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

用于胰腺癌治疗的靶向和基质破坏纳米颗粒药物的转化开发

• 批准号: 9907528
• 负责人: Lily Yang
• 金额: $ 22.44万
• 依托单位: MIGRA-THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907528
• 关键词: Abraxane; Affinity; Basement membrane; Binding; Biology; Cancer Patient; Catalytic Domain; Cell Line; Chimeric Proteins; Chinese Hamster Ovary Cell; Clinical; Clinical Trials; Combined Modality Therapy; Cytoskeleton; Development; Drug Delivery Systems; Drug Targeting; Drug resistance; Duct (organ) structure; Ductal; Engineering; Ensure; Extracellular Matrix; Future; Generations; Human; Hyaluronic Acid; In Vitro; Investigational Drugs; KRAS2 gene; Lead; Ligands; MMP14 gene; Malignant neoplasm of pancreas; Mammalian Cell; Matrigel Invasion Assay; Modeling; Mus; Normal Cell; Nude Mice; Paclitaxel; Pancreas; Patients; Peptide Hydrolases; Pharmacotherapy; Phase; Plasmids; Polymers; Procedures; Production; Property; Proteins; Recombinant Proteins; Recombinants; Research; Research Project Grants; Resistance; Small Business Innovation Research Grant; Specificity; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Transgenic Mice; Translating; Translational Research; Treatment Efficacy; Tumor Biology; Tumor-Derived; Urokinase Plasminogen Activator Receptor; Xenograft Model; Xenograft procedure; advanced pancreatic cancer; cancer cell; cancer survival; cancer therapy; commercialization; design; drug development; effective therapy; gemcitabine; imaging agent; improved; in vitro activity; in vivo; irinotecan; large scale production; nanoparticle; nanoparticle drug; neoplastic cell; novel; novel strategies; novel therapeutics; pancreatic cancer cells; pancreatic cancer patients; phase 1 study; phase 2 study; preclinical study; protein expression; receptor; response; targeted delivery; targeted treatment; therapy resistant; treatment response; tumor; tumor growth; tumor xenograft

Project Summary Resistance to therapy is the major clinical challenge in pancreatic cancer therapy. Low efficiency in drug delivery and aggressive tumor biology are the major causes of a poor therapeutic response. It is well known that the presence of a dense fibrous tumor stroma creates a drug delivery barrier and promotes aggressive biology and drug resistance in pancreatic cancer cells. The objective of our translational research project is to develop a new generation of receptor-targeted and protease active targeting ligand and stroma-breaking nanoparticle drug delivery platform for effective treatment of advanced pancreatic cancer. Our extensive research led to the development of a new tumor targeting approach using a recombinant uPAR targeting ligand containing the amino terminal fragment (ATF) of uPA fused with the catalytic domain of matrix metalloproteinase- 14 (ATFmmp14). Novel designs of ATFmmp14 ligand not only ensure enhanced intratumoral delivery of therapeutic agents, but also enable breaking tumor stroma cellular and extracellular matrix barriers. We also developed a biodegradable hyaluronic acid nanoparticle carrying an active metabolite of irinotecan, SN38 (HANP/SN38). Our results demonstrated that ATFmmp14 conjugated HANP/SN38 significantly enhanced drug delivery to tumors in KRAS-driven transgenic mouse and human pancreatic PDX tumor models. Importantly, the nanoparticle-drug migrated out of tumor stroma and penetrated through the basement membrane lining ductal cancer cells to enter tumor cells. As a result, systemic delivery of ATFmmp14-HANP/SN38 significantly inhibited tumor growth. In comparison with current combination therapies (FOLFRINOX or gemcitabine-Nab-Paclitaxel), ATFmmp14-HANP/SN38 treatment significantly prolonged survival in the PDX tumor models derived from drug resistant pancreatic cancer patients. To translate this novel approach for target therapy in cancer patients, in this phase 1 study, we will develop a new generation of tagless human ATFmmp14 ligands that are optimized for the GMP production and have high binding affinity, target specificity and MMP14 enzymatic activity. The proposed studies in Aim 1 will engineer a stable ATFmmp14(R2) expressing CHO cell line and a B. subtilis secretable protein expression system for large scale production of tagless ATFmmp14(R2). We will then evaluate and compare their production procedure, protein yield, target specificity, and MMP14 activity in vitro and in vivo to select the most suitable targeting ligand for drug development (Aim 2). Finally, therapeutic effect of ATFmmp14(R2) will be determined in a pancreatic PDX tumor model (Aim 3). The milestones of this phase I research project are: 1) to develop ATFmmp14-HANP(R2) as a stroma-breaking and targeted nanoparticle drug delivery platform for future commercialization; and 2) to develop a targeted nanoparticle drug, ATFmmp14(R2)- HANP/SN38, for the Phase II study aimed at the Investigational New Drug (IND)-enabling preclinical studies for the translational development of ATFmmp14-HANP/SN38 for targeted therapy of advanced pancreatic cancer.

项目摘要 对治疗的抵抗是胰腺癌治疗的主要临床挑战。药物输送效率低 和侵袭性肿瘤生物学是治疗反应差的主要原因。众所周知， 致密纤维肿瘤间质的存在产生药物递送屏障并促进侵袭性生物学， 胰腺癌细胞的耐药性。我们的转化研究项目的目标是开发 新一代受体靶向和蛋白酶活性靶向配体和基质破坏 用于有效治疗晚期胰腺癌的纳米颗粒药物递送平台。我们广泛 研究导致了使用重组uPAR靶向配体的新肿瘤靶向方法的开发 含有与基质金属蛋白酶的催化结构域融合的uPA的氨基末端片段（ATF）， 14（ATFmmp14）。ATFmmp 14配体的新设计不仅确保了增强的肿瘤内递送， 本发明的组合物不仅是治疗剂，而且能够打破肿瘤基质细胞和细胞外基质屏障。我们也 开发了携带伊立替康活性代谢物SN 38的生物可降解透明质酸纳米粒 (HANP/SN 38）。我们的结果表明，ATFmmp 14缀合的HANP/SN 38显著增强了药物作用。 在KRAS驱动的转基因小鼠和人胰腺PDX肿瘤模型中递送至肿瘤。重要的是 纳米颗粒药物迁移出肿瘤间质并穿透衬于导管的基底膜， 癌细胞进入肿瘤细胞。结果，ATFmmp 14-HANP/SN 38的全身递送显著抑制了 肿瘤生长与目前的联合治疗（FOLFRINOX或吉西他滨-Nab-Paclitazone）相比， ATFmmp 14-HANP/SN 38治疗显著延长了源自药物治疗的PDX肿瘤模型的存活期。 耐药胰腺癌患者。为了将这种新方法用于癌症患者的靶向治疗， 第1阶段研究，我们将开发新一代无标签的人ATFmmp 14配体，其针对 GMP生产并具有高结合亲和力、靶特异性和MMP 14酶活性。拟议 目的1中的研究将工程化稳定的表达ATFmmp 14（R2）的CHO细胞系和B。枯草杆菌分泌型 用于大规模生产无标签ATFmmp 14（R2）的蛋白表达系统。我们将评估和 比较它们的生产过程、蛋白质产量、靶特异性和MMP 14体外和体内活性， 选择最适合药物开发的靶向配体（目标2）。最后，治疗效果 将在胰腺PDX肿瘤模型中测定ATFmmp 14（R2）（Aim 3）。第一阶段的里程碑 研究项目是：1）开发ATFmmp 14-HANP（R2）作为基质破坏和靶向纳米粒药物 用于未来商业化的递送平台;以及2）开发靶向纳米颗粒药物ATFmmp 14（R2）- HANP/SN 38，用于II期研究，旨在进行试验性新药（IND）的临床前研究， ATFmmp 14-HANP/SN 38的翻译开发用于晚期胰腺癌的靶向治疗。