Fast dissolving antibody tablets for preventing vaginal HSV transmission

项目摘要 尽管在教育和行为干预方面做出了巨大努力来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，据估计 美国14-49岁人群中有12%感染了HSV-2。不幸的是，没有有效的 包括单纯疱疹病毒在内的大多数性传播感染的疫苗或杀微生物剂。按需、快速、安全、有效、 而谨慎的阴道杀菌剂将提供一种强大的预防工具，以弥补 行为学和现代药理学干预。人单抗(MAb)局部注射 给粘膜表面提供了特殊的前景，结合了长期的安全性、抗病毒有效性和 无与伦比的靶标专一性。MuComme一直是为粘膜设计的mAb技术的先驱 应用，包括中和和物理捕获单个病原体的粘液捕捉性单抗 粘液，基于精心调整的IgG-Fc和粘蛋白之间的亲和力。这些“粘液捕捉型”单抗可以完全 人宫颈阴道粘液(CVM)中的HSV颗粒跨月经周期捕获 具有不同阴道微生物区系的妇女，其效力是仅通过中和保护的约10倍。 更重要的是，用阴道给药的单抗将病毒困在粘液中，直接阻断了病毒在 小鼠阴道疱疹模型，在缺乏其他免疫保护功能的情况下。在第一阶段SBIR中，我们 将在我们工作的基础上将我们的病原体捕捉单抗制成快速溶解单抗片剂(FDATs)， 会在与云服务器接触后迅速解体并支付，提供快速而有力的 免疫保护。在目标1中，我们将把针对HSV的粘液捕捉单抗整合到各种FDAT中 含有不同类型/比例的辅料、粘合剂和崩解剂的配方。我们将描述 FDATs的物理性质，测量FDATs在合成粘液和 新鲜的人CVM/精液，以及验证FDAT前和后的mAb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来自目标1的铅FDAT配方以验证 FDAT的崩解时间、单抗的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一个合适的FDAT方案，以推进 IND-启用临床前和临床开发，并为第二阶段提案提供基本数据 支持开发货架稳定的FDAT，其中包括由抗HSV单抗和 我们领先的避孕单抗(MM008)，对两种阴道疱疹提供有效的多用途保护 传播和怀孕。

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.