The ENABLE Study: An Open-Label, Long-Term Safety and Efficacy Study of INZ-701 in Patients With Ectonucleotide Pyrophosphatase/ Phosphodiesterase 1 (ENPP1) Deficiency

The purpose of Study INZ701-108 (ENABLE) is to assess the safety and efficacy of INZ-701 in patients 1 year of age and older with ENPP1 Deficiency who have not previously received INZ-701 and are not eligible for existing Inozyme-sponsored clinical studies that are still open to enrollment.

开始日期2025-01-31

申办/合作机构

Inozyme Pharma, Inc.

NCT06462547 / Recruiting临床2期

The ADAPT Study: An Open-label, Long-term Safety Study of INZ-701 in Patients With ENPP1 Deficiency and ABCC6 Deficiency

The purpose of this study (Study INZ701-304 [ADAPT]) is to assess the long-term safety of INZ-701 in patients with ENPP1 Deficiency or ABCC6 Deficiency who have received INZ-701 in an existing clinical study and choose to continue dosing for the potential treatment of their condition.

开始日期2024-06-19

申办/合作机构

Inozyme Pharma, Inc.

NCT06283589 / Active, not recruiting临床1期

The SEAPORT 1 Study: An Open-label Exploratory Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of INZ-701 in Study Participants With End-Stage Kidney Disease Undergoing Hemodialysis

The purpose of this study is to determine if multiple doses of INZ-701, given once per week over 4 weeks are safe and increase pyrophosphate (PPi) levels in hemodialysis-dependent (HD) end stage kidney disease (ESKD) study participants who have low PPi levels. In addition, the effect of hemodialysis on the pharmacokinetics of INZ-701 and PPi levels will be evaluated.

开始日期2024-02-12

申办/合作机构

Inozyme Pharma, Inc.

100 项与 INZ-701 相关的临床结果

登录后查看更多信息

100 项与 INZ-701 相关的转化医学

登录后查看更多信息

100 项与 INZ-701 相关的专利（医药）

登录后查看更多信息

项与 INZ-701 相关的文献（医药）

2024-11-01·MOLECULAR THERAPY

Novel treatment for PXE: Recombinant ENPP1 enzyme therapy

Article

作者: Stabach, Paul R. ; Braddock, Demetrios T ; Stabach, Paul R ; Jacobs, Ida Joely ; Braddock, Demetrios T. ; Obiri-Yeboah, Dora ; Li, Qiaoli

Pseudoxanthoma elasticum (PXE) is a genetic multisystem ectopic calcification disorder caused by inactivating mutations in the ABCC6 gene encoding ABCC6, a hepatic efflux transporter. ABCC6-mediated ATP secretion by the liver is the main source of a potent endogenous calcification inhibitor, plasma inorganic pyrophosphate (PPi); the deficiency of plasma PPi underpins PXE. Recent studies demonstrated that INZ-701, a recombinant human ENPP1 that generates PPi and is now in clinical trials, restored plasma PPi levels and prevented ectopic calcification in the muzzle skin of Abcc6^-/-mice. This study examined the pharmacokinetics, pharmacodynamics, and potency of a new ENPP1-Fc isoform, BL-1118, in Abcc6^-/- mice. When Abcc6^-/- mice received a single subcutaneous injection of BL-1118 at 0.25, 0.5, or 1 mg/kg, they had dose-dependent elevations in plasma ENPP1 enzyme activity and PPi levels, with an enzyme half-life of approximately 100 h. When Abcc6^-/- mice were injected weekly from 5 to 15 weeks of age, BL-1118 dose-dependently increased steady-state plasma ENPP1 activity and PPi levels and significantly reduced ectopic calcification in the muzzle skin and kidneys. These results suggest that BL-1118 is a promising second generation enzyme therapy for PXE, the first generation of which is currently in clinical testing.

2022-07-01·Experimental dermatology

INZ‐701, a recombinant ENPP1 enzyme, prevents ectopic calcification in an Abcc6^−/− mouse model of pseudoxanthoma elasticum

Article

作者: Thompson, David ; Sabbagh, Yves ; Ralph, Douglas ; Flaman, Lisa ; Jacobs, Ida Joely ; Li, Qiaoli ; Uitto, Jouni ; Howe, Jennifer ; Cheng, Zhiliang ; O'Brien, Kevin

Abstract:

Pseudoxanthoma elasticum (PXE), a heritable multisystem ectopic calcification disorder, is predominantly caused by inactivating mutations in ABCC6. The encoded protein, ABCC6, is a hepatic efflux transporter and a key regulator of extracellular inorganic pyrophosphate (PPi). Recent studies demonstrated that deficiency of plasma PPi, a potent endogenous calcification inhibitor, is the underlying cause of PXE. This study examined whether restoring plasma PPi levels by INZ‐701, a recombinant human ENPP1 protein, the principal PPi‐generating enzyme, prevents ectopic calcification in an Abcc6−/− mouse model of PXE. Abcc6−/− mice, at 6 weeks of age, the time of earliest stages of ectopic calcification, were injected subcutaneously with INZ‐701 at 2 or 10 mg/kg for 2 or 8 weeks. INZ‐701 at both doses increased steady‐state plasma ENPP1 activity and PPi levels. In the 8‐week treatment study, histopathologic examination and quantification of the calcium content in INZ‐701‐treated Abcc6−/− mice revealed significantly reduced calcification in the muzzle skin containing vibrissae, a biomarker of the calcification process in these mice. The extent of calcification corresponds to the local expression of two calcification inhibitors, osteopontin and fetuin‐A. These results suggest that INZ‐701 might provide a therapeutic approach for PXE, a disease with high unmet needs and no approved treatment.

2020-12-01·Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research1区 · 医学

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice

1区 · 医学

Article

作者: Howe, Jennifer ; O'Brien, Kevin ; Lynch, Angela ; Jungles, Steven ; Thompson, David ; Schrier, Denis ; Sabbagh, Yves ; Sullivan, Caitlin ; Cheng, Zhiliang

ABSTRACT:

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ-701 were investigated in Enpp1asj/asj mice, a murine model of ENPP1 deficiency. Enpp1asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1asj/asj mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR).

101

项与 INZ-701 相关的新闻（医药）

2024-11-27

·GlobeNewswire-Health Care

Inozyme Pharma to Participate in the Piper Sandler 36th Annual Healthcare Conference

BOSTON, Nov. 27, 2024 (GLOBE NEWSWIRE) -- Inozyme Pharma, Inc. (Nasdaq: INZY) (“the Company” or “Inozyme”), a clinical-stage biopharmaceutical company developing innovative therapeutics for rare diseases that affect bone health and blood vessel function, today announced that Matt Winton, Ph.D., Senior Vice President and Chief Operating Officer of Inozyme, will participate in a fireside chat at the Piper Sandler 36th Annual Healthcare Conference on Wednesday, December 4, 2024 from 2:30-2:55pm ET. A live webcast of the fireside chat can be accessed from the Investor Relations section of Inozyme’s website under events, where a replay of the event will also be available for a limited time. About Inozyme Pharma Inozyme Pharma is a pioneering clinical-stage biopharmaceutical company dedicated to developing innovative therapeutics for rare diseases that affect bone health and blood vessel function. We are experts in the PPi-Adenosine Pathway, where the ENPP1 enzyme generates inorganic pyrophosphate (PPi), which regulates mineralization, and adenosine, which controls intimal proliferation (the overgrowth of smooth muscle cells inside blood vessels). Disruptions in this pathway impact the levels of these molecules, leading to severe musculoskeletal, cardiovascular, and neurological conditions, including ENPP1 Deficiency, ABCC6 Deficiency, calciphylaxis, and ossification of the posterior longitudinal ligament (OPLL). Our lead candidate, INZ-701, is an ENPP1 Fc fusion protein enzyme replacement therapy (ERT) designed to increase PPi and adenosine, enabling the potential treatment of multiple diseases caused by deficiencies in these molecules. It is currently in clinical development for the treatment of ENPP1 Deficiency, ABCC6 Deficiency, and calciphylaxis. By targeting the PPi-Adenosine Pathway, INZ-701 aims to correct pathological mineralization and intimal proliferation, addressing the significant morbidity and mortality in these devastating diseases. For more information, please visit https://www.inozyme.com/ or follow Inozyme on LinkedIn, X, and Facebook. Contacts Investors:Inozyme PharmaStefan Riley, Senior Director of IR and Corporate Communications(617) 461-2442stefan.riley@inozyme.com Media:Biongage CommunicationsTodd Cooper(617) 840-1637todd@biongage.com

2024-11-27

·CPHI制药在线

英矽智能ENPP1抑制剂获FDA批准临床，或成免疫治疗新搭档

关注并星标CPHI制药在线 2024年11月21日，英矽智能宣布，公司自主研发的小分子创新药ISM5939已经获得美国食品药品监督管理局（FDA）的IND批件，用于治疗实体瘤。ISM5939是一款口服ENPP1抑制剂，有望实现每日一次（QD）给药，具有"同类最佳"的治疗潜力。 ISM5939的快速问世，得益于英矽智能的Pharma.AI平台。平台中生成式AI引擎Chemistry42在分子设计中效率极高，从项目启动到先导化合物仅用3个月时间，远超传统开发模式。 2023年5月，英矽智能提名ISM5939为临床前候选化合物，临床前实验结果显示ISM5939展现出强大的抗肿瘤效果，具有良好安全性特征、体外ADMET特性和体内药代动力学（PK）特征，有望为肿瘤免疫和低磷酸酯酶症（HPP）提供新的治疗选择。 AI驱动的药物发现流程以英矽智能首款AI药物ISM001-055为例。ISM001-055靶向致命罕见病特发性肺纤维化（IPF），该疾病以成纤维细胞增殖和大量细胞外基质沉积导致的肺功能受损为特征，确诊后的中位生存期仅为2-3年。目前，仅有不足30%的患者能从已经获批的针对性疗法中获益，且IPF的发病率还在以惊人的速度不断增长，标志着大量未被满足的临床需求。为搭建最初的疾病靶点假说，研发团队采用隶属英矽智能Pharma.AI平台的靶点发现引擎PandaOmics，首先在按照年龄和性别注释的组学数据和临床数据集上进行训练，再利用2016年发表在Nature Communications的iPANDA算法，通过深度特征合成、因果关系推断和全新通路重建提名潜力靶点。此后，团队融合自然语言处理（NLP）引擎，基于涵盖专利、出版物、研发基金、临床试验等文本数据的百万级文件进行新颖性评估和疾病-靶点关联度评分。在PandaOmics平台揭示的20个潜力靶点中，Traf2 和 Nck 相互作用激酶（TNIK）脱颖而出，最终被确定为重点研究对象。历史研究已经说明TNIK和WNT、TGF-β、Hippo、JNK、NF-k等纤维化驱动通路相关，然而并未提出TNIK作为IPF潜在治疗靶点的可能性。此后，团队利用健康肺组织和IPF患者纤维化肺组织的单细胞基因表达数据集验证了 TNIK 与 IPF 的相关性，并证实了 TNIK 在纤维化组织中的富集。靶点确定后，团队利用同属于Pharma.AI的生成化学平台Chemistry42，采用基于结构的药物设计（SBDD）策略，生成了一种安全、特异性、高效的TNIK抑制剂。平台同时采用30个生成式AI模型进行化合物设计，构成虚拟结构库，并接收专业研发团队的反馈进一步优化虚拟筛选过程。多次筛选后，TNIK ATP结合位点被选为目标结合口袋，其中一个具有潜力的先导化合物表现出了优良的活性，IC50值达到纳摩尔级别。基于上述化合物从头生成步骤，研发团队开展进一步优化，在提高溶解度、优化ADME特性、减低毒性的同时，保留候选分子对TNIK靶点的强大亲和力，最终于2021年初提名ISM001-055为临床前候选化合物（PCC）。此时距离TNIK被PandaOmics提名为潜在IPF治疗靶点，仅仅过去了18个月。值得一提的是，ISM001-055在多种纤维化动物模型中获得了验证，标志着AI驱动的药物发现由理论成为现实。在诱导肺纤维化的小鼠和大鼠中，ISM001-055通过降低成纤维细胞活化、减少纤维化蛋白沉积、减轻肺部炎症改善肺功能。此外，ISM001-055还在两个体内模型中减轻了皮肤和肾脏纤维化，表现出泛纤维化抑制效用，表明了潜在的适应症扩展机会。 ENPP1靶点研究进展胞外核苷酸焦磷酸酶／磷酸二酯酶家族（ENPP）是一类具有相同保守结构的胞外蛋白。迄今为止，已有７个家族成员被鉴定（ENPP1-7）；其中，ENPP1、ENPP3、ENPP4和ENPP5水解核苷酸，而ENPP2、ENPP6和ENPP7通过催化结构域进化为磷酯酶。 ENPP1在许多组织中表达，是胞外环磷酸鸟苷-腺苷合成酶最主要的水解酶，因此，在心血管、神经、免疫、肌肉骨骼、激素和血液功能等调节中起重要作用。ENPP1高表达与肿瘤转移、免疫逃逸、多癌种较差预后相关。研究结果显示，ENPP1抑制剂可通过调节胞外cGAMP水平激活cGAS-STING通路，进而增强宿主免疫系统抗肿瘤效果。有研究表明，ENPP1可能是乳腺癌中肿瘤免疫逃逸的驱动因素。故患者ENPP1的表达水平，可以作为临床研究中的依据，甚至作为区分患者的生物标志物。 STING是肿瘤免疫的潜在靶点，激活STING可促进肿瘤免疫。但目前披露的STING激动剂的临床疗效不佳，促使人们寻找其他激活STING的治疗方案，ENPP1就是其中一个。在肿瘤中，STING被2′3'-cGAMP激活，通过分泌干扰素介导天然免疫和非天然免疫过程。ENPP1是目前发现的唯一能够水解2′3'-cGAMP的酶，抑制ENPP1可以促进STING的激活。由于2′3′-cGAMP是胞质DNA经酶催化生成，DNA正常情况下在细胞核和线粒体中，仅在病原体入侵、肿瘤等病理情况才会进入胞质中。正常细胞不含2′3'-cGAMP，STING信号通路没有活性，也不能通过对ENPP1的抑制激活STING信号通路，所以ENPP1抑制剂能够选择性地激活肿瘤细胞和肿瘤微环境中其他细胞的STING信号通路，实现高选择性。 ENPP1抑制剂可以通过防止细胞外的cGAMP被降解来激活细胞内的STING信号通路，同时减少免疫抑制分子腺苷的生成。所以ENPP1抑制剂在肿瘤免疫治疗中可以起到"一箭双雕"、"一石二鸟"的作用。临床试验中的靶向ENPP1药物 ENPP1仍然是一个较为新颖的药物靶点。据不完全统计，目前在全球研的ENPP1抑制剂约20余种，仅有5款进入临床阶段，其中4款针对的领域为肿瘤，1款针对的是罕见病领域。ENPP1抑制剂与放疗联用在动物模型上取得较好的效果，还可以与免疫检查点抑制剂及PARP抑制剂联用。其中进展最快的是Inozyme Pharma开发的INZ-701，已进入3期临床。INZ-701是一种重组Fc融合蛋白，正在开发中作为ENPP1酶替代疗法，用于治疗血管、软组织和骨骼的罕见疾病。在临床前研究中，这种实验性疗法已显示出预防病理性矿化和内膜增生的潜力，这些问题可导致如ENPP1缺乏症、ABCC6缺乏症和钙化防御等毁灭性遗传疾病的发病率和死亡率。目前，INZ-701已被FDA和欧洲药品管理局（EMA）授予了孤儿药名称，用于治疗ENPP1缺乏症。今年7月，INZ-701还被FDA授予用于治疗ABCC6缺乏症的快速通道资格认定。 INZ-701正在进行3期临床开发，用于治疗ENPP1缺乏症、ABCC6缺乏症和钙化防御。2024年4月，Inozyme Pharma宣布了其在成人ABCC6缺乏症患者中进行的INZ-701持续第1/2期试验的积极顶线安全性和免疫原性数据。在血管病理学、视觉功能和患者报告结果（PROs）方面观察到了临床改善。 RBS 2418是由Riboscience LLC公司研发的口服ENPP1抑制剂，目前处于临床1期。2023 ESMO大会上发布了一项1期剂量递增试验探索了RBS2418单独或联合帕博利珠单抗在难治性实体瘤中的应用。研究结果显示，100 mg、200 mg和400 mg的RBS2418单用或与帕博利珠单抗联用均安全可控且耐受性良好。PK曲线显示，在给药周期内RBS2418可完全抑制ENPP1的血浆水平。目前该研究仍在进行中，其初步分析显示肿瘤中的ENPP1和cGAS共表达水平与RBS2418治疗引起的免疫激活和长期疾病稳定相关。此外，国内征祥医药的一款小分子ENPP1抑制剂ZX-8177片近日也获得CDE临床试验默示许可，拟开发治疗晚期实体瘤。ZX-8177是一款小分子ENPP1抑制剂，该产品的临床前研究结果曾连续两年入选美国癌症研究协会（AACR）年会。根据2022年和2023年AACR年会公布的临床前研究结果，ZX-8177可通过cGAMP-STING通路有效促进IFN-β1的产生。在CT-26同基因小鼠模型中，ZX-8177按2mg/kg BID治疗14天，可达到37%~60%左右的肿瘤生长抑制（TGI），并显著增加肿瘤微环境中NK细胞、T细胞和M1/M2巨噬细胞比例。该产品还具有有良好的DMPK和安全药理学特征，支持其作为进一步开发的临床候选药物。据悉，ZX-8177获批临床后，将在首次人体临床研究中探索其作为单一药物和联合疗法的初步疗效和安全性。参考来源 1、CDE官网 2、1. T.U. Marron, et al. Preliminary safety, pharmacokinetics and immunomodulatory activity of RBS2418, an oral ENPP1 inhibitor, alone and in combination with pembrolizumab in patients with solid tumors. 1025MO. END 【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床申请免疫疗法

2024-11-11

·GlobeNewswire-Health Care

Inozyme Pharma to Present at Upcoming Investor Conferences

BOSTON, Nov. 11, 2024 (GLOBE NEWSWIRE) -- Inozyme Pharma, Inc. (Nasdaq: INZY) (“the Company” or “Inozyme”), a clinical-stage biopharmaceutical company developing innovative therapeutics for rare diseases that affect bone health and blood vessel function, today announced Doug Treco, Ph.D., CEO and Chairman of Inozyme, will present at the following investor conferences: The Stifel 2024 Healthcare Conference. The presentation will take place on Monday, November 18 from 3:35-4:05pm ET.The Jefferies London Healthcare Conference. The presentation will take place on Wednesday, November 20 from 2:30-2:55pm GMT / 9:30-9:55am ET. A live webcast of the presentations can be accessed from the Investor Relations section of Inozyme’s website under events, where a replay of the events will also be available for a limited time. About Inozyme Pharma Inozyme Pharma is a pioneering clinical-stage biopharmaceutical company dedicated to developing innovative therapeutics for rare diseases that affect bone health and blood vessel function. We are experts in the PPi-Adenosine Pathway, where the ENPP1 enzyme generates inorganic pyrophosphate (PPi), which regulates mineralization, and adenosine, which controls intimal proliferation (the overgrowth of smooth muscle cells inside blood vessels). Disruptions in this pathway impact the levels of these molecules, leading to severe musculoskeletal, cardiovascular, and neurological conditions, including ENPP1 Deficiency, ABCC6 Deficiency, calciphylaxis, and ossification of the posterior longitudinal ligament (OPLL). Our lead candidate, INZ-701, is an ENPP1 Fc fusion protein enzyme replacement therapy (ERT) designed to increase PPi and adenosine, enabling the potential treatment of multiple diseases caused by deficiencies in these molecules. It is currently in clinical development for the treatment of ENPP1 Deficiency, ABCC6 Deficiency, and calciphylaxis. By targeting the PPi-Adenosine Pathway, INZ-701 aims to correct pathological mineralization and intimal proliferation, addressing the significant morbidity and mortality in these devastating diseases. For more information, please visit https://www.inozyme.com/ or follow Inozyme on LinkedIn, X, and Facebook. ContactsInvestors:Inozyme PharmaStefan Riley, Senior Director of IR and Corporate Communications(857) 330-8871stefan.riley@inozyme.comMedia:Biongage CommunicationsTodd Cooper(617) 840-1637todd@biongage.com

100 项与 INZ-701 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	美国	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	加拿大	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	法国	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	西班牙	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	土耳其	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	阿拉伯联合酋长国	Inozyme Pharma, Inc.	2023-11-05
外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	临床3期	英国	Inozyme Pharma, Inc.	2023-11-05
ABCC6缺乏症	临床2期	美国	Inozyme Pharma, Inc.	2024-06-19
ABCC6缺乏症	临床2期	法国	Inozyme Pharma, Inc.	2024-06-19
ABCC6缺乏症	临床2期	德国	Inozyme Pharma, Inc.	2024-06-19

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT05030831 (Corporate Publications) 人工标引	临床1/2期	ABCC6缺乏症 \| 外核苷酸焦磷酸酶/磷酸二酯酶 1 缺乏症	9	INZ-701	鬱艱構醖網選鹽壓憲鹽(窪製膚積選製鹽願獵襯) = 製鑰製襯選願衊鏇積鏇範簾積廠鑰蓋積製鑰襯 (憲網鹽醖築繭壓遞窪窪 )	积极	2023-09-26