Bispecific antibody to target FVIII-specific B cells

针对 FVIII 特异性 B 细胞的双特异性抗体

基本信息

批准号：
10598041
负责人：
David William Scott
金额：
$ 18.26万
依托单位：
METIS FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598041
关键词：
Antibodies Antibody Response Antigens B-Cell Antigen Receptor B-Lymphocytes Binding Bispecific Antibodies C2 Domain CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cell Therapy Cells Clinical Clinical Management Cytotoxic T-Lymphocytes Dose Engineering Factor VIII Fc Receptor Future Genes Goals Hemophilia A Human Human Engineering Immune Immune Tolerance Immune response Immunoconjugates Immunoglobulin M In Vitro Knock-out Link Memory B-Lymphocyte Methods Minority Modality Mus Names Patients Plasma Cells Proteins Reagent Receptor Cell Role Specificity Structure T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Transgenic Organisms arm cancer immunotherapy chimeric antigen receptor clinical translation crosslink cytotoxic CD8 T cells cytotoxicity design high risk improved in vivo inhibitor mouse model neutralizing antibody novel prevent receptor response therapeutic protein

项目摘要

Abstract: The antibody response to factor VIII (FVIII) in hemophilia A patients is a critical problem since these antibodies (called inhibitors) block the therapeutic activity of FVIII. The current treatment for inhibitor patients, called immune tolerance induction (ITI) is expensive and fails in many cases. Thus, improved methods to eliminate inhibitors is an unmet need. We propose to achieve this by direct targeting and deletion of FVIII-specific B cells. Our lab has developed several cellular approaches to prevent and reverse inhibitor formation, including the creation of novel engineered FVIII-specific regulatory or cytotoxic T cells. These human and mouse T cells were engineered to express FVIII- specific chimeric receptors or FVIII antigen domains, the latter which can interact with naïve or memory B-cell precursors of FVIII-specific plasma cells to block or reverse inhibitor formation. We named these latter cells “BAR” for B-cell-targeting Antibody Receptor cells. These personalized cellular therapies are effective at suppressing FVIII-specific B-cell responses. Our overall goal herein is to build on our successful cellular approaches by creating protein therapeutics that would target and eliminate FVIII-specific B cells, using new B-cell receptor transgenics specific to a FVIII domain. Thus, we have designed chimeric immune conjugates that link cytotoxic CD8 T cells with FVIII-specific B cells via expression of FVIII domains, as in the “BAR” approach above. We propose to evaluate them for cytotoxicity against FVIII-specific B cells, and to provide proof of principle to modulate anti-FVIII responses in vitro and in vivo in a mouse model of hemophilia A. These immunoconjugates have the potential to eliminate anti-FVIII inhibitors in patients. 1

抽象的： A 型血友病患者对因子 VIII (FVIII) 的抗体反应至关重要问题是因为这些抗体（称为抑制剂）阻断了治疗活性 FVIII. 目前针对抑制剂患者的治疗称为免疫耐受诱导 (ITI) 成本高昂且在许多情况下都失败，因此需要改进消除方法。我们建议通过直接靶向和抑制来实现这一目标。 FVIII 特异性 B 细胞的缺失。我们的实验室开发了多种细胞方法来预防和逆转抑制剂形成，包括创建新颖的工程化 FVIII 特异性监管或这些人类和小鼠 T 细胞经过改造可表达 FVIII- 特异性嵌合受体或 FVIII 抗原结构域，后者可以与 FVIII 特异性浆细胞的幼稚或记忆 B 细胞前体可阻断或逆转我们将这些细胞命名为“BAR”，代表 B 细胞靶向抗体。这些个性化细胞疗法可有效抑制。 FVIII 特异性 B 细胞反应。我们的总体目标是通过创建使用新方法靶向并消除 FVIII 特异性 B 细胞的蛋白质疗法因此，我们设计了针对 FVIII 结构域的 B 细胞转基因受体。将细胞毒性 CD8 T 细胞与 FVIII 特异性 B 细胞连接起来的嵌合免疫偶联物通过 FVIII 结构域的表达，如上面的“BAR”方法。评估它们对 FVIII 特异性 B 细胞的细胞毒性，并提供证据在小鼠模型中体外和体内调节抗 FVIII 反应原理血友病 A。这些免疫偶联物有可能消除抗 FVIII 患者体内的抑制剂。 1