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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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（STI）仍然非常普遍，估计在美国，12% 的 14-49 岁人群感染了 HSV-2，不幸的是，目前还没有有效的治疗方法。针对大多数性传播感染（包括单纯疱疹病毒）的疫苗或杀菌剂一种按需、快速、安全、有效的疫苗。谨慎的阴道杀微生物剂将提供强大的预防工具，以弥补阴道杀微生物剂未解决的空白行为和当前的药物干预措施。粘膜表面提供了非凡的前景，结合了悠久的安全性、抗病毒有效性和 Mucommune 一直是专为粘膜设计的开创性单克隆抗体技术。应用，包括粘液捕获单克隆抗体，可中和并物理捕获单个病原体粘液，基于 IgG-Fc 和粘蛋白之间精心调整的亲和力，这些“粘液捕获”单克隆抗体可以充分发挥作用。在整个月经周期和 CVM 中捕获 HSV 颗粒具有多种阴道微生物群的女性，其效力比单独中和保护的效力高约 10 倍。更重要的是，用阴道给药的单克隆抗体捕获粘液中的病毒可以直接阻止病毒在体内的传播。小鼠阴道疱疹模型，在没有其他免疫保护功能的情况下，在这一阶段的 SBIR 中，我们。将在我们的工作基础上将病原体捕获单克隆抗体配制为快速溶解抗体片剂 (FDAT)，与 CVM 接触后会迅速分解和分散，提供快速有效的在目标 1 中，我们将针对 HSV 的粘膜捕获单克隆抗体纳入各种 FDAT 中。我们将表征含有不同类型/比例的赋形剂、粘合剂和崩解剂的制剂。 FDAT 的物理性质，测量 FDAT 在合成粘液和混合物中的溶解率新鲜人 CVM/精液，并验证 FDAT 制剂后 mAb 的结合亲和力在目标 2 中，我们将在绵羊阴道模型中评估目标 1 中的主要 FDAT 制剂以验证溶出度。 FDAT 崩解时间、mAb 药代动力学和生物分布、药效学和安全性。成功完成这些研究将使我们能够确定合适的 FDAT 配方，以推进支持 IND 的临床前和临床开发，并为 II 期提案提供必要数据支持货架稳定 FDAT 的开发，其中包括由抗 HSV mAb 和我们的主要避孕单克隆抗体 (MM008)，针对阴道疱疹提供有效的多用途保护传播和怀孕。