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Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing.

ABSTRACT: Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a short in vivo half-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-?-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-? muteins with an additional glycosylation, which can overcome the limitation of the cytokine itself. Hence, the molecular design aims to 1) enhance productivity and biophysical properties by adding secondary glycosylation in IFN-?, 2) increase the therapeutic index of IFN-? therapy by preferential retention at the tumor by possessing high affinity for HER2-expressing cancer cells, and 3) improve the pharmacokinetics and, thus, the convenience of IFN-? administration. The yield of trastuzumab-IFN-? mutein was higher than that of trastuzumab-wild-type IFN-? in the mammalian cell culture system. Trastuzumab-IFN-? mutein showed similar IFN activity and HER2-targeting ability equivalent to that of IFN-? mutein and trastuzumab, respectively. Trastuzumab-IFN-? mutein directly inhibited the growth of HER2-positive gastric cancer cell lines and was more effective than trastuzumab or IFN-? mutein alone. Trastuzumab-IFN-? mutein and IFN-? mutein displayed enhanced immune cell-mediated cytotoxicity. Collectively, trastuzumab-IFN-? mutein may have indirect immune cell-mediated antitumor effects and direct cell growth inhibitory effects. Tumor-targeting effect of trastuzumab-IFN-? mutein was analyzed using in vivo fluorescence imaging. The accumulation of trastuzumab-IFN-? mutein was observed in HER2-positive tumors rather than other tissues except the liver. To evaluate the both direct tumor growth inhibition effect and indirect immune cell-mediated antitumor effect, we tested the effect of trastuzumab-IFN-? mutein in HER2-positive cancer xenograft models using nude mice or humanized mice. Trastuzumab-IFN-? mutein could significantly enhance tumor regression when compared with trastuzumab or IFN-? mutein. In addition, an increase in tumor-infiltrating lymphocytes was observed in the trastuzumab-IFN-? mutein-treated group, implying that the tumor-targeting IFN-? may have an enhanced antitumor effect through increased immune response. Therefore, targeting IFN-? with an anti-HER2 monoclonal antibody makes the immunocytokine more potent than either agent alone. These novel findings suggest that trastuzumab-IFN-? mutein merits clinical evaluation as a new candidate of anticancer therapeutics.

SUBMITTER: Lee CG

PROVIDER: S-EPMC7832035 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing.

Lee Chan Gyu CG Kim TaeEun T Hong Sungyoul S Chu Jongwan J Kang Ju Eun JE Park Hee Geon HG Choi Jun Young JY Song Kyoung K Rha Sun Young SY Lee Soohyeon S Choi Joon-Seok JS Kim Sun Min SM Jeong Hae Min HM Shin Young Kee YK

Frontiers in pharmacology 20210108

Type I interferon (IFN) has been approved as an anticancer agent to treat some malignancies. However, IFNs have a short <i>in vivo</i> half-life, systemic toxicity, and poor biophysical properties, which prevent it from being widely used for cancer therapy. This study aimed to construct recombinant IFN-β-1a mutein immunocytokines that comprise a human epidermal growth factor receptor 2 (HER2)-targeting antibody and IFN-β muteins with an additional glycosylation, which can overcome the limitation ...[more]

PMID: 33505314

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Project description:BackgroundHER2 is an oncogene, expression of which leads to poor prognosis in 30% of breast cancer patients. Although trastuzumab is apparently an effective therapy against HER2-positive tumors, its systemic toxicity and resistance in the majority of patients restricts its applicability. In this study we evaluated the effects of phenethyl isothiocyanate (PEITC) in HER2-positive breast cancer cells.MethodsMDA-MB-231 and MCF-7 breast cancer cells stably transfected with HER2 (high HER2 (HH)) were used in this study. The effect of PEITC was evaluated using cytotoxicity and apoptosis assay in these syngeneic cells. Western blotting was used to delineate HER2 signaling. SCID/NOD mice were implanted with MDA-MB-231 (HH) xenografts.ResultsOur results show that treatment of MDA-MB-231 and MCF-7 cells with varying concentrations of PEITC for 24 h extensively reduced the survival of the cells with a 50% inhibitory concentration (IC50) of 8 ?M in MDA-MB-231 and 14 ?M in MCF-7 cells. PEITC treatment substantially decreased the expression of HER2, epidermal growth factor receptor (EGFR) and phosphorylation of signal transducer and activator of transcription 3 (STAT3) at Tyr-705. The expression of BCL-2-associated × (BAX) and BIM proteins were increased, whereas the levels of B cell lymphoma-extra large (BCL-XL) and X-linked inhibitor of apoptosis protein (XIAP) were significantly decreased in both the cell lines in response to PEITC treatment. Substantial cleavage of caspase 3 and poly-ADP ribose polymerase (PARP) were associated with PEITC-mediated apoptosis in MDA-MB-231 and MCF-7 cells. Notably, transient silencing of HER2 decreased and overexpressing HER2 increased the effects of PEITC. Furthermore, reactive oxygen species (ROS) generation, mitochondrial depolarization and apoptosis by PEITC treatment were much higher in breast cancer cells expressing higher levels of HER2 (HH) as compared to parent cell lines. The IC50 of PEITC following 24 h of treatment was reduced remarkably to 5 ?M in MDA-MB-231 (HH) and 4 ?M in MCF-7 (HH) cells, stably overexpressing HER2. Oral administration of 12 ?M PEITC significantly suppressed the growth of breast tumor xenografts in SCID/NOD mice. In agreement with our in vitro results, tumors from PEITC-treated mice demonstrated reduced HER2, EGFR and STAT3 expression and increased apoptosis as revealed by cleavage of caspase 3 and PARP. In addition our results show that PEITC can enhance the efficacy of doxorubicin.ConclusionsOur results show a unique specificity of PEITC in inducing apoptosis in HER2-expressing tumor cells in vitro and in vivo and enhancing the effects of doxorubicin. This unique specificity of PEITC offers promise to a subset of breast cancer patients overexpressing HER2.

Dataset Information

Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing.

Publications

Antibody-Based Targeting of Interferon-Beta-1a Mutein in HER2-Positive Cancer Enhances Antitumor Effects Through Immune Responses and Direct Cell Killing.

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