Design and biological evaluation of novel long-acting adalimumab Fab conjugated with the albumin binding domain
European Journal of Pharmacology, ISSN: 0014-2999, Vol: 904, Page: 174152
2021
- 6Citations
- 10Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations6
- Citation Indexes5
- CrossRef2
- Patent Family Citations1
- Patent Families1
- Captures10
- Readers10
- 10
Article Description
Antigen-binding fragments (Fabs) are preferred alternatives to antibodies for medical application, whereas their short half-lives limit therapeutic effectiveness. Albumin binding domain (ABD) with high affinity for albumin possesses a great potential in enhancing in vivo performance of biotherapeutics. In this study, to mitigate the poor pharmacokinetics of adalimumab Fab targeting tumor necrosis factor-α (TNFα), an ABD fusion strategy was applied innovatively using GA3, ABD035, ABD094 and ABDCon with high affinities for albumin. The prokaryotic expression, bioactivities and half-lives of those novel Fab-ABD fusions were investigated in vitro and in vivo. All Fab-ABD fusions were successfully purified, and they retained similar TNFα-binding activities with the unmodified Fab control, also presented high affinities for human/mouse serum albumin (HSA/MSA). Additionally, the simultaneous binding of the difunctional Fab-ABD fusions to TNFα and albumin was verified, and ABD fused to Fab neither interfered with Fab-TNFα binding nor impaired the association between Fc fragment of IgG receptor and transporter (FcRn) and albumin. Based on the highest binding affinity for HSA and maximal yield, Fab-ABDCon was selected for further evaluation. Fab-ABDCon showed similar thermostability with the Fab control and robust stability in human and mouse plasma. Most notably, the pharmacokinetics of Fab-ABDCon in mice was significantly improved with a 22-fold longer plasma half-life (28.2 h) compared with that of Fab control (1.31 h), which have contributed to its satisfactory therapeutic efficacy in murine TNFα-induced hepatonecrosis model. Thus, Fab-ABDCon could be a promising long-acting candidate suitable for drug development targeting TNFα-mediated inflammatory disease.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S0014299921003058; http://dx.doi.org/10.1016/j.ejphar.2021.174152; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85105557595&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/33964292; https://linkinghub.elsevier.com/retrieve/pii/S0014299921003058; https://dx.doi.org/10.1016/j.ejphar.2021.174152
Elsevier BV
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