Fast dissolving antibody tablets for preventing vaginal HSV transmission

用于预防 HSV 阴道传播的快速溶解抗体片

• 批准号: 10547476
• 负责人: Keiichiro Kushiro
• 金额: $ 30.65万
• 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: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10547476
• 关键词: Address; Affinity; Age; Antibiotics; Antibodies; Aspirate substance; Bacteria; Bacterial Vaginosis; Behavior Therapy; Behavioral; Binding; Biodistribution; Biological Assay; Blinded; Cells; Characteristics; Chlamydia; Chlamydia trachomatis; Clinical Research; Colposcopy; Complex; Contraceptive Agents; Couples; Data; Development; Dose; Drug Kinetics; Educational Intervention; Effectiveness; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Excipients; Female; Formulation; Foundations; Geometry; Gynecologist; HIV; Health; Health Care Costs; Hepatitis B; Herpesvirus 1; Human; Human Herpesvirus 2; Human Papillomavirus; Immobilization; Immune; Immunoglobulin G; Individual; Infection; Inflammation; Intervention; Irrigation; Lead; Light; Liquid substance; Location; Lubricants; Measures; Mechanics; Menstrual cycle; Methods; Modeling; Molecular; Monoclonal Antibodies; Mucins; Mucous Membrane; Mucous body substance; Mus; Neisseria gonorrhoeae; Persons; Pharmacodynamics; Pharmacology; Phase; Polysaccharides; Pregnancy; Prevention; Prevention strategy; Recording of previous events; Research Personnel; Resistance; STI prevention; Safety; Sampling; Seminal fluid; Sexually Transmitted Diseases; Sheep; Simplexvirus; Small Business Innovation Research Grant; Specificity; Surface; Swab; Syphilis; Tablets; Tactile; Technology; Time; Treponema pallidum; United States; Vaccines; Vagina; Viral; Virion; Virus; Vision; Visual; Woman; Work; antigen binding; base; cervicovaginal; clinical development; design; genital herpes; human monoclonal antibodies; immunoprophylaxis; in vivo; meetings; microbicide; neutralizing monoclonal antibodies; novel; pathogen; penis; pharmacokinetic model; pharmacokinetics and pharmacodynamics; physical property; preclinical development; preclinical study; prevent; tablet formulation; tool; transmission process; vaginal fluid; vaginal infection; vaginal microbicide; vaginal microbiota; viral transmission

Project Summary Despite immense efforts in educational and behavioral interventions to promote safer sexual practices, sexually transmitted infections (STIs) such as genital herpes remain highly prevalent, with an estimated 12% of people age 14-49 infected with HSV-2 in the United States. Unfortunately, there are no effective vaccines or microbicides for the majority of STIs, including HSV. An on-demand, fast-acting, safe, effective, and discreet vaginal microbicide would provide a powerful prevention tool to address gaps not addressed by behavioral and current pharmacologic interventions. Human monoclonal antibodies (mAb) delivered locally to mucosal surfaces offer exceptional promise, combining a long history of safety, anti-viral effectiveness, and unparalleled target specificity. Mucommune has been pioneering mAb technologies designed for mucosal applications, including muco-trapping mAbs that neutralizes and physically traps individual pathogens in mucus, based on carefully-tuned affinity between IgG-Fc and mucins. These “muco-trapping” mAbs can fully trap HSV particles in human cervicovaginal mucus (CVM) across the menstrual cycle and in CVM from women with diverse vaginal microflora, with ~10-fold greater potency than protection by neutralization alone. More importantly, trapping viruses in mucus with vaginally-dosed mAbs directly blocked transmission in a mouse vaginal Herpes model, in the absence of other immune protective functions. In this Phase I SBIR, we will build upon our work to formulate our pathogen-trapping mAb into fast dissolving Ab tablets (FDATs), which will rapidly disintegrate and disburse upon contact with CVM, providing rapid and potent immunoprotection. In Aim 1, we will incorporate muco-trapping mAbs against HSV into various FDAT formulations containing different types/ratios of excipients, binders and disintegrants. We will characterize the physical properties of the FDATs, measure the dissolution rates of FDATs in synthetic mucus and mixtures of fresh human CVM/semen, as well as verify the binding affinity of the mAb pre- post- FDAT formulation and dissolution. In Aim 2, we will evaluate our lead FDAT formulations from Aim 1 in a sheep vagina model to verify FDAT disintegration times, mAb pharmacokinetics and biodistribution, pharmacodynamics, and safety. Successful completion of these studies will enable us to identify a suitable FDAT formulation to advance into IND-enabling preclinical and clinical development, and provide the essential data for a Phase II proposal supporting development of shelf-stable FDAT that includes mAb cocktail consisting of both anti-HSV mAb and our lead contraceptive mAb (MM008), providing effective multipurpose protection against both vaginal Herpes transmission and pregnancy.

项目摘要 尽管在教育和行为干预方面做出了巨大努力，以促进更安全的性行为， 生殖器疱疹等性传播感染仍然非常普遍，估计 在美国，14-49岁的人中有12%感染了HSV-2。不幸的是，没有有效的 疫苗或杀微生物剂用于大多数性传播感染，包括单纯疱疹病毒。一种按需、快速、安全、有效、 谨慎的阴道杀微生物剂将提供一个强大的预防工具，以解决没有解决的差距， 行为和当前的药物干预。局部递送的人单克隆抗体（mAb） 粘膜表面提供了特殊的承诺，结合了长期的安全性，抗病毒有效性， 无与伦比的目标特异性。Mucommune一直是设计用于粘膜的mAb技术的先驱 应用，包括粘膜捕获mAb，其中和并物理捕获单个病原体， 粘液，基于IgG-Fc和粘蛋白之间的仔细调节的亲和力。这些“粘膜捕获”mAb可以完全 在整个月经周期中将HSV颗粒捕获在人宫颈阴道粘液（CVM）中， 具有多种阴道微生物区系的女性，其效力比单独中和的保护作用高约10倍。 更重要的是，用阴道给药的mAb在粘液中捕获病毒，直接阻断了病毒在阴道中的传播。 小鼠阴道疱疹模型，在没有其他免疫保护功能的情况下。在第一阶段SBIR中， 将在我们的工作基础上将我们的病原体捕获mAb配制成快速溶解的Ab片剂（FDAT）， 在与CVM接触时，其将迅速崩解并分散， 免疫保护在目标1中，我们将针对HSV的粘膜捕获mAb并入各种FDAT中， 含有不同类型/比例的赋形剂、粘合剂和崩解剂的制剂。我们将描述 FDAT的物理性质，测量FDAT在合成粘液和FDAT的混合物中的溶解速率。 新鲜人CVM/精液，以及验证mAb前-后- FDAT制剂的结合亲和力， 解散在目标2中，我们将在绵羊阴道模型中评估目标1中的主要FDAT制剂，以验证 FDAT崩解时间、mAb药代动力学和生物分布、药效学和安全性。 成功完成这些研究后，我们便可找出合适的FDAT配方， IND支持临床前和临床开发，并为II期提案提供基本数据 支持开发货架稳定的FDAT，包括由抗HSV mAb和 我们的领先避孕mAb（MM 008），提供有效的多用途保护，防止阴道疱疹 传播和怀孕。