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: 10381449
• 负责人: Keiichiro Kushiro
• 金额: $ 79.11万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381449
• 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艾滋病毒预防方法。近一半 美国所有的意外怀孕都是意外怀孕，全球有超过 8500 万例意外怀孕，2 每年新增艾滋病毒感染者数百万。毫不奇怪，意外怀孕最常发生在女性身上 不使用避孕药具的人：许多女性不愿意使用外源性激素，因为它们的真实性和有效性 察觉到副作用，并经常停止激素避孕。这强调了需要 非激素避孕方法，不需要性交定时行为，也不需要日常干预。我们 相信在艾滋病毒预防方法中添加避孕措施也将大大提高使用者的依从性，因为 很少有夫妇认为自己有感染艾滋病毒的风险，而几乎所有夫妇都认为自己有怀孕的风险。 受大自然启发，一些不孕女性表达结合精子表面抗原的抗体 并阻止精子穿过宫颈粘液，我们研究了一种完全人类单克隆抗体 抗体（mAb），能够快速结合仅存在于人类精子表面的独特抗原；我们指的是 该单克隆抗体被称为人类避孕抗体 (HCA)。重要的是，HCA 凝集了超过 90% 的精子 对来自不同人口统计数据的男性进行的所有 100 个新鲜精液样本测试中，该样本的检测时间为 10 秒。类似的单克隆抗体 在高生育力兔子模型中，与兔子精子结合使卵子受精率降低约 95%。已取得重大进展 通过发现和测试针对 HIV 的广泛中和单克隆抗体 (bnAb)，包括预防 阴道艾滋病毒传播。事实上，我们团队的成员领导了 VRC01 的首次阴道分娩临床试验。 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 将 mAb 引入递送系统，以维持女性生殖道中 mAb 的有效水平，以及 (ii) 进一步验证大型动物模型的功效。因此，在快速通道申请的第一阶段，我们将 配制缓释聚合物胶囊，内含单克隆抗体混合物（HCA 和 VRC01+N6，用于 HIV 预防），并且可以嵌入阴道环 (IVR)。目标是证明加载 单克隆抗体在暴露时将保持足够的稳定性和活性（中和/捕获 HIV 并凝集/捕获精子） 并在 35 天的时间内释放到人类宫颈阴道分泌物中。等待成功完成 第一阶段里程碑，我们将重复进行低剂量阴道 SHIV 挑战，以确认 mAb 是否从 工程聚合物胶囊可以有效减少阴道传播。如果成功的话，我们建议 这项工作将有力支持我们的复方避孕药和 HIV 预防 MPT-IVR 的临床开发 这可以解决市场上未满足的主要需求。