IND‐enabling development of MM‐008 IVR, an antibody-based nonhormonal contraceptive intravaginal ring

IND– 促进 MM–008 IVR 的开发，这是一种基于抗体的非激素避孕阴道环

• 批准号: 10385104
• 负责人: RICHARD CONE
• 金额: $ 103.91万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385104
• 关键词: Address; Adherence; Agglutination; Animal Model; Antibodies; Antigen Targeting; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Colposcopy; Contraceptive Agents; Contraceptive Usage; Contraceptive Vaccines; Contraceptive methods; Copper Intrauterine Devices; Counseling; Critical Pathways; Cyclic GMP; Development; Devices; Dose; Embryo; Engineering; Epithelial; Excision; Exogenous Hormone Therapy; Failure; Federal Government; Fertility; Foundations; Future; Goals; Headache; Hemorrhage; Hormones; Human; Immobilization; Immune; Immunoglobulin G; Immunologic Contraception; In Vitro; Individual; Infertility; Intervention; Kinetics; Male Genital Organs; Menstrual cycle; Mental Depression; Methods; Modeling; Monoclonal Antibodies; Moods; Mucins; Mucous body substance; Nausea; Oocytes; Oral; Oryctolagus cuniculus; Parents; Passive Immunization; Pattern; Phase; Pilot Projects; Placebos; Population; Positioning Attribute; Pregnancy; Prevalence; Process; Production; Safety; Sheep; Small Business Innovation Research Grant; Sperm Agglutination; Sperm Motility; Spermatozoa antibody; State Government; Surface; System; Technology; Testing; Time; Tissues; Toxic effect; Translational Research; Vaccines; Vagina; Vaginal Ring; Vaginal delivery procedure; Weight Gain; Woman; Work; base; biomaterial compatibility; bioprocess; cGMP production; capsule; cell motility; contraceptive efficacy; cost; cost effective; cross reactivity; crosslink; cytokine; design; egg; hormonal contraception; in vivo; irritation; manufacturing process; monoclonal antibody production; pathogen; prevent; reproductive tract; research clinical testing; reversible contraceptive; safety assessment; safety study; satisfaction; sex; side effect; sperm cell; translational medicine; unintended pregnancy; uptake; usability; vaccine response; vaccine trial; vaginal fluid

Summary Nearly half of all pregnancies in the U.S. are unintended, and most occur in women who are not using contraceptives. There are diverse reasons for not using contraceptives; one common reason is that many women have a strong aversion to using exogenous hormones due to real and perceived side effects. It is likely that contraceptive use and satisfaction would substantially increase if there were a non-hormonal, user- controlled contraceptive method that does not require coitally-timed actions nor daily dosing. Such product does not currently exist. We believe we can create such a non-hormonal contraceptive based on an intravaginal ring (IVR) releasing an anti-sperm monoclonal antibody (mAb) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization based on vaginal delivery of anti-sperm Ab was validated in animal models in the 80’s-90’s, and directly overcomes the variable intensity and uncertain reversibility of contraceptive vaccines. However, this strategy was not practical until recently due to the high costs of mAb production, and modest agglutination potencies of IgG. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of mAb, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm mAb. We possess an exceptionally potent antibody, MM008, that target a well characterized and validated antigen target present on human sperm, is highly homogeneous and stable, and can reduce progressively motile sperm by 99.9% in the sheep vagina in 2 mins at a dose of just 33 ug per sheep. We have also developed a proprietary capsule-IVR system that can stably release MM008 for over 20 days (more than adequate to cover the fertility window in most women). In pilot studies, MM008-IVR was able to provide complete sperm agglutination in the sheep vagina for over 21 days. Building off of these promising results, we seek to establish in Aim 1 the cGMP production processes that will support the manufacturing of capsule-IVR for IND-enabling and Phase 1-2 studies, and validate the capsule-IVR can provide sustained release of MM008 in vitro and in vivo. We will then perform in Aim 2 a usability and safety assessment of a placebo capsule-IVR in women. Finally, we will complete in Aim 3 other critical path IND-enabling activities, including GLP TCR and GLP Biocompatibility studies. Successful completion of these activities will put us in position to file IND for MM008-IVR quickly after the manufacturing and release of the MM008 clinical trial materials. This project is designed to support clinical evaluation of our non-hormonal contraceptive MM008- IVR that could address a significant unmet need in the marketplace, and lay the foundation for future multifuntional IVRs that also protects against STIs.

概括 美国几乎一半的怀孕是意想不到的，大多数发生在不使用的女性中 避孕药。潜水员的原因是不使用避孕药具；一个常见的原因是很多 由于真实和感知的副作用，妇女对使用外源恐怖症有很大的厌恶。很可能 如果存在非激素，用户 - 受控避孕方法，不需要涂层的动作或每日给药。这样的产品 目前不存在。我们相信我们可以基于一个 释放抗卵形单克隆抗体（MAB）的阴道内环（IVR），该抗体会凝结和陷阱 粘液中的精子，从而防止精子到达鸡蛋。基于局部的被动免疫 在80年代的动物模型中，在80's-90的动物模型中验证了抗植物AB的阴道传递，直接克服了 避孕疫苗的可变强度和不确定的可逆性。但是，这种策略不是 直到最近，由于MAB产量的高成本以及IgG的适度凝集电位，直到最近才实用。 鉴于生物处理方面的显着进步大大降低了制造成本 mab，我们相信现在的时间已经成熟，开发IVR进行持续的被动免疫 具有潜在的抗植物mAb。我们拥有一种具有异常潜在的抗体MM008，该抗体靶向井 人类精子上存在和经过验证的抗原靶标，是高度均匀且稳定的，并且 可以在2分钟内以每剂量的33 ug降低绵羊阴道中的运动精子逐渐减少99.9％ 羊。我们还开发了一个专有的胶囊-IVR系统，该系统可以稳定释放20多个MM008 天（足以覆盖大多数女性的生育窗口）。在试点研究中，MM008-IVR能够 为了在绵羊阴道中提供完全的精子凝集超过21天。建立这些诺言 结果，我们寻求在AIM 1中建立CGMP生产过程，以支持制造 用于辅助和1-2阶段研究的胶囊-IVR，并验证胶囊-IVR可以提供持续的 释放MM008体外和体内。然后，我们将在AIM 2中执行可用性和安全评估 女性安慰剂胶囊。最后，我们将在AIM中完成其他3个关键路径，并将 包括GLP TCR和GLP生物相容性研究。这些活动的成功完成将使我们加入 在制造和发布MM008临床试验后，快速为MM008-IVR提交IND的位置 材料。该项目旨在支持我们非激素避孕药MM008-的临床评估。 IVR可以满足市场中的重大未满足需求，并为未来奠定基础 也可以防止性传播感染的多次IVR。