A Novel VpreB1 Anti-body Drug Conjugate for the Treatment of B-Lineage Acute Lymphoblastic Leukemia/Lymphoma

一种用于治疗 B 系急性淋巴细胞白血病/淋巴瘤的新型 VpreB1 抗体药物偶联物

• 批准号: 10651082
• 负责人: PETER M GORDON
• 金额: $ 21.87万
• 依托单位: CHILDREN'S HOSPITALS AND CLINICS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-07 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651082
• 关键词: Ablation; Acute Lymphocytic Leukemia; Address; Adolescent; Adult; Adverse drug effect; Adverse event; Age; Algorithms; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; B cell repertoire; B cell therapy; B-Cell Acute Lymphoblastic Leukemia; B-Cell Lymphomas; B-Lymphocytes; Biological Products; Blood; Cancer Patient; Cell Surface Receptors; Cell Survival; Cell Therapy; Cell surface; Cells; Central Nervous System; Child; Clinical; Clonal Expansion; Communicable Diseases; Data; Development; Diagnosis; Disease; Dose; Down-Regulation; Ethnic Origin; Event; Face; Family; Future; Genetic; Goals; Hepatic; Hepatocyte; Immune; Immune system; Immunoconjugates; Immunotherapy; In Vitro; Infant; Infection; Investigational Therapies; Leukemic Cell; Life; Liver; Malignant Neoplasms; Mature B-Lymphocyte; Measurable; Mediating; Microvascular Dysfunction; Molecular; Mus; Natural Immunity; Opportunistic Infections; Organ; Pathway interactions; Patients; Pediatric Oncology Group; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Physiology; Population; Positioning Attribute; Precision therapeutics; Precursor B-Lymphoblast; Publishing; Race; Relapse; Residual Neoplasm; Resistance; Risk; Risk Reduction; SYK gene; Safety; Sampling; Science; Sepsis; Signal Transduction; Surface; T-Cell Activation; Therapeutic Agents; Toxic effect; Toxin; Treatment-related toxicity; acute lymphoblastic leukemia cell; adaptive immunity; burden of illness; cancer therapy; cell bank; cell killing; chemotherapy; disorder risk; high risk; humanized mouse; immunoreactivity; improved; in vivo; innovation; insight; leukemia; leukemia relapse; leukemia/lymphoma; liver injury; mortality risk; mouse model; novel; novel therapeutics; patient safety; patient subsets; phase 1 study; pre-B cell receptor; preclinical study; receptor; receptor expression; relapse risk; resistance mechanism; response; septic; side effect; symptom management; targeted treatment; therapy resistant; young adult

A Novel VpreB1 Antibody-Drug Conjugate for the Treatment of B-Lineage Acute Lymphoblastic Leukemia/Lymphoma B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children and young adults. B- ALL relapse is a common problem among infants, adolescents, and adults at all stages. B-ALLs that relapse after cell-based therapies demonstrate antigen remodeling, down-regulation of targeted antigens, and lineage switches to different types of leukemia. However, the molecular and cellular mechanisms that lead to the emergence of resistant leukemic cells are not well understood. Nearly all B-ALL cases share a restricted repertoire of B-cell surface markers. Cell-based therapies targeting these surface receptors unfortunately eliminate all normal B cells, causing pan B-cell ablation and immune dysregulation. This leads to serious complications and the risk of death due to infection in a significant fraction of people who have suffered multiple relapses. To improve patient safety, our project addresses the problems of relapse, opportunistic infections, and organ toxicities in B-ALL. The pre-B-cell receptor (pre-BCR) autonomously signals to carry developing B-cells through the pro- and pre-B stages of differentiation. B-ALL is usually arrested at the pro- and pre-B stages of differentiation, where these cells are subject to pre-BCR-mediated autonomous signaling, survival, and clonal expansion. We hypothesize that our novel VpreB1 ADC against the pre-BCR will de-couple the pathways that allows leukemia cells to survive and become resistant to conventional chemotherapy. Therapies like the one we are developing have lots of toxicities, including side effects that harm liver cells and the cells of the immune system that makes antibodies against infectious diseases. Better immunotherapies can lead to less organ damage, reduce opportunistic infections, and directly target the resistance mechanisms that lead to residual disease in B-ALL. No current B-ALL immunotherapies target autonomous survival signaling. This project is being expressly developed to benefit children, who have unique physiologies and toxicity profiles. By using an AcBut-Calicheamicin linker and payload, we will gain insight into safety data that have been collected by the Children’s Oncology Group for children receiving similar linker-toxin payloads. Our approach is responsive to the FDA’s Best Pharmaceuticals Act of 2017, which calls for new drugs for children and young adults who face life-threatening diseases, including B-ALL in relapse or with high- risk disease at diagnosis. In summary and in response to PAR-20-292, our proposal describes the development of a novel biologic agent, with strategies to mitigate treatment-related toxicities for children and young adults who require treatment for B-ALL. In this proposal, we will:  Continue the developmental trajectory of a novel ADC to address the problems of relapse, opportunistic infections, and other toxicities in the treatment of B-ALL;  Evaluate how well our novel ADC targets residual disease in treatment-resistant B-ALL;  Assess the survival and adverse drug effects of our ADC, especially its effect on organ toxicities and infectious complications;  Evaluate how well our novel ADC spares adaptive immunity in B-ALL.

用于治疗 B 系急性淋巴细胞白血病的新型 VpreB1 抗体药物偶联物 白血病/淋巴瘤 B 细胞急性淋巴细胞白血病 (B-ALL) 是儿童和年轻人中最常见的恶性肿瘤。 ALL 复发是所有阶段 B-ALL 复发的婴儿、青少年和成人中的常见问题。 基于细胞的疗法证明抗原重塑、靶向抗原和谱系下调后 然而，导致不同类型白血病的分子和细胞机制。 耐药性白血病细胞的出现尚不清楚。 几乎所有 B-ALL 病例都具有有限的 B 细胞表面标记物靶向治疗。 不幸的是，这些表面受体消除了所有正常 B 细胞，导致泛 B 细胞消融和免疫 这会导致严重的并发症以及很大一部分因感染而死亡的风险。 为了提高患者的安全性，我们的项目解决了这些问题。 B-ALL 的复发、机会性感染和器官毒性。 前 B 细胞受体 (pre-BCR) 通过 pro- 和 pre-B 自主发出信号以携带发育中的 B 细胞 B-ALL 通常停滞在分化前和前 B 阶段，其中这些阶段 细胞受到前 BCR 介导的信号传导、存活和克隆自主扩增的影响。 我们针对前 BCR 的新型 VpreB1 ADC 将解耦白血病细胞的通路 生存并对传统化疗产生耐药性。 许多毒性，包括损害肝细胞和免疫系统细胞的副作用 对抗传染病的抗体。 更好的免疫疗法可以减少器官损伤，减少机会性感染，并直接针对 导致 B-ALL 残留疾病的耐药机制。目前没有 B-ALL 免疫疗法的目标。 该项目的开发目的是为了让具有独特能力的儿童受益。 通过使用 AcBut-Calicheamicin 连接体和有效负载，我们将深入了解。 儿童肿瘤学小组为接受类似连接毒素的儿童收集的安全数据 我们的方法响应 FDA 2017 年最佳药品法案，该法案要求新的有效负载。 对于吸毒的儿童和年轻人来说，他们面临着危及生命的疾病，包括复发或患有高风险的 B-ALL 诊断时存在疾病风险。 总之，为了回应 PAR-20-292，我们的提案描述了一种新型生物制剂的开发 剂，并采取策略减轻需要治疗的儿童和年轻人的治疗相关毒性 B-ALL 的治疗。 在本提案中，我们将：  继续新型 ADC 的发展轨迹，以解决复发、机会主义问题 B-ALL 治疗中的感染和其他毒性； 评估我们的新型 ADC 针对难治性 B-ALL 中残留疾病的效果；  评估我们的 ADC 的存活率和药物不良反应，特别是其对器官毒性和副作用的影响 感染性并发症；  评估我们的新型 ADC 在 B-ALL 中对适应性免疫的保护效果如何。