Bispecific antibody to target FVIII-specific B cells

摘要： 血友病A患者对因子VIII（FVIII）的抗体应答是一个关键因素， 由于这些抗体（称为抑制剂）阻断了 第VIII节。目前针对抑制剂患者的治疗方法，称为免疫耐受诱导 (ITI)成本昂贵，而且在许多情况下会失败。因此，改进的方法，以消除 抑制剂是未满足的需求。我们建议通过直接瞄准和 缺失FVIII特异性B细胞。 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，包括产生新的工程化的FVIII特异性调节或 细胞毒性T细胞这些人类和小鼠T细胞被工程化以表达FVIII-1。 特异性嵌合受体或FVIII抗原结构域，后者可以与 阻断或逆转FVIII特异性浆细胞的幼稚或记忆B细胞前体 抑制剂形成我们将后者的细胞命名为“BAR”，即B细胞靶向抗体 受体细胞。这些个性化的细胞疗法可以有效抑制 FVIII特异性B细胞应答。 我们的总体目标是在我们成功的细胞方法基础上， 使用新的靶向和消除FVIII特异性B细胞的蛋白质治疗剂， 对FVIII结构域具有特异性的B细胞受体转基因。因此，我们设计 将细胞毒性CD 8 T细胞与FVIII特异性B细胞连接的嵌合免疫缀合物 通过表达FVIII结构域，如上述“BAR”方法。我们建议 评价它们对FVIII特异性B细胞的细胞毒性，并提供证据， 在体外和体内调节抗FVIII应答的原理 血友病A这些免疫缀合物具有消除抗FVIII的潜力 患者体内的抑制剂。 1

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