Capsule-intravaginal ring for sustained release of antibodies for non-hormonal contraception and vaginal protection against HIV

胶囊阴道环，用于持续释放抗体，用于非激素避孕和阴道艾滋病毒保护

• 批准号: 9799170
• 负责人: Keiichiro Kushiro
• 金额: $ 91.1万
• 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: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9799170
• 关键词: AIDS prevention; Address; Adherence; Affect; Anaerobic Bacteria; Animal Model; Animals; Antibodies; Antigen Targeting; Antigens; Binding; Biological Assay; Buffers; Caliber; Cervix Mucus; Clinical Trials; Contraceptive Agents; Contraceptive Usage; Contraceptive methods; Coupled; Couples; Coupling; Development; Dose; Effectiveness; Encapsulated; Engineering; Enzyme-Linked Immunosorbent Assay; Exogenous Hormone Therapy; Failure; Female; Fertilization; Gel; Goals; HIV; HIV Infections; Headache; Hemorrhage; Hormonal; Human; Immunoglobulin G; Incubated; Individual; Infertility; Intervention; Macaca; Male Genital Organs; Mediating; Menstrual cycle; Mental Depression; Methods; Modeling; Monkeys; Monoclonal Antibodies; Moods; Mucins; Mucous body substance; Mus; Nature; Nausea; Oryctolagus cuniculus; Pattern; Performance; Pharmacology; Phase; Placebos; Polymers; Pregnancy; Reproductive Health; Residual state; Risk; Safety; Sampling; Seminal fluid; Specificity; Sperm Agglutination; Sperm Penetration; Surface; Surface Antigens; System; Technology; Testing; Vagina; Vaginal Ring; Vaginal delivery procedure; Virus; Vision; Weight Gain; Woman; Work; base; capsule; cervicovaginal; clinical development; crosslink; demographics; effectiveness evaluation; efficacy validation; egg; genital herpes; hormonal contraception; human monoclonal antibodies; improved; member; men; microbiota; neutralizing antibody; neutralizing monoclonal antibodies; novel; prevent; public health priorities; reproductive tract; sex; side effect; simian human immunodeficiency virus; sperm cell; transmission process; unintended pregnancy; uptake; vaginal fluid; vaginal microbiota; vaginal transmission

Summary There is a critical need for improved methods for both contraception and HIV prevention. Nearly half of all pregnancies in the U.S. are unintended, and globally there are >85 million unintended pregnancies and 2 million new HIV infections each year. Not surprisingly, unintended pregnancies occur most often in women who are non-users of contraception: many women are averse to using exogenous hormones due to real and perceived side effects, and frequently discontinue hormonal contraception. This underscores the need for a non-hormonal contraceptive method that does not require coitally-timed actions, nor daily intervention. We believe adding contraception to an HIV prevention method would also strongly improve user adherence, since few couples self-identify as at risk of HIV, while nearly all self-identify as at risk of pregnancy. Inspired by nature, where some infertile women express antibodies that bind surface antigens on sperm and block sperm penetration through their cervical mucus, we have investigated a fully human monoclonal antibody (mAb) that can quickly bind a unique antigen present only on the surface of human sperm; we refer to this mAb as human contraceptive antibody (HCA). Importantly, HCA agglutinated >90% of sperm within seconds in all 100 fresh semen samples tested from men spanning diverse demographics. A similiar mAb that binds rabbit sperm reduced egg fertilization by ~95% in the highly fertile rabbit model. Major strides have been made with discovering and testing broadly neutralizing mAb (bnAb) against HIV, including protection against vaginal HIV transmission. Indeed, members of our team led the first clinical trial of VRC01 delivered vaginally. To realize the vision of a mAb-based MPT product, the next step in our development is to (i) formulate mAb into a delivery system that maintains effective levels of mAb in the female reproductive tract, and (ii) further validate efficacy in large animal models. Thus, during Phase I of this Fast-Track application, we will formulate sustained release polymeric capsules encapsulating a cocktail of mAbs (HCA and VRC01+N6 for HIV prevention), and can be embedded into intravaginal rings (IVR). The goal is to demonstrate that loaded mAbs will remain sufficiently stable and active (neutralize/trap HIV and agglutinate/trap sperm) when exposed and released into human cervicovaginal secretions over a 35 day period. Pending successful completion of Phase I milestone, we will perform repeated low-dose vaginal SHIV challenges to confirm if mAb released from the engineered polymeric capsules can effectively reduce vaginal transmission. If successful, our proposed work will strongly support clinical development of our combination contraceptive and HIV-prevention MPT-IVR that could address a major unmet need in the marketplace.

概括 迫切需要改进避孕和预防HIV的方法。将近一半 美国的所有怀孕都是意外的，在全球范围内，有8500万个意外怀孕和2个 每年有百万个新的艾滋病毒感染。毫不奇怪，女性经常发生意外怀孕 谁是避孕的非用户：许多妇女因实际和 感知的副作用，并且经常停止荷尔蒙避孕。这突显了需要 非激素避孕方法不需要撒特式操作，也不需要日常干预。我们 认为将避孕措施添加到艾滋病毒预防方法中也将强烈提高用户的依从性，因为 很少有夫妇自我认同为艾滋病毒的风险，而几乎所有人都认为有怀孕的风险。 受自然的启发，一些不育女性表达抗体结合表面抗原在精子上的抗体 并阻止精子穿透其宫颈粘液，我们研究了一个完全人类的单克隆 抗体（mAb）可以迅速结合仅在人类精子表面上存在的独特抗原；我们指的是 将其作为人类避孕抗体（HCA）作为mAb。重要的是，HCA凝集>> 90％的精子 所有100个新鲜的精液样本中的几秒钟都从跨越人口统计学的男性测试。一个类似的mab 在高肥沃的兔子模型中，将兔子精子降低了约95％。大步很大 通过发现和测试对艾滋病毒的广泛中和mab（BNAB）制造，包括防止 阴道HIV传播。的确，我们团队的成员领导了VRC01的第一次临床试验，进行了阴道交付。 为了实现基于mab的MPT产品的愿景，我们开发的下一步是（i）制定 MAB进入递送系统，该系统在女性生殖道中保持有效水平的MAB，并且（ii） 进一步验证大型动物模型的功效。因此，在此快速应用程序的第一阶段，我们将 配制持续释放的聚合物胶囊，封装了mabs的鸡尾酒（HCA和VRC01+N6 预防艾滋病毒），可以嵌入经动脉内环（IVR）中。目标是证明已加载 当暴露时，mAb将保持足够稳定和活跃（中和艾滋病毒和凝集的艾滋病毒和凝集的精子） 并在35天的时间内释放到人宫颈阴道分泌物中。等待成功完成 第一阶段里程碑，我们将执行重复的低剂量阴道SHIV挑战，以确认MAB是否从 工程的聚合物胶囊可以有效地减少阴道传播。如果成功，我们的建议 工作将强烈支持我们组合避孕药和预防HIV的MPT-IVR的临床发展 这可以解决市场上的主要未满足需求。