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，但 性传播感染（STI）（例如生殖器疱疹）仍然很普遍，估计 在美国，有12％的14-49岁的人感染了HSV-2。不幸的是，没有效果 包括HSV在内的大多数性传播感染的疫苗或微生物。点播，快速，安全，有效， 谨慎的阴道杀微生物将提供强大的预防工具，以解决未解决的差距 行为和当前的药理干预措施。人类单克隆抗体（MAB）本地传递 粘膜表面提供了杰出的承诺，结合了悠久的安全，抗病毒效率和 无与伦比的目标特异性。 Mucommune一直在开创专为粘膜设计的MAB技术 应用，包括中和并物理捕获各个病原体的粘液捕获单元 粘液，基于IgG-FC和粘蛋白之间经过精心调整的亲和力。这些“粘液捕获” mab可以完全 在月经周期和从CVM中的人宫颈阴道粘液（CVM）中的陷阱HSV颗粒 具有潜水员阴道菌群的妇女，仅通过中和，其效力比保护高约10倍。 更重要的是，将病毒捕获在粘液中，并用阴道剂量的mAb直接阻塞了A中的传播 在没有其他免疫保护功能的情况下，小鼠阴道疱疹模型。在这个阶段，我们 将基于我们的工作，以将病原体捕获的mAb制成快速溶解的AB片（FDAT）， 这将迅速分解并在与CVM接触时迅速而有效 免疫保护。在AIM 1中，我们将将粘液捕获的单杆与HSV纳入各种FDAT 含有不同类型/比率的赋形剂，粘合剂和崩解剂的公式。我们将表征 FDAT的物理特性，测量合成mutus中FDAT的溶解速率和混合物的混合物 新鲜的人类CVM/精液，并验证mAb前公式的MAB的结合亲和力 解散。在AIM 2中，我们将在绵羊阴道模型中评估AIM 1的铅FDAT公式以验证 FDAT崩解时间，MAB药代动力学和生物分布，药效学和安全性。 这些研究的成功完成将使我们能够确定合适的FDAT公式 促进临床前和临床开发，并为II期建议提供基本数据 支持货架稳定的FDAT的开发，其中包括由抗HSV mab和 我们的铅避孕MAB（MM008），为两种阴道疱疹提供有效的多功能保护 传播和怀孕。