In contrast to protein therapeutics, which are generally cleared from the body within a range of minutes to hours, serum albumin displays a long serum half-life of 19 days in humans. Apart from its size protecting albumin from renal clearance, it is the pH-dependent recycling through the neonatal FcRn receptor that is responsible for albumin’s extended half-life.
Like IgGs, albumin is taken up by cells through nonspecific pinocytosis and is protected from intracellular degradation through pH-dependent binding to the FcRn in acidic endosomes. This interaction with the FcRn allows albumin to then be recycled back to the cell surface where it is released into circulation due to the physiological pH of the blood (Figure 1).
It is this pH-dependent interaction between albumin and FcRn that is the basis for the technology. The fusion of numerous therapeutically relevant proteins and peptides to albumin using this technology has extended their half-life significantly, resulting in improved pharmacokinetic properties.
Understanding the interaction between albumin and FcRn and the impact on albumin half-life has enabled the engineering of this interaction with the potential to modulate albumin’s half-life. Previous studies, which altered the interaction between IgG and FcRn, have been shown to impact the pharmacokinetics of the IgG.
Applying these same kinetic principles, the AlbufuseFlex technology is able to modulate protein half-life through construction of albumin variants with altered binding affinity to FcRn.
In collaboration with scientists at the University of Oslo, analysis of natural polymorphisms, cross-species binding studies, and sequence alignments have identified potential amino acids involved in the binding of albumin to FcRn. Subsequently, numerous albumin variants have been generated from single amino acid substitutions.
Binding affinity studies of each albumin variant to FcRn at acidic pH have identified single amino acid positions capable of generating a range of affinity variants with distinct binding differences. Variants have been measured with both increased and decreased receptor binding affinities potentially translating to modulation of albumin half-life.
Although extension of the therapeutic’s half-life is generally pursued, in situations where a drug is highly toxic a reduced plasma half-life may be desirable. It is this flexibility of the technology to modulate albumin half-life that enables drug-development scientists to control and tailor their drug design.