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 在美国，近一半的怀孕是意外怀孕，而且大多数发生在未使用避孕药的女性身上 避孕药具。不使用避孕药具的原因有多种；一个常见的原因是许多 由于实际和感知到的副作用，女性强烈厌恶使用外源激素。有可能 如果有非激素的、用户使用的避孕药具，避孕药具的使用和满意度将会大幅提高。 控制避孕方法，不需要在性交时采取行动，也不需要每天服用。此类产品 目前不存在。我们相信我们可以基于以下原理创造出这样一种非激素避孕药： 阴道环 (IVR) 释放凝集和捕获的抗精子单克隆抗体 (mAb) 精子在粘液中，从而阻止精子到达卵子。基于局部被动免疫 80-90年代，阴道递送抗精子抗体在动物模型中得到验证，并直接克服了 避孕疫苗的可变强度和不确定的可逆性。然而，这一策略并未 由于 mAb 生产的高成本和 IgG 的凝集能力有限，直到最近才实用。 鉴于生物加工的显着进步大大降低了制造成本 mAb，我们相信开发用于阴道持续被动免疫的 IVR 的时机已经成熟 具有有效的抗精子单克隆抗体。我们拥有一种非常有效的抗体 MM008，它的目标是一个很好的 人类精子上存在的经过表征和验证的抗原靶点具有高度同质性和稳定性，并且 每只 33 微克的剂量即可在 2 分钟内将绵羊阴道中的渐进活动精子减少 99.9% 羊。我们还开发了专有的胶囊-IVR系统，可以稳定释放MM008超过20 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 使精子在绵羊阴道内完全凝集超过 21 天。建立在这些有希望的基础上 结果，我们寻求在目标 1 中建立 cGMP 生产流程，以支持制造 胶囊-IVR 用于 IND 启用和 1-2 期研究，并验证胶囊-IVR 可以提供持续的 MM008的体外和体内释放。然后，我们将在目标 2 中执行可用性和安全性评估 女性安慰剂胶囊-IVR。最后，我们将在目标 3 中完成其他关键路径 IND 支持活动， 包括 GLP TCR 和 GLP 生物相容性研究。成功完成这些活动将使我们 在MM008临床试验生产和发布后迅速提交MM008-IVR IND 材料。该项目旨在支持我们的非激素避孕药 MM008- 的临床评估 IVR 可以解决市场上未满足的重大需求，并为未来奠定基础 多功能 IVR 还可预防性传播感染。