1. Molecular Engineering of Efficacious Mono-Valent Ultra-Long Acting Two-Chain Insulin-Fc Conjugates.
- Author
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Tagmose TM, Pedersen KM, Pridal L, Stidsen CE, Pedersen MØ, Lin Z, Zhang Y, Wan Z, Ferreras M, Naver H, Nielsen PK, Cao Z, Wang Y, Lykke L, Christensen JL, Jensen VS, Manfè V, Pedersen TÅ, Johansson E, Madsen P, Kodra JT, Münzel M, De Maria L, Nishimura E, and Kjeldsen TB
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Diabetes Mellitus, Experimental drug therapy, Humans, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents therapeutic use, Immunoconjugates pharmacokinetics, Immunoconjugates therapeutic use, Immunoglobulin Fc Fragments pharmacology, Immunoglobulin Fc Fragments therapeutic use, Insulin, Long-Acting pharmacokinetics, Insulin, Long-Acting therapeutic use, Male, Mesocricetus, Protein Engineering, Rats, Sprague-Dawley, Rats, Hypoglycemic Agents chemical synthesis, Immunoconjugates chemistry, Immunoglobulin Fc Fragments chemistry, Insulin, Long-Acting chemical synthesis
- Abstract
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.
- Published
- 2022
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