Biomaterials-Enhanced NK Cells for Improved Elimination of the HIV Reservoir

生物材料增强的 NK 细胞可改善 HIV 病毒库的消除

• 批准号: 10247828
• 负责人: Conrad Russell Young Cruz
• 金额: $ 48.57万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-03 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247828
• 关键词: AIDS/HIV problem; Activated Natural Killer Cell; Adoptive Transfer; Anatomy; Animals; Antibodies; Apoptosis; Autologous; Avidin; Biocompatible Materials; Biological Assay; Biomedical Engineering; Biotin; CD4 Positive T Lymphocytes; Cell Therapy; Cells; Chemistry; Clinical Trials; Coupled; Coupling; Encapsulated; Engineering; Ensure; Exposure to; FCGR3B gene; Formulation; Freeze Drying; Future; Glycolates; HIV; HIV Seropositivity; HIV therapy; HIV vaccine; Highly Active Antiretroviral Therapy; Human; Immune; Immune response; Immune system; Immunity; Immunodeficient Mouse; In Vitro; Individual; Infection; Interleukin-15; Interleukin-2; Kinetics; Link; Maleimides; Mediating; Morbidity - disease rate; NK Cell Activation; Natural Killer Cells; Patients; Penetration; Pharmaceutical Preparations; Phase; Phenotype; Proteins; Public Health; Regimen; Research; Role; Sampling; Scheme; Site; Source; Sulfhydryl Compounds; Surface; Testing; Therapeutic; Time; Tissues; Translations; Vaccines; Viral; Viral Cytopathogenic Effect; Viral reservoir; Virus; Virus Diseases; antibody-dependent cell cytotoxicity; arm; base; bryostatin; cell bank; comorbidity; cytotoxic; design; efficacy testing; engineered NK cell; exhaust; humanized mouse; improved; in vivo; insight; latent HIV reservoir; mortality; mouse model; nanoparticle; natural killer cell protein 44-kDa; neutralizing antibody; novel therapeutic intervention; novel therapeutics; prevent; prostratin; reconstitution; response; social; therapeutic development; vaccine trial; viral rebound

PROJECT SUMMARY Highly active antiretroviral therapy has reduced morbidity and mortality from HIV/AIDS but does not lead to a cure. The persistence of the virus within latent reservoirs even in well-treated individuals results in a lifelong commitment to these drug regimens. As a consequence, patients remain burdened by co-morbidities and exposed to the negative social issues that come with being HIV-positive. Therefore, there is an urgent need for the development of therapeutic strategies capable of eradicating virus from individuals, which would greatly improve the lives of people living with HIV/AIDS. In response to this need, we propose to combine the actions of latency reversing agents (LRAs), broadly neutralizing antibodies (bnAbs), and activated natural killer (NK) cells within a single therapeutic platform. More specifically, we propose to use bioengineering strategies to design an ensemble biohybrid therapeutic wherein LRAs and bnAbs are packaged within poly(lactic-co-glycolic acid) (PLGA) nanoparticle depots (nanodepots) and then attached on to the surface of NK cells. We anticipate that the co-localization of LRAs with NK cell activation and local bnAb presence will trigger a more effective and coordinated eradication of persistent HIV reservoirs. In the R21 phase of this project, we propose to engineer NK-nanodepots encapsulating LRAs and bnAbs as off-the-shelf biohybrids that retain the phenotype and function of the constituent NK cells and encapsulated LRAs and bnAbs. The realization of a functional ensemble biohybrid therapeutic that successfully coordinates the actions of LRAs, bnAbs, and NK cells will enable us to proceed to the R33 phase of the project where we will test the efficacy of the ensemble biohybrid therapeutic in eradicating the HIV reservoir in vitro and in a humanized mouse model. Successful completion of this phase of the project will result in a novel therapeutic platform for eradicating persistent HIV reservoirs and will open the way for the translation of our platform to the design and conduct of future clinical trials.

项目摘要 高度活跃的抗逆转录病毒疗法降低了HIV/AIDS的发病率和死亡率，但不会导致 治愈。该病毒在潜在储层中的持久性，即使在经过良好治疗的个体中也导致了一生 对这些药物方案的承诺。结果，患者仍然受到合并症的负担， 暴露于HIV阳性的负面社会问题。因此，迫切需要 能够从个人中消除病毒的治疗策略的发展，这将极大地 改善艾滋病毒/艾滋病的人们的生活。为了应对这种需求，我们建议将行动结合起来 潜伏期逆转剂（LRA），广泛中和抗体（BNAB）和活化的天然杀手（NK） 单个治疗平台内的细胞。更具体地说，我们建议使用生物工程策略来 设计一种合奏生物杂交治疗，其中LRA和BNAB被包装在Poly（乳酸 - 糖浆中） 酸）（PLGA）纳米颗粒仓（纳米植物），然后附着在NK细胞的表面上。我们期待 LRA与NK细胞激活和局部BNAB存在的共定位将触发更有效的 并协调根除持续的艾滋病毒水库。在该项目的R21阶段，我们建议 工程师NK-Nanodepots将LRA和BNAB封装为保留表型的现成生物杂种 成分NK细胞以及包封的LRA和BNAB的功能。实现功能 成功协调LRA，BNAB和NK细胞的作用的集合生物杂交治疗方法将 使我们能够进入项目的R33阶段，我们将测试集成生物杂交的功效 在体外和人性化的小鼠模型中消除HIV储层方面的治疗性。成功完成 该项目的这一阶段将导致一个新颖的治疗平台，用于消除持续的艾滋病毒水库和 将为将我们平台转换为未来临床试验的设计和行为开辟道路。