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.

项目摘要/摘要现代医学创建了精确药物，阻止了具有高亲和力的TGF-β（TGF-β）的单一治疗靶标和特异性。然而，治疗肺部疾病仍然是挑战，部分原因是肺微血管内皮代表有效药物输送的关键限制性障碍。当前的全身疗法仅依靠对流和扩散以被动地进入疾病靶向靶向细胞的组织间质。可以很容易地到达并直接处理。该研究建议的目的是设计，开发和测试免疫治疗药的新型药物输送系统，通过将小窝靶向卡维拉（Caveolae）来克服这一关键障碍静脉注射后，促进活跃的特异性转胞胞病症进入肺部。理想是交付整个肺组织内的治疗剂量，所有其他时机最小暴露。我们试图解决这个问题通过精确地泵入肺组织的稳健的跨内皮泵治疗靶标TGF-β，可调节在解散组织中的炎症和重塑。因为TGF-β 同样在许多器官中都会执行各种稳态效应，当系统性靶向它的时需要谨慎尝试功能。这里提出的精确肺靶向将最大化效率和治疗指数最小化剂量，消除毒性并降低治疗成本。为此，我们一般设计了第一个“双重精度”免疫治疗剂，即以四边形格式的双特异性抗体手臂对介导精度结合/递送与肺组织通过小窝泵送和渗透其他对构成阻断TGF-β效应功能的精确热模态的对。积极的与标准的被动转运相比，跨内皮递送提高了精度肺靶向100倍。在1小时内将大部分注射剂量输送到肺中，以> 1000倍大鼠肺炎模型。现在，我们的目标是扩大这项有希望的初步工作，并进一步改善和严格测试该药物输送系统，以在不同的阶段治疗关键的肺部疾病。对慢性和进行性纤维化的炎症。我们将优化双重精度的肺目标免疫治疗药并研究其特定的肺部递送，渗透，积累，定位和使用多种成像技术（Spect-CT，IVM，EM和IHC）对大鼠的治疗影响。治疗性效果将在大鼠博来霉素模型中进行评估，该模型再现了许多致命人的病理标志包括ALI，ARDS，COVID，肺炎和纤维化在内的疾病。我们的具体目的是：1）工程师和评估针对明确的小窝靶向抗体构建体，以精确地递送到正常的肺组织中，2）量化和优化双特异性免疫治疗药在肺部疾病中的递送，3）测试效率双特异性免疫疗法可改善肺部疾病和阻塞TGF-β途径。这项工作设定了针对小窝靶向疗法的基础，可以开始从被动药物转变为活性药物许多疾病的分娩。