An injectable hydrogel platform for sustained release of eCD4-Ig

用于持续释放 eCD4-Ig 的可注射水凝胶平台

• 批准号: 10170267
• 负责人: Eric Andrew Appel
• 金额: $ 84.63万
• 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: 2020-06-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170267
• 关键词: Acquired Immunodeficiency Syndrome; Adverse event; Animals; Antibodies; Biochemical; Biological; Cell Culture Techniques; Cells; Conscious; Control Animal; Dependovirus; Dose; Drug Kinetics; Drug resistance; Event; Formulation; HIV-1; HIV-2; Half-Life; Healthcare; Human; Hydrogels; Implant; Individual; Infection; Infrastructure; Injectable; Injections; Intramuscular; Intravenous; Laboratories; Life; Macaca; Macaca mulatta; Mediating; Modeling; Mus; Needles; Pathway interactions; Patients; Peptides; Persons; Population; Preparation; Property; Prophylactic treatment; Proteins; SIV; Serum; Serum Proteins; Stigmatization; System; Testing; Therapeutic; Tissues; Toxic effect; Transgenes; Transgenic Mice; Variant; Viral; Virus; adeno-associated viral vector; antiretroviral therapy; biophysical properties; cost; demographics; fitness; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; neonatal Fc receptor; neutralizing antibody; novel; pre-exposure prophylaxis; prevent; protein aggregation; rectal; sexually active; side effect; simian human immunodeficiency virus; time use; transmission process

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.

项目摘要 抗逆转录病毒疗法（CART）和暴露前预防（PREP）代表主要 努力消除艾滋病并防止新的HIV-1感染的里程碑。尽管如此，他们还是 限制。例如，将两到三种化合物的终身用途传递给了大多数每个单元，并且 体内的组织可能会带来不良的，难以预测的副作用。访问和 合规性也仍然关注，尤其是在尚未达到的感染者中 由我们的医疗保健基础设施。同样，准备需要访问和有意识的努力 潜在的传输事件，对于最难到达的最难始终是现实的 国外的人口统计。在这里，我们将开发一种提供强大预防和的方法 单次注射后可能有效六个月或更长时间。特别是我们会的 优化一种非常宽和有效的抗体样分子的ECD4-ig，以递送在可注射剂中 水凝胶，我们将优化此水凝胶以递送ECD4-Ig。 ECD4-Ig提供了非常有效的 SHIV-AD8和SIVMAC239的恒河猕猴保护猕猴的保护。也是如此 具有抑制已建立的SHIV-AD8感染的广度和效力。出现这个宽度 足以抑制个体和人群中广泛的病毒多样性。重要的是， HIV-1并没有像中和那样开发从ECD4-Ig逃脱的途径 抗体。因此，它是安全，有效且持续的水凝胶输送系统的理想有效载荷。 如我们所示，这些水凝胶具有耐受性良好，非免疫原性，易于制造，并且 可交付，需要高规模的需求。重要的是，它们和他们的有效载荷可以立即撤回 如果发生不良事件。建模表明，它们可以维持可以维持的ECD4-Ig浓度 提供有效的预防量超过六个月。我们将在人类的fcrn中测试这种可能性 转基因小鼠和恒河猕猴中 更换准备和/或购物车。