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

基于高效抗精子抗体构建体的非激素避孕阴道环

• 批准号: 10474612
• 负责人: Thomas Ray Moench
• 金额: $ 54.07万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-14 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474612
• 关键词: Address; Affinity; Agglutination; Anatomy; Animal Model; Animals; Antibodies; Antibody Formation; Antigen Targeting; Binding; Biological Assay; Biopsy; Buffers; Cells; Chinese Hamster Ovary Cell; Colposcopy; Contraceptive Agents; Contraceptive Usage; Contraceptive Vaccines; Contraceptive methods; Cyclic GMP; Development; Dose; Drug usage; Ejaculation; Embryo; Encapsulated; Engineering; Evaluation; Excipients; Exogenous Hormone Therapy; Fab domain; Federal Government; Female; Formulation; Foundations; Gel; Goals; Human; Immobilization; Immune; Immunity; Immunoglobulin G; In Vitro; Individual; Infertility; Inflammation; Kinetics; Lead; Link; Male Genital Organs; Methods; Modeling; Molecular; Monoclonal Antibodies; Mucins; Mucous body substance; Mutation; Oocytes; Oryctolagus cuniculus; Parents; Passive Immunization; Pharmaceutical Preparations; Phase; Pregnancy; Preparation; Process; Production; Protocols documentation; Rattus; Research; Safety; Sampling; Semen Donor; Seminal fluid; Sheep; Speed; Sperm Agglutination; Sperm Motility; Spermatozoa antibody; State Government; Surface; System; Tablets; Technology; Testing; Time; Tissues; Toxic effect; Toxicology; Vaccination; Vaccines; Vagina; Vaginal Ring; Vaginal delivery procedure; Validation; Woman; Work; antibody engineering; antigen binding; base; bioprocess; capsule; cell bank; cell motility; clinical development; contraceptive efficacy; cost; crosslink; egg; genital secretion; human monoclonal antibodies; improved; manufacturing process; meetings; novel; pathogen; pre-clinical assessment; preclinical development; preservation; prevent; programs; reproductive tract; research clinical testing; reversible contraceptive; satisfaction; scale up; side effect; sperm cell; substance use; unintended pregnancy; vaccine response; vaccine trial; vaginal fluid

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.

概括 在美国，近一半的怀孕是意外怀孕，而且大多数发生在未使用避孕药的女性身上 避孕药具。不使用避孕药具的原因有多种；一个常见的原因是许多 由于实际和感知到的副作用，女性强烈厌恶使用外源激素。有可能 如果有一种非激素、用户控制的避孕方法，避孕药具的使用和满意度将大大提高 不需要性交定时行为或每日给药的避孕方法。此类产品不 目前存在。我们相信我们可以创造出一种基于阴道内避孕的非激素避孕药 环（IVR）释放精子结合抗体（Ab），将精子凝集并捕获在粘液中，从而 阻止精子到达卵子。通过直接递送抗精子抗体进行局部被动免疫 20世纪80年代至90年代的动物模型中对阴道进行了验证，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，这一策略直到 最近由于抗体生产成本高昂。鉴于生物加工领域取得的显着进步 大大降低了抗体的制造成本，我们相信现在开发 IVR 的时机已经成熟 使用强效抗精子抗体对阴道进行持续被动免疫。我们的方法基于井 对人类精子上存在的抗原靶标进行了表征和验证，我们拥有一种完全人源单克隆抗体 结合该抗原并在几秒钟内凝集所有人类精子，并且在 100 多个精液样本中均如此 来自不同的精液捐赠者。我们通过设计新颖的高凝集能力进一步提高了精子凝集效力 包含六个 Fab 结构域（即连接到亲本 IgG 分子的另外 4 个 Fab）的价构建体，以及 八个 Fab 域（另​​外 6 个 Fab）；我们分别将这些构建体称为 MM006 和 MM007。在 此外，我们通过整合减少与 FcgR 结合的 Fc 突变来增强安全性， 降低对精子产生免疫力的可能性。通过合并多个 Fab 域，同时 保留 Fc，我们大大提高了凝集速度和效力，同时保留了稳定性和 易于商业化生产亲本 IgG。由于抗原靶标仅存在于人类精子上， 这妨碍了对动物避孕效果的直接评估。相反，我们在 R61 阶段的目标是 在MM006和MM007之间进行选择，将mAb配制成胶囊-IVR，并证明IVR可以 维持有效的避孕浓度并评估绵羊阴道内的局部分布和毒性 模型，在解剖学上与人类阴道相似。如果我们达到 R61 里程碑，我们将重点关注 R33 阶段为选定的 mAb 开发符合 cGMP 的生产工艺，最终获得 Master 细胞库 CHO 细胞（IND 申请的重要部分）和大鼠 GLP 毒性研究。如果成功的话，这项工作将 强烈支持对我们的非激素避孕 IVR 进行临床评估，该评估可以解决重大问题 市场上未满足的需求，并为同时预防性传播感染的多功能 IVR 奠定基础。