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

• 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
• 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

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.

摘要 三阴性乳腺癌(TNBCs)是高度侵袭性的，通常在标准细胞毒性后复发。 化疗。免疫检查点阻滞剂(ICBS)等针对PD-1、PD-L1或 CTLA-4代表了癌症治疗的重大突破，但75%-90%的TNBC患者由于 原发抗性和获得性抗性。Sacituzumab-SN38和Pembrolizumab-化疗 开发并应用于治疗难治性转移的TNBC，显示出联合和靶向的巨大潜力 但是，迫切需要针对TNBC的新的有效的治疗策略。我们最近检测到 跨膜CD276(B7-H3)与肿瘤血管生成、转移和免疫耐受的关系 并开发了一种人源化的抗CD276单抗(MAb)，能够靶向CD276+ TNBC和上调肿瘤免疫力。此外，我们还为并发建立了创新的平台 高细胞毒牛血清白蛋白与免疫调节Toll样受体激动剂在一种抗体中的偶联 药物结合物(ADC)。我们的初步评估显示，CD276目标双负载ADC(276- DualADC)有效地杀死了多种TNBC亚型，显著增强了免疫功能，并克服了 ICB对PD-1单抗的抵抗力，在三种动物模型中，肿瘤负荷和转移减少了90-100%。 这些结果表明，276-DualADC是一种很有前途的治疗TNBCs的方法。我们的目标是发展和 检测人源化CD276单抗导向的Hu276-DualADC联合靶向 提供有效的化疗和免疫治疗TLR7/8激动剂和PD-1靶向ADC以消除 体内异种和转移的TNBC细胞。据推测，这一新的组合策略名为 作为Hu276/PD-1-DualADC，协同多种化学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这一假说。目标1号将生产大规模的 Hu276-DualADC携带Mertansine和咪唑喹啉，并鉴定其亲和力，TNBC特异性， 生物分布和毒性。最佳治疗策略将在最大耐受量和 药代动力学研究。最后，将在主要的异种移植模型和远程移植模型中评估抗tnbc的效果。 转移模型。目的2将评估HuCD276/PD-1-DualADC在三个方面的协同效应 免疫活性模型。其基本机制(增殖、凋亡、免疫细胞渗透和 激活、肿瘤细胞因子和ICB修复)也将被描述。目标3将全面评估长期 手术切除和患者来源的转移性同基因异种移植模型的治疗效果 异种移植(PDX)模型。还将对IND前毒理学进行调查，以收集临床前数据，供未来临床使用 试射。该项目的成功完成将为治疗侵袭性TNBCs提供一种新的策略。