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：
10365461
负责人：
David William Scott
金额：
$ 21.92万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10365461
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 F8 gene Factor VIII Fc Receptor Future 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：血友病患者对因子VIII（FVIII）的抗体反应是关键问题由于这些抗体（称为抑制剂）阻止了 FVIII。当前对抑制剂患者的治疗，称为免疫耐受性诱导（ITI）很昂贵，并且在许多情况下失败了。这是改进的消除方法抑制剂是未满足的需求。我们建议通过直接定位和 FVIII特异性B细胞的缺失。我们的实验室已经开发了几种细胞方法来预防和逆转抑制剂形成，包括创建新型工程FVIII特定的调节或细胞毒性T细胞。这些人和小鼠T细胞被设计为表达FVIII- 特定的嵌合受体或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，以阻止或反向抑制剂形成。我们将这些后来的细胞为B细胞靶向抗体命名受体细胞。这些个性化的细胞疗法可有效抑制 FVIII特异性B细胞响应。我们在这里的总体目标是通过创建我们成功的蜂窝方法来建立蛋白质疗法将使用新的 B细胞受体转化特定于FVIII结构域。那我们已经设计了嵌合免疫结合，将细胞毒性CD8 T细胞与FVIII特异性B细胞联系起来通过FVIII域的表达，如上所述的“ bar”方法。我们建议评估它们针对FVIII特异性B细胞的细胞毒性，并提供证明在小鼠模型中调节体外和体内抗FVIII反应的原理血友病A.这些免疫共轭物具有消除抗FVIII的潜力患者的抑制剂。 1