Multipurpose vaginal ring for non-hormonal contraception and preventing bacterial vaginosis

用于非激素避孕和预防细菌性阴道病的多用途阴道环

• 批准号: 10226692
• 负责人: RICHARD CONE
• 金额: $ 26.6万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226692
• 关键词: Address; Adherence; Affect; Age; Anaerobic Bacteria; Anatomy; Animal Model; Anti-Bacterial Agents; Antibiotics; Antibodies; Atopobium vaginae; Bacteria; Bacterial Vaginosis; Binding; Blocking Antibodies; Buffers; Clindamycin; Conceptions; Contraceptive Agents; Cyclic GMP; Defect; Development; Distress; Dose; Drug Kinetics; Engineering; Environment; Epithelial; Ethylenes; Excipients; Fertility; Formulation; Goals; HIV; Hormones; Human; Immune; Immunoglobulin G; In Vitro; Infection; Infertility; Inflammation; Interruption; Kinetics; Lactic acid; Lactobacillus; Lead; Measures; Medical; Menstrual cycle; Methods; Metronidazole; Microbe; Monoclonal Antibodies; Nature; Odors; Oral; Parents; Pathology; Pharmacologic Substance; Phase; Physiological; Polymers; Population; Povidone; Predisposition; Pregnancy; Premature Birth; Prevention; Pruritus; Public Health; Recurrence; Reproductive Health; Residual state; Risk; Safety; Seminal fluid; Sexual Transmission; Sexually Transmitted Diseases; Sheep; Small Business Innovation Research Grant; Spermatozoa antibody; Structure; Swab; Symptoms; Technology; Testing; Time; Toxicology; Vagina; Vaginal Cream; Vaginal Gel; Vaginal Ring; Woman; adverse birth outcomes; adverse pregnancy outcome; base; biomaterial compatibility; capsule; contraceptive target; cost; design; dysbiosis; efficacy study; egg; experience; hormonal contraception; hydrophilicity; in vivo; interest; low and middle-income countries; manufacturing process; microbicide; microbiome; novel; pathogen; preclinical evaluation; prevent; reproductive; research clinical testing; sexually active; side effect; sperm cell; unintended pregnancy; vaginal infection; vaginal lactobacilli; vaginal microbiome; vaginal microbiota; vinyl acetate

Project Summary Mucommune is developing a dual-action intravaginal ring (IVR) that will provide month-long (i) non-hormonal contraception by sustained release of an ultrapotent contraceptive antibody, and (ii) prevention of bacterial vaginosis (BV) by sustained release of lactic acid (LA) to support a protective Lactobacilli-dominant microbiome. Millions of women avoid hormonal contraceptives due to medical contraindication as well as real or perceived side effects of exogenous hormones, and would have strong interest in effective non-hormonal contraceptives that do not require coitally-related interruptions. BV, a vaginal dysbiosis with polymicrobial bacterial populations, depletes protective resident Lactobacilli that would otherwise acidify the vagina with lactic acid (LA), a broad-spectrum microbicide that protects against many sexually transmitted pathogens. BV greatly increases the risks of acquiring various sexually transmitted infections such as HIV, and increases risks of premature births. There is no product on the market that can provide sustained protection against BV or convenient month-long non-hormonal contraception. To meet these challenges, we have engineered a novel ultrapotent anti-sperm antibody (MM0008) that targets a well-validated contraceptive target. MM008 agglutinates human sperm with a greater than 16-fold augmented potency compared to the parent IgG antibody, and completely agglutinated all human sperm dosed to the sheep vagina within 2 mins at just tens of micrograms dosed per sheep. Separately, we have also developed polymer matrix ring formulations that can provide sustained release of LA at rates designed to match those continuously secreted by protective vaginal Lactobacilli. These advances have enabled us to propose developing the multipurpose LA- and MM0008- releasing IVR (LA-MM008-IVR) based on our proprietary capsule-IVR platform, where embedded capsules release MM008 with near zero-order kinetics for one month, while protecting MM008 from LA. The ring is made with a carefully optimized blend of polymer matrix that releases LA at rates likely needed for month-long protection against BV. This unique capsule-IVR design allows us to independently tune the release of LA and MM008, and is easy to manufacture at very low cost and high throughput, which in turn should maximize potential public health impact and commercial viability of the product both in the U.S. and in low- and middle-income countries worldwide. In Specific Aim 1, we will prepare a number of LA-MM008-IVR formulations, and perform rigorous in vitro characterizations quantifying the rate of LA and MM008 release over time. In Specific Aim 2, we will first determine the highest tolerable dose of LA in sheep, which is anatomically similar to the human vagina, followed by vaginal pharmacokinetic study to assess the release of LA and MM008 from the lead LA-MM008- IVR formulation. Successful demonstration of safety and efficacy in this highly relevant animal model would support advancing Mucommune’s LA-MM008-IVR through further preclinical and clinical evaluations. (30 lines)

项目摘要 MuComme正在开发一种双作用阴道内环(IVR)，它将提供长达一个月的非荷尔蒙 通过持续释放超强避孕抗体来避孕，以及(Ii)预防细菌 通过持续释放乳酸(LA)支持保护性乳杆菌占优势的阴道病(BV) 微生物组。数百万女性因医学禁忌和现实情况而避免使用激素避孕药 或感觉到外源性激素的副作用，并对有效的非激素有浓厚的兴趣 不需要性交相关中断的避孕药具。BV，一种含有多种微生物的阴道菌群失调 细菌种群，耗尽保护性常驻乳杆菌，否则会使阴道酸化 乳酸(LA)，一种广谱杀菌剂，可抵御许多性传播病原体。BV 大大增加了感染艾滋病毒等各种性传播疾病的风险，并增加了风险 早产的症状。市场上没有一种产品可以提供持续的预防BV或 方便的为期一个月的非荷尔蒙避孕。为了迎接这些挑战，我们设计了一部小说 超强抗精子抗体(MM0008)，靶向有效的避孕靶点。MM008 与亲本Ig G相比，凝集人精子的效力提高了16倍以上 抗体，并在2分钟内将所有人精子完全凝集到绵羊阴道内，仅需数十分钟 每只羊的剂量是微克。另外，我们还开发了聚合物基质环配方 可提供持续释放LA的速率，旨在与保护性药物持续分泌的LA相匹配 阴道乳杆菌。这些进展使我们能够提议开发多用途LA-和 MM0008-基于我们的专有胶囊-IVR平台发布IVR(LA-MM008-IVR)，其中嵌入 胶囊以近零级动力学释放MM008一个月，同时保护MM008免受LA的影响。这个 环是由精心优化的聚合物基质混合物制成的，它以可能需要的速度释放LA 针对BV的长达一个月的保护。这种独特的胶囊-IVR设计允许我们独立调整释放 并且易于以非常低的成本和高产量制造，这反过来又应该 最大限度地提高该产品在美国和美国的潜在公共健康影响和商业可行性- 世界各地的中等收入国家。 在具体目标1中，我们将制备一些LA-MM008-IVR制剂，并在体外进行严格的试验 量化LA和MM008随时间的释放速率的特征。在具体目标2中，我们将首先 确定绵羊体内LA的最高耐受量，这种剂量在解剖学上与人类阴道相似， 随后进行阴道药代动力学研究，以评估LA-MM008-MM008的释放 IVR配方。在这种高度相关的动物模型中成功证明安全性和有效性将 通过进一步的临床前和临床评估，支持推进MuComme的LA-MM008-IVR。 (30行)