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

一种治疗B系急性淋巴细胞白血病的新型VpreB1抗体-药物结合物 白血病/淋巴瘤 B细胞急性淋巴细胞白血病(B-ALL)是儿童和青壮年最常见的恶性肿瘤。B- 所有复发都是婴幼儿、青少年和成年人在各个阶段的共同问题。B-复发的ALL 在以细胞为基础的治疗显示抗原重塑、靶向抗原下调和谱系后 换成了不同类型的白血病。然而，导致这种疾病的分子和细胞机制 耐药白血病细胞的出现还不是很清楚。 几乎所有的B-ALL病例都共享有限的B细胞表面标志物。基于细胞的治疗靶向 不幸的是，这些表面受体清除了所有正常的B细胞，导致了泛B细胞的消融和免疫 监管失调。这会导致严重的并发症和相当大一部分因感染而死亡的风险。 那些多次复发的人。为了提高患者的安全，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)自主地发出信号，通过前B细胞和前B细胞携带发育中的B细胞 分化阶段。B-ALL通常在分化的前B期和前B期停止，在这种情况下 细胞受制于BCR前介导的自主信号、存活和克隆性扩增。我们假设 我们针对Pre-BCR的新型VpreB1 ADC将解偶联允许白血病细胞 存活下来，并对常规化疗产生抗药性。像我们正在开发的这种疗法有 许多毒性，包括损害肝脏细胞和免疫系统细胞的副作用 针对传染病的抗体。 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。目前没有针对B-ALL免疫疗法的目标 自主生存信号。这个项目是专门为儿童制定的，他们有独一无二的 生理和毒性特征。通过使用AcBut-calicheamicin链接器和负载，我们将深入了解 儿童肿瘤学小组为接受类似链接物毒素的儿童收集的安全数据 有效载荷。我们的方法是对FDA 2017年最佳药品法案的响应，该法案呼吁新的 儿童和年轻人面临危及生命的疾病的药物，包括B-所有复发或高度... 确诊时有患病风险。 综上所述，根据PAR-20-292，我们的建议描述了一种新的生物 制剂，以及减轻与治疗相关的毒性的策略，适用于需要 B-ALL的治疗。 在这项建议中，我们将： 延续了新型模数转换器的发展轨迹，以解决复发、机会主义的问题 B-ALL治疗中的感染和其他毒性反应； 评估我们的新型ADC靶向耐药B-ALL的残留病的情况； 评估我们的ADDC的存活率和药物不良反应，特别是其对器官毒性和 感染性并发症； 评估我们的新型模数转换器在B-ALL中的应用情况。

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.