Therapy and Prophylaxis for Genital Tract Infection

摘要 GneX12是一种正在开发的专利治疗性疫苗，专门用于淋病奈瑟菌感染的女性 (淋病)感染。它是一种新型的重组人白细胞介素12(IL-12)制剂，包裹在 可生物降解的缓释微粒。它是与护理标准相结合的 抗生素将感染转化为活疫苗，产生针对再次感染的保护性免疫力。它也是一种 基于免疫疗法的针对新出现的多重耐药淋病菌株的失败安全治疗。在我们的SBIR中 在小鼠中进行的第一阶段概念验证研究表明，GneX12可诱导抗淋球菌T细胞和抗体 对现有淋球菌感染做出反应，加速细菌清除并产生保护 防止再次感染。对同源和异源菌株的保护范围很广，并持续了 至少六个月。这种保护从未被遵守过。在我们随后的SBIR第二阶段奖中，GneX12 优化给药剂量和给药方案，测定阴道内给药后的初始药动学参数 行政管理。不同自然分离株淋病奈瑟菌的交叉保护机制 为治疗和确定保护性参数提供了科学依据 人体试验的免疫力。开发了药品生产的放大方法，并实现了批次到批次的生产 展示了批次一致性、一致性和稳定性。最后，一份简报和一组疑问句 准备好了，并与FDA举行了C型会议。在我们的SBIR IIb期工作中，FDA建议的毒性 包括生殖毒性在内的研究是在啮齿动物身上进行的。放大的制造方法是 转移到阿森迪亚制药公司的商业GMP设施，以及开发和资格认证 分析方法。适合人体使用的GMP药材(rhIL-12)是在联合生产的条件下生产的。 与Akron Biotech达成开发协议，确保Treatyx获得独家原料药来源 在公开市场上可以买到。最后，我们准备了一套简报和一套问答，并进行了 B类与FDA的会议，为提交IND申请做准备。在此申请资金 制造和验证cGMP药物产品，进行机构要求的猴子毒性研究，以及 最后，对于IND提交。今后，我们将利用单独的公司资金，进行一期/二期试验， 淋病奈瑟菌感染妇女中的GneX12基因试验将与我们的合作伙伴合作进行，网址为 路易斯维尔大学。

ABSTRACT GneX12 is a patented therapeutic vaccine in development specifically for women with Neisseria gonorrhoeae (gonorrhea) infection. It is a novel formulation of recombinant human interleukin-12 (IL-12) encapsulated in biodegradable sustained release micro-particles. It is meant to be given in conjunction with standard of care antibiotics to turn infections into live vaccines that generate protective immunity against re-infection. It is also an immune therapy-based failsafe treatment against emerging multi-drug resistant gonorrhea strains. In our SBIR phase I proof of concept studies in mice, we showed that GneX12 induces anti-gonococcal T-cell and antibody responses against existing gonococcal infections, accelerates bacterial clearance and generates protection against re-infection. Protection was broad, against both homologous and heterologous strains and lasted for at least six months. Such protection had never been observed. In our subsequent SBIR phase II award, GneX12 dose and regimen were optimized, and initial pharmacokinetics parameters determined after intravaginal administration. The mechanisms of cross-protection against diverse strains of naturally occurring N. gonorrhoeae were elucidated, substantiating the scientific basis for the treatment and identifying parameters of protective immunity for testing in humans. Scaled-up methods for drug product production were developed, and batch-to- batch consistency, uniformity and stability demonstrated. Finally, a briefing package and set of interrogatives were prepared and a type C meeting held with the FDA. In our SBIR phase IIb work, FDA-recommended toxicity studies, including reproductive toxicity, were conducted in rodents. Scaled-up manufacturing methods were transferred to commercial GMP facilities at Ascendia Pharmaceuticals, along with development and qualification of analytical methods. GMP drug substance (rhIL-12), suitable for human use, was produced under a co- development agreement with Akron Biotech, securing for Therapyx an exclusive source of API not otherwise available on the open market. Finally, we prepared a briefing package and set of interrogatives and conducted a type B meeting with the FDA in preparation for submission of an IND application. Funds are herein requested to manufacture and validate cGMP drug product, perform agency-required toxicity studies in monkeys, and finally, for IND submission. In the future, with separate company funds, we will conduct a phase I/II trial with GneX12 in women with Neisseria gonorrhoeae. The trial will be conducted in collaboration with our partners at the University of Louisville.