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：
9886056
负责人：
Runhua Runa Liu
金额：
$ 48.72万
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 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9886056
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 Protocols documentation Quality of life Recurrence Relapse Residual state Safety Sampling Side Solid Neoplasm Specificity Surface Survival Rate Testing Therapeutic Toxic effect Tumor Angiogenesis Tumor Suppression Xenograft Model Xenograft procedure anti-cancer antibody inhibitor antibody-dependent cell cytotoxicity base cancer subtypes chemotherapy chimeric antigen receptor curative treatments cytotoxic cytotoxicity design dosage effective therapy engineered T cells folate-binding protein gemcitabine immune activation improved in vivo in vivo imaging system innovation malignant breast neoplasm microscopic imaging neoplastic cell novel outcome forecast overexpression pre-clinical preclinical evaluation prevent rapid growth receptor response side effect small molecule small molecule inhibitor synergism systemic toxicity targeted treatment 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.

三重阴性乳腺癌（TNBC）占所有乳腺癌的10-20％，其特征是快速生长，转移和复发。此外，人类TNBC经常在初级治疗后再生 TNBC患者的预后不良。 TNBC的标准细胞毒性化学疗法的临床不良益处和严重的副作用。靶向疗法，例如单克隆抗体（mAb），抗体 - 药物结合（ADC），嵌合抗原受体工程T细胞和小分子抑制剂已已开发用于治疗实体瘤的同时最小化对正常细胞的副作用，但这些疗法均未已应用于治疗TNBC。因此，有针对性的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），开发了靶向TNBC但非正常细胞的新型肿瘤特异性mAB，测试了多个小分子显示高毒性，建立了抗CD276/CD47 ADC的构建和评估程序，评估了我们ADC在体外和体内的潜在安全性和抗癌功效。我们的中心假设是基于ADC的治疗可以通过综合抗癌者有效地消除具有有限副作用的TNBC 机制。在这项研究中，我们建议开发针对TNBC治疗治疗的靶向疗法。在AIM 1中，我们旨在建立一个有效的ADC疗法平台来治疗CD276+ TNBC，并确定最有效的通过研究靶向特异性，ADC有效载荷介导的抗TNBC功效和抗CD276 mAb诱导的免疫细胞活化和肿瘤血管生成的抑制。在AIM 2中，我们将开发抗CD47基于ADC的靶向疗法，以消除CD47+ TNBC，尤其是化学疗法诱导的 CD47+ TNBC，并防止肿瘤复发和转移。我们将使用使用的抗肿瘤功效多种TNBC细胞系和异种移植肿瘤，并描绘了包括ADC-在内的抗TNBC机制介导的药物细胞毒性，抗CD47 MAB依赖性细胞毒性和ADC药物的协同作用和抗CD47 mAb。在AIM 3中，我们计划使用我们已建立的最大耐受剂量方案，药代动力学，生物分布和抗肿瘤功效，以评估我们组合双重的治疗值在我们的转移性Syngeneic TNBC异种移植模型和/或化学疗法。如果在临床前模型中确认抗癌功效，这将是第一个组合基于ADC的靶向疗法用于TNBC治疗，可以克服耐药性，增强细胞毒性低剂量的肿瘤细胞，限制全身毒性，并防止抗原损伤复发。重要的是，我们的设计将建模潜在转化应用的临床疗法，这将改善生活质量和 TNBC患者与手术和/或化学疗法结合使用的存活率。