic for the hardest-to-reach demographics here and abroad. Here we will develop an approach that provides robust prophylaxis and perhaps effective viral suppression for six months or more after a single injection. Specifically we will optimize eCD4-Ig, a very broad and potent antibody-like molecule, for its delivery in an injectable hydrogel, and we will optimize this hydrogel for delivery of eCD4-Ig. eCD4-Ig provides highly effective protection in rhesus macaques from high-dose challenges with both SHIV-AD8 and SIVmac239. It also has the breadth and potency to suppress an established SHIV-AD8 infection. This breadth appears sufficient to suppress the wide diversity of viruses in an individual and in a population. As importantly, HIV-1 has not developed easily accessible pathways of escape from eCD4-Ig as it has from neutralizing antibodies. It is therefore an ideal payload for a safe, effective, and sustained hydrogel delivery system. As we show, these hydrogels are well-tolerated, non-immunogenic, easily manufactured, and deliverable with a high-gauge need. Importantly, they and their payloads can be immediately withdrawn in case of an adverse event. Modeling suggest that they can sustain eCD4-Ig concentrations that could provide effective prophylaxis for well over six months. We will test this possibility in human FcRn- transgenic mice and in rhesus macaques, and confirm that our best eCD4-Ig/hydrogel formulations could replace PrEP and/or cART.