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

• 批准号: 10439623
• 负责人: Bogdan Olenyuk
• 金额: $ 69.47万
• 依托单位: PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
• 依托单位国家: 美国
• 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/10439623
• 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; Kinetics; Link; Lung Neoplasms; Malignant Neoplasms; Mammary Neoplasms; Membrane; Metastatic breast cancer; Modeling; Modernization; Molds; Names; Neoplasm Metastasis; Pathologic; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Primary Neoplasm; Property; Prostatic Neoplasms; Proteomics; Pump; Quality of life; Recurrence; Recurrent Malignant Neoplasm; Relapse; Resources; Rodent; Safety; Side; Solid; Solid Neoplasm; System; Testing; Therapeutic Agents; Time; Tissues; Toxic effect; Toxin; Translating; Treatment Efficacy; Vascular Endothelium; X-Ray Computed Tomography; alpha Toxin; amatoxin; anti-cancer therapeutic; arm; base; 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

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性跨内皮细胞 运输途径，小凹泵送系统，为输送和毒性提供有效的解决方案 转移性乳腺癌治疗中的化疗问题。我们建议开发新型抗体- 利用我们新发现的内皮细胞 (EC) 小窝靶向系统的药物偶联物 (ADC) 为了改善现代化疗药物的输送和靶向。我们已经确定 EC 临床前模型中的小窝可以快速、特异性地泵送膜联蛋白 A1 (AnnA1) 抗体和附着的抗体 货物穿过血管内皮屏障直接进入实体瘤。基于这一发现，我们建议 设计新型 EC Caveolae 靶向 ADC，可能彻底改变转移性乳腺癌的治疗方法。我们 通过用鹅膏毒素（一类超强毒素）武装 hAnnA1，创建了一个强大的递送平台 可以有效杀死快速分裂和休眠的肿瘤细胞。其中包括 α-鹅膏蕈碱，一种衍生毒素 来自“死亡帽”蘑菇和毛壳素，一种抗增殖的广谱毒素，源自 丝状真菌 Chaetomiun sp.我们的主要假设是小穴靶向抗体药物偶联物 （CTA），将显着增加特异进入肿瘤的超强毒素的输送，因此需要大量 更低的剂量并显着提高癌症治疗的功效。这个假设将被检验 以下具体目标：在目标 1 中，我们将设计并表征新型 hAnnA1 毒素 CTA。我们会优化 它们的理化特性、稳定性、在肿瘤间质中的释放动力学以及对 人类膜联蛋白 A1 蛋白。在目标 2 中，我们将评估治疗效果、药物递送和脱靶情况 使用活体显微镜 (IVM) 观察候选 CTA 对乳腺癌人类肿瘤模型的影响。在目标 3 中， 我们将检查选定的 CTA 在转移性肿瘤模型和患者来源的治疗中的治疗效果 异种移植（PDX）模型。我们还将为临床测试奠定基础，其中成功的目标 治疗方法将被选为未来一期安全试验的候选药物。肿瘤靶向、递送和 将使用 X 射线/CT 成像、IVM 和组织学在啮齿类动物中评估这些新疗法的积累。 长期目标是将我们的关键基础发现转化为一个独特的创新交付平台，该平台可以 极大地改善实体癌的治疗。