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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

基本信息

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
项目类别：
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

项目摘要

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.

一种治疗b系急性淋巴细胞的新型VpreB1抗体-药物偶联物