Bispecific immunotherapeutic delivery system for lung diseases

用于肺部疾病的双特异性免疫治疗递送系统

基本信息

批准号：
10720773
负责人：
Jan Eugeniusz Schnitzer
金额：
$ 92.43万
依托单位：
PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10720773
关键词：
Acute Acute Respiratory Distress Syndrome Address Affect Affinity Animals Antibodies Antiinflammatory Effect Automobile Driving Binding Biodistribution Biological Markers Biological Products Bispecific Antibodies Bleomycin Blood Vessels Cause of Death Caveolae Cells Cessation of life Chimeric Proteins Chronic Clinical Convection Cytokine Signaling Data Diffusion Disease Dose Drug Delivery Systems Drug Targeting Endothelial Cells Endothelium Engineering Exhibits Extravasation Fibrosis Foundations Genetic Engineering Goals Histopathology Hour Image Imaging Techniques Immunotherapeutic agent In Vitro Inflammation Inflammatory Intravenous Lung Lung diseases Magic Mediating Modality Modeling Modern Medicine Organ Pathologic Pathology Pathway interactions Penetration Pharmaceutical Preparations Phosphorylation Physiology Pneumonia Pre-Clinical Model Precision therapeutics Preclinical Testing Property Pulmonary Inflammation Pulmonary Pathology Pump Rattus Research Proposals Rodent Signal Transduction Site Specificity Structure of parenchyma of lung System Testing Therapeutic Therapeutic Effect Therapeutic Index Time Tissues Toxic effect Transforming Growth Factor beta Treatment Cost Treatment Efficacy Vascular Endothelial Cell Vascular Endothelium Work Workplace arm comparative coronavirus disease design dosage drug testing efficacy testing expectation human disease improved intravenous injection novel novel therapeutics passive transport pneumonitis and fibrosis precision drugs prevent prophylactic protein expression prototype research clinical testing response single photon emission computed tomography targeted treatment therapeutic target therapy outcome transcytosis uptake

项目摘要

Project summary/abstract Modern medicine has created precision drugs blocking a single therapeutic target like TGF-β with high affinity and specificity. Yet treating lung diseases remains challenging in part because lung microvascular endothelium represents a key restrictive barrier to effective drug delivery. Current systemic therapeutics rely solely on convection and diffusion to extravasate passively into the tissue interstitium where disease targets and cells can readily be reached and directly treated. The goal of this research proposal is to design, develop and test a novel drug delivery system for immunotherapeutics that overcomes this key barrier by targeting caveolae to facilitate active and specific transcytosis into lungs after intravenous injection. The ideal is to deliver the entire therapeutic dose inside the lung tissue with all other tissues minimally exposed. We attempt to approach this ideal by achieving robust transendothelial pumping precisely into lung tissue to comprehensively block the therapeutic target TGF-β, which regulates inflammation and remodeling in diseased tissues. Because TGF-β also exerts various homeostatic effects in many organs, caution is necessary when systemic targeting of its function is attempted. Precision lung targeting proposed here will maximize efficacy and therapeutic indices by minimizing dosages, eliminating toxicities, and reducing cost of treatment. To that end, we have genetically engineered the first “dual precision” immunotherapeutics, namely bispecific antibodies in quad format with one arm pair mediating precise binding/delivery to and penetration of lung tissue via caveolae pumping and the other pair constituting the precision therapeutic modality that blocks TGF-β effector function. Active transendothelial delivery improved precision lung targeting by 100-fold over standard passive transport. Delivering most of the injected dose into lungs within 1 hour enhanced therapeutic potency by >1000-fold in a rat pneumonitis model. Now our goal is to expand this promising preliminary work and further improve and rigorously test this drug delivery system to treat key lung diseases at distinct stages ranging from early acute inflammation to chronic and progressive fibrosis. We will optimize lung targeting of our dual precision immunotherapeutics and study their specific lung delivery, penetration, accumulation, localization, and therapeutic impact in rats using multiple imaging techniques (SPECT-CT, IVM, EM, and IHC). Therapeutic effects will be assessed in a rat bleomycin model that reproduces pathological hallmarks of many fatal human diseases including ALI, ARDS, COVID, pneumonias, and fibrosis. Our specific aims are: 1) to engineer and evaluate distinct caveolae-targeted antibody constructs for precision active delivery into normal lung tissue, 2) to quantify targeting and optimize delivery of bispecific immunotherapeutics in lung disease, 3) to test efficacy of bispecific immunotherapeutics to ameliorate lung disease and block TGF-β pathways. This work sets a foundation for caveolae-targeted therapies and could begin a paradigm shift from passive to active drug delivery for many diseases.

项目概要/摘要现代医学已经创造出具有高亲和力的阻断单一治疗靶点（如 TGF-β）的精准药物然而，治疗肺部疾病仍然具有挑战性，部分原因是肺微血管内皮。是有效药物输送的关键限制性障碍。对流和扩散被动地渗入疾病目标和细胞所在的组织间质可以很容易地直接达到和处理。本研究提案的目标是设计、开发和测试一个用于免疫治疗的新型药物递送系统，通过靶向小凹来克服这一关键障碍静脉注射后促进主动和特异性的转胞吞进入肺部。理想的情况是输送整个细胞。我们尝试在肺组织内部施加治疗剂量，并尽量减少所有其他组织的暴露。通过实现强大的跨内皮泵精确进入肺组织以全面阻断治疗靶标 TGF-β，调节病变组织的炎症和重塑。还在许多器官中发挥各种稳态作用，因此在全身靶向其时必须谨慎这里提出的精确肺部靶向将通过以下方式最大限度地提高疗效和治疗指数。为此，我们从基因角度出发，减少治疗剂量、消除毒性并降低治疗成本。设计了第一个“双精度”免疫疗法，即四元形式的双特异性抗体臂对通过小凹泵送介导精确结合/输送和渗透肺组织另一对构成阻断 TGF-β 效应子功能的精准治疗方式。与标准被动运输相比，经内皮递送将肺靶向的精确度提高了 100 倍。在 1 小时内将大部分注射剂量输送到肺部，治疗效力提高了 1000 倍以上现在我们的目标是扩大这项有希望的前期工作并进一步改进和改进。严格测试这种药物输送系统，以治疗从早期急性到不同阶段的关键肺部疾病我们将优化肺部靶向的双重精准度。免疫疗法并研究其特定的肺部输送、渗透、积累、定位和使用多种治疗成像技术（SPECT-CT、IVM、EM 和 IHC）对大鼠的影响。将在大鼠博莱霉素模型中评估效果，该模型再现了许多致命人类的病理特征我们的具体目标是：1) 设计和治疗疾病，包括 ALI、ARDS、COVID、肺炎和纤维化。评估不同的小窝靶向抗体构建体，以精确主动递送至正常肺组织，2) 针对肺部疾病的双特异性免疫治疗进行量化和优化，3) 测试疗效这项工作设定了双特异性免疫疗法改善肺部疾病和阻断 TGF-β 途径的方法。为小窝靶向治疗奠定了基础，并可能开始从被动药物到主动药物的范式转变许多疾病的交付。