An engineered human albumin enhances half-life and transmucosal delivery when fused to protein-based biologics

The human albumin variant E505Q/T527M/K573P improves pharmacokinetics of protein-based drugs and facilitates transport across mucosal epithelia. Altering albumin for drug delivery Ideally, protein-based biologic drugs could be given transmucosally, rather than intravenously or subcutaneously, but the efficiency of transmucosal drug uptake is poor. Bern et al. designed an albumin protein with three amino acid substitutions, E505Q/T527M/K573P (QMP), improving binding to the neonatal Fc receptor expressed on mucosal epithelial cells. This prevented intracellular degradation and enhanced mucosal uptake of proteins fused to QMP upon intranasal delivery. Activated factor VII was fused to QMP, prolonging half-life without impeding factor VII function in a mouse model of hemophilia B. QMP may be a suitable carrier for biologic drugs but will require further testing in large-animal models. Needle-free uptake across mucosal barriers is a preferred route for delivery of biologics, but the efficiency of unassisted transmucosal transport is poor. To make administration and therapy efficient and convenient, strategies for the delivery of biologics must enhance both transcellular delivery and plasma half-life. We found that human albumin was transcytosed efficiently across polarized human epithelial cells by a mechanism that depends on the neonatal Fc receptor (FcRn). FcRn also transported immunoglobulin G, but twofold less than albumin. We therefore designed a human albumin variant, E505Q/T527M/K573P (QMP), with improved FcRn binding, resulting in enhanced transcellular transport upon intranasal delivery and extended plasma half-life of albumin in transgenic mice expressing human FcRn. When QMP was fused to recombinant activated coagulation factor VII, the half-life of the fusion molecule increased 3.6-fold compared with the wild-type human albumin fusion, without compromising the therapeutic properties of activated factor VII. Our findings highlight QMP as a suitable carrier of protein-based biologics that may enhance plasma half-life and delivery across mucosal barriers.