主要目的：评价BRG01注射液的初步有效性和耐受性。次要目的：1.评价BRG01注射液的药代动力学（PK）、药效动力学（PD）和免疫原性。2.评价BRG01注射液在复发/转移性鼻咽癌患者的初步疗效。探索性目的：1.探索BRG01注射液的T细胞及其亚型在体内的增值和存续情况与疗效的相关性。2.探索肿瘤组织靶点的表达水平与安全性及疗效的相关性。3.探索血浆中EBV DNA含量与安全性及疗效的相关性。

开始日期2023-05-11

申办/合作机构

广州百吉生物制药有限公司

NCT05864924 / Completed临床1期

A Phase 1 Study Evaluating the Safety and Efficacy of BRG01 in Subjects With Relapsed/Metastatic EBV-positive Nasopharyngeal Carcinoma

Phase 1 study evaluating the safety and efficacy of BRG01 in subjects with relapsed/ metastatic EBV-positive nasopharyngeal carcinoma (NPC).
BRG01 is a Chimeric Antigen Receptor T-Cell therapy targetting on the specific protein of EBV, which is expressed on the EBV associated cancer cells.
This study adopts the traditional "3+3" dose escalation design. Approximately12
18 EBV+ NPC subjects will be enrolled to evaluate the safety of BRG01. An internal safety review team (SRT) will review the safety data and make recommendations on further study conduct and progression to subsequential cohorts.
Subjects will be enrolled into 3 cohorts of different doses, designated as cohort A, B and C.Cohort A: 3.0x10^6 CAR-T cells/kg,3 subjects, Cohort B: 9.0x10^6 CAR-T cells/kg,3 subjects, and Cohort C:1.5x10^7 CAR-T cells /kg, 6 subjects,respectively.
Subjects in each cohort will follow the same treatment schedule and procedural requirements.

开始日期2023-05-10

申办/合作机构

BioSyngen Pte Ltd.初创企业

CTR20232806 / Not yet recruiting临床1期

BRG01注射液治疗复发/难治性EBV阳性淋巴瘤患者安全性和有效性的I期临床试验

主要目的：评价BRG01注射液的安全性和耐受性；次要目的：1.评估BRG01注射液的PK、PD、ADA； 2.评估BRG01注射液的初步有效性

开始日期-

申办/合作机构

广州百吉生物制药有限公司

100 项与 BRG01 相关的临床结果

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100 项与 BRG01 相关的转化医学

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100 项与 BRG01 相关的专利（医药）

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项与 BRG01 相关的文献（医药）

2021-03-01·Journal of biochemical and molecular toxicology4区 · 医学

Activation of Akt‐dependent Nrf2/ARE pathway by restoration of Brg‐1 remits high glucose‐induced oxidative stress and ECM accumulation in podocytes

4区 · 医学

Article

作者: Yan, Hao ; Song, Ming‐Ai ; Xu, Fei ; Wang, Kai ; Wang, Lulu ; Xu, Jun

Abstract:

Brahma‐related gene 1 (Brg‐1) is perceived as a cytoprotective protein due to its role in alleviating oxidative stress and apoptosis. Our study aimed to explore the role and mechanism of Brg‐1 in high glucose (HG)‐stimulated podocytes. The HG exposure downregulated Brg‐1 and inactivated the protein kinase B (Akt) pathway in podocytes. Restoration of Brg‐1 inhibited HG‐induced viability reduction of podocytes. The HG‐induced increase of reactive oxygen species and malondialdehyde levels and decrease of superoxide dismutase activity in podocytes were reversed by the Brg‐1 overexpression. The Brg‐1 overexpression terminated the HG‐induced production of fibronectin, collagen IV, transforming growth factor‐β1, and connective tissue growth factor. In addition, the Brg‐1 overexpression activated Akt‐dependent nuclear factor E2‐related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in HG‐stimulated podocytes. However, inhibition of the Akt pathway or Nrf2 silencing counteracted the protective effects of Brg‐1 in HG‐stimulated podocytes. In conclusion, the Brg‐1 overexpression suppressed HG‐induced oxidative stress and extracellular matrix accumulation by activation of Akt‐dependent Nrf2/ARE signaling in podocytes.

2008-03-01·Cell cycle (Georgetown, Tex.)3区 · 生物学

Inhibition of cyclin D1 gene transcription by Brg-1

3区 · 生物学

Article

作者: Daniel A. Engel ; L. Andrew Shirley ; Mahadev Rao ; Mathew C. Casimiro ; Chenguang Wang ; Michael Stallcup ; Richard G. Pestell ; Manran Liu ; Daniel J. Murphy ; Michael P. Lisanti ; Jennifer E. Leader ; Mark D'Amico

The evolutionarily conserved SWI-SNF chromatin remodeling complex regulates cellular proliferation. A catalytic subunit, BRG-1, is frequently down regulated, silenced or mutated in malignant cells, however, the mechanism by which BRG-1 may function as a tumor suppressor or block breast cancer cellular proliferation is not understood. The cyclin D1 gene is a collaborative oncogene overexpressed in greater than 50% of human breast cancers. Herein, BRG-1 inhibited DNA synthesis and cyclin D1 expression in human MCF-7 breast cancer epithelial cells. The cyclin D1 promoter AP-1 and CRE sites were required for repression by BRG-1 in promoter assays. BRG-1 deficient cells abolished and siRNA to BRG-1 reduced, formation of the BRG-1 chromatin complex. The endogenous cyclin D1 promoter AP-1 site bound BRG-1. Estradiol treatment of MCF-7 cells induced recruitment of BRG-1 to the endogenous hpS2 gene promoter. Estradiol, which induced cyclin D1 abundance, was associated with a reduction in recruitment of the co-repressors HP1alpha/HDAC1 to the endogenous cyclin D1 promoter AP-1/BRG-1 binding sites. These studies suggest the endogenous cyclin D1 promoter BRG-1 binding site functions as a molecular scaffold in the context of local chromatin upon which coactivators and corepressors are recruited to regulate cyclin D1.

2004-11-01·The Journal of biological chemistry2区 · 生物学

Roles of Brahma and Brahma/SWI2-Related Gene 1 in Hypoxic Induction of the Erythropoietin Gene

2区 · 生物学

Article

作者: Ruixue Zhang ; Timothy V. Beischlag ; Feng Wang ; Oliver Hankinson ; Christian Muchardt ; Moshe Yaniv

Upon hypoxia, the human erythropoietin (EPO) gene is transactivated by the heterodimeric hypoxia-inducible factor 1 (HIF-1). Mammalian SWI/SNF is a chromatin-remodeling complex involved in the modulation of gene expression. We demonstrate that Brahma (Brm) and Brahma/SWI2-related gene 1 (Brg-1), alternative ATPase subunits of SWI/SNF, potentiate reporter gene activation mediated by HIF-1 in an ATPase-dependent manner. Brm was more potent than Brg-1 in the reporter gene assays. Simultaneous depletion of both Brm and Brg-1 by small interfering RNAs significantly compromised the transcription of the endogenous EPO gene triggered by hypoxia. Whereas knocking down Brm alone resulted in a moderate reduction in transcription of the EPO gene, depletion of Brg-1 resulted in an augmentation of transcription of both the EPO gene and the Brm gene, indicating that Brm can compensate for loss of Brg-1. Chromatin immunoprecipitation (ChIP) and sequential ChIP (re-ChIP) analysis showed that both Brm and Brg-1 associate with the enhancer region of the EPO gene in vivo in a hypoxia-dependent fashion and that each is present in a complex with HIF-1. Brm and Brg-1 were also recruited to the promoter of the vascular endothelial growth factor (VEGF) gene in a hypoxia-dependent fashion, although hypoxic induction of VEGF transcription was not affected by depletions of either or both Brm and Brg-1. Together these studies reveal a novel role for SWI/SNF in the activation of transcription of the EPO gene, indicate an important communication and compensation between Brm and Brg-1, and suggest that the requirement for SWI/SNF during hypoxic induction is gene-specific.

项与 BRG01 相关的新闻（医药）

2024-11-11

·同写意

百吉生物BRG01第四代肿瘤药关键II期临床试验启动，业内专家共话从0到1的创新突破，解决靶向毒性难题

CSCO会议临床2期临床1期

2024-09-25

·今日头条

肿瘤100%缩小，生存超8年！四大新型CAR-T引爆2024 ESMO大会

CAR-T细胞疗法作为免疫细胞疗法中的佼佼者，被视为有可能攻克癌症的“大杀器”。就在刚刚结束的2024年度欧洲肿瘤内科学会（ESMO）年会上，公布了各国在CAR-T治疗实体瘤方面的重大进展，为实体瘤患者实现长生存的美好愿景带来了新的希望！尤其是我国自研的CAR-T疗法，在本次大会上引得广泛关注。一、2024 ESMO大会：新型CAR-T疗法重磅进展（一）BRG01：我国首创EBV特异性CAR-T榜上有名，晚期鼻咽癌缩小率高达100%！ BRG01是我国首创的一款针对Gp350 （EBV包膜糖蛋白，一种对肿瘤的靶向作用极小的肿瘤特异性抗原）的自体嵌合抗原受体-T（CAR-T）细胞疗法，用于治疗 EBV阳性鼻咽癌，2024 ESMO大会上公布了1期惊艳临床数据（NCT05864924）。本次共入组9例既往接受过铂类化疗、免疫检查点抑制剂（ICI）、ADC（抗体-药物偶联物）治疗失败的晚期转移性鼻咽癌患者。结果显示， 75%患者肿瘤负荷持续减少，部分病灶获得完全缓解（CR），肿瘤缩小率高达100% ，全部入组患者无进展生存期（PFS）超过6个月。值得一提的是，一位晚期鼻咽癌患者经BRG01治疗后，肿瘤病灶明显缩小，由 22mm （治疗前），缩小至 5mm （治疗3个月后），该患者幸运地获得了完全缓解（详见下图）。 ▲图源“PR Newswire”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除（二）OriC613：双靶点CAR-T细胞疗法，抗肿瘤功效持续超100天胰腺癌作为一种高度侵袭性恶性肿瘤，其发病率和致死率都较高，而且目前缺乏有效的治疗手段。 Claudin18.2（CLDN18.2）和间皮素（MSLN）是胰腺癌和胃癌中的常见靶点。近年研究发现，CLDN18.2 CAR-T疗法在治疗胰腺癌和胃癌方面，具有不俗的疗效。2024 ESMO大会上公布的这款 OriC613，是由原启生物研制的一款针对同时靶向Claudin18.2（CLDN18.2）、间皮素（MSLN）两大关键靶点的CAR-T细胞疗法，旨在激发患者自身的免疫系统，来攻击和清除癌细胞；同时可解决靶向毒性问题并实现更高剂量的CAR-T细胞给药。 2024年7月25日，OriC613注射液的临床新药IND申请获得国家药品监督管理局药品审评中心（NMPA）批准，拟用于晚期胰腺癌的治疗。 OriC613表现出强大的抗肿瘤功效，对高肿瘤负担患者具有潜在疗效，而且延长了抗肿瘤疗效的持续时间，抗肿瘤功效可持续超过100天。 ▲截图源自“NMPA” （三）EU307：第四代CAR-T疗法首次临床试验肝细胞癌是最常见的恶性肿瘤之一，全球每年约有78万例发病，迫切需要新的治疗技术和策略来改善患者的预后。 GPC3在肝细胞癌中表达显著，是治疗肝细胞癌的重要靶点。本次ESMO大会公布的这款 EU307是一种第四代创新型抗GPC3CAR-T细胞疗法，专门用于治疗GPC3阳性晚期肝细胞癌。通过分泌白细胞介素18（IL-18），从而增强CAR-T细胞在实体瘤环境中的持久性和功能，专门针对肝细胞癌特异性肿瘤抗原GPC3。首次1期临床研究（NCT05783570）目前正在韩国进行，招募工作预计将于2024 年完成，让我们拭目以待其效果。（四）QH104：新型CAR-γδT细胞治疗脑胶质瘤，疾病控制率高达100% 除了上文提到的这几款CAR-T细胞外，一款新型CAR-γδT细胞（QH104）在ESMO大会上也引起了广泛关注。γδ T细胞是先天淋巴细胞，可检测受感染或恶性宿主细胞，是癌症过继免疫疗法中极具潜力的候选细胞。CAR-γδT细胞是在γδ T细胞基础上进行改造，与天然γδT细胞相比， CAR-γδT细胞在治疗实体瘤和血液肿瘤方面的特异性毒性和安全性更高，可用于治疗中枢神经系统恶性肿瘤。在此次大会上，公布了 QH104（即同种异体B7H3靶向CAR-γδT细胞），治疗复发性胶质母细胞瘤（rGBM）的首例人体临床试验（NCT06018363）结果。截至2024年3月30日，共入组7例高级别复发性胶质母细胞瘤（rGBM）患者，中位年龄为60岁（范围31-66岁），在接受一次以上QH104鞘内输注治疗后，经过为期6.5个月的中位随访。结果显示：QH104表现出良好的持久性，在所有7例患者中，客观缓解率（ORR）达到42.9% （3/7），疾病控制率（DCR）更是高达100% （7/7）。综上，QH104治疗B7H3阳性rGBM中，具有良好的疗效，且安全性可控。二、CAR-T治疗肝癌、胃癌等实体瘤经典案例分析，长生存超8年（一）CAR-GPC3 T细胞联合局部治疗，晚期肝细胞癌患者生存超8年肝癌患者治疗选择有限，整体预后不佳，即使进行手术切除，术后中位总生存期仅为17.8个月，而世界知名期刊《癌症通讯》杂志，报道的一个“ 晚期肝细胞癌（HCC）患者，经创新型CAR-GPC3 T细胞疗法后，生存超8年 ”的经典案例，远超肝细胞癌17.8个月的中位生存期！这位幸运患者是一位54岁男性，确诊为Ib期肝细胞癌（HCC），既往接受过肿瘤切除手术、经导管动脉化疗栓塞术（TACE）、肝癌微波消融治疗（MWA）等治疗，但病情仍迅速进展，MRI显示肝脏多灶性病变、腹膜后淋巴结转移（LM）。入组接受CAR-GPC3 T细胞治疗后，结果显示： 1、转移灶明显缩小：CAR-T细胞治疗后2周，腹膜后淋巴结转移灶（LM）开始缩小，病变短轴直径缩小了 5.2% ，长轴直径缩小了 4.5% 。最后一次输注CAR-GPC3 T细胞后，靶病变短轴进一步减小，在第7次输注后第7天减小了7.4% （详见下图）。 ▼CAR-GPC3 T细胞输注前后，腹膜后淋巴转移的MRI成像（红色箭头） ▲图源“WILEY Online Library”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 2、肿瘤标志物水平：该患者甲胎蛋白（AFP）水平降低了56.6％，从 1,301 ng/mL，骤降至 565 ng/mL（详见下图）。之后在接受伽玛刀放射外科治疗（GKRS）后， AFP水平逐渐下降至正常范围，此后患者一直处于无癌状态。 ▲图源“WILEY Online Library”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除 3、长生存奇迹：患者除了2016年7月接受伽玛刀放射外科治疗（GKRS）治疗外，此后在没有任何进一步抗癌治疗的情况下，保持无病状态超过5年，总生存期超过8年（详见下图）！ ▼CAR-GPC3 T细胞治疗后肝脏MRI图像 ▲图源“WILEY Online Library”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除注：红色箭头表示治疗后的坏死肿瘤。（二）CLDN18.2 CAR-T：助转移性胃癌患者获得完全缓解尽管采取化疗为主的传统治疗+免疫疗法或靶向药物可以获得客观的肿瘤反应和生存益处，但绝大多数胃癌患者仍然无法治愈。而且由于深部组织侵袭和腹膜渗透，很多胃癌患者无法通过手术切除，5年总生存率仅为5%~20%，中位生存期不足1年（11个月）。 Claudin18.2（CLDN18.2）是一种高选择性细胞表面分子，在正常胃组织中表达有限，但在原发性胃癌及其转移灶中的表达明显较高。针对胃癌的这一关键靶点，我国研发了一款名为“CT041”的CLDN18.2靶向嵌合抗原受体-T（CAR-T）细胞。《癌症免疫治疗杂志》报道了 CT041治疗转移性胃癌并获得完全缓解的出色案例。这位30岁患者确诊为CLDN18.2阳性转移性、低分化印戒细胞癌，在四线联合全身化疗、多次细胞减灭手术联合腹腔热灌注化疗（HIPEC）后，病情出现进展。入组接受第一次CT041回输治疗后，两个腹膜靶病变显著减少；腹胀改善且左中腹部包裹性腹水减少。根据 RECIST V.1.1，在治疗第4周时，靶病变消失，患者获得部分缓解（PR），并维持8个月的总体部分缓解。在第二次回输CT041后4周，患者幸运地获得完全缓解（CR），仅出现少量腹水。 ▼该患者增强轴向CT扫描结果 ▲图源“J Immunother Cancer”，版权归原作者所有，如无意中侵犯了知识产权，请联系我们删除注： ①上图：通过增强轴向CT扫描显示，该患者腹膜结节靶病变完全缓解（箭头，顶部）； ②下图：通过增强轴向CT扫描显示，该患者左中腹部包裹性腹水减少（箭头，底部）。三、小编寄语迄今为止，CAR-T细胞疗法已在血液系统恶性肿瘤治疗方面取得了突破性进展。然而，它们在治疗实体瘤方面的成功仍然有限，这可能与实体瘤中T细胞的低浸润性、免疫抑制的肿瘤微环境等因素有关。值得欣慰的是，近年来各国研究人员，在不断研发各种新型策略，以减轻肿瘤抗原异质性、应对免疫抑制，深耕CAR-T在实体瘤领域的应用价值。我国CAR-T发展也已进入“百家争鸣”的局面，相继有驯鹿医疗、复星凯特、科济生物、传奇生物等多家制药巨头纷纷加入CAR-T的研发大军中。想了解详细入排标准的患者，可将出院小结、治疗经历、完整的病理报告等资料，提交至全球肿瘤医生网医学部，进行初步评估。四、参考资料 [1]Ganapathy T,et al.CAR γδ T cells for cancer immunotherapy. Is the field more yellow than green? Cancer Immunol Immunother. 2023 Feb;72(2):277-286. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10992831/ [2]Shi Y,et al.Combined local therapy and CAR-GPC3 T-cell therapy in advanced hepatocellular carcinoma: a proof-of-concept treatment strategy. Cancer Commun (Lond). 2023 Sep;43(9):1064-1068. https://onlinelibrary.wiley.com/doi/10.1002/cac2.12472 [3]Botta GP,et al.Metastatic gastric cancer target lesion complete response with Claudin18.2-CAR T cells. J Immunother Cancer. 2024 Feb 5;12(2):e007927. https://pubmed.ncbi.nlm.nih.gov/38316518/ [4]https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/safety-and-efficacy-of-a-novel-car-t-cell-therapy-brg01-targeting-the-epstein-barr-virus-envelope-glycoprotein-in-advanced-metastatic-nasopharyng [5]https://www.prnewswire.com/news-releases/biosyngens-first-in-class-car-t-asset-targeting-solid-tumors-has-entered-pivotal-phase-ii-trial-phase-i-trial-data-debut-at-esmo-2024-annual-congress-302251709.html [6]https://oncologypro.esmo.org/meeting-resources/esmo-gastrointestinal-cancers-congress-2024/enhanced-antitumor-efficacy-and-safety-through-a-novel-car-t-strategy-targeting-msln-and-cldn18.2 [7]https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/first-in-human-dose-escalation-trial-of-fourth-generation-chimeric-antigen-receptor-car-t-cell-therapy-eu307-in-patients-with-glypican-3-gpc3 [8]https://oncologypro.esmo.org/meeting-resources/esmo-congress-2024/a-phase-i-clinical-trial-of-intrathecal-injection-of-allogeneic-car-gdt-cells-targeting-b7h3-for-the-treatment-of-patients-with-recurrent-glioblastoma 本文为全球肿瘤医生网原创，未经授权严禁转载

细胞疗法免疫疗法抗体药物偶联物临床申请临床1期

2024-09-20

·PRNewswire

Biosyngen Best-in-Class Next-Generation Tumor-Infiltrating Lymphocyte (TIL) Technology Debuts on ESMO 2024 Annual Meeting

BARCELONA, Spain, Sept. 20, 2024 /PRNewswire/ -- The highly anticipated 2024 European Society for Medical Oncology (ESMO) Annual Congress has taken place from September 13 to 17 in Barcelona, Spain. As one of the most influential annual gatherings in oncology, this congress brings together leading cancer experts and researchers from around the globe, showcasing the latest advancements in the field and providing high-quality educational and networking opportunities for oncology professionals. Continue Reading Figure 1 BSGTIL antitumor efficacy Biosyngen, an innovative biotechnology company specializing in immune cell therapies, has showcased its groundbreaking technology on gene-modified, functionally enhanced tumor-infiltrating lymphocytes (TILs) derived from liver cancer biopsy samples. BioSyngen has secured ten clinical trial approvals in China and the U.S. for its innovative fourth-generation oncology therapies. Currently, our leading pipeline product, BRG01, is in the pivotal Phase II clinical trial stage for solid tumors. Additionally, the first patients have been enrolled in the Phase I trials for our other groundbreaking therapies, BST02 and BRL03, with completion of Phase I trials anticipated later this year. Abstract Title Pre-clinical Development of Genetically Modified Tumor-infiltrating Lymphocytes using Biopsy Samples from Liver Cancer Patients Abstract No. 1034P Tumor-infiltrating lymphocytes (TILs) are heterogeneous lymphocyte populations within the tumor microenvironment that contains T cells capable of recognizing tumor- or virus-associated antigens. In February of this year, the FDA approved the first TIL-based therapy used with IL-2 for advanced metastatic/recurrent melanoma. However, due to the variability in T cell infiltration between hot and cold tumors, differential abundance of antigen-specific T cells with robust immune response functionality, and the dependence of TIL anti-tumor efficacy on concomitant use of high-dose IL-2 combination therapy, the therapeutic applications of non-edited TILs are quite limited outside of melanoma. To address these challenges, Biosyngen has developed a proprietary platform for expanding TILs from biopsy samples, achieving production of 1011 cells within four weeks. Additionally, the company has established a stable gene modification platform that reprograms TIL metabolism, enhances TIL activity and sustained antitumor efficacy by expressing membrane anchor proteins. Anti-tumor efficacy has significantly enhanced (without IL-2 co-injection) and no obvious toxicity observed. Biosyngen houses best-in-class proprietary TIL platform aiming to expand the clinical applications of TIL technology with following features: Efficient Automated TILs Manufacturing System: Pioneering the use of tumor biopsy samples for TIL preparation with the ability to cryopreserve both tumor tissue and final products, overcoming logistical constraints. Effective In Vitro Gene-engineering System: Employs viral vector technology for stable gene modification, maintaining high gene expression efficiency in TILs. Enhanced In Vivo Expansion and Persistence: Increased proportion of central memory T cells (TCM) in the final product, leading to prolonged persistence. Powerful Antitumor Efficacy: Demonstrates strong tumor-killing effects without the need for concomitant use of IL-2. SOURCE Biosyngen WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

基因疗法临床1期临床2期上市批准

100 项与 BRG01 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
爱泼斯坦-巴尔病毒相关鼻咽癌	临床2期	中国	BioSyngen Pte Ltd.初创企业	2024-09-18
鼻咽癌	临床2期	美国	BioSyngen Pte Ltd.初创企业	2023-02-17
爱泼斯坦-巴尔病毒阳性淋巴瘤	临床1期	中国	广州百吉生物制药有限公司	2023-09-08

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05864924 (ESMO2024) 人工标引	临床1期	晚期鼻咽癌	11	BRG01	遞廠廠顧鬱餘窪蓋範觸(餘蓋齋遞願艱糧觸糧鹽) = BRG01 was well tolerated in all infused patients without severe adverse effects related to lymphodepletion or BRG01 treatment, demonstrating its safety profile. 製遞糧衊觸蓋網糧夢觸 (窪觸顧鏇鏇築艱觸鏇鬱 ) 更多	积极	2024-09-14