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In vivo dose finding for an antibody based nonhormonal contraceptive intravaginal ring

基于抗体的非激素避孕阴道环的体内剂量发现

基本信息

批准号：
10081772
负责人：
RICHARD CONE
金额：
$ 97.28万
依托单位：
MUCOMMUNE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10081772
关键词：
Address Adherence Agglutination Anatomy Animal Model Antibodies Antigen Targeting Binding Biopsy Blood Buffers Cells Clinical Contraceptive Agents Contraceptive Usage Contraceptive Vaccines Contraceptive methods Copper Intrauterine Devices Counseling Development Dose Drug Kinetics Effectiveness Embryo Engineering Excision Exogenous Hormone Therapy Fab domain Failure Federal Government Formulation Foundations Future Goals Headache Hemorrhage Hormones Human Image Immobilization Immune Immunity Immunoglobulin G Immunologic Contraception Individual Infertility Inflammation Injections Intervention Link Liquid substance Male Genital Organs Mental Depression Methods Modeling Molds Monoclonal Antibodies Moods Mucins Mucous Membrane Mucous body substance Mutation Nausea Oocytes Oral Oryctolagus cuniculus Parents Passive Immunization Pattern Polypropylenes Population Pre-Clinical Model Pregnancy Preparation Prevalence Process Production Safety Sampling Semen Donor Seminal fluid Sheep Sperm Agglutination Sperm Motility Spermatozoa antibody State Government Structure Surface Technology Testing Thinness Time Tissue Sample Toxic effect Translating Vaccines Vagina Vaginal Ring Vaginal delivery procedure Weight Gain Woman Work antigen antibody binding antigen binding base bioprocess capsule cell motility clinical development contraceptive efficacy cost cost effective crosslink egg genital secretion hormonal contraception human monoclonal antibodies improved in vivo monoclonal antibody production novel pathogen preclinical development preclinical evaluation prevent reproductive tract research clinical testing reversible contraceptive satisfaction sex side effect sperm cell unintended pregnancy uptake vaccine response vaccine trial vaginal fluid

项目摘要

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 increase if there were 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 an anti-sperm monoclonal antibody (mAb) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization based on vaginal delivery of anti-sperm Ab was validated in animal models in the 80's-90's, 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 mAb production, and modest agglutination potencies of IgG. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of mAb, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm mAb. We are targeting 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 have further increased the sperm-agglutination potency >50-fold by engineering a novel high-valency mAb construct comprised of ten Fab domains (i.e. 8 additional Fabs linked to the parent IgG molecule); we termed this construct MM008. The greatly increased potency is expected to directly translate to markedly-reduced dose and costs, supporting a commercially viable product. Indeed, MM008 reduced progressively motile sperm by 99.9% in the sheep vagina in 2 mins at a dose of just 33 ug per sheep. We have enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. MM008 possess comparable thermal stability and production and purification yield as IgG. Based on these promising attributes, in Aim 1, we will produce MM008 and formulate capsule-IVRs offering sustained release of MM008 with different release rates for at least 25 days, in support of the dose- finding studies. In Aim 2, we will evaluate the pharmacokinetics, efficacy and safety of different MM008- IVRs to determine if we can sustain contraceptive concentrations in the sheep vagina, which is anatomically similar to the human vagina, for at least 25 days. If successful, the work will strongly support further preclinical and clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for future 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。有可能如果有非激素的、用户使用的避孕药具，避孕药具的使用和满意度将会大幅提高。控制避孕方法，不需要在性交时采取行动，也不需要每天服用。此类产品目前不存在。我们相信我们可以基于以下原理创造出这样一种非激素避孕药：阴道环 (IVR) 释放凝集和捕获的抗精子单克隆抗体 (mAb) 精子在粘液中，从而阻止精子到达卵子。基于局部被动免疫 80-90年代，阴道递送抗精子抗体在动物模型中得到验证，并直接克服了避孕疫苗的可变强度和不确定的可逆性。然而，这一策略并未由于 mAb 生产的高成本和 IgG 的凝集能力有限，直到最近才实用。鉴于生物加工的显着进步大大降低了制造成本 mAb，我们相信开发用于阴道持续被动免疫的 IVR 的时机已经成熟具有有效的抗精子单克隆抗体。我们的目标是一个经过充分表征和验证的抗原靶点人类精子，我们有一种完全人类单克隆抗体，可以结合这种抗原并在几秒钟内凝集人类精子，并在来自不同精液捐赠者的 100 多个精液样本中进行了这项研究。我们还有进一步通过设计新型高效单克隆抗体构建体，将精子凝集效力提高了 50 倍以上由 10 个 Fab 结构域组成（即与亲本 IgG 分子连接的 8 个附加 Fab）；我们称之为构建MM008。效力的大大增加预计将直接转化为剂量的显着减少和成本，支持商业上可行的产品。事实上，MM008 逐渐减少了精子活动能力每只羊只需 33 微克的剂量，2 分钟内即可在羊阴道中消除 99.9%。我们加强了安全性通过整合 Fc 突变来减少与 FcgR 的结合，从而降低发展的可能性对精子的免疫力。 MM008 具有可比的热稳定性以及生产和纯化收率作为 IgG。基于这些有希望的属性，在目标 1 中，我们将生产 MM008 并配制胶囊 IVR 提供不同释放速率的MM008持续释放至少25天，以支持剂量- 寻找研究。在目标 2 中，我们将评估不同 MM008-的药代动力学、功效和安全性 IVR 以确定我们是否可以在绵羊阴道中维持避孕药浓度，这在解剖学上是类似于人类阴道，至少 25 天。如果成功，该工作将有力支持进一步的临床前研究对我们的非激素避孕 IVR 进行临床评估，可以解决以下领域未满足的重大需求市场，并为未来也能预防性传播感染的多功能 IVR 奠定基础。