Nonhormonal contraceptive intravaginal ring based on high valency anti-sperm antibody constructs

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，用户控制的， 避孕方法，不需要性交时间的行动，也不需要每日剂量。该产品不 目前存在。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）释放精子结合抗体（Ab），该抗体凝集并将精子捕获在粘液中，从而 阻止精子到达卵子。通过直接递送抗精子抗体的局部被动免疫 在20世纪80年代至90年代，在动物模型中验证了阴道，并直接克服了变量 避孕疫苗的强度和不确定的可逆性。然而，这一战略并不实用， 最近由于Ab生产的高成本。鉴于生物加工技术的显著进步， 大大降低了抗体的制造成本，我们相信现在是时候开发一个IVR， 持续被动免疫的阴道与一个强大的抗精子抗体。我们的方法是基于一口井 表征和验证了人类精子上存在的抗原靶点，我们有一个完全的人源mAb， 结合这种抗原，在几秒钟内凝集所有人类精子，并在100多个精液样本中进行 来自不同的精子捐赠者我们进一步提高精子凝集效力的工程新的高， 包含6个Fab结构域（即4个与亲本IgG分子连接的另外的Fab）的效价构建体，和 8个Fab结构域（6个额外的Fab）;我们将这些构建体分别命名为MM 006和MM 007。在 此外，我们通过掺入减少与FcgR结合的Fc突变增强了安全性， 降低了对精子产生免疫力的可能性。通过并入多个Fab结构域， 保留Fc，我们大大提高了凝集速度和效力，同时保持了稳定性， 母体IgG的商业生产容易。由于抗原靶标仅存在于人类精子上， 这排除了在动物中直接评价避孕效果。我们在R61阶段的目标是 在MM 006和MM 007之间进行选择，将mAb配制成胶囊-IVR，并证明IVR可以 维持有效的避孕药浓度，并评估绵羊阴道中的局部分布和毒性 模型，在解剖学上类似于人类阴道。如果我们达到R61里程碑，我们将专注于 R33阶段，为选定的mAb开发符合cGMP的生产工艺，最终形成主产品 细胞库CHO细胞（IND备案的基本部分）和大鼠GLP毒性研究。如果成功，这项工作将 强烈支持我们的非激素避孕IVR的临床评价，可以解决一个显着的 这将有助于满足市场上尚未满足的需求，并为多功能IVR奠定基础，同时还可以预防性传播感染。

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 increas if there is 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 a sperm-binding antibody (Ab) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization by direct delivery of anti-sperm Ab to the vagina was validated in animal models in the 1980s-1990s, 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 Ab production. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of Ab, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm Ab. Our approach is based on 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 further increased sperm-agglutination potency by engineering novel high- valency constructs comprising six Fab domains (i.e. 4 additional Fabs linked to the parent IgG molecule) and eight Fab domains (6 additional Fabs); we term these constructs MM006 and MM007, respectively. In addition, we enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. By incorporating multiple Fab domains while preserving Fc, we substantially improved agglutination speed and potency, while retaining the stability and ease of commercial manufacturing of parent IgG. Since the antigen target is present only on human sperm, this precludes direct evaluation of contraceptive efficacy in animals. Instead, our goal in the R61 phase is to select between MM006 and MM007, formulate the mAb into a capsule-IVR, and demonstrate the IVR can sustain effective contraceptive concentrations and assess local distribution and toxicity in the sheep vagina model, which is anatomically similar to the human vagina. If we meet the R61 milestones, we will focus the R33 phase on developing cGMP-compliant manufacturing process for the selected mAb, culminating in Master Cell Banked CHO cells (essential part of IND filing) and GLP tox study in rats. If successful, the work will strongly support clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for multifuntional IVRs that also protects against STIs.