Therapy and Prophylaxis for Genital Tract Infection

项目摘要/摘要 生殖道感染淋球菌不会诱导特定的保护性免疫状态和 可以重复获得。尽管采取了公共卫生措施，但该病仍居高不下，令人无法接受 频率；没有针对它的疫苗，甚至对最新一代的抗生素的耐药性仍在继续 才能出现。Treatation，Inc.正在开发GneX12，这是一种新型免疫疗法，旨在增强 抗生素介导的淋球菌持续感染清除和诱导长期保护 预防随后的暴露，即治疗性疫苗。具体来说，GneX12是典型的1型细胞因子 白介素12(IL-12)被包裹在专利的可生物降解的缓释微粒中。第一阶段 在淋病感染小鼠模型上的研究表明，GneX12经阴道给药 实现了疾病的快速清除，并诱导形成了长期保护性免疫。第二阶段工程 优化治疗方案；证明Th1免疫在疾病清除中的关键作用；揭示 长期保护是由抗淋球菌体液反应介导的；抗体是交叉的。 与抗生素联合给药不会干扰长期保护的诱导。 额外的第二阶段工作建立了扩大的制造流程，并完成了C类会议 FDA，获得机构与我们的单一物种灵长类毒理学计划的协议，以支持调查 新药申请(IND)。目前第二阶段申请的目标是基于机构的建议 在那次会议期间进行了沟通。具体地说，AIM 1研究将完成额外的毒理学研究，包括 Fda建议的啮齿动物生殖毒理学评估。在《目标2》中，一大批类似GMP的生物 GneX12药品是按照FDA的药品物质和药品放行标准生产的 建议在非人类灵长类动物毒理学研究中使用。会议请求和 一揽子，包括最终的CMC和临床前毒理学问题和最终的临床方案，然后将 准备并提交给与FDA举行的B型会议(目标3)。最后，根据FDA获得的指导意见 在目标3中，建立了GneX12在非人灵长类动物中的初始耐受性和PK，并为IND准备 评估(目标4)，为开放的IND和首例临床试验做准备。这个项目的长期目标是 是开发一种生物制剂，当它与抗生素一起使用时，不仅会加剧疾病 清除，但也将诱导长期保护性免疫。目前还没有类似的产品。

PROJECT SUMMARY/ABSTRACT Genital tract infection with Neisseria gonorrhoeae does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. TherapyX, Inc. is advancing GneX12, a novel immune therapeutic that is designed to enhance antibiotic-mediated clearance of persistent Neisseria gonorrhoeae infection and induce long-term protection against subsequent exposure, i.e. a therapeutic vaccine. Specifically, GneX12 is the canonical type 1 cytokine interleukin-12 (IL-12) encapsulated in proprietary biodegradable sustained-release microparticles. Phase I studies in a murine model of gonoccal infection demonstrated that intra-vaginal administration of GneX12 achieved rapid disease clearance and induced the development of long-term protective immunity. Phase II work optimized treatment schedule; demonstrated the critical role of Th1 immunity in disease clearance; revealed that long-term protection was mediated by an anti-gonoccocal humoral response; that the antibodies were cross- protective; and that co-administration with antibiotics did not interfere with the induction of long-term protection. Additional Phase II work established scale-up manufacturing processes and completed a type C meeting with the FDA, garnering agency agreement with our single species primate toxicology plan to support an investigative new drug application (IND). The aims of the current Phase IIb application are based on agency recommendations communicated during that meeting. Specifically, Aim 1 studies will complete additional toxicology, including reproductive toxicology, assessment in rodents as recommend by FDA. In Aim 2, a large-batch “GMP-like” GneX12 drug product is manufactured in compliance with FDA drug substance and drug product release recommendations for use in IND-enabling, non-human primate toxicology studies. A meeting request and package, including final CMC and pre-clinical toxicology questions and finalized clinical protocols, will then be prepared and submitted for a Type B meeting with the FDA (Aim 3). Lastly, based on the FDA guidance obtained in Aim 3, initial tolerability and pK of GneX12 in non-human primates is established and IND readiness is assessed (Aim 4) in preparation for an open IND and first-in-man clinical trials. The long-term goal of this project is to develop a biologic, which when administered in conjunction with antibiotics, will not only enhance disease clearance but will also induce long-term protective immunity. No similar product currently exists.