Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo.
Improvement of Pharmacokinetic Profile of TRAIL via Trimer-Tag Enhances its Antitumor Activity in vivo.
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通过Trimer-TAG改善TRAIL的药代动力学特征可增强其体内的抗肿瘤活性。
DOI：
10.1038/s41598-017-09518-1
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发表时间：
2017-08-21
影响因子：
4.6
通讯作者：
Liang P
中科院分区：
文献类型：
--
作者：
Liu H;Su D;Zhang J;Ge S;Li Y;Wang F;Gravel M;Roulston A;Song Q;Xu W;Liang JG;Shore G;Wang X;Liang P
肿瘤坏死因子相关凋亡诱导配体（TRAIL/Apo 2L）长期以来一直被认为是肿瘤治疗的诱人靶点，因为它通过结合并三聚化其功能性受体DR 4或DR 5以肿瘤特异性方式介导外源性凋亡途径的激活。尽管最初的承诺，重组人TRAIL（天然TRAIL）和二聚体DR 4/DR 5激动剂单克隆抗体（mAb）在多个人类临床试验中失败。在这里，我们表明，人α1（I）胶原蛋白的C-前肽（三聚体-标签）与成熟人TRAIL的C-末端的框内融合导致二硫键连接的同源三聚体，其可以作为CHO细胞的分泌蛋白以高水平表达。所得到的TRAIL-三聚体不仅在体外保留了与天然TRAIL相似的生物活性和受体结合动力学，其比二聚体TRAIL-Fc的生物活性和受体结合动力学高上级4-5个数量级，而且在体内表现出比天然TRAIL更有利的药代动力学和抗肿瘤药效学特征。总之，这项工作提供了直接的证据，体内抗肿瘤疗效的TRAIL是成比例的全身药物暴露，并表明，以前的临床失败可能是由于快速全身清除天然TRAIL和不良的肿瘤诱导效力的二聚体激动剂单克隆抗体，尽管他们的血清半衰期长。
TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) has long been considered a tantalizing target for cancer therapy because it mediates activation of the extrinsic apoptosis pathway in a tumor-specific manner by binding to and trimerizing its functional receptors DR4 or DR5. Despite initial promise, both recombinant human TRAIL (native TRAIL) and dimeric DR4/DR5 agonist monoclonal antibodies (mAbs) failed in multiple human clinical trials. Here we show that in-frame fusion of human C-propeptide of α1(I) collagen (Trimer-Tag) to the C-terminus of mature human TRAIL leads to a disulfide bond-linked homotrimer which can be expressed at high levels as a secreted protein from CHO cells. The resulting TRAIL-Trimer not only retains similar bioactivity and receptor binding kinetics as native TRAIL in vitro which are 4–5 orders of magnitude superior to that of dimeric TRAIL-Fc, but also manifests more favorable pharmacokinetic and antitumor pharmacodynamic profiles in vivo than that of native TRAIL. Taken together, this work provides direct evidence for the in vivo antitumor efficacy of TRAIL being proportional to systemic drug exposure and suggests that the previous clinical failures may have been due to rapid systemic clearance of native TRAIL and poor apoptosis-inducing potency of dimeric agonist mAbs despite their long serum half-lives.
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影响因子：
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作者：
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