Synergistic Targeted Therapy of Antibody-Drug Conjugates for Triple-Negative Breast Cancer

抗体药物偶联物对三阴性乳腺癌的协同靶向治疗

基本信息

批准号：
10542367
负责人：
Runhua Runa Liu
金额：
$ 47.75万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10542367
关键词：
4T1 Animal Model Anti-CD47 Antibodies Antibody-drug conjugates Antigens Biodistribution Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Breast Cancer cell line CD276 gene CD47 gene Cell Death Cell surface Cells Clinical Clinical Trials Cytotoxic Chemotherapy Dose Doxorubicin Drug Kinetics Drug Synergism Drug resistance Epidermal Growth Factor Receptor Evaluation Experimental Designs Extracellular Domain Future Goals Human Imaging Techniques Immune response In Vitro Investigation Laser Scanning Confocal Microscopy Luciferases MDA MB 231 MDA-MB-468 Malignant Neoplasms Maximum Tolerated Dose Mediating Medical Modeling Monoclonal Antibodies Mus Neoplasm Metastasis Normal Cell Operative Surgical Procedures Paclitaxel Patients Pharmaceutical Preparations Positron-Emission Tomography Pre-Clinical Model Procedures Production Prognosis Protocols documentation Quality of life Recurrence Recurrent tumor Relapse Residual state Safety Sampling Solid Neoplasm Specificity Surface Survival Rate Testing Therapeutic Toxic effect Tumor Angiogenesis Tumor Suppression Xenograft Model Xenograft procedure anti-cancer antibody-dependent cell cytotoxicity cancer subtypes chemotherapy chimeric antigen receptor curative treatments cytotoxic cytotoxicity design dosage effective therapy engineered T cells folate-binding protein gemcitabine glycosylation immune activation improved in vivo in vivo imaging system inhibitor innovation malignant breast neoplasm microscopic imaging neoplastic cell novel overexpression pre-clinical preclinical evaluation prevent rapid growth receptor response side effect small molecule small molecule inhibitor synergism systemic toxicity targeted treatment translational applications translational potential treatment strategy triple-negative invasive breast carcinoma tumor tumor xenograft

项目摘要

Triple negative breast cancer (TNBC) comprises 10-20% of all breast cancers and is characterized by rapid growth, metastasis, and recurrence. Furthermore, human TNBC often regrows after primary treatment, leading to poor prognosis in patients with TNBC. The standard cytotoxic chemotherapies for TNBC have the poor clinical benefit and severe side effects. Targeted therapies, such as monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), chimeric antigen receptor engineered T cells and small molecule inhibitors, have been developed to treat solid tumors while minimizing the side effects on normal cells, but none of these therapies has been applied to treat TNBC. Thus, targeted therapy remains an unmet medical need to effectively treat TNBC. Our preliminary studies identified the targeting surface receptors (such as CD276 and CD47) in TNBC, developed novel tumor-specific mAbs that target TNBC but not to normal cells, tested multiple small molecules showing high toxicity, established the construction and evaluation procedures of anti-CD276/CD47 ADCs, and evaluated the potential safety and anticancer efficacy of our ADCs in vitro and in vivo. Our central hypothesis is that the ADCs-based therapy can effectively eliminate TNBC with a limited side effect via integrated anti-cancer mechanisms. In this study, we propose to develop targeted therapies for curative treatment of TNBC. In Aim 1, we aim to build an effective platform of ADC therapies to treat CD276+ TNBC, and identify the most efficient treatment strategy by investigating the targeting specificity, ADC payloads-mediated anti-TNBC efficacy, and anti-CD276 mAb-induced immune cell activation and suppression of tumor angiogenesis. In Aim 2, we will develop anti-CD47 ADC-based targeted therapies to eliminate CD47+ TNBC, especially chemotherapy-induced CD47+ TNBC, and prevent tumor recurrence and metastasis. We will investigate the anti-tumor efficacy using multiple TNBC cell lines and xenograft tumors, and delineate the anti-TNBC mechanisms, including ADC- mediated drug cytotoxicity, anti-CD47 mAb-dependent cellular cytotoxicity, and synergistic action of ADC drug and anti-CD47 mAb. In Aim 3, we plan to use our established protocols of maximal tolerated dose, pharmacokinetics, biodistribution and anti-tumor efficacy to evaluate the therapeutic values of our combined dual CD276 and CD47 targeting ADCs in our metastatic syngeneic TNBC xenograft models after surgery and/or chemotherapy. If the anti-cancer efficacy is confirmed in the preclinical models, this will be the first combined ADCs-based targeted therapy for TNBC treatment, which may overcome drug resistance, enhance cytotoxicity to tumor cells with low dose, limit systemic toxicities, and prevent antigen-loss relapse. Importantly, our designs will model clinical therapies for potential translational application, which would improve life quality and the survival rate of TNBC patients in combination with surgery and/or chemotherapy.

三阴性乳腺癌 (TNBC) 占所有乳腺癌的 10-20%，其特点是发病迅速生长、转移和复发。此外，人类 TNBC 通常在初次治疗后会重新生长，导致 TNBC 患者预后不良。 TNBC的标准细胞毒化疗临床效果不佳益处和严重的副作用。靶向治疗，例如单克隆抗体 (mAb)、抗体药物缀合物（ADC）、嵌合抗原受体工程化T细胞和小分子抑制剂，已被开发用于治疗实体瘤，同时最大限度地减少对正常细胞的副作用，但这些疗法都没有已应用于治疗TNBC。因此，靶向治疗仍然是有效治疗的未满足的医疗需求 TNBC。我们的初步研究确定了 TNBC 中的靶向表面受体（例如 CD276 和 CD47），开发了针对 TNBC 但不针对正常细胞的新型肿瘤特异性 mAb，测试了多种小分子显示出高毒性，建立了抗CD276/CD47 ADC的构建和评估程序，以及评估了我们的 ADC 的体外和体内潜在安全性和抗癌功效。我们的中心假设是基于ADC的疗法可以通过综合抗癌有效消除TNBC且副作用有限机制。在这项研究中，我们建议开发靶向疗法来治愈 TNBC。在目标 1 中，我们的目标是建立一个有效的 ADC 疗法平台来治疗 CD276+ TNBC，并确定最有效的治疗方法通过研究靶向特异性、ADC 有效负载介导的抗 TNBC 功效来制定治疗策略，以及抗 CD276 mAb 诱导免疫细胞激活并抑制肿瘤血管生成。在目标 2 中，我们将开发基于抗 CD47 ADC 的靶向疗法，以消除 CD47+ TNBC，特别是化疗引起的 CD47+ TNBC，预防肿瘤复发和转移。我们将使用以下方法研究抗肿瘤功效多种 TNBC 细胞系和异种移植肿瘤，并描述了抗 TNBC 机制，包括 ADC- 介导的药物细胞毒性、抗 CD47 mAb 依赖性细胞毒性以及 ADC 药物的协同作用和抗CD47单克隆抗体。在目标 3 中，我们计划使用我们既定的最大耐受剂量方案，药代动力学、生物分布和抗肿瘤功效，以评估我们联合的双重治疗的治疗价值在我们的转移性同基因 TNBC 异种移植模型中，手术后和/或化疗。如果抗癌功效在临床前模型中得到证实，这将是第一个联合用药基于ADC的靶向治疗TNBC治疗，可克服耐药性，增强细胞毒性以低剂量作用于肿瘤细胞，限制全身毒性，并防止抗原丢失复发。重要的是，我们的设计将为潜在的转化应用建立临床治疗模型，这将改善生活质量和 TNBC 患者联合手术和/或化疗的生存率。