Passive immunotherapy using plant-derived broadly HIV-1 neutralizing MAbs to prev

使用植物来源的广泛 HIV-1 中和单克隆抗体进行被动免疫疗法来预防

• 批准号: 8210828
• 负责人: Yvonne J Rosenberg
• 金额: $ 74.14万
• 依托单位: PLANTVAX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8210828
• 关键词: ADCC Assay; Address; Antibodies; Biological Assay; Breast Feeding; Clinic; Complex; Data; Disease Progression; Dose; Drug Kinetics; Economics; Exhibits; Feasibility Studies; Fucose; Grant; HIV; HIV Infections; HIV-1; Heterosexuals; Human; Immunotherapy; In Vitro; Infection; Infusion procedures; Intervention; Macaca; Mannose; Mediating; Modeling; Monoclonal Antibodies; Mothers; National Institute of Allergy and Infectious Disease; Nicotiana; Passive Immunotherapy; Phase; Plants; Preclinical Testing; Production; Prophylactic treatment; Recombinants; Safety; Small Business Innovation Research Grant; System; Testing; Tobacco; Universities; Vertical Disease Transmission; Virus Diseases; Xylose; antibody-dependent cell cytotoxicity; base; cost effective; glycosylation; immunogenicity; in vivo; innovation; large scale production; monoclonal antibody production; neutralizing antibody; neutralizing monoclonal antibodies; passive prophylaxis; pre-clinical; prevent; public health relevance; response; simian human immunodeficiency virus; transmission process; vector

DESCRIPTION (provided by applicant): In the absence of specific intervention and with extended breast-feeding mother-to- child-transmission of HIV reaches a rate of ~35 % and infection of ~700,000 babies worldwide. Passive immunotherapy with a small number of broadly neutralizing monoclonal antibodies (MAbs) in SHIV challenged macaques bodes well for the ability of infusion of neutralizing MAb to prevent such transmission in humans. However the amount of MAb required would overwhelm current fermenter-based production systems and an alternate system for MAb production is a high priority. Due to recent innovations, transient plant (Nicotiana bentamiama) expression platforms now represent some of the most rapid, cost effective and productive in existence; capable of producing grams of recombinant MAbs in weeks. In the Phase I feasibility study, high mannose and complex glycoforms of 2G12, 2F5, 4E10 b12, m43 and m9 MAbs were transiently produced at 80-100 mg/kg leaves (except for the scFv m9) and each exhibited similar, and, in the case of b12, better neutralizing titers than their CHO-derived counterparts although differences were observed in antibody dependent cellular cytoxicity activity. In Phase II, high mannose, complex and 11,3-fucose/21,2-xylose-negative/low glycoforms of three new broad and potent MAbs (PG9, PG16, VRC01), in addition to b12 and 2G12 from Phase I, will be produced in a p19 enhanced plant expression system (200- 500mg/kg) and assessed for in vitro for both their neutralizing and F3-mediated antibody effector activity (ADCC and ADCVI). Six hundred mg of those forms with the best neutralizing activity will be produced for pharmacokinetics, immunogenicity and protection studies in macaques. Single MAbs and a cocktail of MAbs will be injected i.v. or s.c. weekly and vaginally challenged with a low dose of SHIV bi-weekly to more closely mimic doses encountered in human heterosexual exposure. These results will provide the preclinical data for transition into human trials. PUBLIC HEALTH RELEVANCE: With an ever increasing number of mother-to-baby-transmissions of the HIV virus in the developing world, the production of and immunotherapy with monoclonal antibodies that strongly neutralizing activity a high priority. However the facilities to manufacture such large amounts has not been available. In Phase I we showed that MAbs can be rapidly produced in a new transient plant expression systems in high levels and have similar (or better) neutralizing activity as the conventional CHO-derived forms. In Phase II we shall used an enhanced transient expression system to produce large amounts of new potent MAbs and assess their ability to protect macaques against SHIV virus infection.

描述（由申请人提供）：在没有具体干预和延长母乳喂养的情况下，艾滋病毒母婴传播率达到35%，全球约有70万婴儿感染。在SHIV攻击的猕猴中使用少量广泛中和的单克隆抗体（MAb）进行被动免疫治疗，预示着输注中和的MAb能够很好地预防SHIV在人类中的传播。然而，所需单克隆抗体的数量将超过当前基于发酵罐的生产系统，因此单克隆抗体生产的替代系统是一个高度优先考虑的问题。由于最近的创新，瞬态植物（烟叶）表达平台现在代表了一些最快速，成本效益和生产力的存在；能够在数周内产生数克重组单克隆抗体。在I期可行性研究中，2G12、2F5、4E10 b12、m43和m9单克隆抗体的高甘露糖和复合糖型在80-100 mg/kg的叶子中短暂产生（scFv m9除外），每种单克隆抗体都表现出相似的中和效价，并且在b12的情况下，比cho衍生的单克隆抗体有更好的中和效价，尽管在抗体依赖的细胞毒性活性上观察到差异。在II期，除了I期的b12和2G12外，还将在p19增强植物表达系统（200- 500mg/kg）中生产三种新的广谱高效单克隆抗体（PG9、PG16、VRC01）的高甘露糖、复合物和11,3-焦点/21,2-木糖阴性/低糖型单克隆抗体（PG9、PG16、VRC01），并在体外评估其中和和f3介导的抗体效应活性（ADCC和ADCVI）。这些具有最佳中和活性的形式将生产600毫克，用于在猕猴体内进行药代动力学、免疫原性和保护研究。每周一次静脉注射单抗和单抗鸡尾酒，每两周一次阴道注射低剂量的SHIV，以更接近于人类异性接触所遇到的剂量。这些结果将为转入人体试验提供临床前数据。