Nonhormonal contraceptive intravaginal ring based on high valency anti-sperm antibody constructs

基于高效抗精子抗体构建体的非激素避孕阴道环

基本信息

批准号：
10018640
负责人：
Thomas Ray Moench
金额：
$ 31.02万
依托单位：
MUCOMMUNE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-14 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018640
关键词：
Address Affinity Agglutination Alcohol or Other Drugs use Anatomy Animal Model Animals Antibodies Antibody Formation Antigen Targeting Binding Biological Assay Biopsy Buffers Cells Chinese Hamster Ovary Cell Colposcopy Contraceptive Agents Contraceptive Usage Contraceptive Vaccines Contraceptive methods Cyclic GMP Development Dose Drug usage Ejaculation Embryo Encapsulated Engineering Evaluation Excipients Exogenous Hormone Therapy Fab domain Federal Government Female Formulation Foundations Gel Goals Human Immobilization Immune Immunity Immunoglobulin G In Vitro Individual Infertility Inflammation Kinetics Lead Link Male Genital Organs Methods Modeling Molecular Monoclonal Antibodies Mucins Mucous body substance Mutation Oocytes Oryctolagus cuniculus Parents Passive Immunization Pharmaceutical Preparations Phase Pre-Clinical Model Pregnancy Preparation Process Production Protocols documentation Rattus Research Safety Sampling Semen Donor Seminal fluid Sheep Speed Sperm Agglutination Sperm Motility Spermatozoa antibody State Government Structure Surface System Tablets Technology Testing Time Tissues Toxic effect Toxicology Vaccination Vaccines Vagina Vaginal Ring Vaginal delivery procedure Validation Woman Work antibody engineering antigen binding base bioprocess capsule cell bank cell motility clinical development contraceptive efficacy cost crosslink egg genital secretion human monoclonal antibodies improved manufacturing process meetings novel pathogen preclinical development preservation prevent programs reproductive tract research clinical testing reversible contraceptive satisfaction scale up side effect sperm cell unintended pregnancy 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 increas if there is 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 a sperm-binding antibody (Ab) that agglutinates and traps sperm in mucus, thereby preventing sperm from reaching the egg. Topical passive immunization by direct delivery of anti-sperm Ab to the vagina was validated in animal models in the 1980s-1990s, 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 Ab production. Given the remarkable advances in bioprocessing that have greatly reduced the manufacturing costs of Ab, we believe the time is now ripe to develop an IVR for sustained passive immunization of the vagina with a potent anti-sperm Ab. Our approach is based on 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 further increased sperm-agglutination potency by engineering novel high- valency constructs comprising six Fab domains (i.e. 4 additional Fabs linked to the parent IgG molecule) and eight Fab domains (6 additional Fabs); we term these constructs MM006 and MM007, respectively. In addition, we enhanced the safety profile by incorporating Fc mutations that reduce binding to FcgR, mitigating the likelihood of developing immunity against sperm. By incorporating multiple Fab domains while preserving Fc, we substantially improved agglutination speed and potency, while retaining the stability and ease of commercial manufacturing of parent IgG. Since the antigen target is present only on human sperm, this precludes direct evaluation of contraceptive efficacy in animals. Instead, our goal in the R61 phase is to select between MM006 and MM007, formulate the mAb into a capsule-IVR, and demonstrate the IVR can sustain effective contraceptive concentrations and assess local distribution and toxicity in the sheep vagina model, which is anatomically similar to the human vagina. If we meet the R61 milestones, we will focus the R33 phase on developing cGMP-compliant manufacturing process for the selected mAb, culminating in Master Cell Banked CHO cells (essential part of IND filing) and GLP tox study in rats. If successful, the work will strongly support clinical evaluation of our non-hormonal contraceptive IVR that could address a significant unmet need in the marketplace, and lay the foundation for 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，用户控制避孕方法不需要涂层式的动作或每日给药。这样的产品不目前存在。我们认为我们可以基于静脉管成的非激素避孕药来创建这种非荷尔蒙避孕药环（IVR）释放一种精子结合抗体（AB），该抗体（AB）在粘液中凝结并捕获精子，从而防止精子到达鸡蛋。局部被动免疫通过直接递送反植物AB 在1980年代至1990年代，在动物模型中对阴道进行了验证，并直接克服了变量避孕疫苗的强度和不确定的可逆性。但是，此策略直到最近，由于AB生产成本很高。鉴于具有显着的生物处理的进步大大降低了AB的制造成本，我们认为现在已经成熟了用有效的抗植物AB对阴道进行持续的被动免疫。我们的方法是基于井人类精子上存在和经过验证的抗原靶标的，我们有一个完全人的mab 结合这种抗原并在几秒钟内凝集所有人类精子，并在100多个精液样品中进行来自不同的精液捐助者。我们通过工程新型高 - 价值构建体，包括六个FAB域（即4个与母体IgG分子相关的其他Fab）和八个Fab域（另外6个Fabs）；我们分别将这些构建体MM006和MM007称为。在此外，我们通过结合减少与FCGR结合的FC突变来增强安全性。减轻对精子产生免疫力的可能性。通过合并多个工厂域而保留足球俱乐部，我们显着提高了凝聚的速度和效力，同时保持稳定性和易于商业生产父母IgG。由于仅在人类精子上存在抗原靶标这排除了动物避孕功效的直接评估。相反，我们在R61阶段的目标是在MM006和MM007之间进行选择，将mAb形成胶囊-IVR，并演示IVR可以维持有效的避孕浓度并评估绵羊阴道中的局部分布和毒性模型在解剖学上与人类阴道相似。如果我们达到R61里程碑，我们将集中精力 R33阶段关于为选定的mAb开发符合CGMP的制造过程，最终达到主人细胞库CHO细胞（IND归档的必不可少的一部分）和GLP TOX研究。如果成功，工作将强烈支持我们非激素避孕IVR的临床评估，该评估可以解决重要的市场上的需求未满足，并为也可以防止性传播感染的多人IVR奠定了基础。