Long-term immunotherapy with bispecific antibodies in a mouse model of Alzheimer's disease

• Background: Brain-directed immunotherapy is an efficient way of targeting Aβ deposits in the brain seen in Alzheimer´s disease. In the present study we compared therapeutic efficacy of RmAb158, an Aβ protofibil targeting antibody, with RmAb158-scFv8D3, a bispecific construct that enters the brain by receptor-mediated transcytosis, in the amyloid-β (Aβ) mouse model, AppNL-G-F.Methods: AppNL-G-F mice were given RmAb158, RmAb158-scFv8D3 or PBS as control in three treatment regimens. First, a single dose was given to 5 months old AppNL-G-F mice and a three-day treatment period. Second, 3 months old AppNL-G-F mice received three doses during a week with a treatment period of two months. Third, 7 month old AppNL-G-F mice were CD4+ T-cell depleted and treated with weekly antibody injections for 8 weeks, including a final dose of [125I]RmAb158-scFv8D3 to determine brain uptake and whole blood and plasma kinetics. Brain Aβ was sequentially extracted in TBS and formic acid and quantified in a sandwich ELISA, using 3D6 and polyclonal anti-Aβ1-42 antibody to measure soluble Aβ protofibrils and Aβ1-42 levels, respectively.  Results: Neither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after single injection treatment. In mice receiving three successive injections, a trend towards reducing soluble Aβ protofibrils was seen in the cortex and hippocampus in the groups treated with RmAb158-scFv8D3. CD4+ T-cell depleted mice receiving long-term treatment with RmAb158-scFv8D3 had a dose-dependent increase in blood retention while lower plasma retention and brain uptake of given [125I]RmAb158-scFv8D3. Soluble Aβ aggregates remained unchanged in mice treated with RmAb158-scFv8D3 and RmAb158, but an observed reduction in total Aβ1-42 was seen in the cortex of mice treated with both antibodies.Conclusions: In this study, the therapeutic efficacy of long-term treatment with RmAb158-scFv8D3 was not better than RmAb158. Still, a trend was with lowering in Aβ protofibrils in mice receiving three successive injections of RmAb158-scFv8D3. Explanations to the lack of treatment efficaticy with RmAb158-scFv8D3 could partly be explained by low plasma concentration leading to reduced brain uptake or structural difference of RmAb158-scFv8D3 reducing Aβ clearance.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Geriatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Geriatrics (hsv//eng)

Nyckelord

Molekylär medicin

Molecular Medicine

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