Reduction of alpha SYN Pathology in a Mouse Model of PD Using a Brain-Penetrating Bispecific Antibody

• Immunotherapy targeting aggregated alpha-synuclein (alpha SYN) 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 alpha SYN and binds to the transferrin receptor for facilitated brain uptake, was investigated to treat alpha SYN 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 alpha SYN transgenic mice (L61) were administered either RmAbSynO2-scFv8D3, RmAbSynO2, or PBS intravenously three times over five days. Levels of TBS-T soluble aggregated alpha SYN 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 alpha SYN antibodies can improve treatment of alpha SYN pathology.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

bispecific antibody

blood-brain barrier (BBB)

alpha-synuclein (alpha SYN)

Parkinson's disease (PD)

immunotherapy

monoclonal antibody

transferrin receptor (TfR)

receptor-mediated transcytosis (RMT)

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)