Therapy and Prophylaxis for Genital Tract Infection

描述（由申请人提供）：淋病奈瑟菌（淋病）的生殖道感染不会诱导特异性保护性免疫状态，并且可以反复获得。尽管采取了公共卫生措施，但这种疾病仍然以令人无法接受的高频率存在；目前还没有针对它的疫苗，甚至对最新一代抗生素的耐药性也在不断出现。最近的研究结果表明，淋病奈瑟菌为了自身的利益而破坏免疫系统，其方式是引发能够使其存活的先天反应，以及抑制能够消灭它的特定适应性反应。然而，这种诱导的免疫抑制可以通过有效地重新定向针对淋病奈瑟菌的免疫反应的治疗来逆转。在第一阶段SBIR项目中，已经建立了一种治疗和预防生殖器淋球菌感染的新策略的原理证明，该策略使用的小鼠模型被认为是目前唯一可用的动物模型。TherapyX, Inc.开发的一种专利产品，由包裹在可生物降解微颗粒中的白细胞介素-12 （IL-12）组成，用于持续释放，经阴道给药于感染淋病奈瑟菌的小鼠。这种被称为GenX12的治疗方法，诱导抗淋球菌t细胞和抗体反应，对抗现有的淋球菌感染，既加速了其清除，又产生了至少几个月的保护，防止同源和异源菌株的再次感染。在本次II期申请中，将对GenX12的给药方案进行优化，并对其阴道内给药后的分布和摄取进行初步的药代动力学研究，为后续在非人灵长类动物中的毒理学试验做准备。将确定针对多种自然产生的淋病奈瑟菌菌株的交叉保护机制，以证实治疗的科学基础，并确定最终需要在人体中进行测试的保护性免疫参数。在准备临床试验时，将进行生产放大和批一致性、纯度、均匀性、稳定性和其他特性的产品评估。在这些研究中获得的数据将用于制定灵长类动物毒理学计划。与临床前数据一起，该毒理学计划将被纳入一份简报包，并在要求召开C类会议时提交给FDA。

DESCRIPTION (provided by applicant): Genital tract infection with Neisseria gonorrhoeae (gonorrhea) 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. Recent findings have revealed that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. However, this induced immunosuppression can be reversed by treatments that effectively redirect the immune response against N. gonorrhoeae. In a Phase I SBIR project, proof-of-principle has been established for a novel strategy of therapy and prophylaxis against genital gonococcal infection using a mouse model that is accepted as the only currently available animal model. A proprietary product developed by TherapyX, Inc., consisting of interleukin-12 (IL-12) encapsulated in biodegradable microparticles for sustained release is administered intravaginally in mice infected with N. gonorrhoeae. This treatment, termed GenX12, induces anti-gonococcal T-cell and antibody responses against the existing gonococcal infection, both accelerating its clearance and generating protection against re- infection with homologous and heterologous strains for at least several months. In this Phase II application, the dose regimen of GenX12 will be optimized, and initial pharmacokinetics studies on its distribution and uptake after intravaginal administration will be performed, in preparation for subsequent toxicological testing in nonhuman primates. The mechanisms of cross-protection against diverse strains of naturally occurring N. gonorrhoeae will be determined to substantiate the scientific basis for the treatment and to identify parameters of protective immunity that will need to be tested ultimately in humans. In preparation for clinical trials, manufacturing scale-up and product evaluation for batch consistency, purity, uniformity, stability, and other characteristics will be performed. The data obtained in these studies will then be used to create a primate toxicology plan. Along with the preclinical data, this toxicology plan will be incorporated into a briefing package that will b submitted to the FDA in a request for a Type C Meeting.