Neonatal Fc Receptor Binding Tolerance toward the Covalent Conjugation of Payloads to Cysteine 34 of Human Albumin Variants

The long circulatory half-life of albumin facilitated by the interaction with the cellular recycling neonatal Fc receptor (FcRn) is utilized for drug half-life extension. FcRn engagement effects following covalent attachment of cargo to cysteine 34, however, have not been investigated. Poly­(ethylen...

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Bibliographic Details
Published in:Molecular pharmaceutics 2016-02, Vol.13 (2), p.677-682
Main Authors: Petersen, Steffan S, Kläning, Eva, Ebbesen, Morten F, Andersen, Birgitte, Cameron, Jason, Sørensen, Esben S, Howard, Kenneth A
Format: Article
Language:English
Subjects:
Binding, Competitive
Cysteine - chemistry
Cysteine - genetics
Cysteine - metabolism
Drug Delivery Systems
Histocompatibility Antigens Class I - genetics
Histocompatibility Antigens Class I - metabolism
Humans
Polymers - chemistry
Polymers - metabolism
Protein Binding
Receptors, Fc - genetics
Receptors, Fc - metabolism
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Serum Albumin - genetics
Serum Albumin - metabolism
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Summary:The long circulatory half-life of albumin facilitated by the interaction with the cellular recycling neonatal Fc receptor (FcRn) is utilized for drug half-life extension. FcRn engagement effects following covalent attachment of cargo to cysteine 34, however, have not been investigated. Poly­(ethylene glycol) polymers were used to study the influence of cargo molecular weight on human FcRn engagement of recombinant wild type (WT) albumin and an albumin variant engineered for increased FcRn binding. Decreased affinity was observed for all conjugates; however, the engineered albumin maintained an affinity above that of unmodified wild type albumin that promotes it as an attractive drug delivery platform.
ISSN:1543-8384
1543-8392
DOI:10.1021/acs.molpharmaceut.5b00605