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Long-term effects o...
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Gustavsson, TobiasUppsala universitet,Geriatrik
(author)
Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease
- Article/chapterEnglish2023
Publisher, publication year, extent ...
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BioMed Central (BMC),2023
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electronicrdacarrier
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LIBRIS-ID:oai:DiVA.org:uu-504962
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-504962URI
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https://doi.org/10.1186/s13195-023-01236-3DOI
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http://kipublications.ki.se/Default.aspx?queryparsed=id:152725391URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Title in Web of Science: Long-term effects of immunotherapy with a brain penetrating A beta antibody in a mouse model of Alzheimer's disease
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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.
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Metzendorf, Nicole G.,1979-Uppsala universitet,Institutionen för farmaci(Swepub:uu)nineu226
(author)
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Wik, ElinUppsala universitet,Geriatrik(Swepub:uu)eliwi520
(author)
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Roshanbin, Sahar,1984-Uppsala universitet,Geriatrik(Swepub:uu)sahro359
(author)
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Julku, UlrikaUppsala universitet,Geriatrik(Swepub:uu)ulrju999
(author)
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Chourlia, AikateriniUppsala universitet,Institutionen för farmaci(Swepub:uu)choai550
(author)
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Nilsson, PerKarolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden.
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Andersson, Ken G.BioArct AB, Stockholm, Sweden.
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Laudon, HannaBioArct AB, Stockholm, Sweden.
(author)
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Hultqvist, Greta,1980-Uppsala universitet,Institutionen för farmaci(Swepub:uu)grhul102
(author)
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Syvänen, StinaUppsala universitet,Geriatrik(Swepub:uu)stsyv838
(author)
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Sehlin, Dag,1976-Uppsala universitet,Geriatrik(Swepub:uu)daseh499
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Uppsala universitetGeriatrik
(creator_code:org_t)
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In:Alzheimer's Research & Therapy: BioMed Central (BMC)15:11758-9193
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