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.

抗生素耐药性是全球主要的公共卫生问题。 性传播感染淋病的病原体，已产生多重耐药性并已达到 此外，成功治疗淋病的女性中有 6% 至 12% 会再次感染。 三个月内迫切需要针对 Ng 的新疗法。 包括 Ng 在内的多种病原体用来逃避 C' 的机制是与宿主 C' 结合。 称为 H 因子 (FH) 的抑制剂包含 20 个结构域，以头尾相连的方式排列。 四个 N 末端结构域（结构域 1-4）具有 C' 抑制活性；分子的其余部分很重要； 用于识别宿主表面的许多病原体，包括 Ng，已进化为通过结构域 6-7 结合 FH。 和/或 18-20。FH 结构域 18-20 的重组融合体（在结构域 19 中具有点突变以消除结合） 宿主细胞）与 IgG Fc (FH*/Fc) 结合并促进 Ng 的 C' 依赖性杀伤。 减弱小鼠阴道定植模型中的 Ng 感染。 我们已经在我们的植物表达系统中生产了具有不同 Fc 或不同 Fc 的变体 FH*/Fc 分子。 我们展示了植物制造的 FH*/Fc 变体的功能优势。 在体外和小鼠阴道感染预防中加入柔性接头 (GGGGS)2 或 (GGGGS)3 我们还表明，这些分子的功能取决于 Fc 的激活能力。 Ng 表面上的补体。 我们设想使用 FH*/GS-hFc 来预防接受单纯性淋病治疗的女性的再次感染。 在这个快速通道项目中，我们寻求进一步开发这种有前途的免疫疗法 在第一阶段，我们将在体外生产和测试五种新的 FH*/GS-hFc 变体，其中 Fc 为 进行修改以改善 C´ 介导的 Ng 杀伤，并鉴定出两个具有最大同相效力的先导变体。 II 我们将比较这些 FH*/GS-hFc 先导变体在体内与四种不同 Ng 分离株的效力， 确定最低有效剂量，我们将测试它们对 50 种不同的 Ng 临床分离株的体外效力。 我们将扩大纯化规模并评估两种先导变体进行喷雾干燥和纯化的能力 根据上述所有实验的总和，我们将选择一种变体作为先导。 我们将在阴道环中配制主要的 FH*/GS-hFc 变体，旨在持续、 我们将进行几周的控制释放，并评估其在恒河猴中的 PK 和安全性。 在大型临床试验的帮助下进行为期六个月的药物稳定性研究。 植物蛋白合同制造商，我们将进行技术经济分析以确定 植物制造的 FH*/GS-hFc 的商业可行性，并寻求 FDA 对未来 FH*/GS-hFc 非 临床和临床发展。