Therapy and Prophylaxis for Genital Tract Infection

生殖道感染的治疗和预防

• 批准号: 10757512
• 负责人: DOMINICK AUCI
• 金额: $ 100万
• 依托单位: THERAPYX, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757512
• 关键词: Acceleration; Agreement; Antibiotic Therapy; Antibiotics; Antibodies; Antibody Response; Antimicrobial Resistance; Attenuated Vaccines; Award; Biological; Biological Sciences; Biotechnology; Cephalosporins; Cicatrix; Clinical; Clinical Research; Clinical Trials; Collaborations; Communicable Diseases; Communication; Consultations; Cyclic GMP; Dedications; Development; Dose; Drug Compounding; Drug Kinetics; Ectopic Pregnancy; Encapsulated; Fluoroquinolones; Formulation; Funding; Future; Goals; Gonorrhea; HIV; Human; Immunity; Immunotherapeutic agent; Immunotherapy; Incidence; Infection; Infertility; Inflammatory; Interleukin-12; Intravaginal Administration; Investigational Drugs; Legal patent; Macaca fascicularis; Marketing; Mediating; Methods; Monkeys; Mucous Membrane; Multi-Drug Resistance; Mus; Neisseria gonorrhoeae; Pelvic Inflammatory Disease; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I/II Clinical Trial; Phase I/II Trial; Pichia; Preparation; Primates; Production; Prophylactic treatment; Public Health; Qualifying; Rattus; Readiness; Recombinants; Recommendation; Regimen; Reporting; Resistance development; Risk; Rodent; Role; Secure; Small Business Innovation Research Grant; Source; Specific qualifier value; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Toxicology; Treatment Protocols; Universities; Vaccines; Woman; Work; acute toxicity; analytical method; comparative; cost effective; cross immunity; cytokine; design; drug-resistant gonorrhea; emerging antibiotic resistance; manufacture; manufacturing process; manufacturing scale-up; meetings; mouse model; nonhuman primate; novel; novel therapeutics; particle; product development; public health relevance; reproductive; reproductive toxicity; reproductive tract; resistant strain; response; scale up; standard of care; symptom treatment; therapeutic vaccine; transmission process; treatment optimization

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.

抽象的 GneX12 是一种专利治疗疫苗，专为患有淋病奈瑟菌的女性而开发 （淋病）感染。它是一种封装有重组人白细胞介素 12 (IL-12) 的新型制剂。 可生物降解的缓释微粒。它应该与标准护理一起给予 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。它也是一个 针对新出现的多重耐药性淋病菌株的基于免疫疗法的故障安全治疗。在我们的 SBIR 中 I 期小鼠概念验证研究表明，GneX12 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 防止再次感染。保护范围广泛，针对同源和异源菌株，并且持续时间为 至少六个月。这种保护从未被观察到。在我们随后的 SBIR II 期奖项中，GneX12 优化剂量和方案，并在阴道内给药后确定初始药代动力学参数 行政。针对天然存在的淋病奈瑟菌不同菌株的交叉保护机制 得到了阐明，证实了治疗的科学依据并确定了保护参数 用于人体测试的免疫力。开发了药品生产的放大方法，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，一份简报和一组疑问句 准备并与 FDA 举行了 C 类会议。在我们的 SBIR IIb 期工作中，FDA 推荐的毒性 在啮齿类动物中进行了研究，包括生殖毒性。放大制造方法是 转移到 Ascendia Pharmaceuticals 的商业 GMP 设施，并进行开发和认证 的分析方法。适合人类使用的 GMP 原料药 (rhIL-12) 是在共同生产的 与 Akron Biotech 签订开发协议，确保 Therapyx 获得 API 的独家来源 可在公开市场上购买。最后，我们准备了一份简报和一组问题，并进行了 与 FDA 举行的 B 类会议，准备提交 IND 申请。此处要求资金 生产和验证 cGMP 药品，在猴子中进行机构要求的毒性研究，以及 最后，进行IND提交。未来，我们将用独立的公司资金，进行I/II期试验 GneX12 用于患有淋病奈瑟菌的女性。该试验将与我们的合作伙伴合作进行 路易斯维尔大学。