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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：
10034134
负责人：
Jing Wen
金额：
$ 35.69万
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/10034134
关键词：
Acetylcholine Address Antibodies Antibody Therapy B-Cell Lymphomas BLR1 gene Binding Biodistribution Biological Biological Factors Biomedical Engineering Blood - brain barrier anatomy Blood Circulation Brain CXCL13 gene Cancer Patient Cell surface Cells Central Nervous System Lymphoma Central Nervous System Neoplasms Cerebrospinal Fluid Chemical Engineering Choline Clinical Crosslinker DNA Data Discipline Disease Drug Kinetics Encapsulated Failure Formulation Gene Delivery Gene Proteins 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 Neuraxis Non-Hodgkin&apos s Lymphoma Nonmetastatic 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 base 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%的癌症会扩散到中枢神经系统（CNS）。治疗