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

• 批准号: 10532233
• 负责人: Qingyun Liu
• 金额: $ 21.44万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10532233
• 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; Disease; FDA approved; G-Protein-Coupled Receptors; Generations; Goals; In Vitro; Incidence; Knock-out; 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; 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 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

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.

神经母细胞瘤是一种发生在15岁以下儿童的脑外神经系统癌症。 年纪大了。它是婴儿期最常见的癌症，约占所有与癌症相关的癌症的12%。 儿童死亡。它被认为是一种罕见的癌症，因为它的总发病率显著低于6%。 美国有100,000人。大约一半的NB病例被治愈，只需很少的时间，有时甚至没有 而另一半是高危患者，他们的长期存活率只有~50%，尽管 密集的多模式治疗，毒性很大。 抗体-药物结合物(Adc)是与细胞杀伤共价连接的单抗。 将有效载荷运送到癌细胞的细胞毒素。多个ADC现已被FDA批准用于 癌症治疗，包括白血病、乳腺癌和膀胱癌。LGR5(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。针对LGR5及其相关途径的治疗药物正在开发中 由这种机制驱动的胃肠道癌症而开发的。值得注意的是，发现了高水平的LGR5 在NB肿瘤细胞中，LGR5表达增加与生存不良相关。然而，LGR5是否可以 是否针对高危NBS的治疗仍不得而知。 我们发现，从NB癌细胞中去除LGR5导致细胞内癌细胞生长急剧下降 培养和动物体内肿瘤的形成。我们还使用抗LGR5抗体生成了ADC，并发现 LGR5 ADC对高水平LGR5的NB癌细胞具有高效的杀伤作用。这样做的目的是 项目是验证LGR5作为使用ADC方法治疗高危国家BS的潜在目标 进一步提高LGR5 ADC的效力和疗效。我们将生成一系列具有不同功能的ADC 并在动物模型中确定它们在阻止肿瘤生长方面的活性。该项目，如果成功， 可能导致对发现和开发高危NBS治疗方法的新方法的验证 以及进一步开发的候选药物。