Anti-Claudin18.2-IL-21 fusion protein bifunctional molecule has more powerful anti-tumor effect and better safety

Zhou, Yangyihua; Quan, Guiqi; Liu, Yujun; Wang, Zhihong; Shi, Ning; Wu, Yahui; Liu, Qiuju; Gao, Xiang; Zhang, Ran; Luo, Longlong

doi:10.1016/j.intimp.2022.109634

Cited by 5 publications

(5 citation statements)

References 46 publications

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“…To address this limitation, various bifunctional fusion proteins have been obtained by binding IL-21 to tumor-targeting antibodies; these products exhibited increased stability and prolonged half-life and allowing IL-21 to be delivered directly to tumor infiltrating lymphocytes. Constructs generated by fusion IL-21 to anti-CD20, anti-EGFR or monoclonal antibody that target Claudin18.2 showed extended half-life and enhanced antitumor efficacy in vitro and in vivo studies ( 59 , 65 ). IL-21 mutein fused to anti-PD-1 antibody improved CD8 + T cell function and antitumor response in a humanized mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…IL-21 was fused to the monoclonal antibody IMAB362 (Zolbetuximab) that binds to Claudin18.2, a target antigen specific to cancer cells. IMAB362-mIL-21 proved potent antitumor effects and increased safety both in vitro and in vivo ( 65 ). Overall, combining IL-21 with other immuno-stimulants, monoclonal antibodies that recognize specific tumor antigens or chemotherapy for cancer treatment showed better performances than monotherapy ( 66 ).…”

Section: Interleukin-21 Exploitation In Preclinical Studiesmentioning

confidence: 99%

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Therapeutic potential of interleukin-21 in cancer

Isvoranu,

Chiritoiu-Butnaru

2024

Front. Immunol.

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Interleukin-21 (IL-21) is an immunostimulatory cytokine which belongs to the common gamma-chain family of cytokines. It plays an import role in the development, differentiation, proliferation, and activation of immune cells, in particular T and natural killer (NK) cells. Since its discovery in 2000, IL-21 has been shown to regulate both adaptive and immune responses associates with key role in antiviral and antitumor responses. Recent advances indicate IL-21 as a promising target for cancer treatment and encouraging results were obtained in preclinical studies which investigated the potency of IL-21 alone or in combination with other therapies, including monoclonal antibodies, checkpoint inhibitory molecules, oncolytic virotherapy, and adoptive cell transfer. Furthermore, IL-21 showed antitumor effects in the treatment of patients with advanced cancer, with minimal side effects in several clinical trials. In the present review, we will outline the recent progress in IL-21 research, highlighting the potential of IL-21 based therapy as single agent or in combination with other drugs to enhance cancer treatment efficiency.

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Section: Discussionmentioning

confidence: 99%

Section: Interleukin-21 Exploitation In Preclinical Studiesmentioning

confidence: 99%

Therapeutic potential of interleukin-21 in cancer

Isvoranu,

Chiritoiu-Butnaru

2024

Front. Immunol.

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“…In addition, an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL-21) can extend the half-life of IL-21, effectively expand cytotoxic T lymphocytes, and improve its anti-tumor efficacy [ 37 ]. Recently, Zhou et al constructed Anti-Claudin18.2-IL-21 fusion protein, which showed stronger anti-tumor effect and better safety [ 38 ]. The activation of CD8 + T cells caused by MWA combined with IL-21 is also accompanied by the increase in immune checkpoint molecules PD-1 and TIM-3.…”

Section: Discussionmentioning

confidence: 99%

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Wu,

Jiang,

Fang

et al. 2024

Cancer Immunol Immunother

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Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies—MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)—has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

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“…in 2023 showed that IL-21 has prominent antitumor effects in tumors. 120 In addition, IL-21 inhibited the growth of H22 HCC tumors by enhancing the levels of IL-2 and IFN-γ. However, it also increased the levels of PD-L1 on APCs and PD-1 in T cells, which might decrease the antitumor effect.…”

Section: Combination Of Anti-pd-1/pdl1 and Anti-ctla-4 Therapy To Tre...mentioning

confidence: 98%

“…Importantly, a study by Zhou t al. in 2023 showed that IL‐21 has prominent antitumor effects in tumors 120 . In addition, IL‐21 inhibited the growth of H22 HCC tumors by enhancing the levels of IL‐2 and IFN‐γ.…”

Section: Combination Icp Inhibitor Therapies To Treat Hccmentioning

confidence: 99%

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

Hou,

Xu,

et al. 2023

BioFactors

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Immune checkpoints (ICPs) can promote tumor growth and prevent immunity‐induced cancer cell apoptosis. Fortunately, targeting ICPs, such as programmed cell death 1 (PD‐1) or cytotoxic T lymphocyte associated protein 4 (CTLA‐4), has achieved great success in the past few years and has gradually become an effective treatment for cancers, including hepatocellular carcinoma (HCC). However, many patients do not respond to ICP therapy due to acquired resistance and recurrence. Therefore, clarifying the specific mechanisms of ICP in the development of HCC is very important for enhancing the efficacy of anti‐PD‐1 and anti‐CTLA‐4 therapy. In particular, antigen presentation and interferon‐γ (IFN‐γ) signaling were reported to be involved in the development of resistance. In this review, we have explained the role and regulatory mechanisms of ICP therapy in HCC pathology. Moreover, we have also elaborated on combinations of ICP inhibitors and other treatments to enhance the antitumor effect. Collectively, recent advances in the pharmacological targeting of ICPs provide insights for the development of a novel alternative treatment for HCC.

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Anti-Claudin18.2-IL-21 fusion protein bifunctional molecule has more powerful anti-tumor effect and better safety

Cited by 5 publications

References 46 publications

Therapeutic potential of interleukin-21 in cancer

Therapeutic potential of interleukin-21 in cancer

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Blockade of PD‐1 and CTLA‐4: A potent immunotherapeutic approach for hepatocellular carcinoma

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