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

• 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
• 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

 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（由申请方提供）：针对HIV-1的高效广谱中和抗体（bnAb）的鉴定，以及被动给药后预防SHIV感染的成功，增加了采用免疫策略预防和治疗HIV-1感染的可能性。然而，虽然广泛和有效的中和活性是一个必要的先决条件，体内性质，如良好的循环稳定性和无免疫原性是同样重要的开发人类治疗。在先前的I期和II期研究中，第一代bnAb和最近的有效高度突变的bnAb 10-1074、NIH 45 - 46 G54 W、10 E8、PGT 121、PGT 128、PGT 145、PGT 135、PG 9、PG 16、VRC 01和b12已经由农杆菌属产生-本氏烟草介导的瞬时转染，并评估中和活性和在猕猴中施用后。迄今为止的结果表明，（i）VL结构域内的N-聚糖损害植物来源的bnAb的血浆稳定性，和（ii）虽然PGT 121和b12在多次注射后在猕猴中不表现出免疫原性，但令人惊讶的是，VRC 01、10-1074和NIH 45 - 46 G54 W在第二次注射后引发高滴度抗独特型抗体，其特异性结合所施用的bnAb或近亲，并且在中和试验中抑制bnAb（iii）在攻击前和攻击后静脉内或皮下递送的两种混合物（VRC 01、10-1074、b12和10 E8）以及单一PGT 121都可以保护成年猕猴。这些结果构成了当前IIB期提案的双重方法的基础，该方法通过（i）在猕猴中进行针对SHIV攻击的围产期保护研究（更接近模拟母婴传播（MTCT）），（ii）延长其循环滞留时间和（iii）开发有效的bnAb混合物。以鉴定这些高度突变的bnAb上的T细胞表位，这些表位有助于它们的免疫原性，并且可能潜在地损害它们用于HIV-1的预防和治疗的价值。此外，在当前研究中快速生产15种广泛中和的植物来源的HIV mAb突出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。