Antibody neutralization for treatment of autoimmune encephalitis

抗体中和治疗自身免疫性脑炎

• 批准号: 432559145
• 负责人: Professor Dr. Stefan Hallermann
• 金额: --
• 依托单位: Carl-Ludwig-Institut für Physiologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/432559145?language=en
• 关键词: Antibody; neutralization; treatment; autoimmune; encephalitis

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.

N-甲基-D-天冬氨酸受体 (NMDAR) 脑炎患者的神经精神症状迅速进展，可能会在数周内导致长期昏迷。免疫抑制治疗仅具有延迟疗效。在第一个资助期间，我们成功开发了由免疫球蛋白 G (IgG) 的 Fc 部分和 NMDAR 部分组成的融合结构，可中和抗 NMDAR 自身抗体的致病作用。该项目的首要目标是研究这些结构的适用性，特别关注穿越血脑屏障（BBB）。我们将设计包含抗体部分的双特异性 Fc 融合蛋白以实现 BBB 交叉，在 BBB 的简化模型中筛选这些构建体，并在小鼠中测试最佳构建体。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。我们将重点关注与针对富含亮氨酸的神经胶质瘤失活 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 脑炎同样常见，并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。