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

摘要 尽管取得了重要进展，但新的艾滋病毒感染率远远超过全球卫生组织设定的目标 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。 感染全球。迫切需要新的艾滋病毒暴露前预防（PrEP）策略来遏制这种情况 这一情况令人震惊，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。高 有可能感染艾滋病毒的妇女中也有一部分对计划生育感兴趣，这表明， 提供艾滋病毒预防和避孕的两用产品将大大增加 与单一用途产品相比，女性的使用率更高，因为不出所料，女性并不认为自己处于 艾滋病毒的风险，但这样做确定怀孕。许多女性不喜欢外源性激素， 强烈偏好非荷尔蒙方法，且不需要在性交前后立即使用。我们 该应用程序集成了开发下一代多用途技术（MPT）的两项领先创新 阴道环（IVR）：（1）开发一种基于多价 单克隆抗体（mAb），阻止精子游过粘液并接近卵子;和（2） 用抗逆转录病毒（ARV）药物配制mAb避孕药， 在行为监测IVR中预防艾滋病。我们最近设计了一种独特的IgG多价 具有10个针对CD 52 g的Fab臂的mAb，CD 52 g是一种经验证的避孕抗原靶点，仅存在于 人类男性的生殖道这种分子，即使在亚纳摩尔浓度下， >99%的精子在几秒钟内，从而提供潜在的有效但具有成本效益的避孕。以补充 我们的团队开发了一种创新的IVR平台，可以提供药物组合，包括 小分子药物和mAb。一个低成本的模块已纳入IVR监测温度 作为一种替代的依从性测量。制定MPT IVR，以提供长期（30天）双重 保护，同时评估遵守情况。在目标1中，我们将进一步增强针对CD 52 g的mAb构建体， 通过使用酵母展示的抗CD 52 g Fab的亲和力成熟，将优化的Fab掺入类似的 多聚体mAb形式，并严格表征其精子凝集效力。在目标2中，我们 制定和评估体外人类和猕猴大小的MPT IVR，以提供我们的领先避孕mAb 基于现有的体内PK-PD数据，以目标体外速率与ARV药物组合的候选药物。我们将 优化和扩展依从性IVR设计，并在绵羊中评估原型。在目标3中，我们将评估 MPT IVR候选药物在绵羊和猪尾中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的既定合作基础上，将推动我们的科学研究。 在预防艾滋病毒方面，了解阴道缓释药物输送的特性， 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.