Plant-derived HIV neutralizing mAbs for passive immunotherapy in newborn macaques

用于新生猕猴被动免疫治疗的植物源性 HIV 中和单克隆抗体

基本信息

批准号：
9312216
负责人：
Yvonne J Rosenberg
金额：
$ 100万
依托单位：
PLANTVAX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-06 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9312216
关键词：
AFP gene Academic Medical Centers Acute Address Adopted Adult Age Agrobacterium Anti-Idiotypic Antibodies Anti-Retroviral Agents Antibodies Binding Biological Assay Birth Blood Circulation Breast Feeding Cells Child Chronic Cloning Coitus Development Drug Kinetics Exhibits Family member Female Generations Grant HIV HIV Antibodies HIV therapy HIV vaccine HIV-1 Human Immune response Immunotherapeutic agent Impairment Individual Infection Infection Control Infection prevention Injection of therapeutic agent Intravenous Macaca Mediating Modeling Monitor Monoclonal Antibodies Mothers Mus Mutate National Institute of Allergy and Infectious Disease Nature Newborn Infant Nicotiana Passive Immunotherapy Perinatal Pharmaceutical Preparations Phase Plants Plasma Polysaccharides Production Property Prophylactic treatment Reporting Research Design SIV Sexual Transmission Small Business Innovation Research Grant Speed Swaziland System T-Lymphocyte Epitopes Techniques Therapeutic Time Transfection Vertical Disease Transmission Viremia Virus base cohort env Gene Products experience fetal gender-based violence high risk immunogenic immunogenicity in vivo neutralizing antibody neutralizing monoclonal antibodies pathogen phase 2 study pre-clinical prevent public health relevance response screening simian human immunodeficiency virus subcutaneous success transmission process vaccine trial young woman

项目摘要

DESCRIPTION (provided by applicant): The identification of highly potent broadly neutralizing antibodies (bnAbs) against HIV-1, and success in preventing SHIV infection following their passive administration, have increased the likelihood that immunotherapeutic strategies can be adopted to prevent and treat HIV-1 infection. However, while broad and potent neutralizing activity is an essential prerequisite, in vivo properties such as good circulatory stability and no-immunogenicity are equally critical for developing a human treatment. In the previous Phase I and Phase II studies, glycoforms of both first generation bnAbs and more recent potent highly mutated bnAbs 10-1074, NIH45-46G54W, 10E8, PGT121, PGT128, PGT145, PGT135, PG9, PG16, VRC01 and b12 have been produced by Agrobacterium-mediated transient transfection of Nicotiana benthamiana and assessed neutralizing activity and following admin- istration in macaques. The results to date indicate that (i) N-glycans within the VL domain impair plasma stability of plant-derived bnAbs and (ii) while PGT121 and b12 exhibit no immunogenicity in macaques after multiple injections, surprisingly VRC01, 10-1074 and NIH45-46G54W elicit high titer anti-idiotypic antibodies following a second injection which specifically bind the administered bnAb or a close family member, and inhibit the bnAb in neutralization assays (iii) both cocktails (VRC01, 10-1074, b12 and 10E8) as well as single PGT121 delivered either intravenously or subcutaneously both pre-and post-challenge administration can protect adult macaques. These results form the basis of the current Phase IIB proposal's dual approach to develop an efficacious bnAb cocktail by (i) performing perinatal protection studies in macaques against SHIV challenge which more closely mimic mother-to-child-transmission (MTCT) (ii) to extend their circulatory retention time and (iii) to identify the T cell epitopes on these highly mutated bnAbs which contribute to their immunogenicity and which could potentially compromising their value for prophylaxis and therapy of HIV-1. In addition, the rapid production of 15 broadly neutralizing plant-derived HIV mAbs in the current study highlights the unique advantages of the transient plant system in terms of speed and versatility, pathogen- free nature and low-tech requirements; particularly in the early developmental stages from "cloning to preclinical protection studies".

描述（由申请人提供）：针对 HIV-1 的高效广泛中和抗体（bnAb）的鉴定，以及被动给药后成功预防 SHIV 感染，增加了采用免疫治疗策略来预防和治疗 HIV-1 的可能性。然而，虽然广泛而有效的中和活性是必要的先决条件，但在之前的第一阶段和第二阶段中，良好的循环稳定性和无免疫原性等体内特性对于开发人类治疗同样重要。研究表明，第一代 bnAb 和更新的强效高度突变 bnAb 10-1074、NIH45-46G54W、10E8、PGT121、PGT128、PGT145、PGT135、PG9、PG16、VRC01 和 b12 的糖型均已通过农杆菌介导的瞬时转染产生本塞姆氏烟草和评估迄今为止的结果表明，(i) VL 结构域内的 N-聚糖会损害植物源性 bnAb 的血浆稳定性，并且 (ii) 令人惊讶的是，PGT121 和 b12 在多次注射后在猕猴中没有表现出免疫原性。 VRC01、10-1074 和 NIH45-46G54W 在第二次实验后引发高滴度抗独特型抗体注射特异性结合所施用的bnAb或近亲，并在中和测定中抑制bnAb (iii) 两种混合物（VRC01、10-1074、b12和10E8）以及单一PGT121在给药前和给药前静脉内或皮下给药攻击后给药可以保护成年猕猴，这些结果构成了当前 IIB 期提案开发有效药物的双重方法的基础。 bnAb 鸡尾酒通过 (i) 在猕猴中进行针对 SHIV 挑战的围产期保护研究，该研究更接近地模拟母婴传播 (MTCT) (ii) 延长其循环保留时间，以及 (iii) 识别这些猕猴上的 T 细胞表位高度突变的 bnAb 有助于其免疫原性，并可能损害其预防和治疗 HIV-1 的价值。此外，15 种广泛中和植物源性 HIV 的快速产生。当前研究中的单克隆抗体强调了瞬时植物系统在速度和多功能性、无病原体性质和低技术要求方面的独特优势；特别是在从“克隆到临床前保护研究”的早期发展阶段。