Dual-payload antibody-drug conjugate for chemo-immunotherapy of triple-negative breast cancers

用于三阴性乳腺癌化学免疫治疗的双有效负载抗体-药物偶联物

基本信息

批准号：
10711488
负责人：
WILLIAM E. CARSON
金额：
$ 58.72万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-25 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10711488
关键词：
4T1 Affinity Agonist Animal Model Antibody-drug conjugates Apoptosis Binding Biodistribution Breast Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment CD276 gene CTLA4 gene Cell Death Cells Circulation Clinic Clinical Trials Combined Modality Therapy Cytotoxic Chemotherapy Data Development Distant Drug Kinetics Drug resistance Engineering Evaluation Event Excision Extracellular Domain Flow Cytometry Future Goals Heterogeneity Histopathology Human Immune Immune Tolerance Immuno-Chemotherapy Immunocompetent Immunohistochemistry Immunotherapy In Vitro Infiltration Interferon Type II Invaded Investigation Laboratories MDA MB 231 Macrophage Malignant Neoplasms Maximum Tolerated Dose Mediating Medical Membrane Membrane Glycoproteins Microtubules Modeling Monoclonal Antibodies Names Neoplasm Metastasis Operative Surgical Procedures Organ Pathology Patients Pharmaceutical Preparations Pharmacotherapy Prognosis Proliferating Proteomics Quality of life Radiation therapy Receptor Activation Recurrence Refractory Relapse Resistance Specificity Surface Survival Rate T-Lymphocyte TLR1 gene TLR7 gene TNF gene Technology Testing Therapeutic Therapeutic Monoclonal Antibodies Tissue Microarray Tissues Toll-like receptors Toxic effect Toxicology Transcript Translations Treatment Efficacy Treatment Protocols Tumor Burden Tumor Immunity Tumor Promotion Xenograft Model Xenograft procedure angiogenesis anti-PD-1 anti-PD1 antibodies anti-cancer cancer cell cancer subtypes cancer therapy cell killing chemotherapy clinically relevant confocal imaging cytokine cytotoxic cytotoxicity dosage effective therapy effectiveness evaluation efficacy study glycosylation high dimensionality humanized mouse immune cell infiltrate immune checkpoint immune checkpoint blockade immune checkpoint blockers immune function immunoregulation improved in vivo innovation mouse model neoplastic cell novel novel therapeutic intervention optimal treatments patient derived xenograft model pembrolizumab phase III trial pre-IND studies pre-clinical programmed cell death ligand 1 programmed cell death protein 1 response restoration standard of care synergism systemic toxicity targeted treatment treatment strategy triple-negative invasive breast carcinoma tumor tumor microenvironment tumor-immune system interactions

项目摘要

SUMMARY Triple-negative breast cancers (TNBCs) are highly aggressive and often relapse post standard cytotoxic chemotherapies. The immunotherapies such as immune checkpoint blockers (ICBs) that target PD-1, PD-L1 or CTLA-4 represent a major breakthrough in cancer treatment, but 75-90% of TNBC patients failed to respond due to primary and acquired resistance. The Sacituzumab-SN38 and Pembrolizumab-chemotherapy have been developed and applied to treat refractory metastatic TNBC, showing the great potential of combined and targeted therapies, but novel effective treatment strategies for TNBC are urgently needed. We recently detected transmembrane CD276 (B7-H3) associated with angiogenesis, metastasis and immune tolerance in most TNBC patients, and developed a humanized anti-CD276 monoclonal antibody (mAb) capable of targeting CD276+ TNBC and upregulating tumoral immunity. Furthermore, we established innovative platforms for concurrent conjugation of highly cytotoxic emtansine and immunoregulating toll-like receptor (TLR) agonist in one antibody- drug conjugate (ADC). Our preliminary evaluations showed that the CD276-targeted dual-payload ADC (276- DualADC) effectively killed multiple TNBC subtypes, significantly enhanced immune functions and overcame ICB resistance to PD-1 mAb, and reduced tumor burden by 90-100% and metastasis in three animal models. These results indicate 276-DualADC is a promising therapeutic to treat TNBCs. Our goal is to develop and examine the effectiveness of combining humanized CD276 mAb-directed Hu276-DualADC, which targeting delivers a potent chemotherapy and immunotherapy TLR 7/8 agonist, and PD-1-targeting ADC to eliminate heterogenous and metastatic TNBC cells in vivo. It is hypothesized that this novel combinatory strategy, named as Hu276/PD-1-DualADC, synergizes multiple chemo- and immuno-mediated anti-cancer mechanisms, i.e., direct cancer cell killing, tumoral immunity, tumoral cytokine, and immune checkpoint blockade, to enhance TNBC treatment efficacy. Three aims were proposed to test the hypothesis. Aim 1 will produce large-scale Hu276-DualADC carrying mertansine and imidazoquinoline, and characterize its affinity, TNBC-specificity, biodistribution and toxicity. Optimal treatment strategy will be determined in maximal tolerated dose and pharmacokinetics studies. Finally, anti-TNBC efficacy will be evaluated in primary xenograft models and distant metastatic models. Aim 2 will assess the synergistic effects of HuCD276/PD-1-DualADC in three immunocompetent models. The underlying mechanisms (proliferation, apoptosis, immune cell infiltration and activation, tumoral cytokine, and ICB restoration) will also be delineated. Aim 3 will fully evaluate the long-term therapeutic efficacy in metastatic syngeneic TNBC xenograft models post surgical resection and patient-derived xenograft (PDX) models. Pre-IND toxicology will also be investigated to collect preclinical data for future clinical trial launching. Successful completion of this project will provide a new strategy to treat aggressive TNBCs.

概括三阴性乳腺癌（TNBC）是高度侵略性的，经常在标准细胞毒性后复发化学疗法。靶向PD-1，PD-L1或 CTLA-4代表了癌症治疗的重大突破，但有75-90％的TNBC患者未能应对应有对主要和获得的阻力。 sacituzumab-sn38和pembrolizumab-rytheraphy一直是开发并应用于治疗难治性转移TNBC，显示合并和靶向的巨大潜力迫切需要疗法，但是针对TNBC的新型有效治疗策略。我们最近检测到在大多数TNBC中，跨膜CD276（B7-H3）与血管生成，转移和免疫耐受性有关患者，并开发了一种人性化的抗CD276单克隆抗体（MAB），能够靶向CD276+ TNBC和上调肿瘤免疫。此外，我们建立了并发的创新平台一种高度细胞毒性emtansine和一种免疫调节的收费受体（TLR）激动剂在一种抗体 - 药物共轭（ADC）。我们的初步评估表明，CD276靶向的双付载ADC（276-- DualAdc）有效杀死多个TNBC亚型，显着增强的免疫功能并克服了 ICB对PD-1 MAB的抵抗力，在三种动物模型中降低了90-100％的肿瘤负担和转移。这些结果表明276-DualADC是治疗TNBC的有前途的治疗方法。我们的目标是发展和检查将人源化CD276 mAb指导的HU276-DualADC组合的有效性提供有效的化学疗法和免疫疗法TLR 7/8激动剂，以及PD-1靶向ADC消除体内异质和转移性TNBC细胞。假设这个新颖的组合策略命名为作为HU276/PD-1-DUALADC，可以协同多种化学和免疫介导的抗癌机制，即直接癌细胞杀伤，肿瘤免疫力，肿瘤细胞因子和免疫检查点封锁，以增强 TNBC治疗功效。提出了三个目的来检验假设。 AIM 1将产生大规模 HU276二元携带墨西哥氨酸和咪唑喹啉，并表征其亲和力TNBC特异性，生物分布和毒性。最佳治疗策略将以最大耐受剂量和药代动力学研究。最后，将在主要异种移植模型和远处评估抗TNBC疗效转移模型。 AIM 2将评估HUCD276/PD-1-DualADC在三个中的协同作用免疫能力模型。基本机制（增殖，凋亡，免疫细胞浸润和激活，肿瘤细胞因子和ICB恢复）也将被描述。 AIM 3将完全评估长期手术切除后的转移性TNBC异种移植模型和患者衍生的转移性TNBC异种移植模型的治疗功效异种移植（PDX）模型。还将研究原始毒理学，以收集临床前数据以进行未来的临床审判发射。该项目的成功完成将为治疗积极的TNBC提供新的策略。