Bispecific antibody to target FVIII-specific B cells

摘要： 血友病A患者对因子(FVIII)的抗体反应是一个关键因素 问题是这些抗体(称为抑制物)阻断了药物的治疗活性 Fviii.目前对抑制剂患者的治疗称为免疫耐受诱导 (ITI)成本高昂，而且在许多情况下都失败了。因此，改进的方法可以消除 抑制剂是一种未得到满足的需求。我们建议通过直接定向和 FVIII特异性B细胞的缺失。 我们的实验室已经开发出几种细胞方法来预防和逆转抑制物 形成，包括创建新的工程FVIII特定的调控或 细胞毒T细胞。这些人和小鼠的T细胞被设计成表达FVIII- 特定的嵌合受体或FVIII抗原域，后者可以与 FVIII特异性浆细胞的幼稚或记忆B细胞前体阻断或逆转 抑制剂的形成。我们将后一种细胞命名为“BAR”，意为B细胞靶向抗体 受体细胞。这些个性化的细胞疗法在抑制 FVIII特异性B细胞反应。 我们的总体目标是在我们成功的蜂窝方法的基础上，通过创建 靶向并消除FVIII特异性B细胞的蛋白质疗法，使用新的 针对FVIII结构域的B细胞受体转基因。因此，我们设计了 连接细胞毒性CD8 T细胞和FVIII特异性B细胞的嵌合免疫结合物 通过FVIII结构域的表达，如上面的“bar”方法。我们建议 评估它们对FVIII特异性B细胞的细胞毒性，并提供证据 调节抗FVIII抗体的原理及其在小鼠体内的应用 血友病A。这些免疫结合物有可能消除抗FVIII抗体。 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