Vault-CCL21 Nanocapsule for Lung Cancer

Vault-CCL21 肺癌纳米胶囊

基本信息

批准号：
9321253
负责人：
LEONARD H ROME
金额：
$ 16.88万
依托单位：
PROTEIN SCIENCES CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-17 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321253
关键词：
Address Adenovirus Vector Advanced Development Animal Model Animals Autologous Dendritic Cells Baculoviruses Biological Assay Breast Bronchogenic Carcinoma CCL21 gene Cancer Etiology Cause of Death Cells Cessation of life Chemotactic Factors Clinical Research Clinical Treatment Colon Carcinoma Dendritic Cells Development Dose Drug Targeting Economic Burden Economics Engineering Eukaryota Evaluation Formulation Freeze Drying Funding Future Gene-Modified Genes Goals Guidelines Healthcare Human Infection Injection of therapeutic agent Insecta Laboratories Lead Lewis Lung Carcinoma Lung Lymphoid Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of lung Methods Mus Non-Small-Cell Lung Carcinoma Outcome Patient-Focused Outcomes Peptides Phase Phase I Clinical Trials Preparation Principal Investigator Process Property Prostate Proteins Reagent Recombinants Recovery Renal carcinoma Research Rome Safety Skin Cancer Small Business Innovation Research Grant Stabilizing Agents Standardization Structural Genes Structure Study models System T memory cell Technology Testing Therapeutic Time Tissues Toxic effect Toxicology United States Value of Life animal efficacy antitumor agent base care burden cell preparation chemokine common treatment cost disability effective therapy evaluation/testing improved innovation major vault protein milligram nanocapsule nanoparticle novel novel therapeutics oral infection particle phase 1 study pre-clinical preclinical study protein expression public health relevance research clinical testing response safety study stability testing therapeutic evaluation tumor tumor eradication tumor growth vector

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death in the United States and is responsible for more deaths each year than breast, prostate, colon, hepatic, renal and skin cancers combined. Viewed in economic terms, in the United States, the value of life lost from lung cancer deaths in the year 2000 was more than $240 billion, which is estimated to rise to more than $433 billion in 2020. Because of the immense health care and economic burden imposed by lung cancer, new therapy strategies that improve patient outcomes will lead to very a significant impact. Collaborators at Chesapeake PERL, Inc. (C-PERL) and UCLA (Laboratory of Leonard Rome) have identified and characterized a unique nanoparticle structure called a vault that is highly stable, and found ubiquitously in all higher eukaryotes. The vault shell is entirely composed of multiple copies of a single protein called Major Vault Protein (MVP). MVP can be readily engineered to permit attachment of other agents, including promising cancer therapeutics like the chemokine CCL21. CCL21 is a lymphoid chemokine that is chemoattractant for mature dendritic cells (DCs), and naive and memory T cells. Preclinical studies in a lung cancer animal model have demonstrated that intratumoral administration of CCL21 gene-modified dendritic cells led to tumor eradication. Vaults have been expressed at Chesapeake PERL, Inc. (C-PERL) to very high levels using the PERLXpress protein expression platform. The unique and powerful system uses recombinant baculovirus expression in whole insects in an automated platform to generate high protein yields cost effectively. MVP and CCL21 (fused to a vault packaging peptide called INT) are readily expressed and correctly assembled to form CCL21-Vault nanoparticles. The particle has been shown to slowly release its chemokine payload over several days. Hundreds of milligrams of highly purified CCL21-Vaults can be readily prepared and stably stored in a lyophilized state for future therapeutic evaluation and testing. Continued development proposed in this Phase II application will support advanced development, pre- clinical safety evaluation including toxicology, efficacy, and formulation, leading to IND preparation to support future GCMP product manufacture. Intratumoral administration of recombinant CCL21-vaults derived from baculovirus infection of whole insects will be tested in a preclinical animal model for destruction of tumors. The CCL21-Vault is proposed to circumvent autologous DC preparation, minimize batch to batch variability and allow for comparability and standardization so that the particle can be used as an off-the-shelf reagent for advanced non-small cell lung cancer (NSCLC).

描述（由申请人提供）：肺癌是美国癌症死亡的主要原因，每年造成的死亡人数比乳房，前列腺，结肠，肝，肾脏，肾脏和皮肤癌的死亡人数更多。从经济角度来看，在美国，2000年因肺癌死亡而丧生的生命价值超过2400亿美元，估计在2020年将增长到超过4330亿美元。由于肺癌所施加的巨大医疗保健和经济负担，新的治疗策略会带来很大的影响。 Chesapeake Perl，Inc。（C-Perl）和UCLA（Leonard Rome的实验室）的合作者已经确定并表征了一种独特的纳米颗粒结构，称为“拱顶”，该结构高度稳定，在所有上等的真核生物中都无处不在。金库外壳完全由称为主要穹顶蛋白（MVP）的单个蛋白质的多个副本组成。可以轻松地设计MVP以允许其他药物的附着，包括有希望的癌症治疗剂，例如趋化因子CCL21。 CCL21是一种淋巴趋化因子，是成熟的树突状细胞（DC）的趋化因子，以及天真的和记忆T细胞。肺癌动物模型中的临床前研究表明，CCL21基因修饰的树突状细胞的肿瘤内给药会导致消除肿瘤。使用Perlxpress蛋白表达平台，在Chesapeake Perl，Inc。（C-Perl）上表达了金库。独特而强大的系统在自动化平台的全昆虫中使用重组杆状病毒的表达，从而产生高蛋白质可有效地产生。 MVP和CCL21（融合到称为INT的金库包装肽）很容易表达并正确组装以形成CCL21-VAULT纳米颗粒。已显示该粒子在几天内缓慢释放其趋化因子有效载荷。数百毫克高度纯化的CCL21资库可以容易制备并稳定地存储在冻干状态下，以进行未来的治疗评估和测试。在此II阶段应用中提出的持续开发将支持高级开发，临床安全评估，包括毒理学，功效和配方，从而为支持未来的GCMP产品制造提供IND准备。将在临床前动物模型中测试源自整个昆虫的杆状病毒感染的重组CCL21-资的肿瘤内给药，以破坏肿瘤。提出了CCL21-vault来规避自体DC制备，最大程度地减少批次变异性并允许可比性和标准化，以便该粒子可以用作晚期非小细胞肺癌（NSCLC）的现成试剂。