Molecular Engineering of Efficacious Mono-Valent Ultra-Long Acting Two-Chain Insulin-Fc Conjugates.

Autor: Tagmose TM; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Pedersen KM; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Pridal L; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Stidsen CE; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Pedersen MØ; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Lin Z; Novo Nordisk A/S, Global Research Technologies, 20 Life Science Park Road, Changping District, 102206 Beijing, China., Zhang Y; Novo Nordisk A/S, Global Research Technologies, 20 Life Science Park Road, Changping District, 102206 Beijing, China., Wan Z; Novo Nordisk A/S, Global Research Technologies, 20 Life Science Park Road, Changping District, 102206 Beijing, China., Ferreras M; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Naver H; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Nielsen PK; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Cao Z; Novo Nordisk A/S, Global Research Technologies, 20 Life Science Park Road, Changping District, 102206 Beijing, China., Wang Y; Novo Nordisk A/S, Global Research Technologies, 20 Life Science Park Road, Changping District, 102206 Beijing, China., Lykke L; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Christensen JL; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Jensen VS; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Manfè V; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Pedersen TÅ; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Johansson E; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Madsen P; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Kodra JT; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Münzel M; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., De Maria L; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Nishimura E; Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark., Kjeldsen TB; Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Feb 10; Vol. 65 (3), pp. 2633-2645. Date of Electronic Publication: 2022 Feb 01.
DOI: 10.1021/acs.jmedchem.1c02039
Abstrakt: 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.
Databáze: MEDLINE
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