Abstract
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.
Highlights
Albumin has an average plasma half-life of three weeks and is an attractive carrier to improve the pharmacokinetics of fused therapeutics
Rugby Park and Venezia are truncated by seven amino acids, and have their C-terminal ends altered from position 572, due to a splice error in intron (Rugby park) or a 30-bp deletion and a 5bp insertion resulting in skipping of exon (Venezia)[35,36,37] (Fig. 1a)
As the human serum albumin (HSA)-human FcRn (hFcRn) co-crystal structure does not directly explain the effect of removing L585, we studied the structural dynamics of HSA with and without the C-terminal leucine using hydrogen/ deuterium exchange mass spectrometry (HDX-MS) at pH 5.5
Summary
Albumin has an average plasma half-life of three weeks and is an attractive carrier to improve the pharmacokinetics of fused therapeutics. Albumin acts as a versatile carrier of a wide range of substances, such as fatty acids, steroids, thyroid hormones, and metals, and plays an important role in stabilizing the extracellular fluid volume[1] It is expressed by hepatocytes in the liver as a single polypeptide of 585 amino acids, and consists of 67% α-helices, which fold into three homologous domains denoted DI, DII, and DIII2,3. 1 and recombinant coagulation factor IX, respectively Both drugs are genetically fused to the N-terminal of HSA, which prolongs the half-life from 2 min to 5 days for the peptide and from 22 h to 102 h for the coagulation factor, giving rise to better dosing options for patients with type II diabetes and hemophilia B6,7. It was discovered that FcRndeficient mice had dramatically reduced serum levels of
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