Nonhormonal contraceptive intravaginal ring based on high valency anti-sperm antibody constructs

基于高效抗精子抗体构建体的非激素避孕阴道环

• 批准号: 10456450
• 负责人: Thomas Ray Moench
• 金额: $ 54.53万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456450
• 关键词: Nonhormonal; contraceptive; intravaginal; ring; based

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 increas if there is 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 a sperm-binding antibody (Ab) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization by direct delivery of anti-sperm Ab to the vagina was validated in animal models in the 1980s-1990s, 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 Ab production. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of Ab, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm Ab. Our approach is based on a well characterized and validated antigen target present on human sperm, and we have a fully human mAb that binds this antigen and agglutinates within seconds all human sperm, and does so in over 100 semen samples from diverse semen donors. We further increased sperm-agglutination potency by engineering novel high- valency constructs comprising six Fab domains (i.e. 4 additional Fabs linked to the parent IgG molecule) and eight Fab domains (6 additional Fabs); we term these constructs MM006 and MM007, respectively. In addition, we enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. By incorporating multiple Fab domains while preserving Fc, we substantially improved agglutination speed and potency, while retaining the stability and ease of commercial manufacturing of parent IgG. Since the antigen target is present only on human sperm, this precludes direct evaluation of contraceptive efficacy in animals. Instead, our goal in the R61 phase is to select between MM006 and MM007, formulate the mAb into a capsule-IVR, and demonstrate the IVR can sustain effective contraceptive concentrations and assess local distribution and toxicity in the sheep vagina model, which is anatomically similar to the human vagina. If we meet the R61 milestones, we will focus the R33 phase on developing cGMP-compliant manufacturing process for the selected mAb, culminating in Master Cell Banked CHO cells (essential part of IND filing) and GLP tox study in rats. If successful, the work will strongly support clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for multifuntional IVRs that also protects against STIs.

摘要 在美国，近一半的怀孕是意外的，大多数发生在没有使用 避孕药。不使用避孕药的原因多种多样；一个共同的原因是 由于实际和感知的副作用，女性对使用外源性激素有强烈的反感。很有可能 如果有一种非荷尔蒙、用户控制的避孕药，避孕用法和满意度将大大增加 一种避孕方法，不需要适时采取行动，也不需要每天服药。这样的产品不会 目前存在。我们相信我们可以创造出这样一种基于阴道内注射的非激素避孕药 环(IVR)释放一种精子结合抗体(Ab)，该抗体能将精子凝集并捕获在粘液中，从而 阻止精子到达卵子。直接注射抗精子抗体的局部被动免疫 在20世纪80年代至90年代的动物模型中得到了验证，并直接克服了变量 避孕疫苗的强度和不确定可逆性。然而，这一战略直到后来才开始实施。 最近，由于抗体的生产成本较高。鉴于生物处理技术的显著进步， 大大降低了抗体的制造成本，我们认为现在开发IVR的时机已经成熟 用有效的抗精子抗体对阴道进行持续被动免疫。我们的方法是基于一口井 鉴定和验证了人类精子上存在的抗原靶标，我们已经有了一种完全人类的mAb 结合这种抗原，并在几秒钟内凝集所有人类精子，并在100多个精液样本中做到这一点 来自不同的捐精者。我们通过设计新型的高凝集力精子进一步提高了精子凝集力。 由六个Fab结构域(即，连接到亲本Ig G分子的另外4个Fab)和 8个FAB结构域(另外6个FAB)；我们分别将这些结构称为MM006和MM007。在……里面 此外，我们通过加入减少与FcgR结合的Fc突变来增强安全性， 降低对精子产生免疫力的可能性。通过合并多个FAB域，同时 保留Fc，我们大大提高了凝集速度和效价，同时保持了稳定性和 亲本免疫球蛋白易于商业化生产。由于抗原靶标只存在于人类精子上， 这排除了对动物避孕效果的直接评估。相反，我们在R61阶段的目标是 在MM006和MM007之间选择，将mAb制成胶囊-IVR，并证明IVR可以 维持有效避孕药浓度，评估绵羊阴道局部分布和毒性 模型，它在解剖上类似于人类的阴道。如果我们达到了R61里程碑，我们将把重点放在 R33阶段，为所选单抗开发符合cGMP的制造工艺，最终形成Master 细胞库CHO细胞(IND归档的重要部分)和大鼠GLP毒性研究。如果成功，这项工作将 我们强烈支持对我们的非激素避孕IVR进行临床评估，这可能会解决显著的 市场上未得到满足的需求，并为多功能静脉注射吸入器奠定了基础，同时也防止性传播感染。