Nanodelivery platform for antibody drugs targeting NHL

针对 NHL 的抗体药物纳米递送平台

基本信息

批准号：
10443535
负责人：
Masakazu Kamata
金额：
$ 45.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2018-07-18 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443535
关键词：
Adsorption Adverse event Affinity Antibodies Antibody Therapy Biodistribution Blood - brain barrier anatomy Blood Circulation Blood Circulation Time Blood-Retinal Barrier Brain Burkitt Lymphoma Bypass Cancer Burden Cell surface Cells Charge Chemistry Clinical Communicable Diseases Contact Lenses Coronary Custom DNA Drug Targeting Drug usage Effectiveness Encapsulated Eye Goals Human Immune response Immunologic Surveillance Individual Inflammation Intraventricular Location Lymphoma Maintenance Malignant Neoplasms Malignant neoplasm of brain Medical Device Modeling Molecular Target Monoclonal Antibodies Mus Nano delivery Nanotechnology Neoplasm Metastasis Neuraxis Nivolumab Non-Hodgkin&apos s Lymphoma Nucleic Acids Patients Penetration Pharmaceutical Preparations Phosphorylcholine Polymers Property Proteins Public Health RNA Resistance Retina Retinal Detachment Ricin Safety Signal Transduction Stents Study Section Surface Testing Therapeutic Monoclonal Antibodies Therapeutic antibodies Thinness Time Tissues Toxin Trastuzumab United States Food and Drug Administration Xenograft procedure anti-cancer base cancer cell cancer immunotherapy cancer therapy cancer type clinically relevant extracellular humanized mouse immunogenicity improved in vivo macromolecule monomer mortality mouse model nanocapsule nanoencapsulated neurotoxicity novel strategies purge response rituximab therapeutically effective

项目摘要

PROJECT SUMMARY Therapeutic monoclonal antibodies (mAbs), such as rituximab, have produced significant improvement in the mortality rates of patients with non-Hodgkin lymphoma (NHL). However, fundamental issues with antibody therapy such as poor tissue penetration of antibodies, non-specific antibody delivery, escape from antibody recognition, and eliciting of an immune response against antibodies, remain unsolved. We have developed a nanodelivery platform for macromolecules whereby an individual “cargo” is encapsulated within a thin polymer shell, termed a “nanocapsule”. Our platform is highly adaptable, allowing us to customize various properties, including cell surface affinity, cargo immunogenicity, cargo release rates, in vivo circulation times, and biodistribution, by altering the surface chemistry of the nanocapsules. Our nanocapsules are inert, highly stable, and resistant to protein adsorption, which are properties necessary for increased blood circulation times and elimination of cargo immunogenicity. Importantly, our nanocapsules do not enter into cells due to their neutral surface charge, but can still efficiently enter the central nervous system (CNS) and reduce cancer burden in the brain and eyes of human Burkitt lymphoma xenograft mice; this could be because the retina is part of the CNS. These indicate that they are ideal carrier vehicles for extracellular delivery of therapeutic mAbs to locations such as the brain and eyes, where penetration of antibodies is extremely poor. The ultimate goal of the proposed studies is to establish a clinically relevant in vivo delivery platform for therapeutic mAb drugs, thus enabling efficient elimination of cancers, especially those that have metastasized into the CNS or eyes.

项目摘要治疗性单克隆抗体（MAB），例如利妥昔单抗，已显着改善非霍奇金淋巴瘤（NHL）患者的死亡率。但是，抗体的基本问题诸如抗体的组织渗透不良，非特异性抗体递送，从抗体中逃脱的治疗识别并引起针对抗体的免疫反应，尚未解决。我们已经开发了大分子的纳米传递平台，从而将单个“货物”封装在薄聚合物中壳，称为“纳米胶囊”。我们的平台具有高度适应性，使我们能够自定义各种属性，包括细胞表面亲和力，货物免疫原性，货物释放速率，体内循环时间和生物分布，通过改变纳米胶囊的表面化学。我们的纳米胶囊是惰性的，高度稳定的，对蛋白质吸附具有抗性，这是增加血液循环时间和消除货物免疫原性。重要的是，我们的纳米胶囊由于中性而不会进入细胞表面电荷，但仍然可以有效地进入中枢神经系统（CNS），并减少癌症的癌症人伯基特淋巴瘤的大脑和眼睛的脑和眼睛；这可能是因为视网膜是中枢神经系统的一部分。这些表明它们是理想的载体车辆，用于细胞外的治疗单元单元于这样的位置作为大脑和眼睛，抗体的渗透非常差。提议的最终目标研究是为了建立一个与治疗性mAb药物的临床相关的体内递送平台，从而使有效消除癌症，尤其是那些转移到中枢神经系统或眼睛的癌症。