期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 904, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2021.174152
关键词
TNF alpha; Fab fragment; Albumin binding domain; Adalimumab; Half-life; Pharmacokinetics
资金
- China State Institute of Pharmaceutical Industry
The fusion of albumin binding domain (ABD) with antibody-binding fragments (Fab) has shown promising results in improving the pharmacokinetics and therapeutic efficacy of drugs targeting TNF alpha. The novel Fab-ABD fusions retained high TNF alpha-binding activities and exhibited significantly longer half-lives in mice, demonstrating their potential as long-acting candidates for treating inflammatory diseases.
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-alpha( )(TNF alpha), 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 TNF alpha-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 TNF alpha and albumin was verified, and ABD fused to Fab neither interfered with Fab-TNF alpha 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 TNF alpha-induced hepatonecrosis model. Thus, Fab-ABDCon could be a promising long-acting candidate suitable for drug development targeting TNF alpha-mediated inflammatory disease.
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