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Single domain antibody-scFv conjugate targeting amyloid ß and TfR penetrates the blood-brain barrier and interacts with amyloid ß.
Faresjö, Rebecca; Sjöström, Elisabet O; Dallas, Tiffany; Berglund, Magnus M; Eriksson, Jonas; Sehlin, Dag; Syvänen, Stina.
Afiliação
  • Faresjö R; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
  • Sjöström EO; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
  • Dallas T; Key2Brain AB, Solna, Sweden.
  • Berglund MM; Department of Public Health and Caring Sciences, Uppsala University, Uppsala, Sweden.
  • Eriksson J; Key2Brain AB, Solna, Sweden.
  • Sehlin D; Key2Brain AB, Solna, Sweden.
  • Syvänen S; PET Centre, Uppsala University Hospital, Uppsala, Sweden.
MAbs ; 16(1): 2410968, 2024.
Article em En | MEDLINE | ID: mdl-39358860
ABSTRACT
Neurodegenerative diseases such as Alzheimer's disease (AD) pose substantial challenges to patients and health-care systems, particularly in countries with aging populations. Immunotherapies, including the marketed antibodies lecanemab (Leqembi®) and donanemab (KisunlaTM), offer promise but face hurdles due to limited delivery across the blood-brain barrier (BBB). This limitation necessitates high doses, resulting in increased costs and a higher risk of side effects. This study explores transferrin receptor (TfR)-binding camelid single-domain antibodies (VHHs) for facilitated brain delivery. We developed and evaluated fusion proteins (FPs) combining VHHs with human IgG Fc domains or single-chain variable fragments (scFvs) of the anti-amyloid-beta (Aß) antibody 3D6. In vitro assessments showed varying affinities of the FPs for TfR. In vivo evaluations indicated that specific VHH-Fc and VHH-scFv fusions reached significant brain concentrations, emphasizing the importance of optimal TfR binding affinities. The VHH-scFv fusions were further investigated in mouse models with Aß pathology, showing higher retention compared to wild-type mice without Aß pathology. Our findings suggest that these novel VHH-based FPs hold potential for therapeutic and diagnostic applications in AD, providing a strategy to overcome BBB limitations and enhance brain targeting of antibody-based treatments. Furthermore, our results suggest that a given bispecific TfR-binding fusion format has a window of "optimal" affinity where parenchymal delivery is adequate, while blood pharmacokinetics aligns with the desired application of the fusion protein.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores da Transferrina / Barreira Hematoencefálica / Peptídeos beta-Amiloides / Anticorpos de Cadeia Única / Doença de Alzheimer / Anticorpos de Domínio Único Limite: Animals / Humans Idioma: En Revista: MAbs Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suécia País de publicação: Estados Unidos
Texto completo
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XML
PubMed Links
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores da Transferrina / Barreira Hematoencefálica / Peptídeos beta-Amiloides / Anticorpos de Cadeia Única / Doença de Alzheimer / Anticorpos de Domínio Único Limite: Animals / Humans Idioma: En Revista: MAbs Assunto da revista: ALERGIA E IMUNOLOGIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Suécia País de publicação: Estados Unidos