Therapy and Prophylaxis for Genital Tract Infection

摘要 GneX 12是一种专为淋病奈瑟菌女性患者开发的专利治疗疫苗 （淋病）感染。它是一种新型的重组人白细胞介素-12（IL-12）制剂， 可生物降解的缓释微粒。这意味着与标准护理结合使用 抗生素将感染转化为活疫苗，产生保护性免疫力，防止再次感染。也是 免疫治疗为基础的故障安全治疗对新兴的多药耐药淋病菌株。在我们的SBIR 在小鼠的I期概念验证研究中，我们表明GneX 12诱导抗淋球菌T细胞和抗体， 针对现有淋球菌感染的反应，加速细菌清除并产生保护作用 防止再次感染保护范围广，对同源和异源菌株都有保护作用， 至少六个月这种保护从未得到遵守。在我们随后的SBIR第二阶段合同中，GneX 12 剂量和方案进行了优化，并在阴道内给药后测定初始药代动力学参数。 局交叉保护机制对自然发生的N。淋病 阐明，证实了治疗的科学依据，并确定了保护性的参数。 用于人体试验的免疫力。开发了用于药物产品生产的规模扩大方法，并进行了批量生产。 证明了批次一致性、均匀性和稳定性。最后，一份简报和一系列问题 并与FDA举行了C类会议。在我们的SBIR IIb期工作中，FDA推荐的毒性 在啮齿动物中进行了研究，包括生殖毒性研究。扩大规模的生产方法是 转移至Ascendia Pharmaceuticals的商业GMP设施，沿着开发和确认 分析方法。GMP原料药（rhIL-12），适用于人类使用，是在一个共同的条件下生产的。 与Akron Biotech签订开发协议，为Therapyx确保API的独家来源，而不是其他来源 可以在公开市场上买到。最后，我们准备了一个简报包和一套询问，并进行了 为准备提交IND申请而与FDA举行的B类会议。现请求提供资金 生产和验证cGMP制剂，在猴中进行机构要求的毒性研究，以及 最后是IND申请。未来，我们将使用单独的公司资金进行I/II期试验， 淋病奈瑟菌女性患者中的GneX 12。该试验将与我们的合作伙伴合作进行， 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.