Antibody neutralization for treatment of autoimmune encephalitis

N-甲基-D-天冬氨酸受体(NMDAR)脑炎患者表现出神经精神症状的快速进展，可能会在几周内导致长期昏迷。免疫抑制治疗只有一个延迟的效果。在第一个资助期，我们成功地开发了由免疫球蛋白G(Ig G)的Fc部分和部分NMDAR组成的融合载体，它可以中和抗NMDAR自身抗体的致病作用。该项目的第一个目标是研究这些结构的适用性，特别是在跨越血脑屏障(BBB)方面。我们将设计含有抗体部分的双特异性Fc融合蛋白，使其能够跨越血脑屏障，在简化的血脑屏障模型中筛选这些结构，并在小鼠身上测试最佳结构。该项目的第二个目标是将开发的概念扩展到其他形式的自身免疫性脑炎。我们将重点介绍与抗富含亮氨酸的胶质瘤灭活蛋白1(LGI1)蛋白的自身抗体相关的边缘脑炎，因为LGI1脑炎几乎与NMDAR脑炎一样常见，而且外周抗体的产生在这里尤其常见。进一步探索抗体中和的概念为开发抗体介导的中枢神经系统疾病的新治疗途径提供了机会。

Patients with N-Methyl-D-Aspartat receptor (NMDAR) encephalitis present with a rapid progression of neuropsychiatric manifestations that may lead to long-lasting coma within weeks. Immunosuppressive treatment has only a delayed efficacy. In the first funding period, we succeeded in developing fusion constructs consisting of the Fc part of immunoglobulin G (IgG) and parts of NMDARs, which neutralize the pathogenic effects of anti-NMDAR autoantibodies. The first aim of this project is to investigate the applicability of these constructs with a particular focus on crossing the blood-brain barrier (BBB). We will engineer bispecific Fc fusion proteins containing antibody parts to enable BBB crossing, screen these constructs in simplified models of the BBB, and test the best constructs in mice. The second aim of this project is to extend the developed concept to other forms of autoimmune encephalitis. We will focus on limbic encephalitis associated with autoantibodies against the leucine-rich glioma inactivated 1 (LGI1) protein, as LGI1 encephalitis is almost equally frequent as NMDAR encephalitis and peripheral antibody production is particularly common here. Further exploring the concept of antibody neutralization offers the chance to develop new treatment avenues in antibody-mediated CNS disease.