An immunotherapeutic to prevent gonorrhea

预防淋病的免疫疗法

• 批准号: 10084961
• 负责人: SANJAY RAM
• 金额: $ 79.85万
• 依托单位: PLANET BIOTECHNOLOGY, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10084961
• 关键词: Affect; Amino Acids; Anti-Bacterial Agents; Antibiotic Resistance; Antibiotics; Antimicrobial Resistance; Attenuated; Azithromycin; Binding; Biological Assay; Biotechnology; Ceftriaxone; Cells; Centers for Disease Control and Prevention (U.S.); Chimeric Proteins; Clinical; Collaborations; Complement; Complement Activation; Complement Factor H; Complement Inactivators; Complement-Dependent Cytotoxicity; Consult; Contracts; Cyclic GMP; Cytolysis; Development; Diagnosis; Dose; Drug Kinetics; Drug-resistant Neisseria Gonorrhoeae; Ensure; Female; Future; GTP-Binding Protein alpha Subunits, Gs; Gonorrhea; Head; Human; Immune; Immunoglobulin G; Immunotherapeutic agent; In Vitro; Infection; Lead; Macaca mulatta; Manufacturer Name; Massachusetts; Mediating; Modeling; Multi-Drug Resistance; Mus; Mutation; N-terminal; Natural Immunity; Neisseria gonorrhoeae; Pelvic Inflammatory Disease; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Planets; Plants; Point Mutation; Prevention; Production; Proteins; Public Health; Recombinants; Reproductive Health; Research Design; Resistance; Safety; Serum; Sexually Transmitted Agents; Sexually Transmitted Diseases; Sum; Superbug; Surface; System; Tail; Technology Transfer; Testing; Topical application; United States; Universities; Vagina; Vaginal Ring; Variant; Woman; Women' s Health; arm; bactericide; base; clinical development; commercialization; controlled release; cost estimate; design; experimental study; flexibility; improved; in vitro Assay; in vivo; large scale production; medical schools; novel therapeutics; pathogen; preclinical development; prevent; prophylactic; scale up; vaginal infection

Antimicrobial resistance is a major public health problem worldwide. Neisseria gonorrhoeae (Ng), the causative agent of the sexually transmitted infection gonorrhea, has become multidrug-resistant and has achieved “superbug” status. In addition, between 6% and 12% of women successfully treated for gonorrhea are re-infected within three months. Novel therapeutics against Ng are urgently needed. Complement (C′) is a key arm of innate immune defenses. A mechanism used by several pathogens, including Ng, to escape C′ is to bind to a host C′ inhibitor called factor H (FH). FH comprises 20 domains, arranged in an extended head-to-tail fashion. Only the four N-terminal domains (domains 1-4) possess C′ inhibiting activity; the remainder of the molecule is important for recognition of host surfaces. Many pathogens, including Ng, have evolved to bind FH through domains 6-7 and/or 18-20. A recombinant fusion of FH domains 18-20 (with a point mutation in domain 19 to abrogate binding to host cells) to IgG Fc (FH*/Fc) binds to and promotes C′-dependent killing of Ng. Topically administered FH*/Fc attenuates Ng infection in the mouse vaginal colonization model. We have produced, in our plant expression system, variant FH*/Fc molecules with different Fc or different linkers between FH and Fc. We demonstrated the functional superiority of plant-made FH*/Fc variants incorporating flexible linkers, (GGGGS)2 or (GGGGS)3, both in vitro and in a mouse vaginal infection prophylactic model. We have also shown that the functionality of these molecules depends on the ability of the Fc to activate complement on the Ng surface. We envision using FH*/GS-hFc to prevent re-infection in women treated for uncomplicated gonorrhea. In this Fast-Track project we seek to further preclinical development of this promising immunotherapeutic against drug-resistant Ng. In Phase I we will produce and test in vitro five new FH*/GS-hFc variants where the Fc is modified to improve C´-mediated killing of Ng and identify two lead variants with the greatest potency. In Phase II we will compare the potency of these FH*/GS-hFc lead variants in vivo against four divergent Ng isolates, determining the minimum effective dose. We will test their in vitro potency against 50 diverse Ng clinical isolates. We will scale up purification and evaluate the ability of the two lead variants to undergo spray-drying and retain in vitro potency. Based on the sum of all the above experiments, we will select one variant as a lead for commercialization. We will formulate the lead FH*/GS-hFc variant in an intravaginal ring designed for sustained, controlled release over several weeks, and evaluate its PK and safety in rhesus macaques. We will perform a six-month drug substance stability study in anticipation of a future Phase 1 clinical trial. With the help of a large contract manufacturer of plant-made proteins, we will conduct a technoeconomic analysis to determine the commercial viability of plant-made FH*/GS-hFc, and seek the guidance of the FDA on future FH*/GS-hFc non- clinical and clinical development.

抗菌素抵抗是全球主要的公共卫生问题。 Neisseria Gonorrhoeae（NG）， 性传播感染淋病的病变剂已变得多用物，已经实现了 “超级分布”状态。此外，成功治疗淋病治疗的女性中有6％至12％被重新感染 在三个月内。迫切需要针对NG的新型治疗。补充（C'）是先天的关键部门 免疫防御。包括NG在内的几种病原体使用的一种机制，用于逃脱C'与宿主C结合。 抑制剂称为因子H（FH）。 FH由20个域组成，以延长的从头到尾方式排列。只有 四个N末端结构域（域1-4）具有C'抑制活性。分子的其余部分很重要 识别宿主表面。包括NG在内的许多病原体已经演变为通过域6-7结合FH 和/或18-20。 FH结构域的重组融合18-20（域19中有点突变以消除结合 宿主细胞）至IgG FC（FH*/FC）与Ng的C依赖性杀害结合并促进。局部管理FH*/FC 减弱小鼠阴道定植模型中的NG感染。 我们在我们的植物表达系统中产生了具有不同fc或不同不同的fh*/fc分子 FH和FC之间的接头。我们证明了植物fh*/fc变体的功能优势 在体外和小鼠阴道感染预防性预防性的柔性接头，（GGGGS）2或（GGGGS）3 模型。我们还表明，这些分子的功能取决于FC激活的能力 补充NG表面。 我们设想使用FH*/GS-HFC防止因淋病不复杂的妇女重新感染。在 这个快速轨道的项目，我们寻求进一步开发这种承诺的免疫治疗性 耐药的NG。在第一阶段，我们将在体外生产和测试FC为FC的五个新的FH*/GS-HFC变体 修改以改善C介导的NG杀死，并确定具有最大效力的两个铅变体。在阶段 ii我们将比较这些FH*/GS-HFC铅变体在体内的效力与四个不同的NG分离株， 确定最小有效剂量。我们将对50种潜水员NG临床分离株进行体外效力。 我们将扩大净化并评估两个铅变体进行喷涂干燥和 保留体外效力。基于上述所有实验的总和，我们将选择一个变体作为引线 商业化。我们将在设计用于持续的，均设计的静脉内环中制定铅fh*/gs-hfc变体 在数周内进行了控制释放，并评估其PK和在恒河猕猴中的安全性。我们将执行 六个月的药物稳定性研究预期未来的1阶段临床试验。在大的帮助下 植物蛋白质合同制造商，我们将进行技术经济分析，以确定 植物FH*/GS-HFC的商业生存能力，并寻求FDA对未来FH*/GS-HFC非 - 的指导 临床和临床发育。