Vault-CCL21 Nanocapsule for Lung Cancer

Vault-CCL21 肺癌纳米胶囊

• 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
• 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

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，每年导致的死亡人数超过乳腺癌、前列腺癌、结肠癌、肝癌、肾癌和皮肤癌的总和。从经济角度看，2000年美国因肺癌死亡而损失的生命价值超过2 400亿美元，估计到2020年将增加到4 330亿美元以上。由于肺癌带来了巨大的医疗保健和经济负担，改善患者预后的新治疗策略将产生非常重大的影响。切萨皮克PERL公司（C-PERL）和加州大学洛杉矶分校（伦纳德·罗马实验室）的合作者已经确定并表征了一种称为拱顶的独特纳米颗粒结构，这种结构高度稳定，在所有高等真核生物中普遍存在。拱顶壳完全由称为主拱顶蛋白（MVP）的单一蛋白质的多个拷贝组成。MVP可以很容易地设计成允许附着其他药物，包括有前途的癌症治疗药物，如趋化因子CCL21。CCL21是一种淋巴样趋化因子，是成熟树突状细胞（dc）、幼稚T细胞和记忆T细胞的趋化因子。肺癌动物模型的临床前研究表明，肿瘤内给药CCL21基因修饰的树突状细胞导致肿瘤根除。在Chesapeake PERL， Inc. （C-PERL）使用PERLXpress蛋白表达平台，将vault表达到非常高的水平。这个独特而强大的系统在整个昆虫中使用重组杆状病毒在自动化平台上表达，以经济有效地产生高蛋白质产量。MVP和CCL21（融合到称为INT的拱顶包装肽）很容易表达并正确组装形成CCL21-拱顶纳米颗粒。该颗粒已被证明在几天内缓慢释放其趋化因子负载。数百毫克的高纯度ccl21 - vault可以很容易地制备并稳定地储存在冻干状态下，用于未来的治疗评估和测试。该II期申请的持续开发将支持高级开发、临床前安全性评估，包括毒理学、疗效和配方，从而导致IND准备，以支持未来的GCMP产品生产。将在临床前动物模型中测试从杆状病毒感染的整只昆虫中获得的重组ccl21 -vault在瘤内的破坏作用。CCL21-Vault旨在避免自体DC制备，最大限度地减少批次间的可变性，并允许可比性和标准化，从而使该颗粒可以用作晚期非小细胞肺癌（NSCLC）的现成试剂。