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。不使用避孕药的原因多种多样；一个共同的原因是 女性对使用外源性激素有强烈的反感，这是由于实际或感知到的副作用以及 医学禁忌症。如果采取以下措施，避孕用具的使用率和满意度可能会大幅提高 有一种非荷尔蒙的、用户控制的避孕方法，在服用之前不需要立即使用 性交，也不是每天服药。我们相信我们可以创造出这样一种非荷尔蒙避孕药 经阴道交付抗精子单抗(MAb)，该单抗可以凝集和捕获粘液中的精子， 从而阻止精子到达卵子。这一策略基于经阴道交付的抗精子抗体， 在1980年的S-90年S的动物模型中得到了验证，与避孕疫苗不同的是，它能够始终如一地 可靠的避孕措施和快速逆转。然而，这一战略直到最近才变得可行，因为 MAb生产的高成本，以及先前的抗精子免疫球蛋白的适度凝集力。我们有 开发了一种高度多价的免疫球蛋白MM008，它针对的是一种经过充分表征和验证的避孕药 普遍存在于所有人类精子上的抗原。MM008高度均匀和稳定，可以 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 超强的精子凝集力是最好的抗精子免疫球蛋白的16倍 在文学中广为人知。MM008可以聚集精子，甚至低至100毫微克/毫升，并且可以逐渐减少。 以每只羊仅33微克的剂量，在2分钟内将99.9%的活动精子送入绵羊的阴道。此外， 我们已经证明，我们可以稳定地从专有的胶囊-IVR系统中释放MM008，该系统支持 MM008在绵羊阴道中的高效浓度超过20天(足以覆盖 大多数妇女的生育窗口)。我们还创造了高度多价免疫球蛋白的阴道涂膜剂 在绵羊体内能在2分钟内完全凝集所有精子的单抗。这些极具希望的结果 激励我们积极推进MM008进入临床。在这项建议中，我们寻求回应RFA HD- 22-018，并建立了一种高灵敏度的定量检测MM008浓度的方法 在各种与IND相关的生物基质和临床研究中。在具体目标1中，我们将 用一组抗独特型(抗ID)抗体建立抗MM008的夹心ELISA法。具体而言 目的2、进一步优化和完善包括人血清在内的基质中MM008的定量检测方法。 人宫颈阴道粘液，人宫颈中期粘液和大鼠血清。这些化验是 通过启用IND的GLP研究和早期临床研究推进MM008的关键途径。成功 拟议工作的完成将加快我们推动MM008进入临床的努力。