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) 具有高度侵袭性，并且在标准细胞毒性治疗后经常复发化疗。免疫疗法，例如针对 PD-1、PD-L1 或 PD-1 的免疫检查点阻断剂 (ICB) CTLA-4代表了癌症治疗的重大突破，但 75-90% 的 TNBC 患者由于以下原因未能做出反应原发性和获得性抵抗。 Sacituzumab-SN38 和 Pembrolizumab 化疗已开发并应用于治疗难治性转移性TNBC，显示出联合靶向治疗的巨大潜力疗法，但迫切需要针对 TNBC 的新的有效治疗策略。我们最近检测到跨膜 CD276 (B7-H3) 与大多数 TNBC 中的血管生成、转移和免疫耐受相关患者，并开发了能够靶向 CD276+ 的人源化抗 CD276 单克隆抗体 (mAb) TNBC 和上调肿瘤免疫。此外，我们还建立了并发的创新平台将高细胞毒性 emtansine 和免疫调节 Toll 样受体 (TLR) 激动剂结合在一种抗体中药物偶联物（ADC）。我们的初步评估表明，针对 CD276 的双有效负载 ADC (276- DualADC）有效杀灭多种TNBC亚型，显着增强免疫功能，攻克 ICB 对 PD-1 mAb 产生耐药性，并在三种动物模型中将肿瘤负荷和转移减少了 90-100%。这些结果表明 276-DualADC 是一种有前途的治疗 TNBC 的疗法。我们的目标是开发和检查结合人源化 CD276 mAb 导向的 Hu276-DualADC 的有效性，其靶向提供有效的化疗和免疫疗法 TLR 7/8 激动剂和 PD-1 靶向 ADC，以消除体内异质性和转移性TNBC细胞。假设这种新颖的组合策略名为 Hu276/PD-1-DualADC 可协同多种化疗和免疫介导的抗癌机制，即直接杀伤癌细胞、肿瘤免疫、肿瘤细胞因子和免疫检查点阻断，以增强 TNBC治疗效果。提出了三个目标来检验该假设。目标1：大规模生产 Hu276-DualADC 携带美坦辛和咪唑喹啉，并表征其亲和力、TNBC 特异性、生物分布和毒性。最佳治疗策略将根据最大耐受剂量和药代动力学研究。最后，将在原代异种移植模型和远端移植模型中评估抗 TNBC 疗效。转移模型。目标 2 将评估 HuCD276/PD-1-DualADC 在三个方面的协同效应免疫活性模型。潜在的机制（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。目标3将充分评估长期手术切除后和患者来源的转移性同基因 TNBC 异种移植模型的治疗效果异种移植（PDX）模型。还将研究 IND 前毒理学，为未来的临床收集临床前数据试运行。该项目的成功完成将为治疗侵袭性 TNBC 提供新策略。