Next Generation Multipurpose Prevention Technology: An Intravaginal Ring for HIV Prevention and Nonhormonal Contraception

摘要 新的艾滋病毒感染率远远超过全球卫生组织设定的目标，尽管取得了重大进展 在遏制疫情发展方面的作用。2017年，估计有180万人成为新的艾滋病毒感染者 在全球范围内感染。迫切需要新的艾滋病毒暴露前预防(PrEP)战略来遏制这种情况 令人震惊的情况，特别是撒哈拉以南非洲的年轻妇女，她们面临的风险不成比例。一次高潮 有感染艾滋病毒风险的妇女的比例也对计划生育感兴趣，这表明 提供艾滋病毒预防和避孕的双重用途产品将显著增加 相对于单一用途的产品，摄取量更高，因为毫不奇怪，女性并不自我认同为 艾滋病毒的风险，但这样做是为了确认怀孕。许多女性反对外源性激素，并会 强烈推荐一种非荷尔蒙的方法，这种方法不需要在性行为之前或之后立即使用。我们的 应用集成了开发下一代多用途技术(MPT)的两项领先创新 阴道内环(IVR)：(1)开发一种基于多价激素的新型非激素避孕药 阻止精子游过粘液和接触卵子的单抗；以及(2) 抗逆转录病毒药物单抗避孕药的研制及其临床效果 在行为监测IVR中预防艾滋病毒。我们最近设计出了一种独特的基于免疫球蛋白的多价 CD52g是一种有效的避孕抗原靶标，仅在 人类的男性生殖道。这种分子，即使在亚纳摩尔浓度下，也能有效地凝集 -gt；99%的精子在几秒钟内完成，从而提供潜在的有效且成本效益高的避孕方法。来补充 我们的团队开发了一种创新的IVR平台，提供包括以下药物组合的药物组合 小分子药物和单抗。IVR中加入了一个低成本的模块来监控温度 作为遵守的替代措施。MPT IVR将被制定为提供长期(30天)的双重 在评估遵从性的同时提供保护。在目标1中，我们将进一步增强针对CD52g的mAb构建 通过酵母展示亲和成熟抗CD52g Fab，将优化后的Fab整合到类似的 形成多聚体mAb，并严格表征其精子凝集力。在目标2中，我们将 制备和评估体外人和猕猴大小的MPT IVR以传递我们的铅避孕mAb 根据现有的体内PK-PD数据，候选药物与ARV药物在体外以目标速率联合使用。我们会 优化和扩展依从性IVR设计，并在绵羊身上评估原型。在目标3中，我们将评估 MPT IVR候选药物在绵羊和猪尾的药代动力学和药效学(安全性和有效性) 猕猴。该项目建立在研究人员已建立的合作基础上，并将推动我们的科学 在艾滋病毒预防和预防的背景下，对缓释阴道给药特性的认识 避孕。

ABSTRACT New HIV infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. In 2017, an estimated 1.8 million people became newly HIV infected globally. New HIV pre-exposure prophylaxis (PrEP) strategies are needed urgently to curb this alarming situation, particularly in young sub-Saharan African women who are disproportionately at risk. A high proportion of women at risk of becoming HIV-infected also are interested in family planning, suggesting that a dual-purpose product providing HIV prevention and contraception would significantly increase the likelihood of higher uptake relative to single-purpose products, since unsurprisingly, women do not self-identify as being at risk of HIV, but do so identify for pregnancy. Many women are averse to exogenous hormones and would strongly prefer a nonhormonal method, and one that does not require use immediately before or after sex. Our application integrates two leading innovations in developing a next generation multi-purpose technology (MPT) intravaginal ring (IVR): (1) developing a novel, nonhormonal contraceptive agent based on a multivalent monoclonal antibody (mAb) that blocks sperm from swimming through mucus and accessing the egg; and (2) formulating the mAb contraceptive with antiretroviral (ARV) agents with demonstrated clinical efficacy in preventing HIV in a behavior-monitoring IVR. We have recently engineered a unique IgG-based multivalent mAb with 10 Fab arms against CD52g, a validated antigen target for contraception that is found only on cells in the human male genital tract. This molecule, even at sub-nanomolar concentrations, effectively agglutinates >99% of sperm within seconds, thus offering potentially potent yet cost-effective contraception. To complement this novel agent, our team has developed an innovative IVR platform that delivers drug combinations including small molecule drugs and mAbs. A low-cost module has been incorporated into the IVR to monitor temperature as a surrogate measure of adherence. The MPT IVR will be formulated to provide long-term (30 days) dual protection while evaluating adherence. In Aim 1, we will further enhance the mAb constructs against CD52g through affinity maturation of anti-CD52g Fab using yeast-display, incorporate the optimized Fab into similar multimeric mAb formats, and characterize their sperm agglutination potencies rigorously. In Aim 2, we will formulate and evaluate in vitro human- and macaque-sized MPT IVRs to deliver our lead contraceptive mAb candidate in combination with ARV drugs at target in vitro rates based on existing in vivo PK-PD data. We will optimize and expand the adherence IVR design and evaluate prototypes in sheep. In Aim 3, we will assess the pharmacokinetics and pharmacodynamics (safety and efficacy) of MPT IVR candidates in sheep and pigtailed macaques. This project builds on an established collaboration of investigators and will advance our scientific knowledge on the properties of sustained-release vaginal drug delivery in the context of HIV prevention and contraception.