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：
10264884
负责人：
RICHARD CONE
金额：
$ 75.7万
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 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264884
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 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 pre-clinical assessment 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

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 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 pre-clinical assessment 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

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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。有不同的原因不使用避孕药。一个常见的原因是很多由于实际和感知的副作用，妇女对使用外源激素有很大的厌恶。很可能如果存在非激素，用户 - 受控避孕方法，不需要涂层的动作或每日给药。这样的产品目前不存在。我们相信我们可以基于一个释放抗卵形单克隆抗体（MAB）的阴道内环（IVR），该抗体会凝结和陷阱粘液中的精子，从而防止精子到达鸡蛋。基于局部的被动免疫在80's-90年代的动物模型中验证了抗植物AB的阴道递送，直接克服了避孕疫苗的可变强度和不确定的可逆性。但是，这种策略不是直到最近，由于MAB生产的高成本以及IgG的适度凝集效果，直到最近才实用。鉴于生物处理方面的显着进步大大降低了制造成本 mab，我们相信现在的时间已经成熟，开发IVR进行持续的被动免疫带有有效的抗植物mAb。我们针对的是一个良好的表征和验证的抗原靶标人类精子，我们有一个完全人的mab，可以在几秒钟内结合这种抗原并凝结人类精子，并在来自不同精液供体的100多种精液样品中这样做。我们还有更多通过设计新型的高价值mAB构建由十个Fab域组成（即与母体IgG分子相关的另外8个FAB）；我们称之为这个构造MM008。预计效力将大大提高直接转化为明显减少的剂量和成本，支持商业上可行的产品。实际上，MM008降低了逐步运动精子每只绵羊只有33 ug，在2分钟内，绵羊阴道中的阴道中的99.9％下降了99.9％。我们提高了安全性通过合并减少与FCGR结合的FC突变，减轻发展的可能性对精子的免疫力。 MM008具有可比的热稳定性，生产和纯化产量作为IgG。基于这些有希望的属性，在AIM 1中，我们将产生MM008并制定胶囊-IVRS 提供至少25天的不同释放率的持续释放MM008，以支持剂量寻找研究。在AIM 2中，我们将评估不同MM008-的药代动力学，功效和安全性 IVR确定我们是否可以在绵羊阴道中维持避孕浓度，这在解剖学上是与人类阴道类似，至少25天。如果成功，这项工作将强烈支持进一步的临床前以及我们非激素避孕IVR的临床评估，该评估可以满足很大的未满足需求市场，并为未来的多元自发IVR奠定了基础，该IVR也可以防止性传播感染。