In vivo dose finding for 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。我们的目标是一个特性良好且经过验证的抗原目标 人类精子，我们有一种完全人类的mAb，它能结合这种抗原，并在几秒钟内凝集 人类精子，并在来自不同精液捐赠者的100多个精液样本中进行检测。我们还有更多 通过设计一种新的高价mAb结构使精子凝集力提高50倍 由10个Fab结构域组成(即8个额外的Fab连接到亲本免疫球蛋白分子)；我们将其命名为 构建MM008。大幅增加的效力预计将直接转化为显著减少的剂量 和成本，支持商业上可行的产品。事实上，MM008逐渐减少了可运动的精子 在每只羊只需33微克的剂量下，2分钟内在绵羊阴道中的降幅为99.9%。我们已经增强了安全性 通过加入Fc突变来减少与FcgR的结合，降低发病的可能性 对精子的免疫力。MM008具有相当的热稳定性和生产和提纯收率 作为免疫球蛋白。基于这些有希望的属性，在目标1中，我们将生产MM008并制定胶囊-IVRS 提供不同释放率的MM008缓释至少25天，以支持剂量- 寻找研究。在目标2中，我们将评估不同MM008的药代动力学、疗效和安全性。 IVRS以确定我们是否可以在绵羊阴道内维持避孕药浓度，这是解剖学上的 类似于人类的阴道，至少持续25天。如果成功，这项工作将有力地支持进一步的临床前工作 和临床评估我们的非激素避孕IVR可以解决一个重要的未得到满足的需求 市场，并为未来的多功能IVR奠定基础，这种IVR也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 are targeting 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 have further increased the sperm-agglutination potency >50-fold by engineering a novel high-valency mAb construct comprised of ten Fab domains (i.e. 8 additional Fabs linked to the parent IgG molecule); we termed this construct MM008. The greatly increased potency is expected to directly translate to markedly-reduced dose and costs, supporting a commercially viable product. Indeed, MM008 reduced progressively motile sperm by 99.9% in the sheep vagina in 2 mins at a dose of just 33 ug per sheep. We have enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. MM008 possess comparable thermal stability and production and purification yield as IgG. Based on these promising attributes, in Aim 1, we will produce MM008 and formulate capsule-IVRs offering sustained release of MM008 with different release rates for at least 25 days, in support of the dose- finding studies. In Aim 2, we will evaluate the pharmacokinetics, efficacy and safety of different MM008- IVRs to determine if we can sustain contraceptive concentrations in the sheep vagina, which is anatomically similar to the human vagina, for at least 25 days. If successful, the work will strongly support further preclinical and clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for future multifuntional IVRs that also protects against STIs.