An injectable hydrogel platform for sustained release of eCD4-Ig

项目总结 联合抗逆转录病毒疗法(CART)和暴露前预防(PrEP)是主要的 在努力消除艾滋病和预防新的艾滋病毒-1感染方面具有里程碑意义。尽管如此，他们还是有 限制。例如，两到三种化合物的终身使用几乎传递到每个细胞，并且 体内的组织可能会带来令人不快的、难以预料的副作用。访问和 遵守情况也仍然令人关切，特别是在尚未接触到的感染者中。 通过我们的医疗保健基础设施。同样，PrEP既需要访问权限，也需要有意识的努力才能 潜在的传播事件，对于最难到达的人来说并不总是现实的事情 国内外的人口统计数据。在这里，我们将开发一种方法，提供强有力的预防和 可能在一次注射后有效地抑制病毒六个月或更长时间。具体来说，我们将 优化eCD4-Ig，一种非常广泛和有效的类似抗体的分子，使其以注射形式递送 水凝胶，我们将对这种水凝胶进行优化，使其能够输送eCD4-Ig。ECD4-Ig提供高效免疫球蛋白 用SIV-AD8和SIVmac239保护恒河猴免受高剂量攻击。它还 具有抑制已建立的SHV-AD8感染的广度和效力。此宽度显示为 足以抑制病毒在个体和群体中的广泛多样性。同样重要的是， HIV-1没有像它从中和中和一样容易地从eCD4-Ig中逃脱 抗体。因此，它是安全、有效和持续的水凝胶输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、非免疫原性、易于制造和 具有高规格需求的可交付产品。重要的是，它们和它们的有效载荷可以立即撤回 以防发生不良事件。模拟表明，它们可以维持eCD4-Ig的浓度， 提供超过六个月的有效预防措施。我们将在人类FcRN中测试这种可能性- 转基因小鼠和恒河猴，并证实我们最好的eCD4-Ig/水凝胶配方可以 更换PrEP和/或购物车。

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.