A Phase IIb/III, Randomised, Double-blind, Placebo-controlled, Multicentre,Study of CA-170 in Combination with Chemotherapy and Radiation in Patients with Unresectable Stage III or IVa Non-Squamous Non-Small Cell Lung Cancer (ASIAD-2) - ASIAD-2

开始日期2020-08-03

申办/合作机构-

CTRI/2017/12/011026

/ Terminated临床2期

A Phase 2, Open-Label Randomized Trial Evaluating the Efficacy and Safetyof Two Dosages of Once Daily Oral CA-170 in Patients with Selected RelapsedAdvanced Tumors (ASIAD)

开始日期2018-01-12

申办/合作机构

Aurigene Oncology Ltd.

NCT02812875

/ Completed临床1期

A Phase 1, Open-Label, Dose Escalation and Dose Expansion Trial Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Effects of Orally Administered CA-170 in Patients With Advanced Tumors and Lymphomas

CA-170 is a rationally designed and orally available, small molecule that directly targets the Programmed death-ligands 1 and 2 (PD-L1/PD-L2), and V-domain Ig suppressor of T cell activation (VISTA) immune checkpoints and results in activation of T cell proliferation and cytokine production. This is a multi-center, open-label, Phase 1 trial of orally administered CA-170 in adult patients with advanced solid tumors or lymphomas who have progressed or are non-responsive to available therapies and for which no standard therapy exists.

开始日期2016-05-01

申办/合作机构

Curis, Inc.

100 项与 CA-170 相关的临床结果

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100 项与 CA-170 相关的转化医学

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100 项与 CA-170 相关的专利（医药）

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项与 CA-170 相关的文献（医药）

2025-06-01·MOLECULAR DIVERSITY

Pyroptosis and chemical classification of pyroptotic agents

Review

作者: Mohamed, Khaled O ; Hara, Mohammed A ; Ramadan, Mohamed ; Abdelhameid, Mohammed K ; Taher, Ehab S

Abstract:

Pyroptosis, as a lytic-inflammatory type of programmed cell death, has garnered considerable attention due to its role in cancer chemotherapy and many inflammatory diseases. This review will discuss the biochemical classification of pyroptotic inducers according to their chemical structure, pyroptotic mechanism, and cancer type of these targets. A structure-activity relationship study on pyroptotic inducers is revealed based on the surveyed pyroptotic inducer chemotherapeutics. The shared features in the chemical structures of current pyroptotic inducer agents were displayed, including an essential cyclic head, a vital linker, and a hydrophilic tail that is significant for π-π interactions and hydrogen bonding. The presented structural features will open the way to design new hybridized classes or scaffolds as potent pyroptotic inducers in the future, which may represent a solution to the apoptotic-resistance dilemma along with synergistic chemotherapeutic advantage.Graphical Abstract

2024-10-10·JOURNAL OF MEDICINAL CHEMISTRY

Small-Molecule Radiotracers for Visualization of V-Domain Immunoglobulin Suppressor of T Cell Activation

Article

作者: Zeng, Xinying ; Liang, Yuanyuan ; Zhang, Xianzhong ; Guo, Zhide ; Yang, Hongzhang ; Du, Jin ; Liu, Jia ; Zhuang, Rongqiang ; Wang, Xueqi

V-domain immunoglobulin suppressor of T cell activation (VISTA) plays a critical role in regulating innate and adaptive immune responses within the tumor immune microenvironment. Quantifying VISTA expression is necessary to determine whether patients respond to a related combination immunotherapy. This study developed two ⁶⁸Ga-labeled small-molecule probes ([⁶⁸Ga]Ga-DCA and [⁶⁸Ga]Ga-DNCA) for visualizing and differentiating VISTA expression. These probes exhibited excellent targeting capabilities for multiple tumor types (including B16-F10, 4T1, MC38, and CT26 tumors), consistent with the levels of VISTA expression determined by immunoblotting. Co-injection of inhibitor CA-170 led to decreased tumor uptake of both [⁶⁸Ga]Ga-DCA and [⁶⁸Ga]Ga-DNCA. [⁶⁸Ga]Ga-DCA was used to verify the feasibility of monitoring VISTA expression in lung metastasis models. In summary, this study describes the use of ⁶⁸Ga-labeled CA-170 analogues as small-molecule probes for imaging VISTA. This could provide a visual method and enable personalized immunotherapy in patients.

2024-01-01·Bioinformatics and Biology Insights

Unlocking Benzosampangine’s Potential: A Computational Approach to Investigating, Its Role as a PD-L1 Inhibitor in Tumor Immune Evasion via Molecular Docking, Dynamic Simulation, and ADMET Profiling

Article

作者: Ramli, Youssef ; Hadad, Salah Eddine El ; Fadoua, Elkamili ; Kettani, Anass ; Aherkou, Marouane ; Mouad, Mkamel ; Ouchaoui, Abderrahim Ait ; Bourais, Ilhame

The interaction between programmed cell death protein 1 (PD-1) and its ligand PD-L1 plays a crucial role in tumor immune evasion, presenting a critical target for cancer immunotherapy. Despite being effective, current monoclonal antibodies present some drawbacks such as high costs, toxicity, and resistance development. Therefore, the development of small-molecule inhibitors is necessary, especially those derived from natural sources. In this study, benzosampangine is predicted as a promising PD-L1 inhibitor, with potential applications in cancer immunotherapy. Utilizing the high-resolution crystal structure of human PD-L1 (PDB ID: 5O45), we screened 511 natural compounds, identifying benzosampangine as a top candidate with exceptional inhibitory properties. Molecular docking predicted that benzosampangine exhibits a strong binding affinity for PD-L1 (−9.4 kcal/mol) compared with established controls such as CA-170 (−6.5 kcal/mol), BMS-202 (−8.6 kcal/mol), and pyrvinium (−8.9 kcal/mol). The compound’s predicted binding efficacy is highlighted by robust interactions with key amino acids (ILE54, TYR56, GLN66, MET115, ILE116, SER117, ALA121, ASP122) within the active site, notably forming 3 Pi-sulfur interactions with MET115—an interaction absents in control inhibitors. In addition, ADMET profiling suggests that over the control molecules, benzosampangine has several key advantages, including favorable solubility, permeability, metabolic stability, and low toxicity, while adhering to Lipinski’s rule of five. Molecular dynamic simulations predict the stability of the benzosampangine-PD-L1 complex, reinforcing its potential to sustain inhibition of the PD-1/PD-L1 pathway. MMGBSA analysis calculated a binding free energy (ΔGbind) of −39.39 kcal/mol for the benzosampangine-PD-L1 complex, with significant contributions from Coulombic, lipophilic, and Van der Waals interactions, validating the predicted docking results. This study investigates in silico benzosampangine, predicting its better molecular interactions and pharmacokinetic profile compared with several already known PD-L1 inhibitors.

项与 CA-170 相关的新闻（医药）

2024-03-05

·今日头条

代谢重塑！厦门大学/上海交大季天海团队发现胶质瘤治疗新药

本文为转化医学网原创，转载请注明出处作者：Jerry 导读：最近，晶体学研究表明，BMS-202是一种以甲氧基-1-吡啶化学结构为特征的小分子化合物，对PD-L1二聚化具有很高的亲和力。然而，其在胶质母细胞瘤(glioblastoma, GBM)中的作用和机制尚不清楚。 3月4日，厦门大学/上海交大季天海研究团队在期刊《Cell Death&Disease》上发表了研究论文，题为“Metabolic remodeling by the PD-L1 inhibitor BMS-202 significantly inhibits cell malignancy in human glioblastoma”。研究结果表明，BMS-202在体外和体内均明显抑制GBM细胞的增殖。此外，它还具有体外阻断细胞迁移和侵袭的功能。综上所述，研究人员得出结论，BMS-202是一款很有前景的治疗候选药物，通过重塑GBM患者的细胞代谢方案，从而提高患者的生存率。 https://www.nature.com/articles/s41419-024-06553-5#Sec1 研究背景 01 胶质母细胞瘤(GBM)是中枢神经系统最常见的侵袭性脑肿瘤，发病率为5.8/10万，5年生存率<10%，中位生存期14.6个月。目前，高级别胶质瘤的诊断和治疗仍有较大的改进空间，如成本高、耐药性强、跨血脑屏障能力差等。CA-170、JQ1、BMS-202等小分子药物是克服上述困境的一种途径。在GBM的发生发展中多种因素和机制发挥重要作用。支链氨基酸(BCAAs)是合成谷氨酸的主要氮源，而谷氨酸是分解代谢和合成代谢的关键底物，对细胞生长不可或缺。因此，针对BCAAs的治疗将有可能改善肿瘤治疗。程序性细胞死亡配体-1(PD-L1)通常在胶质瘤细胞中过度表达，并影响PI3K/AKT信号通路，从而替代重塑BCAAs的产生。然而，目前尚不清楚BCAA的代谢是否与GBM中PD-L1的表达有关。研究进展 02 研究人员首先使用CCK-8实验评估了BMS-202在GBM细胞中的抗肿瘤活性。结果显示，在BMS-202(10 μM)处理24小时后，U251和LN229细胞的细胞活力显著降低(p < 0.01)，而正常胶质细胞系(HEB)的细胞活力没有显著影响。此外，来自荷瘤裸鼠异种移植物的数据支持BMS-202在体内显著抑制U251细胞的生长。总之，这些体内外数据表明，BMS-202在不影响正常胶质细胞的情况下显著抑制GBM细胞的生长，这意味着其在GBM抗肿瘤应用中有一个安全的治疗窗口。 BMS-202抑制GBM细胞株的恶性细胞生长其次，研究人员进一步评估了BMS-202在细胞迁移和侵袭中的作用，有趣的是，BMS-202在25 μM时显著抑制了细胞迁移，在10 μM时抑制了细胞侵袭，同样，研究人员进一步检测了参与上皮-间充质转化(EMT)过程的关键因子。之后，研究人员进一步研究了BMS-202对GBM细胞表面或细胞质中PD-L1表达的抑制活性。首先，研究人员使用流式细胞术检测了10 μM BMS-202处理24 h后U251细胞表面PD-L1的表达。有趣的是，U251细胞表面的PD-L1在IFN-γ刺激下显著增加(p < 0.05)，而在上述相同条件下，用BMS-202处理时，增加不显著。同时，研究人员分别使用RT-PCR和蛋白质印迹分析进一步检测了BMS-202处理U251细胞中PD-L1的mRNA和蛋白水平。出乎意料的是，结果显示它对PD-L1的mRNA和蛋白水平没有显著影响。然而，它对转染靶向PD-L1的siRNA的U251细胞的细胞迁移有显著的抑制作用。综上，结果表明BMS-202通过影响细胞表面PD-L1的活性，而不是影响其转录和翻译水平，显著抑制GBM细胞的增殖、侵袭和迁移。研究结论 03 综上所述，BMS-202作为抑癌剂，通过抑制肿瘤恶性表型，抑制PD-L1，在胶质瘤细胞中发挥代谢重塑作用。参考资料： https://www.nature.com/articles/s41419-024-06553-5#Sec1 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。

放射疗法临床研究

2024-01-16

·药时代

靶向PD-1/PD-L1小分子药物的研究进展

前言利用免疫途径治疗癌症的免疫疗法正在迅速成为继手术、化疗和放疗之后的一种公认的癌症治疗方法。其中利用针对细胞毒性T淋巴细胞相关蛋白4（CTLA-4）、程序性死亡受体1（PD-1）或程序性死亡配体1（PD-L1）的单克隆抗体进行检查点阻断，在癌症免疫治疗方面取得了显著突破。然而，尽管免疫疗法有其优点，但它只在一小部分患者中获得成功，而广泛预测其疗效的生物标志物仍有待确定。此外，治疗期间还可能发生严重的治疗相关毒性，称为免疫相关不良事件（irAE），主要是由于免疫系统平衡失调。因此，小分子药物又回到人们的视野，因为这类药物相比单抗有许多优点。特别是，较短半衰期的小分子有利于急性和可逆的作用，并可能减少持久的全身副作用。与抗体不同的是，小分子通常以细胞内蛋白质为靶点，并具有不同的毒性特征，使其成为适用联合治疗的候选者。此外，与抗体相比，它们可以以更低的成本生产，并且通常可以口服给药。因此，需要基于免疫学和肿瘤学过程的分子洞察力的新策略来提高小分子在免疫治疗中的潜力，重点是小分子有望提高检查点阻断对癌症治疗的成功率。靶向PD-1/PD-L1小分子的设计PD-1/PD-L1受体-配体相互作用是蛋白质-蛋白质相互作用（PPI）的经典例子；因此，为这些相互作用设计抑制剂是极具挑战性的。这主要是因为（a）相互作用的大范围接触面积（1500–3000Å），（b）存在平坦的界面，没有深而明确的结合口袋，适合以高亲和力结合配体，（c）缺乏内源性小分子配体作为参考标准。在分析PD-1:PD-L1和PD-1:PD-L2复合物的晶体结构的进展方面，人们发现了几个潜在热点区域。基于PD-1:PD-L1晶体结构在PD-L1上鉴定的三个主要热区包括（1）由Tyr56、Glu58、Arg113、Met115和Tyr123的侧链组成的疏水口袋；（2）由Met115、Ala121和Tyr123组成的疏水位点附近的第二口袋；和（3）由Asp122、Tyr123、Lys124和Arg125的主链和侧链组成的延伸槽。这些区域被认为是使用常规小分子结合PD-L1的理想区域。目前，主要有两类不同的靶向PD-L1的小分子抑制剂，即（a）基于联苯支架的化合物；以及（b）在功能测定中鉴定的模仿受体-配体界面的氨基酸启发的小分子。1）联苯衍生物BMS的科学家基于PD-1:PD-L1相互作用的机制，开发了一系列联苯衍生物。此外，过去6年来，包括Incyte Corporation、Arising International Inc.、Chemocentryx Inc.、Polaris Pharmaceuticals和Guangzhou Maxinovel Pharmaceeticals Co.在内的多家公司已经发现了一系列基于联苯核心的小分子PD-L1抑制剂。在新的改性联苯支架中，具有C2对称性或含有极性基团的假对称性的化合物比不对称结构获得了很多关注。2）多肽检查点蛋白是膜蛋白，其中大多数来自B7家族。B7家族的大多数成员及其配体属于免疫球蛋白超家族（IgSF）。IgSF蛋白的受体-配体相互作用通过环、链或环和链介导。基于这些相互作用界面的多肽设计是PPI抑制剂设计的一种行之有效的策略。利用上述设计原理，已经开发出了了几种拟肽分子。靶向PD-1/PD-L1小分子的作用机制尽管多数分子设计来自于能够与PD-1:PD-L1复合物中的一个结合并阻止相互作用，但新出现的数据表明，一些化合物拮抗PD-1信号传导具有额外的复杂性。诱导PD-L1二聚并抑制PD-1:PD-L1相互作用通过晶体结构研究，一些化合物被证明通过诱导PD-L1二聚化来抑制PD-1:PD-L1相互作用。例如BMS的小分子抑制剂倾向于首先与一种PD-L1单体相互作用，然后形成二聚体，以获得稳定性优势。而Incyte和Arbutus还利用了PD-L1二聚体中固有的C2对称性，通过对称化其分子来获得更大的效力。阻断PD-L1从内质网向高尔基体输出PD-L1胞外结构域中存在的四个N-糖基化位点（Asn35、Asn192、Asn 200和Asn 219）对配体蛋白的稳定性是必需的，除Asn35外，所有其他糖基化位置对其与受体的相互作用都非常关键。BMS-1166特异性抑制部分PD-L1的糖基化，并通过阻断PD-L1从内质网向高尔基体的输出而使其功能失活。诱导PD-L1二聚和内化化合物ARB-272572通过顺式相互作用的同源二聚体诱导细胞表面PD-L1二聚来抑制PD-1/PD-L1轴，这种同源二聚物通过快速内化到胞质中触发细胞表面PD-L1的快速丢失，从而防止与表达PD-1的细胞发生进一步相互作用。与PD-L1结合而不干扰PD1:PD-L1复合物的形成与基于联苯的小分子抑制剂相比，CA-170是高度极性的，在细胞环境中观察到的PD-L1信号传导的功能拮抗作用，而其与PD-L1的直接结合却不破坏PD1:PD-L1复合物导致形成有缺陷的三元复合物。CA-170的这种作用模式类似于两种已报道的抗PD-1抗体的作用模式，它们在不干扰PD-1:PD-L1复合物形成的情况下拮抗PD-1信号传导。靶向PD-1/PD-L1小分子的临床研究进展CA-170是第一个于2016年进入临床试验的口服小分子PD-L1抑制剂，目前正在进行2b/3期试验（由Curis和Aurigene共同开发）。Incyte化合物INCB-086550的临床试验于2018年启动，第一阶段预计将于2022年完成。下表综合了临床上所有小分子抑制剂的最新发现。小结自首个PD-1——Opdivo单抗于2014年获FDA批准上市后，截止目前，中国也已有10款PD-1抑制剂、5款PD-L1抑制剂上市。PD-1/L1抗体可以说是目前癌症靶向药物研发中的“超热”赛道。然而，单抗存在诸多固有缺点，包括口服生物利用度差、延长的组织滞留时间和半衰期、较差的膜通透性、运输储存等方面的弊端，另外，抗体药物成本较高也是不可忽视的问题。因此，越来越多的研究人员在探索小分子药物作为PD-1/L1抑制剂以规避治疗性抗体的缺点。另外，与PD-1/L1抗体相比，口服小分子药物可以很容易地渗透到组织中，因此可以针对细胞外和细胞内的目标来促进抗肿瘤免疫，实现对肿瘤微环境的调节，甚至有望将“冷”肿瘤转为“热”肿瘤。而且它们的半衰期通常很短，降低了产生不良影响的机会。基于这些特点，在癌症免疫治疗领域开发基于小分子的策略引起了广泛的兴趣，其未来的前景仍然广阔而令人兴奋。参考文献：1.Immune-checkpoint inhibitors: long-termimplications of toxicity. Nat Rev Clin Oncol. 2022 Jan 26 : 1–14.封面图来源：123rf点击阅读原文，查看更多精彩内容

免疫疗法

2023-10-06

·BioSpace

Curis Reports Inducement Grants Under NASDAQ Listing Rule 5635(c)(4) - October 06, 2023

LEXINGTON, Mass., Oct. 6, 2023 /PRNewswire/ -- Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, today announced that on October 2, 2023, the independent Compensation Committee of the Board of Directors of Curis approved the grant of inducement stock options to purchase a total of 11,340 shares of Curis common stock to two new employees, with a grant date of October 2, 2023 (the "Q4 2023 Inducement Grants"). Each of the Q4 2023 Inducement Grants has an exercise price per share equal to the closing price of the Company's common stock on October 2, 2023. Each stock option has a 10 year term and vests over four years, with 25% of the original number of shares underlying the award vesting on the first anniversary of the employee's date of hire and an additional 6.25% of the original number of shares underlying the award vesting on each successive three-month period thereafter, subject to the employee's continued service with the Company through the respective vesting dates. Each stock option was granted as an inducement equity award outside of the Company's Fourth Amended and Restated 2010 Stock Incentive Plan and was made as an inducement material to the employee's acceptance of employment with the Company. About Curis, Inc. Curis is a biotechnology company focused on the development of emavusertib, an orally available, small molecule IRAK4 inhibitor for the treatment of hematologic malignancies. In 2015, Curis entered into a collaboration with Aurigene in the areas of immuno-oncology and precision oncology. As part of this collaboration, Curis has exclusive licenses to oral small molecule antagonists of immune checkpoints including the VISTA/PDL1 antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as the IRAK4 kinase inhibitor, emavusertib (CA-4948). Emavusertib is currently undergoing testing in the Phase 1/2 TakeAim Lymphoma trial in patients with hematologic malignancies, such as non-Hodgkin's lymphoma and other B cell malignancies, both as a monotherapy and in combination with BTK inhibitor ibrutinib, and the Phase 1/2 TakeAim Leukemia trial in patients with acute myeloid leukemia and myelodysplastic syndrome, for which it has received Orphan Drug Designation from the U.S. Food and Drug Administration. In addition, Curis is engaged in a collaboration with ImmuNext for development of CI-8993, a monoclonal anti-VISTA antibody. Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis's website at . View original content to download multimedia: SOURCE Curis, Inc. Company Codes: NASDAQ-NMS:CRIS

免疫疗法孤儿药引进/卖出

100 项与 CA-170 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15772

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
非小细胞肺癌	临床3期	印度	Aurigene Oncology Ltd.	2020-08-03
膀胱癌	临床3期	印度	Aurigene Oncology Ltd.	-
肾肿瘤	临床3期	印度	Aurigene Oncology Ltd.	-
淋巴瘤	临床2期	印度	-	2018-02-17
肿瘤	临床2期	-	Curis, Inc.	-
间皮瘤	临床1期	韩国	Curis, Inc.	2019-01-24
晚期恶性实体瘤	临床1期	美国	Curis, Inc.	2016-05-01
晚期恶性实体瘤	临床1期	西班牙	Curis, Inc.	2016-05-01
晚期恶性实体瘤	临床1期	英国	Curis, Inc.	2016-05-01
结直肠癌	临床1期	美国	Curis, Inc.	2016-05-01

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临床结果

适应症

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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


NCT02812875 (CA-170-101, SITC2019) 人工标引	临床1期	恶性胸膜间皮瘤	12	CA 170	衊顧鏇憲製憲鏇廠醖淵(廠醖齋製鹽鹽鑰衊襯鑰) = 鑰構淵膚鏇鏇餘糧鑰觸築遞遞鏇齋鹹遞夢獵齋 (鏇蓋窪繭蓋範膚窪鬱積 ) 更多	积极	2019-11-10
NCT02812875 (ESMO2019)	临床2期	鳞状非小细胞肺癌三线	62	400mg CA-170	鬱選艱齋顧獵範鹹願鑰(鹽醖蓋網齋衊衊簾鑰醖) = 艱壓鏇構築遞齋鹽製範餘製齋衊襯製餘遞鏇網 (構構窪衊範構鑰鹹餘選 ) 更多	-	2019-09-30
NCT02812875 (ESMO2019)	临床2期	鳞状非小细胞肺癌三线	62	800mg CA-170	鬱選艱齋顧獵範鹹願鑰(鹽醖蓋網齋衊衊簾鑰醖) = 廠鏇餘齋簾構壓蓋醖夢餘製齋衊襯製餘遞鏇網 (構構窪衊範構鑰鹹餘選 ) 更多	-	2019-09-30
NCT02812875 (P714, SITC2018)	临床2期	霍奇金淋巴瘤 \| 晚期恶性实体瘤	58	CA-170 400mg	醖構蓋簾淵願壓鏇積遞(繭壓遞築選蓋觸範願蓋) = two patients developed skin rash, one patient developed hypothyroidism, and one patient developed Grade 3 neutropenia and anemia. Both anemia and neutropenia resolved upon drug interruption, however, neutropenia re-appeared after re-exposure, confirming causality. CA-170 was permanently discontinued without any sequalae, suggesting that smaller half life (6-8 hours) of CA-170 provides an advantage over longer lasting antibodies, from safety perspective. 夢築夢築獵願簾遞觸夢 (窪願網獵憲構願範夢壓 )	积极	2018-12-01
NCT02812875 (P139, SITC2018)	临床1期	霍奇金淋巴瘤 \| 实体瘤 \| 晚期恶性实体瘤 ... 更多	41	CA-170 50 mg QD	簾鑰壓鏇顧糧獵夢鹽構(鬱醖選蓋願觸蓋齋構憲) = 鬱遞願積積選製願鬱艱範壓獵願壓獵遞鹽顧廠 (衊膚艱繭鑰範餘製憲網, 1.5 ~ 5) 更多	积极	2018-11-06
NCT02812875 (P139, SITC2018)	临床1期	霍奇金淋巴瘤 \| 实体瘤 \| 晚期恶性实体瘤 ... 更多	41	CA-170 100 mg QD	簾鑰壓鏇顧糧獵夢鹽構(鬱醖選蓋願觸蓋齋構憲) = 淵遞鹽鑰觸衊遞網夢蓋範壓獵願壓獵遞鹽顧廠 (衊膚艱繭鑰範餘製憲網, 1.5 ~ 5) 更多	积极	2018-11-06