Precision immunotherapies targeting the 9G4 idiotype in lupus erythematosus

针对红斑狼疮 9G4 独特型的精准免疫疗法

基本信息

批准号：
10682014
负责人：
Felipe Andrade
金额：
$ 24.56万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2023-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10682014
关键词：
Affect Alleles Antibodies Antigens Antinuclear Antibodies Autoantibodies Autoimmune Diseases Autoimmunity Autologous B cell therapy B-Cell Acute Lymphoblastic Leukemia B-Cell Antigen Receptor B-Lymphocyte Subsets B-Lymphocytes Binding Biological Assay Biological Models Bispecific Antibodies Bite CAR T cell therapy CD19 gene CD3 Antigens Cardiolipins Cell Compartmentation Cell Line Cell Separation Cells Clinical Trials Development Disease Disease remission Engineering Exclusion Flow Cytometry Foundations Goals Human Human Engineering Immunoglobulin G Immunoglobulin Idiotypes Immunoglobulins Immunotherapy Impairment Individual Infection Ku70 protein Life Lupus Lupus Erythematosus MS4A1 gene Mediating Memory Memory B-Lymphocyte Monoclonal Antibodies Morbidity - disease rate Muromonab-CD3 Nuclear Nucleic Acids Pathogenesis Pathogenicity Patients Peripheral Peripheral Blood Mononuclear Cell Pharmaceutical Preparations Plasma Cells Play Population Precision therapeutics Proteins Reaction Refractory Research Project Grants Role SLEB3 gene Serum Specificity Structure of germinal center of lymph node Surface Antigens Surface Plasmon Resonance System Systemic Lupus Erythematosus T cell therapy T-Cell Receptor T-Lymphocyte Testing Therapeutic Therapeutic Uses Tissues Work autoreactive B cell autoreactivity cancer cell crosslink cytotoxic design ds-DNA efficacy testing efficacy validation fighting in vitro Model infection risk innovation mortality novel novel therapeutic intervention pathogen peripheral blood personalized immunotherapy preservation primary endpoint rituximab targeted treatment treatment strategy vaccine response

项目摘要

PROJECT SUMMARY/ABSTRACT B cells are immunopathogenic drivers of systemic lupus erythematosus (SLE), an autoimmune disease characterized by a large repertoire of autoantibodies targeting self-protein and nucleic acids. While B cell- directed T-cell therapies have curative potential in the treatment of B-cell cancers and can achieve complete disease remission in refractory lupus, therapies that deplete all B cells are associated with excess morbidity and mortality from infection, precluding their use beyond life-threatening disease. Precision therapies that selectively target autoreactive B cells that drive SLE, while preserving normal B cell populations, are therefore critically needed, but targeting the plethora of autoreactive B cells in SLE poses practical challenges. The autoreactive B cell compartment in SLE is uniquely characterized by the expansion B cells bearing B-cell receptors (BCRs) using the variable heavy-chain allele VH4-34, which encodes the idiotype 9G4 (9G4id B cells). 9G4id B cells contribute 10–45% of total IgG in patients with active SLE, including antibodies against canonical lupus autoantigens. 9G4id B cells are therefore promising targets for the selective depletion of the autoreactive B cell pool, opening opportunities to treat lupus without increasing the risk of infection. Here, we hypothesize that autologous T cells can be redirected to selectively bind and kill 9G4id B cells expanded in SLE. To achieve this, we will develop 9G4id-targeted bispecific T cell-engaging antibodies designed to cross-link 9G4id B cells with any T cell, thereby inducing killing of target B cells. In this proposal, we will graft single chain variable fragments of an anti-9G4id-specific antibody and those of well-characterized CD3-specific antibodies (i.e., OKT3, UCHT1v9) into different therapeutic bispecific formats (i.e., BiTE and scDb). The efficacy and specificity of anti-9G4 bispecific antibodies to selectively bind and deplete 9G4id B cells will be established in fully-controlled in vitro model systems using engineered human B cell lines expressing 9G4id autoreactive BCRs cloned from patients with SLE, human B cell lines expressing monoclonal non-9G4id BCRs, and using autologous B cells and T cells isolated from the peripheral blood of patients with SLE. The final goal of this work is to lay the foundation for evaluating these precision immunotherapies as a novel therapeutic strategy in SLE.

项目摘要/摘要 B细胞是全身性红斑狼疮（SLE）的免疫发病驱动因素，一种自身免疫性疾病以靶向自蛋白和核酸的自身抗体的大量曲目。而B细胞 - 定向的T细胞疗法具有治疗B细胞癌的治疗潜力，可以实现完整在难治性狼疮中缓解疾病，将所有B细胞的疗法与过多的发病率相关感染导致的死亡率，排除了它们超出威胁生命的疾病的使用。有选择地的精确疗法因此，靶向驱动SLE的靶向自动反应性B细胞，同时保留正常的B细胞群体，因此是至关重要的需要，但针对SLE中大量自动反应性B细胞具有实际挑战。自动反应性b SLE中的细胞室的特征是带有B细胞受体（BCR）的膨胀B细胞（BCR）使用可变的重链等位基因VH4-34，该等位基因编码9G4（9G4ID B细胞）。 9G4ID B细胞在活性SLE的患者中贡献总IgG的10–45％，包括针对狼疮的抗体自动抗原。因此，9G4ID B细胞是自动反应性B细胞选择性部署的承诺目标游泳池，开放的机会治疗狼疮而不增加感染风险。在这里，我们假设可以重定向自体T细胞，以选择性地结合并杀死SLE中扩展的9G4ID B细胞。为此，我们将开发9G4ID靶向双特异性T细胞启动抗体，旨在与任何任何 T细胞，从而诱导靶B细胞杀死。在此提案中，我们将移植单链可变片段一种抗9G4ID特异性抗体和特征良好的CD3特异性抗体（即OKT3，UCHT1V9）分为不同的双特异性格式（即咬合和SCDB）。抗9G4的效率和特异性双特异性抗体选择性结合和复制9G4ID B细胞将在完全控制的体外建立使用工程的人类B细胞系使用表达9G4ID自动反应性BCR的模型系统用SLE表达单克隆非9G4ID BCR的人类B细胞系，并使用自体B细胞和T细胞从SLE患者的外周血中分离出来。这项工作的最终目标是为将这些精度免疫疗法评估为SLE的一种新型治疗策略。