An intact C-terminal end of albumin is required for its long half-life in humans
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An intact C-terminal end of albumin is required for its long half-life in humans. / Nilsen, Jeannette; Trabjerg, Esben; Grevys, Algirdas; Azevedo, Claudia; Brennan, Stephen O; Stensland, Maria; Wilson, John; Sand, Kine Marita Knudsen; Bern, Malin; Dalhus, Bjørn; Roopenian, Derry C; Sandlie, Inger; Rand, Kasper Dyrberg; Andersen, Jan Terje.
In: Communications Biology, Vol. 3, No. 1, 181, 20.04.2020.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - An intact C-terminal end of albumin is required for its long half-life in humans
AU - Nilsen, Jeannette
AU - Trabjerg, Esben
AU - Grevys, Algirdas
AU - Azevedo, Claudia
AU - Brennan, Stephen O
AU - Stensland, Maria
AU - Wilson, John
AU - Sand, Kine Marita Knudsen
AU - Bern, Malin
AU - Dalhus, Bjørn
AU - Roopenian, Derry C
AU - Sandlie, Inger
AU - Rand, Kasper Dyrberg
AU - Andersen, Jan Terje
PY - 2020/4/20
Y1 - 2020/4/20
N2 - 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.
AB - 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.
U2 - 10.1038/s42003-020-0903-7
DO - 10.1038/s42003-020-0903-7
M3 - Journal article
C2 - 32313072
VL - 3
JO - Communications Biology
JF - Communications Biology
SN - 2399-3642
IS - 1
M1 - 181
ER -
ID: 239914591