A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities

Lv, Liangyin; Wang, Hui; Shi, Wenqiang; Wang, Yan; Zhu, Weihua; Liu, Zexin; Chen, Xiaoqu; Chen, Zheng; Kong, Wencheng; Li, Wei; Zhu, Jianwei; Lu, Huili

doi:10.1007/s00253-022-12209-1

Cited by 5 publications

(2 citation statements)

References 36 publications

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“…Despite the less pronounced increase in PD-L1 expression by TH1579 in murine cancer cells as compared to human cells, we performed a proof-of-concept in vivo study using a B16F10 syngeneic allograft mouse model. Atezolizumab is a PD-L1 blockade and has been previously utilised in a syngeneic mouse model, either as a monotherapy or in combination with other inhibitors [ 35 , 36 ]. From our previous studies, it is well documented that TH1579 significantly suppresses tumour growth in various human tumour xenograft in vivo models [ 26 , 28 ].…”

Section: Resultsmentioning

confidence: 99%

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

Shen,

Guillén Mancina,

Chen

et al. 2024

Oncogenesis

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The mitotic MTH1 inhibitor TH1579 is a dual inhibitor that inhibits mitosis and incorporation of oxidative DNA damage and leads to cancer-specific cell death. The response to immune checkpoint inhibitor (ICI) treatment is often augmented by DNA damaging agents through the cGAS-STING pathway. This study investigates whether TH1579 can improve the efficacy of immune checkpoint blockades through its immunomodulatory properties. Various human and murine cancer cell lines were treated with mitotic MTH1i TH1579, and the expression of PD-L1 and T-cell infiltration-related chemokines was analysed by flow cytometry and real-time qPCR. Syngeneic mouse models were established to examine the combined effect of TH1579 and PD-L1 blockade. In our investigation, we found that TH1579 upregulates PD-L1 expression at both the protein and mRNA levels in human cancer cell lines. However, in murine cell lines, the increase was less pronounced. An in vivo experiment in a syngeneic mouse melanoma model showed that TH1579 treatment significantly increased the efficacy of atezolizumab, an anti-PD-L1 antibody, compared to vehicle or atezolizumab monotherapy. Furthermore, TH1579 exhibited immune-modulatory properties, elevating cytokines such as IFN-β and chemokines including CCL5 and CXCL10, in a cGAS-STING pathway-dependent manner. In conclusion, TH1579 has the potential to improve ICI treatment by modulating immune checkpoint-related proteins and pathways.

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Section: Resultsmentioning

confidence: 99%

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

Shen,

Guillén Mancina,

Chen

et al. 2024

Oncogenesis

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“…Jiangyin Lv combined IgG4 Fc segments, soluble IL-15Rα, and IL-15 (N72D) into a homodimeric IL-15 superagonist (F4RLI). F4RLI significantly stimulated the proliferation of human CD3 + CD8 + T cells and NK cells in vitro ( 92 ). Jin-Qing Liu generated novel LNPs encapsulated with mRNA encoding cytokines (including IL-12, IL-27, and GM-CSF) that induced potent infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8+T cells into tumors, offering a new strategy for oncology immunotherapy ( 93 ).…”

Section: Regulatory Mechanisms and Research Strategies Of Nk Cells An...mentioning

confidence: 99%

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Liu

2022

Front. Immunol.

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Human epidermal growth factor receptor 2 (HER2)-positive breast cancer has a high metastatic potential. Monoclonal antibodies (mAbs) that target HER2, such as trastuzumab and pertuzumab, are the cornerstone of adjuvant therapy for HER2-positive breast cancer. A growing body of preclinical and clinical evidence points to the importance of innate immunity mediated by antibody-dependent cellular cytotoxicity (ADCC) in the clinical effect of mAbs on the resulting anti-tumor response. In this review, we provide an overview of the role of natural killer (NK) cells and ADCC in targeted therapy of HER2-positive breast cancer, including the biological functions of NK cells and the role of NK cells and ADCC in anti-HER2 targeted drugs. We then discuss regulatory mechanisms and recent strategies to leverage our knowledge of NK cells and ADCC as an immunotherapy approach for HER2-positive breast cancer.

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Oxidation and reduction analysis of therapeutic recombinant human interleukin-15 by HPLC and LC-MS

Wang

Chen

Zhao

et al. 2023

Appl Microbiol Biotechnol

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A homodimeric IL-15 superagonist F4RLI with easy preparation, improved half-life, and potent antitumor activities

Cited by 5 publications

References 36 publications

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

Mitotic MTH1 inhibitor TH1579 induces PD-L1 expression and inflammatory response through the cGAS-STING pathway

Focusing on NK cells and ADCC: A promising immunotherapy approach in targeted therapy for HER2-positive breast cancer

Oxidation and reduction analysis of therapeutic recombinant human interleukin-15 by HPLC and LC-MS

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