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

总结 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的妇女身上。 避孕药不使用避孕药具的原因多种多样;一个常见的原因是，许多人 由于真实的和感觉到的副作用，妇女对使用外源激素有强烈的反感。很可能 如果有一个非激素的使用者， 控制避孕方法，不需要性交定时行动，也不需要每日剂量。此类产品 目前不存在。我们相信，我们可以创造这样一种非激素避孕药的基础上， 阴道内环（IVR）释放抗精子单克隆抗体（mAb）， 精子在粘液中，从而阻止精子到达卵子。局部被动免疫， 在80 -90年代，抗精子Ab的阴道递送在动物模型中得到验证，并且直接克服了 避孕疫苗的可变强度和不确定的可逆性。然而，这一战略并没有 由于mAb生产的高成本和IgG的适度凝集效力，直到最近才实用。 鉴于生物加工的显著进步大大降低了生物制品的制造成本， mAb，我们认为现在时机已经成熟，可以开发用于阴道持续被动免疫的IVR 一种有效的抗精子抗体我们拥有一种非常有效的抗体，MM 008，它靶向一个井， 存在于人精子上的经表征和验证的抗原靶标，是高度同质和稳定的，并且 可以减少99.9%的渐进运动精子在绵羊阴道在2分钟内，剂量仅为33微克/ 羊我们还开发了一个专有的胶囊IVR系统，可以稳定地释放MM 008超过20 天（足以覆盖大多数女性的生育窗口）。在初步研究中，MM 008-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 结果，我们寻求在目标1中建立cGMP生产工艺，以支持 胶囊-IVR用于IND启动和1-2期研究，并验证胶囊-IVR可提供持续的 MM 008的体外和体内释放。然后，我们将在目标2中对 安慰剂胶囊-女性IVR。最后，我们将在目标3中完成其他关键路径IND使能活动， 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MM 008临床试验生产和发布后，能够快速提交MM 008-IVR的IND 材料.该项目旨在支持我们的非激素避孕药MM 008的临床评价- IVR可以解决市场上一个重大的未满足的需求，并为未来奠定基础。 多功能IVRs也能预防性传播感染。

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.