Development of caveolae-targeted antibody-drug conjugates

开发小凹靶向抗体药物偶联物

基本信息

批准号：
9974488
负责人：
Bogdan Olenyuk
金额：
$ 44.12万
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/9974488
关键词：
Address Affinity Annexin A1 Antibodies Antibody-drug conjugates Antineoplastic Agents Attenuated BT 474 Binding Biodistribution Biological Biometry Blood Blood Vessels Breast Cancer Cell Breast Cancer Treatment Buffers Cancer Model Carboplatin Caveolae Cell Wall Cell surface Chemistry Cisplatin Cleaved cell Clinic Complex Data Data Analyses Development Dextrans Disseminated Malignant Neoplasm Dose Drug Delivery Systems Drug Kinetics Drug resistance Endothelial Cells Endothelium Goals Half-Life Histology Human Image Immunoconjugates In Vitro Injections Intravenous Kinetics MDA MB 231 Mammary Neoplasms Maximum Tolerated Dose Measures Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Modernization Monitor Multi-Drug Resistance Multimodal Imaging Mus Neoplasm Metastasis Normal tissue morphology Pathway interactions Patients Penetration Pharmaceutical Preparations Phase Plasma Platinum Pre-Clinical Model Property Proteins Publishing Pump Quality Control Rattus Risk Rodent Safety Services Side Solid Solid Neoplasm Solubility Specificity Speed System Testing Therapeutic Toxic effect Translating Translations Treatment Efficacy Vascular Endothelial Cell Vascular Endothelium X-Ray Computed Tomography Xenograft procedure animal imaging base cGMP production cancer therapy carboxylate carcinogenicity chemotherapy clinical candidate clinical efficacy clinical translation design dosage drug efficacy humanized antibody improved in vivo innovation intravital microscopy lung metastatic malignant breast neoplasm neoplastic cell novel novel therapeutics oxaliplatin pre-clinical replication factor C research clinical testing response side effect single photon emission computed tomography systemic toxicity targeted delivery targeted treatment therapeutic effectiveness therapy outcome treatment response tumor uptake vascular endothelium permeability

项目摘要

PROJECT 2 SUMMARY The overall objective of the Project 2 is to utilize a newly discovered, active transendothelial transport pathway, the caveolae pumping system, in order to provide an effective solution to the delivery and toxicity problem of chemotherapeutics in metastatic breast cancer treatment. In order to address these problems and significantly improve therapeutic outcome we propose to develop novel antibody-drug conjugates (ADCs) that exploit our newly discovered endothelial cell (EC) caveolae targeting system in order to sidestep passive delivery problem of modern chemotherapeutics. We have established that EC caveolae in preclinical models can rapidly and specifically pump anti-Annexin A1 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 for greatly enhanced efficacy in tumor destruction in breast cancer. Our main hypothesis is that immunoconjugates that fully utilize the advantages of the EC caveolae-pumping system will dramatically increase delivery of chemotherapeutic drugs into tumors, thereby requiring much lower dosages and dramatically enhancing efficacy of treatment. This hypothesis will be tested by the following specific aims: In Aim 1, we will design and synthesize Pt(II)-carboxymethyl dextran (CMD) ADCs and optimize carboxylate derivatization of CMD, conjugation chemistry, and Pt(II) loading in order to maximize binding affinity toward human Annexin A1 protein. We will test and optimize physicochemical properties, stability on storage, in human plasma, and Pt(II) release kinetics in the tumor interstitium. In Aim 2 we will assess therapeutic efficacy of the ADCs in metastatic cancer models. The efficacy of our targeted delivery system will be examined in MDA-231-LM2-4, and rat tumor models with 13762 breast cancer cells metastasized to lung using whole-body animal imaging with X-ray/CT. In Aim 3 we will examine the therapeutic efficacy of the ADCs in tumors with human blood vessels using intravital microscopy (IVM). We will monitor tumor size in response to therapy in human-on-human IVM model using BT-474 tumor spheroids, and in patient-derived xenografts (PDX) IVM model. In this Aim we will also translate our select preclinical candidate for clinical testing, where successful targeted therapeutic will be selected as clinical candidates for cGMP production (Core B) for subsequent testing in a Phase 1 safety trial in Project 3. Antibodies for conjugation to form ADCs will be provided by Core B. Core B will also provide quality control analysis of ADCs and confirmation of antibody binding affinity following conjugation. Tumor targeting, delivery and accumulation of these novel therapies will be assessed in rodents using multi-modality imaging services provided by Core C, which includes X-ray/CT, SPECT-CT, IVM, and histology. Core E will handle the biostatistical analysis of data generated during the course of the project. The long-term goal is to translate our key basic discoveries into unique, innovative delivery platform in order to improve therapeutic efficacy of human cancer therapy.

项目2摘要项目2的总体目的是利用新发现的活跃的跨内皮运输途径， Caveolae泵送系统，以便为输送和毒性问题提供有效的解决方案转移性乳腺癌治疗中的化学治疗药。为了解决这些问题改善治疗结果，我们建议开发利用我们的新型抗体 - 药物结合物（ADC）新发现的内皮细胞（EC）Caveolae靶向系统，以避开被动输送问题现代化学治疗学。我们已经确定，临床前模型中的Ec Caveolae可以迅速，并且特别是在血管内皮障碍物上泵送抗抗动物A1 A1抗体和附着的货物直接进入实体瘤。基于这一发现，我们建议设计针对ec Caveolae的新颖靶向ADC 大大提高了乳腺癌肿瘤破坏的功效。我们的主要假设是完全利用EC Caveolae-Pumping系统的优势的免疫共轭物将极大地利用增加化学治疗药物进入肿瘤的递送，从而需要较低的剂量和急剧增强治疗的功效。该假设将通过以下特定目的进行检验： AIM 1，我们将设计和合成PT（II） - 羧甲基脱氧剂（CMD）ADC并优化羧酸盐 CMD的衍生化，共轭化学和PT（II）加载，以最大化结合亲和力人膜联蛋白A1蛋白。我们将测试和优化物理化学特性，在存储中的稳定性，在人血浆和PT（II）在肿瘤间质中释放动力学。在AIM 2中，我们将评估治疗功效转移性癌症模型中的ADC。我们的目标交付系统的功效将在 MDA-231-LM2-4和具有13762乳腺癌细胞的大鼠肿瘤模型使用全身转移为肺用X射线/CT进行动物成像。在AIM 3中，我们将检查ADC在具有的肿瘤中的治疗功效使用浸润显微镜（IVM）的人体血管。我们将监测肿瘤的大小，以应对治疗使用BT-474肿瘤球体和患者衍生异种移植物（PDX）IVM的人类IVM模型模型。在此目标中，我们还将翻译我们的临床测试的精选临床前候选者有针对性的治疗方法将作为CGMP生产（核心B）的临床候选者在项目3中的第1阶段安全试验中进行测试。将由Core提供结合的抗体形成ADC的抗体 B. Core B还将提供ADC的质量控制分析和抗体结合亲和力的确认结合后。这些新疗法的肿瘤靶向，分娩和积累将在使用Core C提供的多模式成像服务的啮齿动物，其中包括X射线/CT，SPECT-CT，IVM，IVM，和组织学。核心E将处理项目过程中生成的数据的生物统计分析。长期目标是将我们的关键基本发现转化为独特的创新交付平台，以便提高人类癌症治疗的治疗功效。