Endothelial Cell-Targeted Amatoxin Conjugates for Effective Therapy of Breast Cancer

内皮细胞靶向鹅膏毒素缀合物可有效治疗乳腺癌

基本信息

批准号：
10653843
负责人：
Bogdan Olenyuk
金额：
$ 68.08万
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：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10653843
关键词：
Active Biological Transport Affinity Amanitins Annexin A1 Antibodies Antibody-drug conjugates Binding Blood Blood Circulation Blood Vessels Breast Cancer Model Breast Cancer Treatment Breast Cancer therapy Cancer Intervention Caveolae Cell surface Cells Cessation of life Clinical Trials Coupled Development Disease-Free Survival Dose Dose Limiting Drug Delivery Systems Drug resistance Endothelial Cells Endothelium Exhibits Foundations Frequencies Future Goals Histology Human Image In complete remission Injections Investments Kinetics Link Lung Neoplasms Malignant Neoplasms Mammary Neoplasms Membrane Metastatic breast cancer Modeling Modernization Molds Names Neoplasm Metastasis Pathologic Pathway interactions Patients Penetration Permeability Pharmaceutical Preparations Phase Pre-Clinical Model Primary Neoplasm Property Prostatic Neoplasms Proteomics Pump Quality of life Recurrent Malignant Neoplasm Recurrent tumor Relapse Resources Rodent Roentgen Rays Safety Side Solid Solid Neoplasm System Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Toxin Translating Treatment Efficacy Vascular Endothelium X-Ray Computed Tomography amatoxin anti-cancer therapeutic arm cancer recurrence cancer therapy chaetocin design dosage driving force effective therapy improved innovation interstitial intravenous injection intravital microscopy malignant breast neoplasm neoplastic cell novel novel therapeutics patient derived xenograft model precision drugs precision medicine pressure prevent public health relevance replication factor C research clinical testing response side effect stem stem-like cell targeted delivery targeted treatment therapeutic evaluation therapeutic target therapeutically effective tumor

项目摘要

SUMMARY The overall objective of the proposed project is to harness a newly discovered, active transendothelial transport pathway, the caveolae pumping system, to provide an effective solution to the delivery and toxicity problem of chemotherapeutics in metastatic breast cancer treatment. We propose to develop novel antibody- drug conjugates (ADCs) that exploit our newly discovered endothelial cell (EC) caveolae targeting system in order to improve the delivery and targeting of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and specifically pump Annexin A1 (AnnA1) antibodies and attached cargo across the vascular endothelial barrier directly into solid tumors. Based on this discovery, we propose to design novel EC caveolae-targeted ADCs that may revolutionize treatments for metastatic breast cancer. We have created a robust delivery platform by arming hAnnA1 with amatoxins, a class of ultra-potent toxins that can effectively kill both rapidly dividing and dormant tumor cells. These include α-Amanitin, a toxin derived from the “death cap” mushroom and Chaetocin, an anti-proliferative, broad-spectrum toxin derived from the filamentous fungus Chaetomiun sp. Our main hypothesis is that caveolae-targeted antibody-drug conjugates (CTAs), will dramatically increase delivery of ultra-potent toxins specifically into tumors, thereby requiring much lower dosages and dramatically enhancing efficacy of cancer treatment. This hypothesis will be tested by the following specific aims: In Aim 1, we will design and characterize novel hAnnA1-toxin CTAs. We will optimize their physicochemical properties, stability, release kinetics in the tumor interstitium, and binding affinity towards the human Annexin A1 protein. In Aim 2, we will evaluate therapeutic efficacy, drug delivery and off-target effects of candidate CTAs in human tumor models of breast cancer using intravital microscopy (IVM). In Aim 3, we will examine the therapeutic efficacy of the select CTAs in metastatic tumor models and in patient-derived xenograft (PDX) models. We will also prepare a foundation for clinical testing, where successful targeted therapeutics will be selected as candidates for future Phase 1 safety trial. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in rodents using x-ray/CT imaging, IVM, and histology. The long-term goal is to translate our key basic discoveries into a unique, innovative delivery platform that may vastly improve treatments for solid cancers.

概括拟议项目的总体目标是利用新发现的活跃的跨内皮 Caveolae Pumping系统的传输途径，为输送和毒性提供有效的解决方案转移性乳腺癌治疗中化学治疗剂的问题。我们建议开发新型抗体 - 利用我们新发现的内皮细胞（EC）Caveolae靶向系统的药物共轭物（ADC）为了改善现代化学治疗剂的交付和靶向。我们已经确定了EC 临床前模型中的小窝可以迅速，特别是泵送膜联蛋白A1（ANNA1）抗体并附着直接进入实体瘤的血管内皮屏障。基于这一发现，我们建议设计新颖的Ec Caveolae靶向ADC，可能会彻底改变转移性乳腺癌的治疗方法。我们通过用amatoxins武装Hanna1（一种超级毒素）来创建一个强大的交付平台可以有效地杀死快速分裂和休眠的肿瘤细胞。这些包括α-氨氨酸蛋白，毒素得出源自“死亡帽”肌肉和卫生素，一种抗增殖剂，广谱毒素，源自该毒素丝状真菌Chaetomiun sp。我们的主要假设是，小窝靶向抗体 - 药物缀合物（CTA），将大大增加专门为肿瘤的超功能毒素的递送，从而需要很多降低剂量，并大大提高癌症治疗的效率。该假设将通过遵循特定目的：在AIM 1中，我们将设计和表征新型Hanna1-Toxin CTA。我们将优化它们的物理特性，稳定性，在肿瘤间质中释放动力学以及对人膜联蛋白A1蛋白。在AIM 2中，我们将评估治疗效率，药物输送和脱靶候选CTA在人类肿瘤模型的乳腺癌模型中的影响，使用浸润显微镜（IVM）。在AIM 3中，我们将检查转移性肿瘤模型中选择CTA的治疗效率以及患者衍生的异种移植（PDX）模型。我们还将为临床测试准备一个基础，并成功针对目标治疗将被选为未来1阶段安全试验的候选人。肿瘤靶向，分娩和这些新型疗法的积累将在啮齿动物中使用X射线/CT成像，IVM和组织学评估。长期目标是将我们的主要基本发现转化为一个独特的创新交付平台，可能大大改善了固体癌症的治疗方法。