Sehlin Dag, Roshanbin Sahar, Zachrisson Olof, Ingelsson Martin, Syvänen Stina
Department of Public Health and Caring Sciences, Uppsala University, 751 85, Uppsala, Sweden.
BioArctic AB, Warfvinges väg 35, 112 51, Stockholm, Sweden.
Neurotherapeutics. 2025 Mar;22(2):e00510. doi: 10.1016/j.neurot.2024.e00510. Epub 2024 Dec 14.
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons, linked to aggregation of alpha-synuclein (αSYN) into Lewy bodies. Current treatments are symptomatic and do not halt or reverse the neurodegeneration. Immunotherapy targeting aggregated αSYN shows potential, but therapeutic efficacy is limited by poor brain penetration of antibodies. We developed a bispecific antibody, RmAb38E2-scFv8D3, based on αSYN oligomer selective RmAb38E2 fused to a transferrin receptor (TfR)-binding domain to enhance brain delivery. Both RmAb38E2 and RmAb38E2-scFv8D3 showed higher affinity for αSYN oligomers than for monomers or fibrils. In vivo, RmAb38E2-scFv8D3 exhibited higher brain and lower blood concentrations compared to RmAb38E2, suggesting a better brain uptake and reduced peripheral exposure for the bispecific antibody. Treatment over five days of 3-4 months old transgenic L61 mice, which overexpress human αSYN, with three doses of RmAb38E2-scFv8D3 reduced brain αSYN oligomer levels and increased microglial activation, as indicated by elevated soluble TREM2 levels. Treatment with the monospecific RmAb38E2, however, showed no significant effect compared to PBS. This study demonstrates that TfR-mediated delivery enhances the therapeutic potential of αSYN-targeted immunotherapy by resulting in a higher concentration and a more uniform distribution of antibodies in the brain. The use of bispecific antibodies offers a promising strategy to improve the efficacy of antibody therapies in PD and other α-synucleinopathies.
帕金森病（PD）的特征是多巴胺能神经元进行性丧失，这与α-突触核蛋白（αSYN）聚集成路易小体有关。目前的治疗方法只是对症治疗，无法阻止或逆转神经退行性变。针对聚集的αSYN的免疫疗法显示出潜力，但治疗效果受到抗体脑渗透性差的限制。我们基于与转铁蛋白受体（TfR）结合域融合的αSYN寡聚体选择性RmAb38E2开发了一种双特异性抗体RmAb38E2-scFv8D3，以增强脑内递送。RmAb38E2和RmAb38E2-scFv8D3对αSYN寡聚体的亲和力均高于对单体或原纤维的亲和力。在体内，与RmAb38E2相比，RmAb38E2-scFv8D3在脑内的浓度更高，在血液中的浓度更低，这表明双特异性抗体具有更好的脑摄取和更低的外周暴露。用三剂RmAb38E2-scFv8D3对3-4月龄过表达人αSYN的转基因L61小鼠进行为期五天的治疗，降低了脑内αSYN寡聚体水平，并增加了小胶质细胞活化，可溶性触发受体表达量2（TREM2）水平升高表明了这一点。然而，与用磷酸盐缓冲盐水（PBS）处理相比，用单特异性RmAb38E2处理没有显示出显著效果。这项研究表明，TfR介导的递送通过在脑内产生更高的抗体浓度和更均匀的分布，增强了针对αSYN的免疫疗法的治疗潜力。使用双特异性抗体为提高PD和其他α-突触核蛋白病的抗体治疗效果提供了一种有前景的策略。
