Antineoplastic activity of a novel tri-specific single chain antibody targeting the hERG1/β1 integrin complex and TRAIL receptors

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.