MOLECULAR PHARMACEUTICS
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2024
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IF 4.5
Xiaomeng Lu,Xinyu Zhan,Guozi Xia,Feifei Wang,Mingjia Lv,Renwei Liu,Yuxue Liu,Chen Zi,Guangyong Li,Rui Wang,Jun Li,Fengjiao Yuan,Dianlong Jia
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive candidate for anticancer therapeutics due to its efficient pro-apoptotic activity against tumor cells and its well-tolerated safety profile. However, the in vivo antitumor efficacy of TRAIL is often limited by its poor tumor targeting capacity. Nowadays, the B7 homologue 3 (B7–H3) immune checkpoint has emerged as a promising target for tumor immunotherapy and drug delivery. Here, we report the achievement of tumor-targeted delivery of TRAIL by genetically fusing it with a B7H3-antagonistic affibody. The affibody–TRAIL fusion protein, named ACT, was easily expressed in Escherichia coli with a high yield and could form the active trimeric state. In vitro ACT showed significantly increased cellular binding to multiple B7H3-positive tumor cells and improved cytotoxicity by 2–3 times compared to the parent TRAIL. In vivo ACT demonstrated a 2.4-fold higher tumor uptake than TRAIL in mice bearing B7H3-positive A431 tumor grafts. More importantly, ACT exhibited significantly improved antitumor efficacy against tumors in vivo. In addition, ACT treatment did not cause body weight loss or histopathological changes in the major organs of mice, indicating its good safety profile. Overall, our findings demonstrate that targeting B7H3 to enhance TRAIL delivery is a viable approach to improve its therapeutic efficacy, and ACT may be a potential agent for targeted therapy of B7H3-positive tumors.
研究领域:
肿瘤学
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免疫治疗
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CLINICAL INVESTIGATION
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2025
·Vol. 135
·期 6
·
IF 13.6
Lei Xia,Yan Wu,Yanan Ren,Zhen Wang,Nina Zhou,Wenyuan Zhou,Lixin Zhou,Ling Jia,Chengxue He,Xiangxi Meng,Hua Zhu,Zhi Yang
BACKGROUND. B7H3, also known as CD276, is notably overexpressed in various malignant tumor cells in humans, with extremely high expression rates. The development of a radiotracer that targets B7H3 may provide a universal tumor-specific imaging agent and allow the noninvasive assessment of the whole-body distribution of B7H3-expressing lesions.
METHODS. We enhanced and optimized the structure of an affibody (ABY) that targets B7H3 to create the radiolabeled radiotracer [68Ga]Ga-B7H3-BCH, and then, we conducted both foundational experiments and clinical translational studies.
RESULTS. [68Ga]Ga-B7H3-BCH exhibited high affinity (equilibrium dissociation constant [KD] = 4.5 nM), and it was taken up in large amounts by B7H3-transfected cells (A549CD276 and H1975CD276 cells); these phenomena were inhibited by unlabeled precursors. Moreover, PET imaging of multiple xenograft models revealed extensive [68Ga]Ga-B7H3-BCH uptake by tumors. In a clinical study including 20 patients with malignant tumors, the [68Ga]Ga-B7H3-BCH signal aggregated in both primary and metastatic lesions, surpassing fluorine-18 fluorodeoxyglucose (18F-FDG) in overall diagnostic efficacy for tumors (85.0% vs. 81.7%), including differentiated hepatocellular and metastatic gastric cancers. A strong correlation between B7H3 expression and [68Ga]Ga-B7H3-BCH uptake in tumors was observed, and B7H3 expression was detected with 84.38% sensitivity and 100% specificity when a maximum standardized uptake value (SUVmax) of 3.85 was set as the cutoff value. Additionally, B7H3-specific PET imaging is expected to predict B7H3 expression levels in tumor cells, intratumoral stroma, and peritumoral tissues.
CONCLUSION. In summary, [68Ga]Ga-B7H3-BCH has potential for the noninvasive identification of B7H3 expression in systemic lesions in patients with malignant tumors. This agent has prospects for improving pretreatment evaluation, predicting therapeutic responses, and monitoring resistance to therapy in patients with malignancies.
TRIAL REGISTRATION. ClinicalTrials.gov NCT06454955.
FUNDING. This research was financially supported by the Natural Science Foundation of Beijing Municipality (no. 7242266), the National Natural Science Foundation of China (no. 82202201), and the Young Elite Scientists Sponsorship Program by China Association for Science and Technology (CAST) (no. YESS20220230).
研究领域:
肿瘤学
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分子成像
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核医学
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诊断学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2023
·Vol. 21
·期 1
·1-19
·
IF 10.2
Chen Bing,Zheng Kaifan,Fang Shubin,Huang Kangping,Chu Chengchao,Zhuang Junyang,Lin Jin,Li Shaoguang,Yao Hong,Liu Ailin,Liu Gang,Lin Jizhen,Lin Xinhua
Background The combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC). Results In vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts. Conclusion This study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.
研究领域:
癌症治疗
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纳米医学
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药物递送系统
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免疫学
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生物偶联化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）