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; 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.

项目摘要： 美国几乎一半的怀孕是意想不到的，大多数发生在不使用的女性中 避孕药。潜水员的原因是不使用避孕药具；一个常见的原因是很多 由于真实或感知的副作用以及 医疗避孕。如果避孕药的使用和满意度可能会大大增加 有一种非激素，用户控制的避孕方法，在此之前不需要立即使用 性交，也不是日常给药。我们相信我们可以基于 阴道递送抗植物单克隆抗体（MAB），该抗体会在粘液中凝结并捕获精子， 从而防止精子到达鸡蛋。该策略基于抗植物AB的阴道传递 在1980年代90年代的动物模型中得到了验证，与避孕疫苗不同，可以始终如一地实现 可靠的避孕和快速可逆性。但是，直到最近，由于 MAB生产的高成本以及先前的抗植物IgGs的适度凝集。我们有 开发了高度多价IgG MM008，该IgG针对特征和验证的避孕药 抗原普遍存在于所有人类精子上。 MM008高度均匀且稳定，可以是 使用常规的生物制造过程以很高的产量生产。更重要的是，MM008是 与最佳的抗植物IgG相比，具有极具潜力的精子效力> 16倍> 16倍 在文献中闻名。 MM008凝集的精子甚至降低到<100 ng/ml，并且可以逐步减少 在2分钟内，绵羊阴道中的运动精子在每羊只有33 ug。此外， 我们已经表明，我们可以从专有胶囊系统中释放MM008，该系统维持 绵羊阴道中MM008的高效浓度超过20天（足以覆盖 大多数女性的生育窗口）。我们还创建了高度多价IgG的阴道膜公式 在绵羊2分钟内完全凝集所有精子的mAb。这些高度有希望的结果 激励我们积极将MM008推进诊所。在此提案中，我们试图回应RFA HD- 22-018，并为测量MM008浓度开发高度敏感和定量检测测定法 在各种与辅助和临床研究有关的生物材料中。在特定目标1中，我们将 使用一组针对MM008的抗IDiotype（抗ID）Fabs建立三明治ELISA测定法。具体 AIM 2，我们将进一步优化和限定评估，以量化包括人血清在内的矩阵中的MM008， 人宫颈阴道粘液，人循环遗传粘液和大鼠血清。这些测定是 通过辅助GLP研究和早期临床研究来推进MM008的关键途径。成功的 拟议工作的完成将加速我们将MM008推进诊所的努力。