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

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.

The characteristics and the multiple functions of integrin β1 in human cancers

“…have reported that compared with EGFR single inhibition, the combination of integrin β1 and EGFR targeting resulted in enhanced cytotoxicity and radiosensitization of head and neck cancer cells, which responded with FAK dephosphorylation [ 92 ]. In addition, the combination of gemcitabine and hERG1/integrin β1 complex antibody reduced the volume of tumor masses and produced an increase in survival without significant toxic side effects in pancreatic cancer [ 93 ]. However, in melanomas, although the combination of MAPK and PI3K/AKT inhibitors was successfully used in preclinical experiments and early clinical trials, dual-drug resistance was inevitably observed.…”

Ion channels in lung cancer: biological and clinical relevance

“…Importantly, not all Kv11.1 blockers are arrhythmogenic ( Wallis, 2010 ), examples are represented by Verapamil and sertindole ( D’Amico et al, 2013 ). In order to overcome the cardiotoxicity induced by IC blockers different strategies can be applied ( D’Amico et al, 2013 ): i) using non torsadogenic blockers; ii) using state-specific blockers such as R -roscovitine ( Ganapathi et al, 2009 ); iii) using tumour-specific drugs such as CD 160130 ( Gasparoli et al, 2015 ); iv) using monoclonal antibodies ( Iorio et al, 2019 ) and v) using bispecific antibodies directed against tumour-specific macromolecular complexes such as the Kv11.1/β1 integrin complex ( Duranti et al, 2021a ; 2021b ; Iorio et al, 2022 ; Lottini et al, 2023 ).…”

The role of potassium channels in tumours of the gastrointestinal tract: a focus on the human ether‐à‐go‐go related gene 1 channels

“…Overall, we favour the possible exploitation of the hERG1-β1 complex as a molecular target for therapeutic purposes with a specific therapeutic antibody (the single-chain diabody hERG1-β1) which impacts on cancer-relevant signalling pathways, such as AKT and HIF-1α, which control proliferation, migration and cancer progression . In this regard, a proper validation of this new tool is mandatory to better outline the possible therapeutic application, alone or in combination with standard drugs such a gemcitabine (Lottini et al, 2022) or bevacizumab (Lottini et al, 2020).…”