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

基本信息

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
项目类别：
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

项目摘要

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 Mucommune正在开发一个双动作静脉内环（IVR），该环将提供长达一个月的（i）非激素通过持续释放超容量避孕抗体和（ii）预防细菌来避孕阴道化（BV）通过持续释放乳酸（LA）来支持受保护的乳酸杆菌占主导地位微生物组。数以百万计的妇女避免由于医疗避孕和真实而导致的马避孕药具或感知的外源激素的副作用，对有效的非激素有浓厚的兴趣避孕不需要与同犯相关的中断。 BV，一种阴道营养不良，多发性疾病细菌种群，耗尽的保护居民乳酸杆菌，否则会用乳酸（LA），一种宽光谱菌心，可预防许多性传播病原体。 BV 大大增加了获得各种性传播感染（例如艾滋病毒）的风险，并增加了风险早产。市场上没有产品可以为BV提供持续的保护或长达一个月的非荷尔蒙违规行为。为了应对这些挑战，我们设计了一本小说超能力抗植物抗体（MM0008）靶向验证良好的避孕靶标。 MM008 与母体IgG相比抗体，并完全凝结在仅数十分之二的绵羊阴道上的所有人类精子每只绵羊的微克。另外，我们还开发了聚合物基质环公式可以以旨在与保护性持续分泌的速度相匹配的速度持续释放阴道乳酸杆菌。这些进步使我们能够提出开发多用途的LA-和 MM0008释放IVR（LA-MM008-IVR）基于我们的专有胶囊-IVR平台，该平台嵌入胶囊释放MM008，其接近零级动力学一个月，同时保护MM008免受LA的保护。这环由精心优化的聚合物矩阵混合物制成，该矩阵以可能需要的速率释放LA 为期一个月的保护BV。这种独特的胶囊-IVR设计使我们能够独立调整释放 LA和MM008，易于以非常低的成本和高吞吐量制造，这反过来应该在美国以及低 - 和低 - 和低 - 和低 - 和低 - 和低 - 和低 - 和低 - 和低 - 和低 - 全球中等收入国家。在特定的目标1中，我们将准备许多LA-MM008-IVR公式，并在体外进行严格特征量化了LA和MM008释放的速率。在特定的目标2中，我们将首先确定LA在绵羊中的最高耐受剂量，该绵羊在解剖学上与人类阴道相似，然后进行阴道药代动力学研究，以评估LA和MM008从铅LA-MM008-释放 IVR公式。在这种高度相关的动物模型中，成功证明安全性和效率将通过进一步的临床前和临床评估，支持粘膜的LA-MM008-IVR推进。（30行）