Harnessing the hERG1/β1 Integrin Complex via a Novel Bispecific Single-chain Antibody: An Effective Strategy against Solid Cancers
| Autor: | Rayhana Bouazzi, Silvia Crescioli, Elena Lastraioli, Laura Carraresi, Hugo de Jonge, Tiziano Lottini, Chiara Capitani, Matteo Lulli, Jessica Iorio, Claudia Duranti, Annarosa Arcangeli, Luisa Iamele, Matteo Stefanini, Giacomo Bagni |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
medicine.drug_class Mice Nude Apoptosis Monoclonal antibody Mice Pharmacokinetics Cell Movement In vivo Antibodies Bispecific Tumor Cells Cultured medicine Animals Humans Cell Proliferation Neovascularization Pathologic biology Chemistry Integrin beta1 Xenograft Model Antitumor Assays Ether-A-Go-Go Potassium Channels Potassium channel In vitro Pancreatic Neoplasms Oncology Colonic Neoplasms Toxicity Cancer cell Cancer research biology.protein Female Antibody Protein Binding Single-Chain Antibodies |
| Zdroj: | Molecular Cancer Therapeutics. 20:1338-1349 |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | mAbs, either mono- or bispecific (bsAb), represent one of the most successful approaches to treat many types of malignancies. However, there are certain limitations to the use of full length mAbs for clinical applications, which can be overcome by engineered antibody fragments. The aim of this study was to develop a small bsAb, in the format of a single-chain diabody (scDb), to efficiently target two proteins, the hERG1 potassium channel and the β1 subunit of integrin receptors, which specifically form a macromolecular complex in cancer cells. We provide evidence that the scDb we produced binds to the hERG1/β1 complex in cancer cells and tissues, but does not bind to the hERG1 channel in nonpathologic tissues, in particular the heart. The scDb-hERG1-β1 (i) downregulates the formation of the hERG1/β1 complex, (ii) inhibits Akt phosphorylation and HIF-1α expression, and (iii) decreases cell survival, proliferation, and migration in vitro. These effects only occur in cancer cells (either colon, pancreatic, or breast), but not in normal cells. In vivo, the scDb-hERG1-β1 shows a good pharmacokinetic profile, with a half-life of 13.5 hours and no general, cardiac, or renal toxicity when injected intravenously up to the dose of 8 mg/kg. The scDb-hERG1-β1 accumulates into subcutaneous xenografted tumors, arising from either colon or pancreatic human cancer cells, and induces a reduction of tumor growth and vascularization. Overall, the scDb-hERG1-β1 represents an innovative single-chain bispecific antibody for therapeutic applications in solid cancers that overexpress the hERG1/β1 integrin signaling complex. |
| Databáze: | OpenAIRE |
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