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

用于治疗B系急性淋巴细胞白血病的新型VpreB 1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。B- ALL复发是婴儿、青少年和成人在各个阶段的常见问题。复发的B-ALL 在基于细胞的治疗显示抗原重塑、靶向抗原下调和谱系改变后， 会转变成不同类型的白血病然而，导致这种疾病的分子和细胞机制， 对耐药白血病细胞的出现还没有很好的了解。 几乎所有的B-ALL病例都有一个有限的B细胞表面标记。基于细胞的治疗靶向 不幸的是，这些表面受体消除了所有正常的B细胞，导致全B细胞消融和免疫反应。 失调这会导致严重的并发症和很大一部分患者因感染而死亡的风险 多次复发的人。为了提高患者安全，我们的项目解决了这些问题 复发、机会性感染和器官毒性。 前B细胞受体（pre-BCR）自主发出信号，通过前B细胞受体和前B细胞受体携带发育中的B细胞。 分化阶段。B-ALL通常在分化的前B阶段和前B阶段被阻止，其中这些 细胞经历前BCR介导的自主信号传导、存活和克隆扩增。我们假设 我们针对前BCR的新型VpreB 1 ADC将使白血病细胞能够解偶联的途径 存活下来并对常规化疗产生耐药性。像我们正在开发的这种疗法 许多毒性，包括损害肝细胞和免疫系统细胞的副作用， 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中残留疾病的耐药机制。目前尚无B-ALL免疫治疗靶点 自主生存信号该项目的制定是为了使儿童受益，他们拥有独特的 生理学和毒性特征。通过使用AcBut-Calicheamicin接头和有效载荷，我们将深入了解 儿童肿瘤学小组收集的接受类似连接毒素的儿童的安全性数据 有效载荷我们的方法是响应FDA的2017年最佳药品法案，该法案要求新的 用于面临危及生命的疾病的儿童和年轻人的药物，包括复发的B-ALL或高 诊断时的风险。 总之，作为对PAR-20-292的回应，我们的提案描述了一种新型生物制剂的开发， 药物，以及减轻需要治疗的儿童和年轻人的治疗相关毒性的策略 治疗B-ALL。 在本提案中，我们将： 继续新型ADC的发展轨迹，以解决复发、机会主义和药物滥用等问题。 B-ALL治疗中的感染和其他毒性; 评估我们的新型ADC在治疗难治性B-ALL中靶向残留疾病的效果; 评估ADC的生存率和药物不良反应，特别是对器官毒性的影响， 感染并发症; 评估我们的新型ADC在B-ALL中的适应性免疫能力。

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.