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.

抗生素耐药性是世界范围内的一个主要公共卫生问题。淋病奈瑟菌（Ng） 性传播感染淋病的病原体，已成为多药耐药性，并已实现 “超级细菌”状态此外，6%至12%的淋病成功治疗的妇女再次感染 三个月内。迫切需要针对Ng的新疗法。补体（C′）是先天免疫系统的一个关键分支， 免疫防御包括Ng在内的几种病原体逃避C′的机制是与宿主C′结合， 因子H（FH）。FH包含20个结构域，以扩展的头对尾方式排列。只有 四个N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。包括Ng在内的许多病原体已经进化为通过结构域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 与IgG Fc（FH*/Fc）结合并促进Ng的C′依赖性杀伤。局部给药FH*/Fc 在小鼠阴道定殖模型中减弱Ng感染。 我们已经在我们的植物表达系统中产生了具有不同Fc或不同Fc区的变体FH*/Fc分子。 FH和Fc之间的接头。我们证明了植物制造的FH*/Fc变体的功能优越性， 在体外和小鼠阴道感染预防剂中掺入柔性接头（GGGGS）2或（GGGGS）3， 模型我们还表明，这些分子的功能性取决于Fc的激活能力， Ng表面上的互补。 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感染。在 这个快速通道项目，我们寻求进一步的临床前开发这种有前途的免疫抑制剂， 耐药Ng.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是 修饰以改善C ′介导的Ng杀伤，并鉴定具有最大效力的两种先导变体。同相 我们将比较这些FH*/GS-hFc前导变体在体内针对四种不同Ng分离株的效力， 确定最小有效剂量。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 保持体外效力。基于上述所有实验的总和，我们将选择一个变体作为先导， 商业化我们将在阴道环中配制先导FH*/GS-hFc变体， 控制释放数周，并评估其在恒河猴中的PK和安全性。我们将执行一个 6个月的原料药稳定性研究，预期未来将进行1期临床试验。在一个大型 作为植物蛋白的合同制造商，我们将进行技术经济分析，以确定 植物制造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。