Combination Therapy with a Bispecific Antibody Targeting the hERG1/β1 Integrin Complex and Gemcitabine in Pancreatic Ductal Adenocarcinoma

SIMPLE SUMMARY: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is forecasted to become the second most common cause of cancer-related deaths by 2030. Its therapy has proven extremely difficult and, consequently, there is an urgent need for novel therapeutic strategies for PDAC. Although Gemcitabine chemotherapy has long been used as a standard of care for PDAC, it suffers from limited efficacy and high toxicity. Here, we describe a new therapeutic strategy based on a single chain bispecific antibody (scDb-hERG1-β1) which targets a cancer-specific antigen, i.e., the complex formed by the K(+) channel hERG1 and the β1 integrin (hERG1/β1 integrin complex). The combination of scDb-hERG1-β1 with sub-optimal doses of Gemcitabine in mice implanted with PDAC showed good therapeutic efficacy, low toxicity and, consequently, prolonged survival time. Our data pave the way for improving the therapy of PDAC, and possibly other cancers, by combining chemotherapy with ion channel modulators. ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) represents an unmet medical need. Difficult/late diagnosis as well as the poor efficacy and high toxicity of chemotherapeutic drugs result in dismal prognosis. With the aim of improving the treatment outcome of PDAC, we tested the effect of combining Gemcitabine with a novel single chain bispecific antibody (scDb) targeting the cancer-specific hERG1/β1 integrin complex. First, using the scDb (scDb-hERG1-β1) in immunohistochemistry (IHC), Western blot (WB) analysis and immunofluorescence (IF), we confirmed the presence of the hERG1/β1 integrin complex in primary PDAC samples and PDAC cell lines. Combining Gemcitabine with scDb-hERG1-β1 improved its cytotoxicity on all PDAC cells tested in vitro. We also tested the combination treatment in vivo, using an orthotopic xenograft mouse model involving ultrasound-guided injection of PDAC cells. We first demonstrated good penetration of the scDb-hERG1-β1 conjugated with indocyanine green (ICG) into tumour masses by photoacoustic (PA) imaging. Next, we tested the effects of the combination at either therapeutic or sub-optimal doses of Gemcitabine (25 or 5 mg/kg, respectively). The combination of scDb-hERG1-β1 and sub-optimal doses of Gemcitabine reduced the tumour masses to the same extent as the therapeutic doses of Gemcitabine administrated alone; yielded increased survival; and was accompanied by minimised side effects (toxicity). These data pave the way for a novel therapeutic approach to PDAC, based on the combination of low doses of a chemotherapeutic drug (to minimize adverse side effects and the onset of resistance) and the novel scDb-hERG1-β1 targeting the hERG1/β1 integrin complex as neoantigen.