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Long-term effects o...
Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease
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- Gustavsson, Tobias (författare)
- Uppsala universitet,Geriatrik
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- Metzendorf, Nicole G., 1979- (författare)
- Uppsala universitet,Institutionen för farmaci
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- Wik, Elin (författare)
- Uppsala universitet,Geriatrik
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- Roshanbin, Sahar, 1984- (författare)
- Uppsala universitet,Geriatrik
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- Julku, Ulrika (författare)
- Uppsala universitet,Geriatrik
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- Chourlia, Aikaterini (författare)
- Uppsala universitet,Institutionen för farmaci
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- Nilsson, Per (författare)
- Karolinska Institutet
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- Andersson, Ken G. (författare)
- BioArct AB, Stockholm, Sweden.
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- Laudon, Hanna (författare)
- BioArct AB, Stockholm, Sweden.
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- Hultqvist, Greta, 1980- (författare)
- Uppsala universitet,Institutionen för farmaci
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- Syvänen, Stina (författare)
- Uppsala universitet,Geriatrik
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- Sehlin, Dag, 1976- (författare)
- Uppsala universitet,Geriatrik
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(creator_code:org_t)
- BioMed Central (BMC), 2023
- 2023
- Engelska.
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Ingår i: Alzheimer's Research & Therapy. - : BioMed Central (BMC). - 1758-9193. ; 15:1
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- BackgroundBrain-directed immunotherapy is a promising strategy to target amyloid-β (Aβ) deposits in Alzheimer’s disease (AD). In the present study, we compared the therapeutic efficacy of the Aβ protofibril targeting antibody RmAb158 with its bispecific variant RmAb158-scFv8D3, which enters the brain by transferrin receptor-mediated transcytosis.MethodsAppNL−G−F knock-in mice received RmAb158, RmAb158-scFv8D3, or PBS in three treatment regimens. First, to assess the acute therapeutic effect, a single antibody dose was given to 5 months old AppNL−G−F mice, with evaluation after 3 days. Second, to assess the antibodies’ ability to halt the progression of Aβ pathology, 3 months old AppNL−G−F mice received three doses during a week, with evaluation after 2 months. Reduction of RmAb158-scFv8D3 immunogenicity was explored by introducing mutations in the antibody or by depletion of CD4+ T cells. Third, to study the effects of chronic treatment, 7-month-old AppNL−G−F mice were CD4+ T cell depleted and treated with weekly antibody injections for 8 weeks, including a final diagnostic dose of [125I]RmAb158-scFv8D3, to determine its brain uptake ex vivo. Soluble Aβ aggregates and total Aβ42 were quantified with ELISA and immunostaining.ResultsNeither RmAb158-scFv8D3 nor RmAb158 reduced soluble Aβ protofibrils or insoluble Aβ1-42 after a single injection treatment. After three successive injections, Aβ1-42 was reduced in mice treated with RmAb158, with a similar trend in RmAb158-scFv8D3-treated mice. Bispecific antibody immunogenicity was somewhat reduced by directed mutations, but CD4+ T cell depletion was used for long-term therapy. CD4+ T cell-depleted mice, chronically treated with RmAb158-scFv8D3, showed a dose-dependent increase in blood concentration of the diagnostic [125I]RmAb158-scFv8D3, while concentration was low in plasma and brain. Chronic treatment did not affect soluble Aβ aggregates, but a reduction in total Aβ42 was seen in the cortex of mice treated with both antibodies.ConclusionsBoth RmAb158 and its bispecific variant RmAb158-scFv8D3 achieved positive effects of long-term treatment. Despite its ability to efficiently enter the brain, the benefit of using the bispecific antibody in chronic treatment was limited by its reduced plasma exposure, which may be a result of interactions with TfR or the immune system. Future research will focus in new antibody formats to further improve Aβ immunotherapy.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Geriatrik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Geriatrics (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Alzheimer's disease (AD)
- Immunotherapy
- Amyloid-beta (A beta)
- Monoclonal antibody
- Blood-brain barrier (BBB)
- Transferrin receptor (TfR)-mediated transcytosis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Gustavsson, Tobi ...
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Metzendorf, Nico ...
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Wik, Elin
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Roshanbin, Sahar ...
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Julku, Ulrika
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Chourlia, Aikate ...
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Nilsson, Per
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Andersson, Ken G ...
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Laudon, Hanna
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Hultqvist, Greta ...
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Syvänen, Stina
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Sehlin, Dag, 197 ...
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