Roshanbin Sahar, Julku Ulrika, Xiong Mengfei, Eriksson Jonas, Masliah Eliezer, Hultqvist Greta, Bergström Joakim, Ingelsson Martin, Syvänen Stina, Sehlin Dag
Department of Public Health and Caring Sciences, Uppsala University, 751 85 Uppsala, Sweden.
Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden.
Pharmaceutics. 2022 Jul 5;14(7):1412. doi: 10.3390/pharmaceutics14071412.
Immunotherapy targeting aggregated alpha-synuclein (αSYN) is a promising approach for the treatment of Parkinson's disease. However, brain penetration of antibodies is hampered by their large size. Here, RmAbSynO2-scFv8D3, a modified bispecific antibody that targets aggregated αSYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat αSYN pathology in transgenic mice. Ex vivo analyses of the blood and brain distribution of RmAbSynO2-scFv8D3 and the unmodified variant RmAbSynO2, as well as in vivo analyses with microdialysis and PET, confirmed fast and efficient brain uptake of the bispecific format. In addition, intravenous administration was shown to be superior to intraperitoneal injections in terms of brain uptake and distribution. Next, aged female αSYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated αSYN in the brain following treatment with RmAbSynO2-scFv8D3 were decreased in the cortex and midbrain compared to RmAbSynO2 or PBS controls. Taken together, our results indicate that facilitated brain uptake of αSYN antibodies can improve treatment of αSYN pathology.
靶向聚集的α-突触核蛋白（αSYN）的免疫疗法是治疗帕金森病的一种有前景的方法。然而，抗体因其较大的尺寸而难以穿透血脑屏障。在此，研究了RmAbSynO2-scFv8D3，一种修饰的双特异性抗体，它靶向聚集的αSYN并与转铁蛋白受体结合以促进脑摄取，用于治疗转基因小鼠的αSYN病理。对RmAbSynO2-scFv8D3和未修饰变体RmAbSynO2的血液和脑分布进行的体外分析，以及使用微透析和PET进行的体内分析，证实了双特异性形式能够快速有效地被脑摄取。此外，在脑摄取和分布方面，静脉注射显示优于腹腔注射。接下来，对老年雌性αSYN转基因小鼠（L61）在五天内静脉注射三次RmAbSynO2-scFv8D3、RmAbSynO2或PBS。与RmAbSynO2或PBS对照组相比，用RmAbSynO2-scFv8D3治疗后，大脑中TBS-T可溶性聚集αSYN的水平在皮质和中脑中降低。综上所述，我们的结果表明，促进αSYN抗体的脑摄取可以改善αSYN病理的治疗。
