Novo Nordisk A/S, Global Research Technologies, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
Novo Nordisk A/S, Global Drug Discovery, Novo Nordisk Park, DK-2760 Maaloev, Denmark.
J Med Chem. 2022 Feb 10;65(3):2633-2645. doi: 10.1021/acs.jmedchem.1c02039. Epub 2022 Feb 1.
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.
在这里，我们描述了单价超长效双链胰岛素-Fc 缀合物的分子工程改造。胰岛素-Fc 缀合物是使用带有一个氨基反应基团的三功能接头合成的，该基团可与胰岛素的一个赖氨酸残基反应，而两个巯基反应基团则用于重新桥接 Fc 分子内的二硫键。胰岛素-Fc 缀合物的超长药代动力学特征是由于协同作用降低胰岛素受体清除率的结果：（1）引入降低胰岛素受体亲和力的氨基酸取代；（2）将胰岛素与 Fc 元件缀合。Fc 缀合通过新生儿 Fc 受体的循环和分子大小的增加导致超长的药代动力学和药效学特征，这两者都有助于超长的药代动力学和药效学特征。
