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: 10158504
• 负责人: Marc Michael Baum
• 金额: $ 74.49万
• 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/10158504
• 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; 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 尽管取得了重大进展，但新的艾滋病毒感染率仍远远超过全球卫生组织设定的目标 以遏制疫情的发展。 2017 年，估计有 180 万人新感染艾滋病毒 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 情况令人震惊，尤其是撒哈拉以南非洲的年轻女性，她们面临的风险尤其大。一个高 有感染艾滋病毒风险的女性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着增加感染艾滋病毒的可能性 相对于单一用途产品的使用率更高，因为毫不奇怪，女性并不认为自己处于 有感染艾滋病毒的风险，但这样做可以确定是否怀孕。许多女性厌恶外源性激素，并会 强烈喜欢非激素方法，并且不需要在性行为之前或之后立即使用。我们的 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）开发一种基于多价的新型非激素避孕剂 单克隆抗体 (mAb)，可阻止精子游过粘液并进入卵子；和（2） 使用抗逆转录病毒 (ARV) 药物配制单克隆抗体避孕药，并在 通过行为监测 IVR 预防艾滋病毒。我们最近设计了一种独特的基于 IgG 的多价 具有 10 个针对 CD52g 的 Fab 臂的单克隆抗体，CD52g 是一种经过验证的避孕抗原靶标，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，也能有效地凝集 几秒钟内超过 99% 的精子，从而提供潜在有效且具有成本效益的避孕措施。来补充 对于这种新型药物，我们的团队开发了一个创新的 IVR 平台，可提供药物组合，包括 小分子药物和单克隆抗体。 IVR 中集成了一个低成本模块来监控温度 作为依从性的替代衡量标准。 MPT IVR 将制定为提供长期（30 天）双重 评估依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 构建体 通过使用酵母展示对抗 CD52g Fab 进行亲和力成熟，将优化的 Fab 整合到类似的 多聚体单克隆抗体形式，并严格表征其精子凝集效力。在目标 2 中，我们将 制定和评估体外人类和猕猴大小的 MPT IVR，以提供我们的领先避孕单克隆抗体 根据现有的体内 PK-PD 数据，候选药物与 ARV 药物以体外目标速率联合使用。我们将 优化和扩展依从性 IVR 设计并评估绵羊原型。在目标 3 中，我们将评估 MPT IVR 候选药物在绵羊和猪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已建立的合作基础上，并将推进我们的科学发展 关于艾滋病毒预防和缓释阴道给药特性的知识 避孕。