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

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 如果有非荷尔蒙的使用者，避孕药的使用和满意度将大大提高- 一种受控的避孕方法，既不需要适时的行动，也不需要每天的剂量。这类产品 目前还不存在。我们相信我们可以创造出这样一种非激素避孕药 阴道内环(IVR)释放抗精子单抗(MAb)，可凝集和捕获 精子在粘液中，从而阻止精子到达卵子。局部被动免疫的基础上 经阴道交付抗精子抗体在80‘S-90’S的动物模型中得到了验证，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，这一战略并不是 实用，直到最近，由于mAb生产的高成本，以及适度的免疫球蛋白凝集力。 鉴于生物加工的显著进步极大地降低了 Mab，我们认为现在开发IVR用于阴道持续被动免疫的时机已经成熟 用一种强大的抗精子单抗。我们拥有一种特别有效的抗体MM008，它可以针对一口井 存在于人类精子上的特征化和有效的抗原靶标，高度均一和稳定，以及 仅33微克/只，在2分钟内可使绵羊阴道内逐渐活动的精子减少99.9%。 羊。我们还开发了一种专有的胶囊IVR系统，可以稳定地释放MM008超过20 天数(足以覆盖大多数妇女的生育窗口)。在试点研究中，MM008-IVR能够 在绵羊阴道内提供超过21天的完全精子凝集。在这些有希望的基础上建设 结果，我们试图在目标1中建立cGMP生产工艺，以支持 胶囊-IVR用于IND使能和1-2阶段研究，并验证胶囊-IVR可以提供持续的 MM008的体内外释放。然后，我们将在目标2中执行可用性和安全性评估 安慰剂胶囊-女性的IVR。最后，我们将在AIM 3中完成其他关键路径支持IND的活动， 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 在MM008临床试验制造和发布后，快速申请MM008-IVR的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可以解决市场上未得到满足的重大需求，并为未来奠定基础 多功能IVR，还可以防止性传播感染。

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.