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Targeting delivery of mAbs to CNS metastases

将单克隆抗体靶向递送至中枢神经系统转移灶

基本信息

批准号：
10622457
负责人：
Jing Wen
金额：
$ 34.97万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10622457
关键词：
Acetylcholine Address Antibodies Antibody Therapy Authorization documentation B-Cell Lymphomas BLR1 gene Binding Biodistribution Biological Biological Factors Biomedical Engineering Blood - brain barrier anatomy Brain CXCL13 gene Cancer Patient Cell surface Cells Central Nervous System Central Nervous System Lymphoma Central Nervous System Neoplasms Cerebrospinal Fluid Chemical Engineering Choline Circulation Clinical Collaborations Crosslinker DNA Data Discipline Disease Drug Kinetics Encapsulated Environment Failure Formulation Gene Delivery Genes Immunotherapy In Situ Individual Intravenous Intraventricular Ligands Lymphoma Malignant Neoplasms Malignant neoplasm of central nervous system Mediating Metastatic Neoplasm to the Central Nervous System Metastatic malignant neoplasm to brain Modeling Molecular Target Monoclonal Antibodies Monoclonal Antibody Therapy Mus Nanotechnology Nature Neoplasm Metastasis Non-Hodgkin&apos s Lymphoma Oncology Pharmaceutical Preparations Polymers Positioning Attribute Property Proteins Publishing RNA Reagent Recording of previous events Relapse Reporting Research Personnel Risk Rodent Route Surface Systemic disease Technology Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Thinness Time Trastuzumab Treatment Efficacy Tumor Burden Xenograft Model Xenograft procedure analog anti-CD20 authority blood-brain barrier crossing blood-brain barrier penetration cancer therapy chemical property chemical substitution choline analog controlled release design effective therapy experience improved ineffective therapies innovation macromolecule malignant breast neoplasm materials science monomer nanocapsule nanoencapsulated nanotechnology platform neoplastic cell neuropathology neurotoxicity new technology nonhuman primate novel novel strategies polymerization receptor rituximab success targeted delivery therapeutic evaluation therapeutic protein tumor tumor growth virtual

项目摘要

It is estimated that around 15% to 40% of cancers spread to the central nervous system (CNS). The treatment of cancers with brain metastases, however, has been limited by the inefficient deliver of therapeutics to the CNS. We propose herein a novel strategy, which enables effective delivery of monoclonal antibodies (mAbs), a class of highly specific and potent protein therapeutics, to the CNS, for the treatment of cancers with brain metastases. This strategy is based on a nano-encapsulating technology, where mAbs molecules are encapsulated within nanocapsules of which the surface contains abundant choline and acetylcholine analogues. Such nanocapsules can be effectively transported across the BBB and deliver the mAbs to the CNS upon systemic administration. Furthermore, the nanocapsules can be targeted by conjugation with ligands which recognize cell surface markers on tumor cells. We recently published effective delivery into the CNS of rituximab (anti-CD20) mAbs through intravenous route using the nanocapsule technology. The nanocapsules were targeted to CXCR5 on the surface of the tumor cells via conjugation with CXCL13. This therapeutic approach significantly reduced the tumor burden in the brains of mice xenografted with B-cell lymphomas in comparison with direct native mAbs. In this proposal, we will further improve the therapeutic efficacy by optimizing the design of the rituximab nanocapsules based on understanding of the mechanisms of BBB passage and tumor clearance. Success of this project could potentially enable effective delivery of many other therapeutic mAbs to the CNS, opening a new avenue for treatments of cancers with CNS metastases.

据估计，大约15%到40%的癌症扩散到中枢神经系统(CNS)。治疗方法然而，由于向中枢神经系统提供治疗药物的效率低下，对脑转移癌症的研究一直受到限制。我们在这里提出了一种新的策略，它能够有效地传递一类单抗(MAbs) 将高度特异和有效的蛋白质疗法应用于中枢神经系统，用于治疗脑转移的癌症。这一策略是基于纳米封装技术，其中mAbs分子被封装在表面含有丰富胆碱和乙酰胆碱类似物的纳米胶囊。这样的纳米胶囊可以有效地跨血脑屏障运输，并在系统给药后将单抗递送到中枢神经系统。此外，纳米胶囊可以通过与识别细胞表面标记的配体的结合而成为靶点在肿瘤细胞上。我们最近发表了通过以下途径将利妥昔单抗(抗CD20)有效地传递到中枢神经系统的研究报告使用纳米胶囊技术的静脉注射。纳米胶囊针对表面的CXCR5 通过与CXCL13的偶联，对肿瘤细胞进行鉴定。这种治疗方法显著减轻了肿瘤负担。在移植了B细胞淋巴瘤的小鼠的大脑中，与直接的天然单抗进行了比较。在这份提案中，我们将通过优化利妥昔单抗纳米胶囊的设计来进一步提高治疗效果了解血脑屏障通路和肿瘤清除的机制。这个项目的成功可能会使许多其他治疗性单抗能够有效地输送到中枢神经系统，为治疗有中枢神经系统转移的癌症。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Real-Time Quantification of Cell Internalization Kinetics by Bioluminescent Probes.

通过生物发光探针实时定量细胞内化动力学。

DOI：
10.1007/978-1-0716-2473-9_7
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Castillo,Roxanne;Wu,Di;Cao,Zheng;Yan,Ran;Fajardo,Kalea;Ren,Jie;Lu,Yunfeng;Wen,Jing
通讯作者：
Wen,Jing

Targeted Nanocarrier Delivery of RNA Therapeutics to Control HIV Infection.

DOI：
10.3390/pharmaceutics14071352
发表时间：
2022-06-26
期刊：
PHARMACEUTICS
影响因子：
5.4
作者：
Agbosu, Esinam E.;Ledger, Scott;Kelleher, Anthony D.;Wen, Jing;Ahlenstiel, Chantelle L.
通讯作者：
Ahlenstiel, Chantelle L.

Reactive oxygen species associated immunoregulation post influenza virus infection.