Translational Development of a Targeted and Stroma-penetrating Nanoparticle Drug for Pancreatic Cancer Therapy

用于胰腺癌治疗的靶向基质穿透纳米颗粒药物的转化开发

基本信息

批准号：
10705200
负责人：
Lily Yang
金额：
$ 84.19万
依托单位：
MIGRA-THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-19 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705200
关键词：
Acceleration Adverse event Award Biochemical Biodistribution Biological Markers Biology Biophysics Cancer Biology Cancer Patient Catalytic Domain Clinical Clinical Trials Development Dose Drug Delivery Systems Drug Kinetics Drug Targeting Drug resistance Duct (organ) structure Ductal Carcinoma Endotoxins Engineering Evaluation Future Gene Expression Gene Expression Profile Generations Genetic Goals Good Manufacturing Process Histologic Human Hyaluronic Acid In Vitro Industrialization Investigational Drugs Investigational New Drug Application Joints Lead Ligands MMP14 gene Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of pancreas Methods Monitor Mus Names Nanotechnology Outcome Pathologic Patients Penetration Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Procedures Production Property Protocols documentation Quality Control Recombinants Recommendation Research Research Project Grants Resistance Rodent Schedule Small Business Innovation Research Grant Structure System Systemic Therapy Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Translation Process Translational Research Treatment Efficacy Tumor Biology Unresectable Urokinase Plasminogen Activator Receptor advanced pancreatic cancer cancer cell cancer survival cancer therapy cancer type chemotherapy clinical translation density design drug development first-in-human good laboratory practice improved in vivo innovation irinotecan large scale production lead candidate migration mouse model nanodrug nanoformulation nanoparticle nanoparticle drug nanotherapeutic neoplastic cell novel novel strategies pancreatic PDX models pancreatic cancer cells pancreatic cancer patients patient derived xenograft model phase 1 study phase 2 study pre-clinical preclinical evaluation preclinical study programs receptor binding standard care systemic toxicity targeted delivery targeted therapy trials targeted treatment therapy resistant treatment response tumor tumor growth tumor xenograft

项目摘要

Project Summary Low efficiency in drug delivery and aggressive tumor biology are the major causes of resistance to therapy in pancreatic cancer. The presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cells. We have developed a targeted stroma penetrating hyaluronic acid nanoparticle carrying SN38, an active metabolite of irinotecan. Results of preclinical studies demonstrated significantly enhanced nanoparticle/drug delivery into ductal carcinoma cells to produce strong therapeutic effects in drug resistant pancreatic cancer patient derived xenograft (PDX) models. Importantly, the stroma-penetrating nanodrug has unique properties to modulate tumor stroma that allows the nanodrug to pass through the stromal barrier but retain a protective stromal structure. For clinical translation of this novel nanodrug, our SBIR phase I study focused on the re-engineering a tagless stroma penetrating ligand, ATFmmp14 (R2), that consists of a urokinase plasminogen activator receptor (uPAR) binding domain and a catalytic domain of MMP14, following the recommendation of the FDA Pre-IND team. We have developed the tagless ATFmmp14(R2) with the capacity of large scale production in an endotoxin-free bacterial expressing system. We also demonstrated that ATFmmp14 (R2) conjugated HANP/SN38 has comparable tumor targeting ability and therapeutic efficacy to the first generation of His-tagged ATFmmp14(R1)-HANP/SN38 in pancreatic cancer PDX models. The proposed phase II project aims to accelerate the translational process by conducting important Investigational New Drug (IND)-enabling preclinical studies. In Aim 1, we will optimize and finalize nanoformulation of MIGRA-NP01 for large-scale production under GLP/GMP conditions. We will then characterize in vitro and in vivo properties of MIGRA-NP01, including biophysical and biochemical parameters in vitro, and systemic toxicity, pharmacokinetics/pharmacodynamics, biodistribution, and clearance in normal and tumor bearing mice (Aim 2). During those studies, we will establish the Stand Operating Protocols (SOPs) and metrics for quality control (QC) of MIGRA-NP01 for drug development (Aim 2). Next, we will determine an optimized dose and schedule for MIGRA-NP01 in pancreatic PDX models with different pathological and genetic features, and sensitivity to chemotherapy (Aim 3). Finally, therapeutic responses of pancreatic PDX tumors will be correlated with the gene expression signatures to identify the potential predicative biomarkers for MIGRA- NP01 treatment (Aim 3). The outcomes of this translational research project include: 1) obtaining the final optimized nanoformulation of MIGRA-NP01 with established SOPs for the GLP/GMP production of MIGRA-NP01 and producing two lots of the GLP grades of MIGRA-NP01; and 2) determining systemic toxicity, biodistribution, therapeutic dose/schedule of the MIGRA-NP01 in normal mice and pancreatic PDX tumor bearing mice. Results of the SBIR phase II project should have a great impact on the future submission of an IND application for the FDA approval of a phase 1 clinical trial in advanced pancreatic cancer patients.

项目摘要药物输送和侵略性肿瘤生物学的效率低是抗药性治疗的主要原因胰腺癌。致密纤维肿瘤基质的存在会产生药物输送屏障并促进胰腺癌细胞中的侵略性生物学和耐药性。我们已经开发了靶向基质穿透的透明质酸纳米颗粒，带有SN38，这是一种活性的伊立替康代谢产物。临床前的结果研究表明，纳米颗粒/药物递送到导管癌细胞中显着增强以产生在耐药性胰腺癌患者衍生的异种移植（PDX）模型中的强烈治疗作用。重要的是，基质 - 穿透纳米果具有独特的特性来调节肿瘤基质，从而可以纳米果可以通过基质屏障，但保留了保护性基质结构。用于临床翻译这款新型纳米果，我们的SBIR I期研究重点是重新设计无标记的基质穿透配体， ATFMMP14（R2），由尿激酶纤溶酶原激活剂受体（UPAR）结合结构域和A组成遵循FDA预印度团队的建议，MMP14的催化域。我们已经开发了无标记的ATFMMP14（R2），具有无内毒素的细菌表达的大规模产生的能力系统。我们还证明了ATFMMP14（R2）共轭HANP/SN38具有可比的肿瘤靶向胰腺中第一代ATFMMP14（R1）-HANP/SN38的能力和治疗功效癌症PDX模型。拟议的第二阶段项目旨在通过进行转化过程来加速转化过程重要的研究新药（IND） - 临床前研究。在AIM 1中，我们将优化和最终确定 GLP/GMP条件下的大规模生产的Migra-NP01的纳米制剂。然后我们会表征体外和体内特性的迁移型NP01，包括生物物理和生化参数体外和全身毒性，药代动力学/药效学，生物分布和正常清除率和肿瘤轴承小鼠（AIM 2）。在这些研究中，我们将建立立场操作方案（SOP）和用于药物开发的偏移NP01质量控制的指标（QC）（AIM 2）。接下来，我们将确定在具有不同病理和遗传的胰腺PDX模型中，迁移NP01的优化剂量和时间表特征和对化学疗法的敏感性（AIM 3）。最后，胰腺PDX肿瘤的治疗反应将与基因表达特征相关 NP01治疗（AIM 3）。该翻译研究项目的结果包括：1）获得最终用已建立的SOP的偏移/GMP生产的Migra-NP01的SOP对Migra-NP01进行了优化的纳米制剂并产生两个迁移NP01的GLP等级； 2）确定全身毒性，生物分布，正常小鼠和胰腺PDX肿瘤轴承小鼠的迁移NP01的治疗剂量/时间表。结果 SBIR第二阶段项目应对未来提交IND申请的提交产生重大影响在晚期胰腺癌患者中，FDA批准了1期临床试验。