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

开发合格的药代动力学生物测定法以支持非激素避孕抗体 MM-008 的临床前和临床研究

• 批准号: 10459074
• 负责人: Keiichiro Kushiro
• 金额: $ 27.77万
• 依托单位: MUCOMMUNE, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459074
• 关键词: Adherence; Affinity; Agglutination; Animal Model; Animals; Antibodies; Antigen Targeting; Antigens; Binding; Biodistribution; Biological; Biological Assay; Biomanufacturing; Cervical; Clinic; Clinical; Clinical Research; Contraceptive Agents; Contraceptive Usage; Contraceptive Vaccines; Contraceptive methods; Contracts; Copper; Critical Pathways; Detection; Development; Dose; Drug Kinetics; Engineering; Ensure; Enzyme-Linked Immunosorbent Assay; Exogenous Hormone Therapy; Female; Fertility; Film; Formulation; Healthcare Systems; Hormones; Human; IgG1; Immune; Immunoglobulin G; Immunoglobulin Idiotypes; Infertility; Lead; Liquid substance; Literature; Measures; Medical; Methods; Modeling; Monoclonal Antibodies; Mucous body substance; Phase; Pregnancy; Process; Rattus; Reproducibility; Robot; Sampling; Sensitivity and Specificity; Serum; Sheep; Sperm Agglutination; Sperm Motility; Spermatozoa antibody; Streptavidin; System; Testing; Toxicokinetics; Vagina; Vaginal Ring; Vaginal delivery procedure; Variant; Woman; Work; assay development; base; capsule; cell motility; cervicovaginal; clinical development; cost; design; detection assay; detection method; detection sensitivity; early phase clinical trial; egg; hormonal contraception; insight; male; monoclonal antibody production; phase 2 study; phase II trial; pre-clinical; preclinical development; preclinical study; prevent; reproductive tract; response; satisfaction; sex; side effect; sperm cell; unintended pregnancy; uptake; vaginal fluid

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.

项目概要： 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 由于实际或感知到的副作用以及 医疗禁忌症。如果采取以下措施，避孕药具的使用和满意度可能会大幅提高： 有一种非激素、使用者控制的避孕方法，不需要在避孕前立即使用 性交，也不是每日给药。我们相信我们可以创造出这样一种基于的非激素避孕药 阴道输送抗精子单克隆抗体（mAb），将精子凝集并捕获在粘液中， 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， 于 20 世纪 80 年代至 90 年代在动物模型中得到验证，并且与避孕疫苗不同，它能够始终如一地 可靠的避孕和快速的可逆性。然而，这一策略直到最近才实用，因为 mAb 生产成本高，且先前抗精子 IgG 的凝集效力有限。我们有 开发了一种高度多价 IgG MM008，其目标是经过充分表征和验证的避孕药 抗原普遍存在于所有人类精子上。 MM008 高度均一且稳定，可 使用传统的生物制造工艺以非常高的产量生产。更重要的是，MM008是 非常有效，其精子凝集效力比最好的抗精子 IgG 高 16 倍 文献中已知。 MM008 凝集精子甚至低至 <100 ng/mL，并且可以逐渐减少 每只羊只需 33 微克的剂量，2 分钟内就能使羊阴道内的精子活动率提高 99.9%。此外， 我们已经证明，我们可以从专有的胶囊 IVR 系统中稳定地释放 MM008，该系统可维持 MM008 在绵羊阴道中的高效浓度可维持 20 多天（足以覆盖 大多数女性的生育窗口）。我们还创建了高多价 IgG 的阴道膜配方 单克隆抗体在绵羊体内 2 分钟内实现所有精子的完全凝集。这些非常有希望的结果 激励我们积极将MM008推进临床。在此提案中，我们寻求回应 RFA HD- 22-018，并开发用于测量 MM008 浓度的高灵敏度和定量检测方法 与 IND 启用和临床研究相关的各种生物基质中。在具体目标 1 中，我们将 使用一组针对 MM008 的抗独特型（抗 ID）Fab 建立夹心 ELISA 测定。具体来说 目标 2，我们将进一步优化和鉴定定量基质（包括人血清）中 MM008 的检测方法， 人宫颈阴道粘液、人周期中期宫颈内膜粘液和大鼠血清。这些测定是 通过支持 IND 的 GLP 研究和早期临床研究推进 MM008 的关键路径。成功的 完成拟议的工作将加速我们将 MM008 推向临床的努力。