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Precision Delivery and Imaging to Enhance Solid Tumor Therapy

精准输送和成像增强实体瘤治疗

基本信息

批准号：
9974485
负责人：
Jan Eugeniusz Schnitzer
金额：
$ 266.71万
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：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974485
关键词：
Active Biological Transport Annexin A1 Antibodies Antibody-drug conjugates Antineoplastic Agents Binding Biodistribution Blood Vessels Bypass Cancer Patient Caveolae Cells Cisplatin Clinic Clinical Clinical Trials Cyclic GMP Cytotoxic agent Development Diagnostic Disease Disseminated Malignant Neoplasm Dose Drug Delivery Systems Drug resistance Endothelial Cells Endothelium Environment Exhibits Genes Goals Grant Hematologic Neoplasms Human Image Immunoconjugates Lesion Life Style Lung Malignant Neoplasms Mammary Neoplasms Mediating Modeling Molecular Multi-Drug Resistance Neoplasm Metastasis Pathway interactions Patients Penetration Pharmaceutical Preparations Pharmacotherapy Phase Phase I Clinical Trials Platinum Pre-Clinical Model Preclinical Testing Prevention Primary Neoplasm Program Research Project Grants Pump Radiation therapy Radiolabeled Safety Solid Solid Neoplasm Surface System Testing Therapeutic Therapeutic Agents Therapeutic Index Tissues Toxic effect Toxicology Translating Treatment Efficacy Tumor Tissue Vascular Endothelium War Work antibody conjugate base cancer imaging cancer therapy chemoradiation chemotherapy cytotoxic disease diagnosis dosage drug efficacy drug sensitivity expectation first-in-human imaging agent imaging study improved in vivo individual patient intravenous injection molecular targeted therapies novel novel therapeutics patient variability pre-clinical precision drugs precision medicine precision oncology programs research clinical testing targeted imaging targeted treatment tool treatment optimization tumor

项目摘要

PROJECT 1 SUMMARY Existing antibody-based interventions for cancer rely on passive delivery of the circulating drug that depends on a large concentration gradient across the semi-permeable wall of blood vessels to get inside tumors. The forces driving the drug from the bloodstream into tumors result in sub-optimal delivery and poor access to tumor cells, in part because endothelial cells (EC) forming the vascular wall constitute a significant, limiting barrier. We intend to boost precision delivery into primary and metastatic tumors by overcoming the vascular EC barrier through a highly precise, active transport pathway that we discovered through proteomic imaging and named the caveolae pumping system. The approach proposed here to enhance delivery goes well beyond typical so- called 'active targeting' of antibodies. Our lead humanized antibody against Annexin A1 (hAnnA1), a tumor- specific antibody concentrated in EC caveolae, not only binds its intended target but is actually the first antibody to penetrate solid tumors actively, rapidly and specifically. It does so even at very low dosages and reaches unprecedented intra-tumoral concentrations well beyond the highest blood levels after injection. It is now time to test this unprecedented immunotargeting in humans. We propose here to develop a radiolabeled humanized mAnnA1 to detect and destroy primary and metastatic lesions. Major aims of this project are to: 1-2) evaluate in vivo delivery and efficacy of novel caveolae-targeting radioimmunoconjugates in hard-to-treat metastatic tumor models of breast cancer; 3) test the effectiveness of caveolae pumping in human tumor blood vessels using PDX and novel human IVM tumor models; and translate hAnnA1 towards clinical testing. We will 4) determine here the degree to which caveolae can be targeted to pump radiolabeled antibodies across vascular EC to concentrate them inside solid tumors as means to improve image-guided drug delivery and enhance their efficacy. Antibodies will be provided by Core B and radiolabeled with assistance provided by Core D for preclinical work. Several mammary tumor models will be used to assess the ability of radiolabeled hAnnA1 to target primary and metastatic tumors via imaging services provided in Core C. We will study by intravenously injected hAnnA1 with advanced multimodality in vivo imaging to quantify and optimize precision transvascular delivery and tumor penetration. As the utility of caveolae targeting in humans requires AnnA1 expression in tumor EC caveolae, we will use Core C imaging services to compare vascular expression of AnnA1 in preclinical tumor models and human tumors. To translate our findings for clinical testing, we will test hAnnA1, humanize further if needed and partner with NCI's NExT program for cGMP production, quality control and toxicology of hAnnA1. With Core D, Project 3 will optimize hAnnA1 radiolabeling necessary to conduct a first-in-human imaging trial as a direct result of successful translation of our findings from Project 1 into the clinic.

项目1总结