Feedback

Inhalation of biologics with transglutaminases results in long-lasting pulmonary drug exposure

Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Kappus, Maximilian;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Hauptstein, Niklas;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Hamm, Prisca;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Braun, Alexandra;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Gutmann, Marcus;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Wurzel, Joel;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Drießen, Marc;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Lühmann, Tessa;
Affiliation
University of Wuerzburg, Institute of Pharmacology and Toxicology, Versbacher Str. 9, DE-97078 Wuerzburg, Germany
Brand, Theresa;
Affiliation
University of Wuerzburg, Institute of Pharmacology and Toxicology, Versbacher Str. 9, DE-97078 Wuerzburg, Germany
Lorenz, Kristina;
Affiliation
University of Wuerzburg, Institute for Pharmacy and Food Chemistry, Am Hubland, DE-97074 Wuerzburg, Germany
Meinel, Lorenz

Approved lung depots of biological therapeutics have represented a gap in treatment options for decades, caused by the limited number of excipients approved for inhalation, none of which is applicable for engineering lasting drug depots. In the present text, we outline the results of a proof-of-concept study on a bio-inspired strategy used to address this issue. In the study, biologics, and factor XIIIa - a marketed transglutaminase (TGase) - were inhaled by mice to catalyze covalent bonding between the biological therapeutic and the surface of the lungs. In specific, genetically engineered interferon alpha-2a (IFN-α2a) fusion proteins were designed and elongated by a C-terminal TGase substrate peptide sequence. In vitro, those constructs bound to artificial extracellular matrix (ECM) and to fibronectin as main component of ECM. Binding partners of TGase in mice lungs were investigated using LC-MS/MS. In vivo, co-inhalation of this IFN-α2a fusion protein with TGase using a commonly available Pari-Boy® was found to significantly increase the mice’s IFN-α2a lung exposure by about twelvefold and lasted for at least 48 hours after inhalation compared with the inhalation of the IFN-α2a without TGase, for which IFN-α2a levels approached physiological levels within eight hours. Biological stability and activity of the proteins during nebulization was checked previously. The generic nature of using fusion proteins with TGase substrate peptide sequences and TGase points to a universal platform for engineering pulmonary drug depots. The employed enzymatic strategy addresses the treatment gap – namely non-existent lung depots for biological therapeutics – with an attractive design for clinical translation, thereby expanding the armament of tools to use in the fight against lung diseases.

Cite

Citation style:
Could not load citation form.

Access Statistic

Total:
Downloads:
Abtractviews:
Last 12 Month:
Downloads:
Abtractviews:

Rights

Use and reproduction: