An intact C-terminal end of albumin is required for its long half-life in humans.

Albumin has an average plasma half-life of three weeks and is thus an attractive carrier to improve the pharmacokinetics of fused therapeutics. The half-life is regulated by FcRn, a cellular receptor that protects against intracellular degradation. To tailor-design the therapeutic use of albumin, it is crucial to understand how structural alterations in albumin affect FcRn binding and transport properties. In the blood, the last C-terminal residue (L585) of albumin may be enzymatically cleaved. Here we demonstrate that removal of the L585 residue causes structural stabilization in regions of the principal FcRn binding domain and reduces receptor binding. In line with this, a short half-life of only 3.5 days was measured for cleaved albumin lacking L585 in a patient with acute pancreatitis. Thus, we reveal the structural requirement of an intact C-terminal end of albumin for a long plasma half-life, which has implications for design of albumin-based therapeutics

A human endothelial cell-based recycling assay for screening of FcRn targeted molecules.

Albumin and IgG have remarkably long serum half-lives due to pH-dependent FcRn-mediated cellular recycling that rescues both ligands from intracellular degradation. Furthermore, increase in half-lives of IgG and albumin-based therapeutics has the potential to improve their efficacies, but there is a great need for robust methods for screening of relative FcRn-dependent recycling ability. Here, we report on a novel human endothelial cell-based recycling assay (HERA) that can be used for such pre-clinical screening. In HERA, rescue from degradation depends on FcRn, and engineered ligands are recycled in a manner that correlates with their half-lives in human FcRn transgenic mice. Thus, HERA is a novel cellular assay that can be used to predict how FcRn-binding proteins are rescued from intracellular degradation. Nat Commun 2018 Feb 12; 9(1):621

Shale gas policy in the United Kingdom: An argumentative discourse analysis

Shale gas has become an energy policy priority in the United Kingdom in light of profitable extraction activities in the United States. Since 2012 the Coalition Government has created key economic drivers to encourage shale exploration, whilst growing activism in affected site communities has stirred significant media and academic commentary. This study examines the growing national debate as a matter of discourse, adopting an argumentative discourse analytic approach to assess data collected from stakeholder interviews (n=21) and key policy actor statements quoted in broadsheet newspapers. We explore three dominant "storylines" emerging in relation to shale gas policy: (1) "cleanliness and dirt" concerns the relative framing of the environmental benefits and harms of shale gas; (2) "energy transitions - pathways and diversions" concerns geographic metaphors of transitions to carbon intensive and low-carbon energy systems; and (3) "geographies of environmental justice" concerns divisions of economic benefit distribution, environmental impact and procedural fairness. We find that central government policy rhetoric emphasises economic development, regulatory oversight and distribution of benefits to site communities, whilst minimising discussion of the implications of shale gas for anthropogenic climate change. The role of these discourses in influencing shale gas policy is discussed

Rational engineering of a novel factor IX albumin fusion protein results in enhanced coagulant activity and pharmacokinetic profile

No abstract availabl

Design of a novel factor IX albumin fusion protein with enhanced coagulant activity and pharmacokinetic profile

No abstract availabl

A next-generation rFVIIa fusion protein with enhanced half-life as a novel by-passing tool in hemophilia

No abstract availabl

Unraveling the interaction between FcRn and albumin: Opportunities for design of albumin-based therapeutics

The neonatal Fc receptor (FcRn) was first found to be responsible for transporting antibodies of the immunoglobulin G (IgG) class from the mother to the fetus or neonate as well as for protecting IgG from intracellular catabolism. However, it has now become apparent that the same receptor also binds albumin and plays a fundamental role in homeostatic regulation of both IgG and albumin, as FcRn is expressed in many different cell types and organs at diverse body sites. Thus, to gain a complete understanding of the biological function of each ligand, and also their distribution in the body, an in-depth characterization of how FcRn binds and regulates the transport of both ligands is necessary. Importantly, such knowledge is also relevant when developing new drugs, as IgG and albumin are increasingly utilized in therapy. This review discusses our current structural and biological understanding of the relationship between FcRn and its ligands, with a particular focus on albumin and design of albumin-based therapeutics