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

下一代多用途预防技术：用于艾滋病毒预防和非激素避孕的阴道环

• 批准号: 10359111
• 负责人: Marc Michael Baum
• 金额: $ 74.07万
• 依托单位: OAK CREST INSTITUTE OF SCIENCE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359111
• 关键词: AIDS prevention; Adherence; Affinity; African; Agglutination; Animal Model; Anti-Retroviral Agents; Antibodies; Antigen Targeting; Automobile Driving; Behavior monitoring; Biological Assay; Biology; Blocking Antibodies; Cells; Chemistry; Clinical; Clinical Trials; Collaborations; Complement; Contraceptive Agents; Contraceptive methods; Data; Development; Dose; Drug Combinations; Drug Delivery Systems; Drug Kinetics; Drug Stability; Engineering; Epidemic; Family Planning; Future; Goals; HIV; HIV Infections; Hormones; Hour; Human; Hybrids; Immunoglobulin G; In Vitro; Individual; Infection; Kinetics; Knowledge; Lead; Macaca; Macaca nemestrina; Measures; Methods; Modeling; Monitor; Monoclonal Antibodies; Mucous body substance; Oral; Persons; Pharmaceutical Preparations; Pharmacology; Pre-Clinical Model; Pregnancy; Preparation; Prevention; Process; Property; Public Health; Regimen; Research; Research Personnel; Risk; Safety; Sheep; Sperm Agglutination; Swimming; Technology; Temperature; Temperature Sense; Vagina; Vaginal Ring; Woman; Yeasts; arm; base; biocompatible polymer; clinical efficacy; contraceptive efficacy; cost; cost effective; design; egg; global health; health organization; human male; in vivo; infection rate; innovation; interest; lead candidate; multiple omics; nanomolar; next generation; nonhuman primate; novel; pharmacokinetics and pharmacodynamics; pre-clinical; pre-exposure prophylaxis; prevent; prototype; reproductive tract; response; sex; simian human immunodeficiency virus; small molecule; sperm cell; success; transmission process; unintended pregnancy; uptake; vaginal microbiome

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.

抽象的 尽管进展重要，但新的艾滋病毒感染率远远超过了全球卫生组织设定的目标 在遏制流行病的进展中。 2017年，估计有180万人成为新的艾滋病毒 全球感染。迫切需要采取新的HIV暴露前预防（PREP）策略来遏制这一点 令人震惊的局势，特别是在撒哈拉以南非洲妇女中，他们的危险不成比例。高 患有艾滋病毒感染的妇女的比例也对计划生育感兴趣，这表明 双用药产品提供预防HIV和避孕的产品将显着增加 相对于单活产品的吸收较高，因为毫不奇怪，女性并没有自我识别为 艾滋病毒的风险，但要确定怀孕。许多女性反对外源激素，将 强烈喜欢一种非激素方法，而一种方法不需要在性爱之前或之后使用。我们的 应用程序集成了两项领先的创新，以开发下一代多功能技术（MPT） 阴道内环（IVR）：（1）基于多价的新型非激素避孕剂 单克隆抗体（MAB）阻止精子穿过粘液游泳并进入鸡蛋； （2） 用抗逆转录病毒（ARV）制定具有临床功效的抗逆转录病毒（ARV）避孕药 在行为监测IVR中预防艾滋病毒。我们最近设计了一个独特的基于IgG的多价 用10 fab臂对抗CD52G的mAb，这是一个经过验证的抗原靶标，仅在细胞中发现 人类男性生殖道。该分子即使在亚纳摩尔浓度下也有效地凝集 在几秒钟内> 99％的精子，因此提供了潜在的有效但具有成本效益的避孕。补充 这个小说的特工，我们的团队开发了一个创新的IVR平台，可提供药物组合 小分子药物和mAb。低成本模块已纳入IVR，以监测温度 作为依从性的替代度量。 MPT IVR将被配制为长期（30天）双重 在评估依从性的同时进行保护。在AIM 1中，我们将进一步增强针对CD52G的MAB构建体 通过使用酵母 - 播放的抗CD52G Fab的亲和力成熟，将优化的Fab纳入相似的Fab 多聚体MAB格式，并严格地表征其精子凝集效果。在AIM 2中，我们将 制定和评估体外人类和猕猴大小的MPT IVR，以提供我们的铅避孕mAb 基于现有的体内PK-PD数据，候选与ARV药物在目标体外速率上结合使用。我们将 优化和扩展依从性IVR设计并评估绵羊的原型。在AIM 3中，我们将评估 MPT IVR候选绵羊的药代动力学和药效学（安全性​​和功效） 猕猴。该项目建立在研究人员的既定合作基础上，并将推进我们的科学 在预防HIV和 避孕。