posted on 2022-02-01, 19:15authored byTina M. Tagmose, Karen-Margrethe Pedersen, Lone Pridal, Carsten E. Stidsen, Marie Ø. Pedersen, Zhaosheng Lin, Yuanyuan Zhang, Zhe Wan, Mercedes Ferreras, Helle Naver, Peter K. Nielsen, Zheng Cao, Yi Wang, Lennart Lykke, Josefine L. Christensen, Victoria S. Jensen, Valentina Manfè, Thomas Å. Pedersen, Eva Johansson, Peter Madsen, János T. Kodra, Martin Münzel, Leonardo De Maria, Erica Nishimura, Thomas B. Kjeldsen
Here, we describe molecular engineering
of monovalent ultra-long
acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were
synthesized using trifunctional linkers with one amino reactive group
for reaction with a lysine residue of insulin and two thiol reactive
groups used for re-bridging of a disulfide bond within the Fc molecule.
The ultra-long pharmacokinetic profile of the insulin-Fc conjugates
was the result of concertedly slowing insulin receptor-mediated clearance
by (1) introduction of amino acid substitutions that lowered the insulin
receptor affinity and (2) conjugating insulin to the Fc element. Fc
conjugation leads to recycling by the neonatal Fc receptor and increase
in the molecular size, both contributing to the ultra-long pharmacokinetic
and pharmacodynamic profiles.