Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3.
Novel treatment option for MUC16-positive malignancies with the targeted TRAIL-based fusion protein Meso-TR3.
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DOI：
10.1186/1471-2407-14-35
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发表时间：
2014-01-21
期刊：
影响因子：
3.8
通讯作者：
Spitzer D
中科院分区：
文献类型：
--
作者：
Garg G;Gibbs J;Belt B;Powell MA;Mutch DG;Goedegebuure P;Collins L;Piwnica-Worms D;Hawkins WG;Spitzer D
癌症治疗剂的靶向递送代表了药物开发领域中的持续挑战。TRAIL是一种很有前途的癌症药物，但其活性特征可能受益于癌症选择性递送机制，这将减少潜在的副作用并提高治疗效率。我们最近开发了新的基于TRAIL的药物平台TR 3，这是一种基因融合的三聚体，具有进一步分子修饰的能力，例如添加肿瘤定向靶向部分。MUC 16（CA 125）是包括卵巢癌、胰腺癌和乳腺癌在内的几种人类恶性肿瘤中的充分表征的生物标志物。已知间皮素以高亲和力与MUC 16相互作用。为了将TR 3选择性地递送至表达MUC 16的癌症，我们研究了采用高亲和力间皮素/MUC 16配体/受体相互作用靶向TR 3递送的可能性。利用基因工程，我们设计了新型抗癌药物Meso-TR 3，这是一种天然间皮素和TR 3之间的融合蛋白。用哺乳动物HEK 293 T细胞产生重组蛋白。表征了Meso-TR 3针对MUC 16阳性癌细胞和缺乏MUC 16表达的对照的结合选择性和杀伤功效。采用卵巢癌的腹膜内异种移植小鼠模型在体外和体内进行药物功效实验。与可溶性间皮素本身类似，在Meso-TR 3融合蛋白中保留了强MUC 16结合特性。高亲和力配体/受体相互作用与抗癌药物在表达MUC 16的癌症靶点上的选择性积累有关，并与体外和卵巢癌异种移植小鼠模型中杀伤活性的增加直接相关。通过使用可溶性间皮素的竞争性阻断实验验证了间皮素/MUC 16相互作用对于将Meso-TR 3附着至癌细胞的相关性。使用可溶性DR 5-Fc和半胱天冬酶阻断试验的机制研究证实了外源性死亡受体途径的参与。与非靶向TR 3相比，Meso-TR 3对缺乏MUC 16的细胞显示出大大降低的杀伤效力。可溶性Meso-TR 3在体外和体内靶向癌症生物标志物MUC 16。在通过表面结合的MUC 16附着到肿瘤后，Meso-TR 3获得完全活化，与非靶向TR 3相比具有上级杀伤特征，而其生物活性在缺乏肿瘤标志物的细胞上显著降低。这种前药现象代表了高度期望的性质，因为它具有增强癌症杀伤的潜力，而副作用比非靶向的基于TRAIL的治疗剂少。因此，进一步探索这种新的融合蛋白是必要的，作为一种可能的治疗与MUC 16阳性恶性肿瘤患者。
The targeted delivery of cancer therapeutics represents an ongoing challenge in the field of drug development. TRAIL is a promising cancer drug but its activity profile could benefit from a cancer-selective delivery mechanism, which would reduce potential side effects and increase treatment efficiencies. We recently developed the novel TRAIL-based drug platform TR3, a genetically fused trimer with the capacity for further molecular modifications such as the addition of tumor-directed targeting moieties. MUC16 (CA125) is a well characterized biomarker in several human malignancies including ovarian, pancreatic and breast cancer. Mesothelin is known to interact with MUC16 with high affinity. In order to deliver TR3 selectively to MUC16-expressing cancers, we investigated the possibility of targeted TR3 delivery employing the high affinity mesothelin/MUC16 ligand/receptor interaction. Using genetic engineering, we designed the novel cancer drug Meso-TR3, a fusion protein between native mesothelin and TR3. The recombinant proteins were produced with mammalian HEK293T cells. Meso-TR3 was characterized for binding selectivity and killing efficacy against MUC16-positive cancer cells and controls that lack MUC16 expression. Drug efficacy experiments were performed in vitro and in vivo employing an intraperitoneal xenograft mouse model of ovarian cancer. Similar to soluble mesothelin itself, the strong MUC16 binding property was retained in the Meso-TR3 fusion protein. The high affinity ligand/receptor interaction was associated with a selective accumulation of the cancer drug on MUC16-expressing cancer targets and directly correlated with increased killing activity in vitro and in a xenograft mouse model of ovarian cancer. The relevance of the mesothelin/MUC16 interaction for attaching Meso-TR3 to the cancer cells was verified by competitive blocking experiments using soluble mesothelin. Mechanistic studies using soluble DR5-Fc and caspase blocking assays confirmed engagement of the extrinsic death receptor pathway. Compared to non-targeted TR3, Meso-TR3 displayed a much reduced killing potency on cells that lack MUC16. Soluble Meso-TR3 targets the cancer biomarker MUC16 in vitro and in vivo. Following attachment to the tumor via surface bound MUC16, Meso-TR3 acquires full activation with superior killing profiles compared to non-targeted TR3, while its bioactivity is substantially reduced on cells that lack the tumor marker. This prodrug phenomenon represents a highly desirable property because it has the potential to enhance cancer killing with fewer side-effects than non-targeted TRAIL-based therapeutics. Thus, further exploration of this novel fusion protein is warranted as a possible therapeutic for patients with MUC16-positive malignancies.
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影响因子：
3.3
作者：
Moritani, Suzuko;Ichihara, Shu;Kushima, Ryoji
通讯作者：
Kushima, Ryoji
影响因子：
11.2
作者：
Singh, AP;Moniaux, N;Batra, SK
通讯作者：
Batra, SK
影响因子：
3.8
作者：
El-Zawahry A;McKillop J;Voelkel-Johnson C
通讯作者：
Voelkel-Johnson C
影响因子：
4.8
作者：
Rump, A;Morikawa, Y;Miyajima, A
通讯作者：
Miyajima, A
影响因子：
4.8
作者：
Mühlenbeck, F;Schneider, P;Wajant, H
通讯作者：
Wajant, H