Monoclonal antibodies (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 the present 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, whereas does not bind to the hERG1 channel in non-pathological tissues, in particular the heart. The scDb-hERG1-β1 (1) downregulates the formation of the hERG1/β1 complex, (2) inhibits Akt phosphorylation and HIF-1α expression and (3) 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 which over express the hERG1/β1 integrin signaling complex.

Harnessing the hERG1/β1 integrin complex via a novel bispecific single-chain antibody: an effective strategy against solid cancers / Duranti, Claudia; Iorio, Jessica; Lottini, Tiziano; Lastraioli, Elena; Crescioli, Silvia; Bagni, Giacomo; Lulli, Matteo; Capitani, Chiara; Bouazzi, Rayhana; Stefanini, Matteo; Carraresi, Laura; Iamele, Luisa; Jonge, Hugo de; Arcangeli, Annarosa. - In: MOLECULAR CANCER THERAPEUTICS. - ISSN 1535-7163. - ELETTRONICO. - (2021), pp. 1-37. [10.1158/1535-7163.MCT-20-1111]

Harnessing the hERG1/β1 integrin complex via a novel bispecific single-chain antibody: an effective strategy against solid cancers

Duranti, Claudia;Iorio, Jessica;Lottini, Tiziano;Lastraioli, Elena;Crescioli, Silvia;Bagni, Giacomo;Lulli, Matteo;Capitani, Chiara;Bouazzi, Rayhana;Stefanini, Matteo;Carraresi, Laura;Arcangeli, Annarosa
2021

Abstract

Monoclonal antibodies (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 the present 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, whereas does not bind to the hERG1 channel in non-pathological tissues, in particular the heart. The scDb-hERG1-β1 (1) downregulates the formation of the hERG1/β1 complex, (2) inhibits Akt phosphorylation and HIF-1α expression and (3) 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 which over express the hERG1/β1 integrin signaling complex.
2021
1
37
Goal 3: Good health and well-being for people
Duranti, Claudia; Iorio, Jessica; Lottini, Tiziano; Lastraioli, Elena; Crescioli, Silvia; Bagni, Giacomo; Lulli, Matteo; Capitani, Chiara; Bouazzi, Rayhana; Stefanini, Matteo; Carraresi, Laura; Iamele, Luisa; Jonge, Hugo de; Arcangeli, Annarosa
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1238954
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