A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.

中文翻译：

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与 PAS 和 XTENylation 相比，通过 ABD 融合实现的半衰期延长导致肿瘤对 Affibody-药物缀合物的摄取更高。

蛋白质治疗药物开发过程中的一个关键参数是赋予它们合适的药代动力学和药效学特性。小蛋白药物会通过肾脏过滤迅速消除，因此通常需要延长半衰期。在这里，研究了不同的半衰期延长技术，其中比较了 PAS 多肽（PAS300、PAS600）、XTEN 多肽（XTEN288、XTEN576）和白蛋白结合结构域（ABD）的抗人表皮生长因子的半衰期延长受体 2 (HER2) 亲和体-药物缀合物。结果显示，PAS或XTEN多肽的延伸或ABD的添加在一定程度上降低了对HER2的亲和力，但不会对细胞毒性潜力产生负面影响。小鼠中的半衰期范围为包含PAS300的构建体的7.3小时至包含PAS600的构建体的11.6小时。发现包括 ABD 的构建体的绝对肿瘤摄取最高，比 PASylated 或 XTENylated 构建体高 60% 至 160%，尽管它没有最长的半衰期（9.0 小时）。肿瘤与正常器官比率的比较显示 ABD 融合构建体的最佳整体性能。总之，PASylation、XTENylation 和添加 ABD 是延长亲和体-药物缀合物半衰期的可行策略，其中包括 ABD 的构建体观察到最佳性能。