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LGR5 antibody drug conjugate for the treatment of neuroblastoma

LGR5抗体药物缀合物用于治疗神经母细胞瘤

基本信息

批准号：
10356494
负责人：
Qingyun Liu
金额：
$ 18.23万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356494
关键词：
15 year old Ablation Accounting Adult Adverse effects Animal Model Animals Antibodies Antibody-drug conjugates Antigen Targeting Brain Cancer Cell Growth Cancer Etiology Carcinoma Cell Adhesion Cell Culture Techniques Cell Line Cells Child Colon Carcinoma Combined Modality Therapy Cytotoxin Development Diagnosis Digestive System Cancer Disease FDA approved G-Protein-Coupled Receptors Generations Goals In Vitro Incidence Knock-out LGR5 gene Lead Leucine-Rich Repeat Ligands Link MYCN gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of urinary bladder Medical Membrane Monoclonal Antibodies Mus Neoplasm Metastasis Neoplasms Nervous system structure Neuroblastoma Pathway interactions Patients Persons Play Refractory Relapse Reporting Role Series Specificity Sympathetic Nervous System System Testing Therapeutic Therapeutic Agents Tissues Validation WNT Signaling Pathway adult stem cell antitumor effect cancer cell cancer diagnosis cancer stem cell cancer therapy cancer type cell growth cell killing cell motility chemotherapy childhood cancer mortality clinical development cytotoxic drug candidate fitness gastrointestinal system high risk improved in vitro testing in vivo in vivo Model infancy leukemia malignant breast neoplasm neoplastic cell neuroblastoma cell novel novel strategies novel therapeutics organ growth patient derived xenograft model public health relevance rare cancer receptor receptor density sialogangliosides side effect stem cells targeted treatment therapeutic target therapy development tumor tumor growth tumor initiation

项目摘要

Neuroblastoma (NB) is a cancer of the nervous system outside the brain that occurs in children under 15 years of age. It is the most frequently diagnosed cancer during infancy, accounting for ~12% of all-cancer related death in children. It is considered a rare cancer since its overall incidence is significantly less than 6 per 100,000 people in the U.S. Approximately half of NB cases are cured with minimal and sometimes no chemotherapy while the other half are high-risk patients who only have a long-term survival of ~50% despite intensive multimodal treatment that is quite toxic. Antibody–drug conjugates (ADCs) are monoclonal antibodies (mAbs) that are covalently linked to cell-killing cytotoxins to deliver the payloads into cancers cells. Multiple ADCs have now been approved by FDA for cancer treatment, including leukemia, breast cancer, and bladder cancer. LGR5 (leucine-rich repeat containing, G protein-coupled receptor 5) is a membrane receptor that is associated with formation and metastasis of cancers in the gastrointestinal system. Therapeutic agents targeting LGR5 and its associated pathway are being developed for gastrointestinal cancers driven by this mechanism. Remarkably, high levels of LGR5 are found in NB tumor cells, and more LGR5 expression is correlated with poor survival. However, whether LGR5 can also be targeted for the treatment of high-risk NBs remains unknown. We have found that ablation of LGR5 from NB cancer cells led to drastic decrease in cancer cell growth in cell cultures and tumor formation in animals. We also generated an ADC using an anti-LGR5 antibody and found that the LGR5 ADC is highly effectively in killing NB cancer cells with high level of LGR5. The goals of this project are to validate LGR5 as a potential target for the treatment of high-risk NBs using the ADC approach and further improve the potency and efficacy of LGR5 ADC. We will generate a series of ADCs with different payloads and determine their activities in blocking tumor growth in animal models. The project, if successful, may lead to the validation of a new approach for the discovery and development of treatments of high-risk NBs and drug candidates for further development.

神经母细胞瘤（NB）是一种发生在15岁以下儿童的脑外神经系统癌症年龄。它是婴儿期最常见的癌症，占所有癌症相关疾病的12%。儿童死亡。它被认为是一种罕见的癌症，因为它的总发病率明显低于6%。在美国，大约有一半的NB病例在最小的，有时甚至没有治愈。化疗，而另一半是高危患者，尽管化疗，密集的多模式治疗是相当有毒的。抗体-药物偶联物（ADC）是与细胞杀伤活性物质共价连接的单克隆抗体（mAb）。细胞毒素来将有效载荷递送到癌细胞中。FDA现已批准多种ADC用于癌症治疗，包括白血病、乳腺癌和膀胱癌。LGR 5（富含亮氨酸的重复序列， G蛋白偶联受体5）是一种膜受体，与肿瘤的形成和转移有关。胃肠道系统的癌症。靶向LGR 5及其相关通路的治疗剂正在被研究。用于治疗由这种机制驱动的胃肠道癌症。值得注意的是，高水平的LGR 5被发现，在NB肿瘤细胞中，更多的LGR 5表达与较差的存活率相关。然而，LGR5是否可以是否也可用于治疗高风险NB仍然未知。我们已经发现，从NB癌细胞中去除LGR 5导致细胞中癌细胞生长的急剧减少，培养物和动物肿瘤形成。我们还使用抗LGR 5抗体产生ADC，并发现 LGR 5 ADC在杀死具有高水平LGR 5的NB癌细胞方面是高度有效的。这个的目标项目旨在验证LGR 5作为使用ADC方法治疗高风险NB的潜在靶点并进一步提高LGR 5 ADC的效力和功效。我们将生成一系列ADC，有效载荷，并确定它们在动物模型中阻断肿瘤生长的活性。该项目如果成功，这可能会导致一种新的方法的发现和开发治疗高风险NB的验证以及用于进一步开发的候选药物。