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.

一种新型的VPREB1抗体 - 药物结合物，用于治疗B-linege急性淋巴细胞 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- 在各个阶段，所有接力赛都是婴儿，青少年和成人的常见问题。 B-alls中继 基于细胞的疗法显示抗原重塑，靶向抗原的下调和谱系 切换到不同类型的白血病。但是，导致的分子和细胞机制 抗性白血病细胞的出现尚不清楚。 几乎所有B-ALL病例都有B细胞表面标记的局限性受限的曲目。基于细胞的疗法靶向 不幸的是，这些表面受体消除了所有正常的B细胞，导致PAN B细胞消融和免疫 失调。这会导致严重的并发症和由于大量部分感染而导致死亡的风险 遭受了多个继电器的人。为了提高患者安全，我们的项目解决了问题 B-all的救济，机会性感染和器官毒性。 前B细胞接收器（BER-BCR）自主信号通过Pro和Pre-B携带开发B细胞 差异阶段。 b-所有人通常在分化的亲和前阶段被捕，在这些阶段 细胞受到前BCR介导的自主信号传导，存活和克隆扩张的约束。我们假设 我们的新型VPREB1 ADC针对前BCR的ADC将解开允许白血病细胞的途径 生存并耐药地对常规化疗。像我们正在开发的疗法一样 许多毒性，包括伤害肝细胞和免疫系统细胞的副作用 针对传染病的抗体。 更好的免疫疗法会导致器官损伤减少，减少机会性感染，并直接针对 抗性机制导致B-all中残留疾病。当前没有B-ALL免疫疗法目标 自主生存信号传导。该项目正在明确开发以使其受益的儿童，他们拥有独特的儿童 生理和毒性谱。通过使用acbut-calicheamicin链接器和有效载荷，我们将深入了解 儿童肿瘤学小组收集的安全数据接受了类似的接头毒素 有效载荷。我们的方法是对2017年FDA最佳药品法案的反应，该法案要求新 面临威胁生命的疾病的儿童和年轻人的药物，包括退休或高级疾病 诊断时风险疾病。 总而言之并回应Par-20-292，我们的建议描述了一种新型生物学的发展 代理商，采用减轻需要治疗相关的毒性的策略 B-all的处理。 在此提案中，我们将： 继续新型ADC的发展轨迹，以解决救济，机会主义的问题 在B-all治疗中的感染和其他毒性； 评估我们的新型ADC对抗治疗抗性B-All的残留疾病的靶向程度； 评估ADC的生存和不良药物影响，尤其是其对器官毒性的影响 传染性并发​​症； 评估我们的新型ADC备用B-all中的自适应免疫力。