Therapy and Prophylaxis for Genital Tract Infection

描述(申请人提供)：生殖道感染淋球菌(淋病)不会诱导特定的保护性免疫状态，可以反复获得。尽管采取了公共卫生措施，这种疾病仍然以令人无法接受的高频率持续存在；没有针对它的疫苗，甚至对最新一代抗生素的耐药性也在继续出现。最近的研究结果表明，淋病奈瑟菌为了自身的利益而颠覆免疫系统，是通过激发其能够存活的先天反应，并通过抑制将其消灭的特定适应性反应。然而，这种诱导的免疫抑制可以通过有效地重定向针对淋球菌的免疫反应的治疗而逆转。在第一阶段的SBIR项目中，利用被认为是目前唯一可用的动物模型的小鼠模型，为治疗和预防生殖器淋球菌感染的新策略建立了原则证明。由TreatyX公司开发的一种专利产品，由可生物降解的微粒包裹的白细胞介素12(IL-12)组成，用于缓释，经阴道给药给感染淋病奈瑟菌的小鼠。这种名为GenX12的治疗方法可以诱导针对现有淋球菌感染的抗淋球菌T细胞和抗体反应，加速其清除，并在至少几个月的时间内防止同源和异种菌株再次感染。在这一第二阶段的应用中，GenX12的给药方案将得到优化，并将对其在阴道内的分布和吸收进行初步的药代动力学研究，为后续的非人灵长类动物毒理学试验做准备。将确定对自然产生的不同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类身上进行测试的保护性免疫参数。在准备临床试验时，将进行生产放大和产品评估，以确保批次一致性、纯度、一致性、稳定性和其他特性。在这些研究中获得的数据将被用来制定灵长类毒理学计划。与临床前数据一起，这一毒理学计划将被纳入一份简报，该简报将提交给FDA，要求召开一次C型会议。

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.