Gonorrhea and HIV prevention with intravaginal ring drug delivery

通过阴道环给药预防淋病和艾滋病毒

基本信息

批准号：
10378501
负责人：
John A Moss
金额：
$ 47.74万
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：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378501
关键词：
AIDS prevention Academia Anti-Infective Agents Antibiotics Attenuated Bacteria Binding Biological Assay Biotechnology Cells Centers for Disease Control and Prevention (U.S.)Clinical Clinical Trials Cloning Clostridium difficile Collaborations Complement Complement 1q Complement Activation Complement Factor H Complement Inactivators Consultations Contracts Development Drug Delivery Systems Drug-resistant Neisseria Gonorrhoeae Ectopic Pregnancy Epitopes Formulation Fumarates Funding Gold Gonorrhea HIV HIV Infections Health High Risk Woman Human IgG1 Immunoglobulin G Immunotherapy In Vitro Individual Industry Infection Infertility Institutes Intravaginal Administration Investigation Lead Macaca Measures Methods Modeling Monoclonal Antibodies Morbidity - disease rate Multi-Drug Resistance Mus Mutation Neisseria gonorrhoeae Nicotiana Organism Pelvic Inflammatory Disease Persons Phagocytes Pharmaceutical Preparations Phase Planets Plants Polysaccharides Positioning Attribute Powder dose form Process Prodrugs Production Resistance Safety Science Serum Sexually Transmitted Diseases Superbug Technology Transfer Tenofovir Testing Tobacco Toxic effect Transgenic Mice Vaccines Vagina Vaginal Ring Vaginal delivery procedure Woman Work World Health Organization attenuation bactericide base carbapenem-resistant Enterobacteriaceae complement 4b-binding protein cost design disorder control efficacy evaluation efficacy testing fitness human monoclonal antibodies humanized monoclonal antibodies immunogenic in vivo lipooligosaccharide macrophage meetings mortality mouse model murine monoclonal antibody novel plant growth/development preclinical development prevent priority pathogen prophylactic research and development safety study scale up sheep model simian human immunodeficiency virus transmission process trend vaccine candidate

项目摘要

ABSTRACT Sexually transmitted infections, such as HIV and gonorrhea, are a major threat to human health worldwide. Antibiotic-resistant N. gonorrhoeae have emerged in all parts of the world. Safe and effective vaccines against gonorrhea and HIV remain elusive. Further, gonorrhea can increase transmission of HIV about 5-fold. Thus, there is an urgent need to develop novel methods to prevent these STIs. We have identified a murine monoclonal antibody (mAb) called 2C7 that is directed against a gonococcal lipooligosaccharide (LOS) epitope that is expressed by ~95% of clinical isolates, has complement-dependent bactericidal and opsonic activity and attenuates gonococcal infection in the mouse model. A chimeric version of mAb 2C7 (Ximab 2C7), created in an ongoing collaboration with Genmab, was also efficacious when administered intravaginally to mice. Introduction of a mutation in human IgG1 Fc that increases IgG hexamerization and enhances complement activation further enhanced activity of Ximab 2C7. This collaborative proposal between UMass, Planet Biotechnology, Inc., Oak Crest Institute of Science and MassBiologics seeks to develop intravaginal rings (IVRs) to deliver fully humanized mAb 2C7 in combination with tenofovir disoproxil fumarate (intravaginal TDF; proven efficacious in preventing HIV transmission to women) to prevent gonorrhea and HIV infections. In the R61 phase (years 1 and 2) of this proposal, we will i) fully humanize mAb 2C7 that contains the complement-enhancing Fc mutation (Humab 2C7), ii) produce functional Humab 2C7 at a relatively low cost in tobacco plants, iii) formulate Humab 2C7 along with the tenofovir into IVRs for local vaginal delivery and iv) prepare for and participate in a pre-IND meeting with the FDA. In the R33 phase (years 3-5) we will i) perform PK, release and toxicity studies following tenofovir and Humab 2C7 delivery via IVR in an ovine model, ii) test the efficacy of Humab 2C7 against contemporary clinical multidrug-resistant isolates in novel human factor H (FH) and C4b-binding protein (C4BP) dual transgenic mice (gonococci bind these complement inhibitors in a human specific manner, thus these mice will provide the `obstacles' that Humab 2C7 will have to surmount in humans), iii) elucidate the mechanism of action of Humab 2C7 in vivo using mice that lack complement components (C1q, C3, C5, C5aR) and /or phagocytes (PMNs, macrophages) and iv) develop a scalable purification process and a set of drug product release assays appropriate for technology transfer to a contract manufacturing organization. Successful completion of the proposed work will result in a clinically effective deliverable to prevent HIV and gonorrhea at the end of the funding period.

抽象的艾滋病毒和淋病等性传播感染是全世界人类健康的主要威胁。世界各地都出现了对抗生素具有耐药性的淋病奈瑟菌。安全有效的疫苗淋病和艾滋病毒仍然难以捉摸。此外，淋病可使 HIV 传播增加约 5 倍。因此，迫切需要开发新方法来预防这些性传播感染。我们已经鉴定出一种名为 2C7 的鼠单克隆抗体 (mAb)，可针对淋球菌脂寡糖 (LOS) 表位约 95% 的临床分离株表达，具有补体依赖性在小鼠模型中具有杀菌和调理活性并减轻淋球菌感染。嵌合版本与 Genmab 持续合作创建的 mAb 2C7 (Ximab 2C7) 在以下情况下也有效：对小鼠进行阴道内给药。在人类 IgG1 Fc 中引入突变，从而增加 IgG 六聚化和增强补体激活进一步增强了 Ximab 2C7 的活性。这麻省大学、Planet Biotechnology, Inc.、Oak Crest Institute of Science 和 MassBiologics 寻求开发阴道环 (IVR) 以提供完全人源化的 mAb 2C7 组合与富马酸替诺福韦二吡呋酯（阴道内 TDF；经证明可有效预防 HIV 传播）女性）预防淋病和艾滋病毒感染。在本提案的 R61 阶段（第 1 年和第 2 年），我们将 i) 完全人源化 mAb 2C7，其中包含补体增强 Fc 突变 (Humab 2C7)，ii) 以相对较低的成本生产功能性 Humab 2C7 烟草植物，iii) 将 Humab 2C7 与替诺福韦一起配制到 IVR 中用于局部阴道给药，以及 iv) 准备并参加 FDA 的 IND 前会议。在 R33 阶段（第 3-5 年），我们将 i) 在替诺福韦和 Humab 后进行 PK、释放和毒性研究在绵羊模型中通过 IVR 进行 2C7 递送，ii) 测试 Humab 2C7 针对当代临床的功效新型人 H 因子 (FH) 和 C4b 结合蛋白 (C4BP) 双转基因中的多重耐药分离株小鼠（淋球菌以人类特有的方式结合这些补体抑制剂，因此这些小鼠将提供 Humab 2C7 在人体中必须克服的“障碍”），iii) 阐明其作用机制 Humab 2C7 在体内使用缺乏补体成分（C1q、C3、C5、C5aR）和/或吞噬细胞的小鼠（PMN、巨噬细胞）和 iv) 开发可扩展的纯化工艺和一套药物产品释放适用于向合同制造组织转让技术的测定。成功完成拟议工作将产生临床有效的成果，以预防艾滋病毒和资助期结束时淋病。