In vivo dose finding for 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针对的是一种经过充分表征和验证的抗原靶点， 人类精子，我们有一个完全的人类单克隆抗体，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了研究。我们进一步 通过工程改造一种新的高效价mAb构建体，使精子凝集效力增加>50倍 由10个Fab结构域组成（即8个额外的Fab连接至亲本IgG分子）;我们将其称为 构建体MM 008。预期大大增加的效力将直接转化为显著降低的剂量 和成本，支持商业上可行的产品。事实上，MM 008逐渐减少了活动精子， 在每只绵羊33微克的剂量下，2分钟内绵羊阴道中的99.9%。我们加强了安全性 通过掺入减少与FcgR结合的Fc突变，减轻发展成FcgR的可能性， 对精子免疫MM 008具有相当的热稳定性以及生产和纯化收率 如IgG。基于这些有希望的属性，在目标1中，我们将生产MM 008并配制胶囊式IVR 提供具有不同释放速率的MM 008持续释放至少25天，以支持剂量- 寻找研究。在目标2中，我们将评估不同MM 008 - 1000的药代动力学、有效性和安全性。 IVRs来确定我们是否能在绵羊阴道中维持避孕药的浓度， 类似于人类阴道，至少25天。如果成功，这项工作将有力地支持进一步的临床前研究。 我们的非激素避孕IVR的临床评价，可以解决一个重大的未满足的需求， 市场，并为未来的多功能IVR奠定基础，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.