Tumor caveolae-targeted systemic therapy of breast cancer with antibody drug conjugates

使用抗体药物缀合物对乳腺癌进行肿瘤小窝靶向全身治疗

• 批准号: 10237875
• 负责人: Adrian Chrastina
• 金额: $ 42.32万
• 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: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237875
• 关键词: Active Biological Transport; Annexin A1; Antibodies; Antibody-drug conjugates; Antineoplastic Agents; Blood; Blood Circulation; Blood Vessels; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Cause of Death; Caveolae; Chemistry; Clinical; Data; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Drug Targeting; ERBB2 gene; Endothelial Cells; Endothelium; Glutathione; Human; Intravenous; Malignant Neoplasms; Mammary Gland Parenchyma; Mammary Neoplasms; Maximum Tolerated Dose; Medicine; Metastatic breast cancer; Modeling; Molecular; Nature; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Operating System; Organ; Pathway interactions; Patient-derived xenograft models of breast cancer; Patients; Penetration; Pharmaceutical Preparations; Phase; Production; Publishing; Pump; Rattus; Regimen; Rodent; Safety; Series; Site; Solid Neoplasm; Specificity; Speed; Surface; System; Systemic Therapy; Therapeutic; Therapeutic Agents; Therapeutic Studies; Time; Tissues; Toxic effect; Translations; Treatment Efficacy; Tumor Tissue; Validation; Vascular Endothelial Cell; Woman; base; cancer diagnosis; chemotherapy; clinical application; clinical translation; clinically relevant; efficacy evaluation; efficacy validation; experimental study; human model; humanized antibody; immunoreactivity; improved; intravital microscopy; malignant breast neoplasm; neoplastic cell; novel; novel therapeutics; personalized medicine; screening; targeted treatment; therapeutic evaluation; treatment response; treatment strategy; tumor; vascular endothelium permeability

Breast cancer is the most commonly diagnosed cancer in women and is a second leading cause of death among woman. Despite the significant progress in molecular understanding and personalized therapies of breast cancer, this disease in progressed metastatic stage remains incurable and treatment options available to patients provide only modest survival benefit. Efficacy of existing systemic chemotherapy is limited in delivery, access and penetration into solid tumors, as well as by toxicity to patients. Thus, to develop more effective and safer therapies of breast cancer, it is necessary to implement an efficient targeted drug delivery system. Caveolae at the surface of tumor endothelial cells act as a transendothelial transport system that actively pumps targeted antibodies from the blood circulation into the tumor tissue. Our findings support that targeting caveolae provides a platform for rapid pumping of targeted antibodies with attached cargo specifically into breast tumors at concentrations greatly exceeding maximum levels in the blood. Using these recent findings, we intend to target antibody drug conjugates (ADC) of DM1 maytansinoid, one of the most potent anticancer drugs to target truncated form of Annexin A1 in tumor endothelial caveolae in order to deliver this powerful therapeutic effectively inside of breast tumors. We have demonstrated that AnnA1 is expressed in the vasculature and caveolae of human tumors. Recently, we have generated humanized antibody against AnnA1 (hAnnA1) and our preliminary experiments demonstrate strong therapeutic response of breast cancer to hAnnA1 conjugated to DM1 (hAnnA1-DM1 ADC). We hypothesize that by pumping targeted antibodies armed with DM1 drug into breast tumors, caveolae can rapidly and specifically accumulate this therapeutic agent inside tumors, leading to tumor destruction with significantly reduced toxicity. We propose these Specific Aims: Aim 1. To generate and characterize ADCs. We will prepare series of conjugates with DM1 drug covalently attached to hAnnA1 antibody using non-cleavable and cleavable linkers. Based on the screening in Aim2, we will generate THIOMAB hAnnA1 with select linker chemistry. Aim 2. Screening for optimal linker chemistry, production, validation and pharmacokinetic analysis of tumor vascular caveolae-targeted DM1 THIOMAB ADC in rodent tumor model of breast cancer. These studies will enable implementing optimal linker chemistry to develop ADC with site-specific attachment of DM1. Aim 3. Evaluation of therapeutic efficacy of the tumor vascular caveolae-targeted DM1 ADCs in clinically-relevant models of breast cancer. Therapeutic studies in clinically-relevant orthotopic models of breast cancer, including intravital microscopy model of human tumor spheroids engrafted into human breast tissue, and patient-derived breast cancer xenografts, including triple-negative and HER2+ models, will provide platform to evaluate novel hAnnA1-DM1 ADC therapy. The proposed project will help to establish framework for clinical translation of tumor-caveolae targeted ADC for treatment of breast cancer.

乳腺癌是女性中最常见的癌症，是死亡的第二大原因 在女人中。尽管在分子理解和个性化疗法方面取得了重大进展 乳腺癌，这种正在进行的转移阶段的疾病仍然无法治愈，可用的治疗选择 对于患者，仅提供适中的生存益处。现有系统化疗的功效有限 分娩，进入和穿透实体瘤以及对患者的毒性。因此，发展更多 有效，更安全的乳腺癌疗法有必要实施有效的目标药物 系统。肿瘤内皮细胞表面的小窝是一种跨内皮转运系统 从血液循环到肿瘤组织中靶向抗体的积极泵。我们的发现支持 定位小窝为快速泵送具有连接货物的目标抗体提供了一个平台 以浓度大大超过血液中最大水平的乳腺肿瘤。使用这些最近 调查结果，我们打算靶向DM1 Maytansinoid的抗体药物缀合物（ADC），这是最有效的之一 抗癌药以靶向肿瘤内皮小窝中截短的膜联蛋白A1的截短形式，以实现 在乳腺肿瘤内有效地治疗。我们已经证明了Anna1在 人类肿瘤的脉管系统和小窝。最近，我们对Anna1产生了人性化抗体 （Hanna1）和我们的初步实验表明乳腺癌对 Hanna1与DM1（Hanna1-DM1 ADC）共轭。我们通过泵送目标抗体来假设这一点 Caveolae将DM1药物进入乳腺肿瘤，可以迅速有特定地积累这种治疗剂 内部肿瘤，导致肿瘤破坏，毒性显着降低。我们提出了这些具体目标： 目标1。生成和表征ADC。我们将与DM1药物共同准备一系列的共轭物 使用不可裂解和可裂解的接头连接到Hanna1抗体上。根据AIM2的筛选，我们 将使用精选的接头化学产生硫族HANNA1。 目标2。筛选最佳接头化学，生产，验证和药代动力学分析 肿瘤血管caveolae靶向的DM1硫瘤ADC在啮齿动物肿瘤模型中。这些 研究将使实施最佳的接头化学能够通过DM1的特定地点附着来开发ADC。 目标3。评估肿瘤血管口腔靶向DM1 ADC的治疗功效 临床上与乳腺癌相关的模型。与临床相关的原位模型的治疗研究 乳腺癌，包括植入人类乳房的人类肿瘤球体的插入显微镜模型 组织和患者来源的乳腺癌异种移植物，包括三阴性和HER2+模型，将提供 评估新型Hanna1-DM1 ADC疗法的平台。拟议的项目将有助于建立框架 用于肿瘤胶质的临床翻译针对ADC治疗乳腺癌的临床翻译。