Liposomal Disintegrin: Novel and Effective Antitumor Agent Phase I

脂质体解整合素：新型有效的抗肿瘤剂 I 期

基本信息

批准号：
7272217
负责人：
FRANCIS S MARKLAND
金额：
$ 24.86万
依托单位：
MOLECULAR EXPRESS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-04 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7272217
关键词：
Achievement Address Affinity Angiogenesis Inhibitors Animals Biodistribution Biological Biological Assay Breast Cancer Cell Breast Cancer Model Breast Carcinoma Canis familiaris Cell Line Characteristics Clinical Clinical Data Clinical Trials Collaborations Collection Combined Modality Therapy Commercial Sources Condition Cyclic GMP Dependence Development Diagnostic Disease Disintegrins Dose Drug Formulations Drug Kinetics Encapsulated Evaluation Human Image Immune response In Vitro Integrins Intravenous Laboratories Lead Liposomes Los Angeles Luciferases Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Methods Modality Modeling Molecular Monitor Mus Normal tissue morphology Nude Mice Organ Pathway interactions Phase Phase II Clinical Trials Preparation Principal Investigator Procedures Process Production Property Proteins Radiolabeled Recombinants Relapse Reliance Rodent Rodent Model Safety Small Animal Imaging Systems Small Business Technology Transfer Research Snake Venoms Sonication Survival Rate System Techniques Technology Testing Toxicology Translations Tumor Burden United States Food and Drug Administration Vascular Endothelial Cell Venoms Woman Xenograft procedure angiogenesis antiangiogenesis therapy anticancer activity antitumor agent base body system cancer cell chemotherapeutic agent chemotherapy clinical application clinically relevant contortrostatin in vivo intravenous administration malignant breast neoplasm mouse model novel pre-clinical preclinical study radiotracer research clinical testing scale up targeted delivery tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Despite significant improvements in the management of breast cancer, the 5-year survival rate for advanced disease remains dismal, and a majority of women will eventually relapse and die from their disease. It is imperative, therefore, that new treatment modalities be developed for this devastating disease. This Phase I STTR application proposes studies that will facilitate the clinical translation of a novel antiangiogenic agent with potent antitumor activity against breast cancer. To address a major obstacle to the clinical translation of this technology, the reliance on snake venom to produce the protein, we have recently produced a recombinant form of the protein, which we call vicrostatin (VN); VN is as active as the native venom protein, contortrostatin (CN), in vitro and in vivo. Our aims will focus on the optimization of production of VN and preparation of a liposomal encapsulated form of VN (LVN) suitable for large scale production and clinical application. We will demonstrate efficacy of LVN alone or in combination with chemotherapy in a human mammary cancer mouse model. The mammary carcinoma cells will be stably-transfected with luciferase and we will use the Xenogen small animal imaging system to monitor tumor burden and metastatic spread during therapy. Additionally, we will carry out preliminary toxicological analysis in a rodent model to demonstrate safety of LVN. We hypothesize that: (i) VN can be made at acceptable production levels in a bacterial cell line suitable for cGMP production; (ii) LVN can be prepared by a homogenization method appropriate for mass production; (iii) LVN so produced will have biological efficacy identical to native CN (LCN) following intravenous (IV) delivery in a human breast cancer model, and (iv) LVN will have toxicologic properties suitable for clinical translation. We have established the following Specific Aims and milestones for successful completion of this application: Specific Aim #1 - Prepare VN in sufficient quantity for clinical application (Milestone 1, months 0-6), and prepare a liposomal formulation of VN (LVN) with appropriate stability characteristics and in amounts suitable for clinical application (Milestone 2, months 0-12). Specific Aim #2 - Demonstrate biological efficacy of LVN alone and in combination with a currently used chemotherapeutic agent in a mouse model of human breast cancer (Milestone 3, months 9-12). Specific Aim #3 - Examine toxicologic properties of LVN in rodents using single dose and dose escalation studies (Milestone 4, months 6-12). In Phase II of this STTR we will continue preclinical studies, which will include further examining toxicologic properties to determine safety of LVN, characterizing its pharmacokinetic and organ distribution profile, and further examining animal survival and efficacy of LVN alone and in combination with chemotherapeutic agents.

描述（由申请人提供）：尽管乳腺癌的治疗取得了显着进步，但晚期疾病的 5 年生存率仍然很低，大多数女性最终会复发并死于疾病。因此，必须针对这种毁灭性疾病开发新的治疗方法。这一 I 期 STTR 申请提出的研究将有助于一种具有有效抗乳腺癌活性的新型抗血管生成剂的临床转化。为了解决该技术临床转化的一个主要障碍，即依赖蛇毒来生产蛋白质，我们最近生产了该蛋白质的重组形式，我们将其称为 Vicrostatin (VN)；在体外和体内，VN 与天然毒液蛋白 Contortrostatin (CN) 一样活跃。我们的目标将集中于优化 VN 的生产和制备适合大规模生产和临床应用的脂质体封装形式的 VN (LVN)。我们将在人乳腺癌小鼠模型中证明单独使用 LVN 或与化疗联合使用的疗效。乳腺癌细胞将被荧光素酶稳定转染，我们将使用 Xenogen 小动物成像系统来监测治疗过程中的肿瘤负荷和转移扩散。此外，我们将在啮齿动物模型中进行初步毒理学分析，以证明 LVN 的安全性。我们假设： (i) VN 可以在适合 cGMP 生产的细菌细胞系中以可接受的生产水平生产； (ii) LVN可以通过适合大规模生产的均质方法来制备； (iii)如此产生的LVN在人类乳腺癌模型中静脉内(IV)递送后将具有与天然CN (LCN)相同的生物功效，并且(iv)LVN将具有适合临床转化的毒理学特性。为了成功完成本申请，我们制定了以下具体目标和里程碑：具体目标 #1 - 制备足够数量的 VN 用于临床应用（里程碑 1，第 0-6 个月），并制备 VN (LVN) 的脂质体制剂适当的稳定性特征和适合临床应用的量（里程碑 2，第 0-12 个月）。具体目标#2 - 在人类乳腺癌小鼠模型中证明 LVN 单独使用以及与当前使用的化疗药物联合使用的生物学功效（里程碑 3，第 9-12 个月）。具体目标#3 - 使用单剂量和剂量递增研究检查 LVN 在啮齿类动物中的毒理学特性（里程碑 4，第 6-12 个月）。在该 STTR 的第二阶段，我们将继续进行临床前研究，其中包括进一步检查毒理学特性以确定 LVN 的安全性，表征其药代动力学和器官分布特征，并进一步检查动物存活率以及 LVN 单独使用以及与化疗药物联合使用的疗效。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Development of a chimeric recombinant disintegrin as a cost-effective anti-cancer agent with promising translational potential.

开发嵌合重组解整合素作为具有成本效益的抗癌剂，具有良好的转化潜力。

DOI：
10.1016/j.toxicon.2011.02.020
发表时间：
2012
期刊：
Toxicon : official journal of the International Society on Toxinology
影响因子：
0
作者：
Minea,Radu;Helchowski,Corey;Rubino,Barbara;Brodmann,Kyle;Swenson,Stephen;MarklandJr,Francis
通讯作者：
MarklandJr,Francis

Vicrostatin - an anti-invasive multi-integrin targeting chimeric disintegrin with tumor anti-angiogenic and pro-apoptotic activities.