SwePub
Sök i LIBRIS databas

  Utökad sökning

onr:"swepub:oai:DiVA.org:uu-504962"
 

Sökning: onr:"swepub:oai:DiVA.org:uu-504962" > Long-term effects o...

  • Gustavsson, TobiasUppsala universitet,Geriatrik (författare)

Long-term effects of immunotherapy with a brain penetrating Aβ antibody in a mouse model of Alzheimer's disease

  • Artikel/kapitelEngelska2023

Förlag, utgivningsår, omfång ...

  • BioMed Central (BMC),2023
  • electronicrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-504962
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-504962URI
  • https://doi.org/10.1186/s13195-023-01236-3DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:152725391URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • 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
  • 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 och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • Metzendorf, Nicole G.,1979-Uppsala universitet,Institutionen för farmaci(Swepub:uu)nineu226 (författare)
  • Wik, ElinUppsala universitet,Geriatrik(Swepub:uu)eliwi520 (författare)
  • Roshanbin, Sahar,1984-Uppsala universitet,Geriatrik(Swepub:uu)sahro359 (författare)
  • Julku, UlrikaUppsala universitet,Geriatrik(Swepub:uu)ulrju999 (författare)
  • Chourlia, AikateriniUppsala universitet,Institutionen för farmaci(Swepub:uu)choai550 (författare)
  • Nilsson, PerKarolinska Inst, Dept Neurobiol Care Sci & Soc, Div Neurogeriatr, Stockholm, Sweden. (författare)
  • Andersson, Ken G.BioArct AB, Stockholm, Sweden. (författare)
  • Laudon, HannaBioArct AB, Stockholm, Sweden. (författare)
  • Hultqvist, Greta,1980-Uppsala universitet,Institutionen för farmaci(Swepub:uu)grhul102 (författare)
  • Syvänen, StinaUppsala universitet,Geriatrik(Swepub:uu)stsyv838 (författare)
  • Sehlin, Dag,1976-Uppsala universitet,Geriatrik(Swepub:uu)daseh499 (författare)
  • Uppsala universitetGeriatrik (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Alzheimer's Research & Therapy: BioMed Central (BMC)15:11758-9193

Internetlänk

Hitta via bibliotek

Till lärosätets databas

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

 
pil uppåt Stäng

Kopiera och spara länken för att återkomma till aktuell vy