Development of a protein drug for pancreatic cancer treatment

开发治疗胰腺癌的蛋白质药物

基本信息

批准号：
9765276
负责人：
Zhi-Ren Liu
金额：
$ 99.98万
依托单位：
PRODA BIOTECH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-26 至 2021-03-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765276
关键词：
Antibodies Apoptosis Binding Sites Biological Biotechnology Blood Vessels CASP8 gene Cancer Cell Growth Cancer Model Cell Survival Cells Chemistry Clinical Clinical Research Clinical Trials Collagen Consult Cytoplasmic Tail Data Desmoplastic Development Diagnosis Disease Drug Delivery Systems Drug Kinetics Drug effect disorder Drug resistance Effectiveness Endothelial Cells Extracellular Matrix Foundations Future Genetically Engineered Mouse Grant Immune Immunotherapy Induction of Apoptosis Infiltration Integrins Legal patent Licensing Ligand Binding Malignant Neoplasms Malignant neoplasm of pancreas Marketing Medical Methods Mission Modeling Monkeys Neoplasm Metastasis Nude Mice Pancreas Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Phase Property Protein Engineering Proteins Rattus Regulatory T-Lymphocyte Research Research Project Grants Resistance Sampling Seasons Serum Site Small Business Technology Transfer Research Structure Supporting Cell Survival Rate Technology Testing Therapeutic Toxic effect Toxicology Treatment Efficacy Treatment Protocols United States Food and Drug Administration Universities Work Xenograft procedure advanced disease angiogenesis anti-PD-L1 base cancer cell cancer therapy clinical development clinical toxicology commercialization cytokine density design dosage drug candidate effective therapy experimental study feeding gemcitabine immune checkpoint blockade improved improved outcome invention macrophage manufacturing facility melanoma mouse model novel novel therapeutics off-patent pancreatic cancer model pancreatic cancer patients pancreatic neoplasm phase 1 study pre-clinical preclinical development preclinical study recruit response stellate cell success therapeutic protein tumor tumorigenic

项目摘要

Abstract Pancreatic cancers are devastating diseases with five year survival rate less than 7%. Currently, there is no effective treatment for advanced disease. One major barrier to efficacy of anti-tumor therapeutics is the dense desmoplastic stromal response. Evidence suggests that cancer associated pancreatic stellate cells (CAPaSC) produce the stromal collagen. The ECM laid down by CAPaSC is considered to be one of the major contributors of resistance to established therapies of the diseases. Depleting CAPaSC and altering vessel density could significantly improve efficacy of existing pancreatic ductal adenocarcinoma (PDAC) treatments. However, currently, there are no approved therapies that are able to deplete CAPaSCs in PDAC. We have developed a novel therapeutic protein (ProAgio) using rational protein design. ProAgio is designed to target integrin v3 at a novel site (not the ligand binding site). ProAgio specifically induces apoptosis of integrin v3 expressing cells with high efficacy by a novel mechanism of drug action (recruiting & activating caspase 8 at cytoplasmic domain of). We reasoned that, since both CAPaSC and angiogenic endothelial cells express high levels of integrin v3, and since ProAgio is very effective in inducing apoptosis of integrin v3 expressing cells, ProAgio should both deplete CAPaSC and eliminate new blood vessels in and around pancreatic tumors. This unique strategy may prove advantageous in treatment of PDAC. Our STTR phase I studies demonstrated efficacy of ProAgio potentially as a PDAC treatment via various cancer models. The studies support our hypothesis that ProAgio can provide treatment benefit by simultaneously depleting the collagen-producing CAPaSCs that support tumor desmoplasia and cancer cell growth, while also eliminating newly grown cancer associated blood vessels that feed cancer cells and enable cancer metastasis. Data from our STTR phase I studies provides proof of principle for future clinical tests. To facilitate future clinical studies of ProAgio in PDAC patients, we propose to: (Aim 1) analyze the pre-clinical toxicology (TOX) and pharmacokinetics (PK) of ProAgio with rats and monkey. TOX/PK studies will enable IND application with US Food and Drug Administration (FDA). (Aim 2) Determine whether ProAgio can synergistically enhance treatment efficacy and delivery of immune checkpoint blockades. This study will explore new therapeutic avenue for PDAC patients.

抽象的胰腺癌是一种毁灭性疾病，目前五年生存率不足7%。对于晚期疾病没有有效的治疗方法是抗肿瘤功效的一大障碍。治疗方法是致密促纤维增生基质反应，有证据表明癌症。相关胰腺星状细胞 (CAPaSC) 产生基质胶原蛋白。 CAPaSC 认为是抵抗既定的主要因素之一消耗 CAPaSC 和改变血管密度可以显着治疗这些疾病。提高现有胰腺导管腺癌（PDAC）治疗的疗效。目前，尚无批准的疗法能够消除 PDAC 中的 CAPaSC。使用合理的蛋白质设计开发了一种新型治疗性蛋白质（ProAgio）。旨在将整合素 v3 定位在一个新位点（不是专门针对 ProAgio 的配体结合位点）。通过一种新机制高效诱导整合素 αvβ3 表达细胞凋亡药物作用（在  的细胞质结构域招募并激活 caspase 8）。因为 CAPaSC 和血管生成内皮细胞都表达高水平的整合素 αvβ3，并且由于 ProAgio 在诱导整合素 αvβ3 表达细胞凋亡方面非常有效，因此 ProAgio 应该既消耗 CAPaSC 又消除胰腺肿瘤内部和周围的新血管。这种独特的策略可能在我们的 STTR I 期研究中具有优势。通过各种癌症模型证明了 ProAgio 作为 PDAC 治疗的潜在功效。这些研究支持我们的假设，即 ProAgio 可以同时提供治疗益处消耗支持肿瘤结缔组织增生和癌细胞的产生胶原蛋白的 CAPaSC 生长，同时还消除了为癌细胞提供营养的新生长的癌症相关血管 STTR 第一阶段研究的数据为癌症转移提供了原理证明。为了促进未来 ProAgio 在 PDAC 患者中的临床研究，我们建议。目的：（目标 1）分析 ProAgio 的临床前毒理学 (TOX) 和药代动力学 (PK) 大鼠和猴子的 TOX/PK 研究将使美国食品和药物管理局的 IND 申请成为可能。管理 (FDA)（目标 2）确定 ProAgio 是否可以协同地加强治疗这项研究将探索新的疗法。 PDAC 患者的途径。