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

三阴性乳腺癌(TNBC)占所有乳腺癌的10%-20%，其特点是迅速 生长、转移和复发。此外，人类TNBC经常在初次治疗后重新生长，导致 转归为TNBC患者预后不良。标准的细胞毒化疗治疗TNBC的临床效果较差 益处和严重的副作用。靶向治疗，如单抗、抗体-药物 结合物(ADC)、嵌合抗原受体工程T细胞和小分子抑制剂已被 开发用于治疗实体肿瘤，同时将对正常细胞的副作用降至最低，但这些疗法都不是 已被应用于治疗TNBC。因此，靶向治疗仍然是有效治疗的一个未得到满足的医学需求。 TNBC。我们的初步研究确定了TNBC中的靶向表面受体(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单抗，测试了多种小分子 显示出高毒性，建立了抗CD276/CD47 ADC的构建和评价程序，并 评估我们的ADC在体内外的潜在安全性和抗癌效果。我们的中心假设是 以ADC为基础的治疗可以通过综合抗癌有效地消除TNBC，副作用有限 机械装置。在这项研究中，我们建议开发治疗TNBC的靶向疗法。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 通过研究靶向特异性、ADC有效载荷介导的抗TNBC疗效和 抗CD276单抗诱导免疫细胞活化和抑制肿瘤血管生成。在目标2中，我们将 发展以抗CD47 ADC为基础的靶向治疗以消除CD47+TNBC，特别是化疗诱导的 CD47+TNBC，防止肿瘤复发转移。我们将研究其抗肿瘤效果。 多种TNBC细胞系和异种移植瘤，并阐明了抗TNBC的机制，包括ADC- 介导的药物细胞毒作用、抗CD47单抗依赖的细胞毒作用及ADC药物的协同作用 和抗CD47单抗。在目标3中，我们计划使用我们已建立的最大耐受量方案， 联合用药的药代动力学、生物分布和抗肿瘤疗效评价 CD276和CD47在手术和/或转移的同基因TNBC异种移植模型中靶向ADC 化疗。如果抗癌效果在临床前模型中得到证实，这将是第一次联合使用 以ADC为基础的靶向治疗TNBC可克服耐药性，增强细胞毒作用 对肿瘤细胞低剂量，限制全身毒性，防止抗原丢失复发。重要的是，我们的设计 将为潜在的翻译应用建立临床疗法的模型，这将改善生活质量和 手术和/或化疗联合治疗的TNBC患者的生存率。

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.