Duranti Claudia, Iorio Jessica, Capitani Chiara, Lottini Tiziano, Martinelli Michele, Roosz Julia, Anderle Nicole, Maulana Tengku Ibrahim, Loskill Peter M, Colasurdo Rossella, Sala Cesare, Magni Lara, Arcangeli Annarosa
University of Florence, Firenze, Italy.
University of Florence, florence, Italy.
Mol Cancer Ther. 2025 Jun 18. doi: 10.1158/1535-7163.MCT-24-0646.
Targeted therapies and immunotherapies have largely improved cancer treatment in the last years. One of the most promising approaches is the induction of tumor apoptosis by the Tumor Necrosis Factor (TNF) Related Apoptosis Inducing Ligand (TRAIL) through its binding to apoptosis-inducing receptors DR4 and DR5 on the plasma membrane of target cells. However, some constraints (e.g. the short in vivo half-life, the poor activity on DR5 receptors) hinder the use of naked, soluble forms of TRAIL. Previous studies have shown that fusing TRAIL sequences with antibody-based moieties may represent a novel and efficacious strategy to overcome such hindrances. On these bases, novel TRAIL-related anticancer therapeutic strategies are being developed. In the present paper we describe a novel antibody represented by a single chain diabody directed against a cancer-specific target, i.e. the hERG1/β1 integrin complex-scDb-hERG1-β1- fused with three TRAIL sequences. The scDb-hERG1-b1-TRAIL antibody combines the specific targeting and the down regulation of cancer-specific signaling pathways by the scDb-hERG1-b1 with the pro-apoptotic activity triggered by TRAIL. We provide substantial evidence of the efficacy of the scDb-hERG1-b1-TRAIL antibody to decrease tumor growth triggering apoptotic cell death in vitro in Breast Cancer (BCa) cells as well as in vivo in a mouse model of Triple Negative BCa (TNBCa). Being characterized by a favorable pharmacokinetic and toxicity profile, the scDb-hERG1-b1-TRAIL antibody can be proposed for the treatment of difficult to treat cancers, such as TNBCa, which express the hERG1/β1 complex and TRAIL receptors.
在过去几年中，靶向治疗和免疫治疗极大地改善了癌症治疗。最有前景的方法之一是肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）通过与靶细胞质膜上的凋亡诱导受体DR4和DR5结合来诱导肿瘤细胞凋亡。然而，一些限制因素（如体内半衰期短、对DR5受体活性差）阻碍了裸溶性TRAIL的使用。先前的研究表明，将TRAIL序列与基于抗体的部分融合可能是克服此类障碍的一种新颖且有效的策略。基于这些依据，正在开发新型的TRAIL相关抗癌治疗策略。在本文中，我们描述了一种新型抗体，它是由针对癌症特异性靶点即hERG1/β1整合素复合物的单链双抗体（scDb）表示，即scDb-hERG1-β1与三个TRAIL序列融合。scDb-hERG1-b1-TRAIL抗体将scDb-hERG1-b1的特异性靶向和癌症特异性信号通路的下调与TRAIL触发的促凋亡活性结合起来。我们提供了大量证据，证明scDb-hERG1-b1-TRAIL抗体在体外乳腺癌（BCa）细胞以及三阴性乳腺癌（TNBCa）小鼠模型体内均可有效减少肿瘤生长并触发凋亡性细胞死亡。由于具有良好的药代动力学和毒性特征，scDb-hERG1-b1-TRAIL抗体可用于治疗难治性癌症，如表达hERG1/β1复合物和TRAIL受体的TNBCa。
