Development of a qualified pharmacokinetic bioassay to support preclinical and clinical studies of MM-008, a non-hormonal contraceptive antibody

项目摘要： 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 由于真实的或感觉到的副作用， 医学禁忌症。避孕药具的使用和满意度可能会大幅提高， 有一种非激素的，用户控制的避孕方法，不需要在怀孕前立即使用。 性交，也不是每天给药。我们相信我们可以创造出这样一种非激素避孕药， 阴道递送抗精子单克隆抗体（mAb），其凝集并将精子捕获在粘液中， 从而阻止精子到达卵子。该策略基于抗精子抗体的阴道递送， 在20世纪80 -90年代的动物模型中得到验证，并且与避孕疫苗不同， 可靠的避孕和快速可逆性。然而，由于最近， mAb生产的高成本和现有抗精子IgG的中等凝集效力。我们有 开发了一种高度多价的IgG，MM 008，其靶向一种充分表征和验证的避孕药 人类精子中普遍存在的抗原MM 008具有高度的均匀性和稳定性， 使用传统的生物制造方法以非常高的产率生产。更重要的是，MM 008是 特别有效，精子凝集效力比最好的抗精子IgG高16倍以上 在文献中已知。MM 008凝集精子甚至低至<100 ng/mL，并可逐渐降低 在每只绵羊33微克的剂量下，2分钟内绵羊阴道中的活动精子减少99.9%。此外，委员会认为， 我们已经证明，我们可以从一个专有的胶囊IVR系统中稳定地释放MM 008， 在绵羊阴道中保持高效浓度的MM 008超过20天（足以覆盖 大多数女性的生育窗口）。我们还创造了高多价IgG的阴道膜制剂， 在绵羊中2分钟内实现所有精子完全凝集的mAb。这些非常有希望的结果 促使我们积极推动MM 008进入临床。在这项建议中，我们寻求回应RFA HD- 22-018，并开发用于测量MM 008浓度的高灵敏度和定量检测试验 在IND启动和临床研究相关的各种生物基质中。具体目标1： 使用一组抗MM 008的抗独特型（抗ID）Fab建立夹心ELISA测定。在特定 目的2，我们将进一步优化和鉴定用于定量基质（包括人血清）中MM 008的测定方法， 人宫颈阴道粘液、人月经中期宫颈内粘液和大鼠血清。这些试验是 通过IND使能GLP研究和早期临床研究推进MM 008的关键路径。成功 建议工作的完成将加速我们推进MM 008进入临床的努力。

Project 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 or perceived side effects as well as medical contraindications. It is likely that contraceptive use and satisfaction would substantially increase if there were a non-hormonal, user-controlled contraceptive method that did not require use immediately prior to intercourse, nor daily dosing. We believe we can create such a non-hormonal contraceptive based on vaginal delivery of an anti-sperm monoclonal antibody (mAb) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. This strategy, based on vaginal delivery of anti-sperm Ab, was validated in animal models in the 1980’s-90’s, and, unlike contraceptive vaccines, enables consistently reliable contraception and rapid reversibility. However, this strategy was not practical until recently due to the high costs of mAb production, and modest agglutination potencies of prior anti-sperm IgGs. We have developed a highly multivalent IgG, MM008, that targets a well-characterized and validated contraceptive antigen universally present on all human sperm. MM008 is highly homogeneous and stable, and can be produced at very high yields using conventional biomanufacturing processes. More importantly, MM008 is exceptionally potent, possesing >16-fold greater sperm-agglutinaton potency than the best anti-sperm IgG known in the literature. MM008 aggulutinates sperm even down to <100 ng/mL, and can reduce progressively motile sperm by 99.9% in the sheep vagina within 2 mins, at a dose of just 33 ug per sheep. Furthermore, we have shown that we can steadily release MM008 from a proprietary capsule-IVR system that sustains highly effective concentrations of MM008 in the sheep vagina for over 20 days (more than adequate to cover the fertility window in most women). We have also created vaginal film formulations of highly multivalent IgG mAbs that achieved complete agglutination of all sperm within 2 mins in sheep. These highly promising results motivated us to actively advance MM008 into the clinic. In this proposal, we seek to respond to the RFA HD- 22-018, and develop a highly sensitive and quantitative detection assay for measuring MM008 concentrations in a variety of biological matrices relevant for IND-enabling and clinical studies. In Specific Aim 1, we will establish a sandwich ELISA assay using a panel of anti-idiotype (anti-ID) Fabs against MM008. In Specific Aim 2, we will further optimize and qualify the assays to quantify MM008 in matrices including human serum, human cervicovaginal mucus, human mid-cycle endocervical mucus, and rat serum. These assays are part of the critical path for advancing MM008 through IND-enabling GLP studies and early clinical studies. Successful completion of the proposed work will accelerate our efforts to advance MM008 into the clinic.