Novo Nordisk A/S Global Research , DK-2760 Maaloev , Denmark.
Novo Nordisk Research Center China , 20 Life Science Park Road , Changping District, Beijing 102206 , China.
Bioconjug Chem. 2018 Sep 19;29(9):3129-3143. doi: 10.1021/acs.bioconjchem.8b00463. Epub 2018 Aug 31.
The present work describes a series of human growth hormone (hGH) albumin binder conjugates with an extended in vivo half-life. A broad range of different conjugates were studied by varying the albumin binder structure and conjugation site. Conjugates were conveniently obtained by reductive alkylation or by alkylation to introduced cysteines using functionalized albumin-binding side chains. In vitro and in vivo profiling provided the basis for identification of position L101C in human growth hormone as the most optimal position for conjugation, where both a sufficient level of receptor binding and a suitably long half-life could yield a molecule with potential for a once-weekly dosing regimen.
本工作描述了一系列具有延长体内半衰期的人生长激素（hGH）白蛋白结合物缀合物。通过改变白蛋白结合物的结构和缀合部位，研究了广泛的不同缀合物。缀合物可以通过还原烷基化或使用功能化的白蛋白结合侧链对引入的半胱氨酸进行烷基化来方便地获得。体外和体内分析为鉴定人生长激素的位置 L101C 作为缀合的最佳位置提供了基础，在该位置，受体结合的水平足够高，半衰期也足够长，可以得到一种有潜力的每周一次给药方案的分子。
