Novel immunotherapeutics against multidrug-resistant Neisseria gonorrhoea

针对多重耐药淋病奈瑟菌的新型免疫疗法

基本信息

批准号：
10207360
负责人：
SANJAY RAM
金额：
$ 86.28万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-11 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10207360
关键词：
Academia Amino Acids Anti-Infective Agents Antibiotics Antimicrobial Resistance Attenuated Binding Biological Sciences Biotechnology Cell surface Cells Centers for Disease Control and Prevention (U.S.)Clinical Clostridium difficile Collaborations Complement Complement Activation Complement Factor H Complement Inactivators Complement Membrane Attack Complex Cytolysis Drug resistance Drug-resistant Neisseria Gonorrhoeae Ectopic Pregnancy Epitopes Gonorrhea Head Health High Risk Woman Human Immunoglobulin G Immunotherapeutic agent Immunotherapy In Vitro Individual Industry Infection Infertility Institutes Lead Length Macaca fascicularis Mediating Microbe Modeling Monoclonal Antibodies Multi-Drug Resistance Mus Mutation N-terminal Neisseria gonorrhoeae Nicotiana Pathogenesis Pelvic Inflammatory Disease Pharmaceutical Preparations Planets Plants Point Mutation Polysaccharides Positioning Attribute Preparation Production Proteins Rattus Reporting Resistance Sexually Transmitted Agents Sexually Transmitted Diseases Superbug Surface System Tail Testing Tissues Tobacco Topical application Toxic effect Toxicokinetics Toxicology Transgenic Mice United States Vagina Vaginal Ring Virulence Woman arm bactericide carbapenem-resistant Enterobacteriaceae comparative complement 4b-binding protein cost cross reactivity drug development human monoclonal antibodies immunogenic immunoprophylaxis in vivo lipooligosaccharide macrophage man meetings men multi-drug resistant pathogen novel novel therapeutics pathogen pre-clinical preclinical development synergism vaccine candidate

项目摘要

ABSTRACT In 2013, the CDC listed Neisseria gonorrhoeae (Ng) is listed as one of the three multidrug-resistant pathogens that represented ‘urgent’ threats to human health worldwide. Ng has become resistant to almost every antibi-otic and has achieved “superbug” status. Complications of gonorrhea include pelvic inflammatory disease, which may lead to infertility and ectopic pregnancy. Novel therapeutics against this pathogen are urgently needed. This collaboration between industry and academia seeks to further preclinical development of two immunotherapeutics against drug-resistant Ng. Each molecule targets a distinct epitope on Ng; both are im-portant for pathogenesis and thus ubiquitously expressed in vivo. Advantages of targeting distinct epitopes im-portant for virulence include i) synergistic activity and ii) raising the barrier for the development of drug re-sistance, if it were to occur. A chimeric mAb targets Ng and mediates complement (C′)-dependent killing of Ng in vivo. Several pathogens including Ng evade C′ by binding to a host C′ inhibitor called factor H (FH). FH comprises 20 domains, arranged in an extended head-to-tail fashion. FH domains 18-20 (lacks C′ inhibitory function) fused to IgG Fc effects C′-dependent killing of Ng. FH domains 19 and 20 are important to limit un-wanted C′ activation on host tissue. We introduced a D→G amino acid point mutation in domain 19 of FH18-20/Fc. This protein, called FH*/Fc, retains its efficacy against Ng in vitro and in vivo but does not lyse host cells. In Aim 1 Planet Biotechnology, Inc. will produce the chimeric mAb and FH*/Fc in tobacco plants. This will permit efficient and low cost production. The efficacy of plant-produced FH*/Fc and the chimeric mAb against Ng in vitro and in mice will be tested by UMass in Aim 2. The drugs will be administered: i) systemically (mod-eling adjunctive treatment of established infection in men and women) or ii) intravaginally (modeling topical immunoprophylaxis in high-risk women). Each molecule will be tested individually and in combination for syn-ergy and to raise the barrier for drug resistance. Efficacy will also be assessed in novel transgenic (Tg) mice that express the human C′ inhibitors, FH and C4b-binding protein, which Ng bind to in a human-specific man-ner to evade C′, and therefore represent barriers to the drugs that may be encountered in humans. In Aim 3, Oak Crest Institute will formulate both drugs in combination in slow-release vaginal rings for use as topical im-munoprophylactics. In Aim 4 Xenometrics will perform toxicology and toxicokinetic (TK) studies in rats and cynomolgus monkeys and Comparative Biosciences will perform tissue-cross reactivity studies. In Aim 5, the mechanism of action of the chimeric mAb and FH*/Fc and will be defined in vivo using mice that lack C3, C5, PMNs and/or macrophages to define correlates of protection in vivo. These studies may lead to preparation for and participation in a pre-IND meeting with FDA (Aim 6).

抽象的 2013年，疾病预防控制中心将淋病奈瑟菌 (Ng) 列为对全球人类健康构成“紧急”威胁的三种多重耐药病原体之一，Ng 已对几乎所有抗生素产生耐药性，并已达到“超级细菌”状态。淋病的并发症包括可能导致不孕和宫外孕的盆腔炎，迫切需要针对这种病原体的新疗法。学术界寻求进一步开发两种针对耐药 Ng 的免疫疗法；每种分子都针对 Ng 上的不同表位；两者都对发病机制很重要，因此在体内普遍表达。 i) 协同活性和 ii) 提高耐药性发展的障碍（如果发生）嵌合 mAb 靶向 Ng 和体内介导补体 (C') 依赖性杀灭 Ng，包括 Ng 在内的多种病原体通过与称为 H 因子 (FH) 的宿主 C' 抑制剂结合而逃避 C'，FH 包含 20 个结构域，以头尾相连的方式排列。 FH 结构域 18-20（缺乏 C' 抑制功能）与 IgG Fc 融合，对 Ng 产生 C' 依赖性杀伤作用，对于限制不需要的 C' 激活非常重要。我们在 FH18-20/Fc 的结构域 19 中引入了 D→G 氨基酸点突变，这种称为 FH*/Fc 的蛋白质在体外和体内保留了针对 Ng 的功效，但不会裂解宿主细胞。在 Aim 1 中，Planet Biotechnology, Inc. 将在烟草植物中生产嵌合 mAb 和 FH*/Fc，这将实现植物生产的 FH*/Fc 和 FH*/Fc 的高效和低成本生产。麻省大学将在目标 2 中对针对 Ng 的嵌合单克隆抗体进行体外和小鼠体内测试。这些药物将通过以下方式给药：i）全身给药（模拟男性和女性已确诊感染的辅助治疗）或 ii）阴道内给药（模拟男性和女性的局部免疫预防）高风险女性）。每种分子将单独和组合进行协同作用测试，并评估新型转基因（Tg）的功效。表达人类 C' 抑制剂、FH 和 C4b 结合蛋白的小鼠，Ng 以人类特异性方式结合以逃避 C'，因此代表了 Aim 3 中可能遇到的药物障碍。 Oak Crest Institute 将在缓释阴道环中配制这两种药物，用作局部免疫预防剂 In Aim 4 Xenometrics 将在大鼠和小鼠身上进行毒理学和毒代动力学 (TK) 研究。在目标 5 中，食蟹猴和 Comparison Biosciences 将使用缺乏 C3、C5、PMN 和/或巨噬细胞的小鼠体内确定嵌合 mAb 和 FH*/Fc 的作用机制。定义体内保护的相关性。这些研究可能会帮助您准备并参与 FDA 的 IND 前会议（目标 6）。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Human Factor H Domains 6 and 7 Fused to IgG1 Fc Are Immunotherapeutic against Neisseria gonorrhoeae.

与 IgG1 Fc 融合的人因子 H 结构域 6 和 7 可针对淋病奈瑟菌进行免疫治疗。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Shaughnessy, Jutamas;Lewis, Lisa A;Zheng, Bo;Carr, Caleb;Bass, Isaac;Gulati, Sunita;DeOliveira, Rosane B;Gose, Severin;Reed, George W;Botto, Marina;Rice, Peter A;Ram, Sanjay
通讯作者：
Ram, Sanjay

Candida albicans Factor H Binding Molecule Hgt1p - A Low Glucose-Induced Transmembrane Protein Is Trafficked to the Cell Wall and Impairs Phagocytosis and Killing by Human Neutrophils.

白色念珠菌 H 因子结合分子 Hgt1p - 一种低葡萄糖诱导的跨膜蛋白被运输到细胞壁并损害人类中性粒细胞的吞噬作用和杀伤作用。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Kenno, Samyr;Speth, Cornelia;Rambach, Günter;Binder, Ulrike;Chatterjee, Sneha;Caramalho, Rita;Haas, Hubertus;Lass;Shaughnessy, Jutamas;Ram, Sanjay;Gow, Neil A R;Orth;Würzner, Reinhard
通讯作者：
Würzner, Reinhard

An optimized Factor H-Fc fusion protein against multidrug-resistant Neisseria gonorrhoeae.

针对多重耐药淋病奈瑟菌的优化因子 H-Fc 融合蛋白。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Shaughnessy, Jutamas;Chabeda, Aleyo;Tran, Y;Zheng, Bo;Nowak, Nancy;Steffens, Carolynn;DeOliveira, Rosane B;Gulati, Sunita;Lewis, Lisa A;Maclean, James;Moss, John A;Wycoff, Keith L;Ram, Sanjay
通讯作者：
Ram, Sanjay

Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion.

人类 IgG 通过补体逃避增加化脓性链球菌的毒力。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Ermert, David;Weckel, Antonin;Magda, Michal;Mörgelin, Matthias;Shaughnessy, Jutamas;Rice, Peter A;Björck, Lars;Ram, Sanjay;Blom, Anna M
通讯作者：
Blom, Anna M

Role of Gonococcal Neisserial Surface Protein A (NspA) in Serum Resistance and Comparison of Its Factor H Binding Properties with Those of Its Meningococcal Counterpart.

淋球菌奈瑟氏球菌表面蛋白 A (NspA) 在血清耐药中的作用及其与脑膜炎球菌对应物的 H 因子结合特性的比较。