Theranostics
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2026
·Vol. 16
·期 1
·17
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IF 13.3
Kang Yi Lee,Heng Sun,Yu Mei,Emily Nickles,Clemence Wei Xia Lai,Sashigala Ponnalagu,Mukul Prasad,Haiyan Liu,Herbert Schwarz
CD137 is a powerful T cell costimulatory molecule, and CD137 agonists are being evaluated for human cancer immunotherapy. Urelumab and utomilumab, are two agonistic anti-CD137 antibodies that are most advanced in clinical trials but suffer from liver toxicity and low potency, respectively. Here we describe the development of a new type and formulation of a CD137 agonist that combines high potency and a strong safety profile. Methods: The extracellular domain of recombinant human CD137 ligand (rhCD137L) was conjugated onto mesoporous silica nanoparticles (MSNs) of approximately 50 nm in diameter, and the ratio of rhCD137L to MSNs was optimized based on their ability to costimulate the cytotoxic activity of T cells. As nasopharyngeal carcinoma (NPC) cells often express CD137, the in vitro effect of rhCD137L-MSNs on T cell-mediated tumor cytotoxicity was evaluated using the NPC cell lines C666 and HK-1, each tested as CD137-expressing and -deficient variants. Results were compared with those obtained using MSNs conjugated with urelumab (ure-MSNs) or unconjugated urelumab. The biodistribution, therapeutic efficacy and toxicity of rhCD137L-MSNs were subsequently assessed in humanized mouse NPC models. Results: rhCD137L-MSNs were of higher potency than ure-MSNs or unconjugated urelumab in inducing in vitro T cell killing of the NPC cell lines C666 and HK-1, of both CD137-expressing and -deficient phenotypes. C666-CD137 and HK1-CD137 cells were eliminated more efficiently than the CD137-deficient cells. In vivo , in humanized mouse NPC models, both rhCD137L-MSNs and ure-MSNs inhibited tumor growth, with rhCD137L-MSNs being slightly more potent. This was reflected in an increase in T cell activation markers and an increased infiltration of effector memory CD8 + T cells into the tumor. In contrast to ure-MSNs, rhCD137-MSN treatment did not induce liver damage, thereby demonstrating a more favorable safety profile than ure-MSNs. Conclusions: This study identifies a formulation of rhCD137L on MSNs that combines high potency with excellent safety.
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DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Yanjiao Jiang,Wenyue Li,Yuqiang Ma,Yi Hou
Alzheimer's disease (AD) that is an important contributor to dementia, is a chronic and irreversible neurodegenerative disease, with high rates of disability and mortality. Recently, more and more therapeutic methods have been developed to delay the progression of AD, but it remains a great challenge to achieve the early diagnosis of AD. In this work, we developed a magnetic resonance imaging (MRI) nanoprobe (NP@angiopep-2/CD137) based on angiopep-2 peptide and CD137 antibody with a NaGdF4 nanoparticle as the core and realized neuroinflammation-targeted imaging on APP/PS1 model mice using a clinical 7.0 T MRI scanner. CD137 expression was upregulated in neuroglial cells and cerebral vascular endothelial cells in inflammatory state. In the APP/PS1 mouse model, after administration, the nanoprobe-enhanced images showed specific dot-like signals in the susceptibility-weighted imaging (SWI) sequence. In summary, we designed and synthesized NP@angiopep-2/CD137 nanoprobes using the activation-dependent expression of CD137, which were applied to the pathological assessment of AD based on the hypothesis of AD neuroinflammation, and provided a reliable idea for the early molecular imaging diagnosis of AD.
研究领域:
神经科学
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医学影像学
·
分子生物学
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高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Chen Chuan-jun,Guo Ding-wen,Yuan Qing-yun,Zhuo You-qiong,Yang Shi-fen,Xu Hao-min,Wang You-rong,Guan Xiao-hui,Deng Ke-yu,Xin Hong-bo
Macrophage migration inhibitory factor (MIF) is a cytokine that possesses multiple enzymatic activities, such as keto-enol tautomerase and thiol-oxidoreductase. We previously found that lack of MIF tautomerase activity significantly alleviated high fat diet (HFD)-induced obesity in mice. In this study, we investigated the regulatory mechanisms of MIF tautomerase in obesity. HFD-induced obese mouse model was established. Adipogenic differentiation was induced in mouse preadipocyte cell line 3T3-L1 and mouse adipose-derived mesenchymal stem cells (ADSCs) in vitro. We showed that MIF tautomerase inhibitors ISO-1 or 4-IPP dose-dependently promoted lipid degradation and mitochondrial thermogenesis by enhancing basal oxygen consumption rate and proton leak, accompanied by increased expression of browning markers (UCP1, PGC-1α, DIO2, CD137) in 3T3-L1 cells under adipogenic induction conditions. In HFD-induced obese mice, administration of 4-IPP (5, 10 mg/kg, i.p.) every 2 days for 12 weeks significantly ameliorated HFD-induced obesity, improved insulin sensitivity, and enhanced energy expenditure. In white adipocytes, 4-IPP (1, 5, 10 μM) dose-dependently promoted CD137 expression, and restored CD137-mediated activation of the PI3K/AKT signaling to improve lipid metabolism. CD137 deficiency abrogated the browning effect of 4-IPP in white adipocytes in vitro. CD137 −/− mice exhibited increased susceptibility to HFD-induced obesity and almost abolished the anti-obesity effects of 4-IPP. Simulation of the protein interaction revealed a direct interaction between MIF and CD137: MIF competitively bound to CD137 on white adipocytes with the endogenous ligand of CD137, which was further confirmed by co-immunoprecipitation. Furthermore, 4-IPP and recombinant CD137 protein inhibited the tautomerase activity of MIF in vitro. In conclusion, MIF promotes obesity by binding CD137 through its tautomerase domain, suppressing CD137-mediated the activation of the PI3K/AKT signaling. MIF tautomerase inhibitors disrupt this interaction, restore CD137 function, and enhance adipocyte browning, offering a promising therapeutic strategy for obesity management.
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PubMed
高影响因子
Cancer Cell International
·
2024
·Vol. 24
·期 1
·1-15
·
IF 5.3
Cen Lanqi,Zhang Zhe,Sun Yi,Wu Nandie,Shao Jie,Qian Zhaoye,Tian Manman,Ke Yaohua,Liu Baorui
Background The clinical application of peptide vaccines in tumor immunotherapy holds significant promise. Peptide-based tumor vaccines are currently subject to certain limitations in clinical trials, including the challenge of inducing a sustained response from CD4 + T helper cells and cytotoxic T lymphocytes (CTL), as well as human leukocyte antigen (HLA) restrictions. Methods Through the utilization of biological information methodology, a screening process was conducted to identify three potential long peptides that are specifically targeted by the MAGE-A4 antigen. The candidate long peptides were subjected to in vitro testing using human peripheral blood lymphocytes as samples to evaluate their immunogenicity and immune function. The antitumor properties and preliminary mechanism of the long peptide vaccine were investigated through the use of a mouse model designed for the prevention of triple negative breast cancer (TNBC). Results Three predicted multi-epitope long peptides targeting MAGE-A4 have shown to have a strong immunogenicity, with a total positive rate of 72% across different HLA subtypes in Chinese populations. they can also increase the levels of the costimulatory factor CD137 and tumor necrosis factor-alpha (TNF-α), activate T cells, and boost the cytotoxic activity. Results from an animal study have revealed that the long-peptide vaccine, both on its own and in combination with R848, has displayed impressive anti-tumor and target-specific capabilities. Moreover, it has the ability to increase the expression of effector memory T cells and central memory T cells. Conclusions This study was the first to screen three multi-epitope long peptides targeting MAGE-A4 and assess their immunogenicity, immune function, and potential as adjuvant peptides. The results showed that the MAGE-A4 long peptide vaccine can be used as a novel immunoprophylaxis method to prevent TNBC. Moreover, the proposed development model is capable of screening multiple target antigens, which lead to its clinical application.
研究领域:
肿瘤学
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免疫学
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疫苗学
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PubMed
高影响因子
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