An open, randomised phase I/II dose escalation study evaluating the safety and tolerability, pharmacokinetics, antigenicity and efficacy of Iodine-131-Kab201 when given intra-arterially or intravenously in patients with surgically unresectable pancreatic ductal adenocarcinoma

开始日期2002-09-01

申办/合作机构

Xenova Ltd.

100 项与 XR-303 相关的临床结果

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100 项与 XR-303 相关的转化医学

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100 项与 XR-303 相关的专利（医药）

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172

项与 XR-303 相关的文献（医药）

2024-11-01·SCIENCE OF THE TOTAL ENVIRONMENT

How nitrate and ammonium impact soil organic carbon transformation with reference to aggregate size

Article

作者: Owens, Gary ; Su, Shixun ; Zhang, Zhenjun ; Chen, Zuliang ; Lin, Jiajiang

While nitrogen (N) deposition and over-fertilization enrich N in soil, it is unclear how it impacts soil organic carbon (SOC) transformation at the aggregate scale. Herein, a 90-day study reveals the transformation mechanisms of SOC in soil aggregates under nitrate and ammonium enrichment conditions. Results showed that nitrate treatment (NT) and ammonium treatment (AT) significantly increased SOC content by 15.6 % and 18.9 %, respectively. In addition, NT increased SOC accrual in large macro-aggregates (LMA), while AT increased SOC accrual in small macro-aggregates (SMA) and micro-aggregates (MA). Further analysis of pyrolysis products showed that N enrichment drove the transformation of labile soil organic matter (SOM) composition into recalcitrant SOM, with polysaccharides declining from 19-30 % to 2-13 %, while lipids rose from 18-27 % to 33-45 %. LMA and SMA contained more aromatic compounds than MA. This is linked to the inhibition of the expression of C degradation function genes, while almost all genes encoding SOC degradation are down-regulated under N enrichment. In the meantime, NT increased the abundance of genes encoding the degradation of N-containing compounds in LMA. Moreover, NO₃^- enrichment exerted a higher inhibitory effect on labile SOC degradation while NH₄⁺ enrichment substantially inhibited recalcitrant SOC. Finally, Random Forest analysis confirmed that N enrichment elevated the importance of N-containing compounds' metabolism, which diminished when the size of soil aggregates decreased. In contrast, the importance of genes encoding saccharides and cellulose metabolism increased in smaller aggregates. This study highlights that both N type and aggregate size were determining factors in shaping SOC transformation in the N enrichment process.

2024-10-22·JOURNAL OF VIROLOGY

Conformations of membrane human immunodeficiency virus (HIV-1) envelope glycoproteins solubilized in Amphipol A18 lipid-nanodiscs

Article

作者: Kappes, John C. ; Anang, Saumya ; Zhang, Zhiqing ; Zhang, Shijian ; Ding, Haitao ; Sodroski, Joseph ; Nguyen, Hanh T.

ABSTRACT:

Upon binding to the host cell receptor, CD4, the pretriggered (State-1) conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer undergoes transitions to downstream conformations important for virus entry. State 1 is targeted by most broadly neutralizing antibodies (bNAbs), whereas downstream conformations elicit immunodominant, poorly neutralizing antibody (pNAb) responses. Extraction of Env from the membranes of viruses or Env-expressing cells disrupts the metastable State-1 Env conformation, even when detergent-free approaches like styrene-maleic acid lipid nanoparticles (SMALPs) are used. Here, we combine three strategies to solubilize and purify mature membrane Envs that are antigenically native (i.e., recognized by bNAbs and not pNAbs): (1) solubilization of Env with a novel amphipathic copolymer, Amphipol A18; (2) use of stabilized pretriggered Env mutants; and (3) addition of the State-1-stabilizing entry inhibitor, BMS-806. Amphipol A18 was superior to the other amphipathic copolymers tested (SMA and AASTY 11–50) for preserving a native Env conformation. A native antigenic profile of A18 Env-lipid-nanodiscs was maintained for at least 7 days at 4°C and 2 days at 37°C in the presence of BMS-806 and was also maintained for at least 1 h at 37°C in a variety of adjuvants. The damaging effects of a single cycle of freeze-thawing on the antigenic profile of the A18 Env-lipid-nanodiscs could be prevented by the addition of 10% sucrose or 10% glycerol. These results underscore the importance of the membrane environment to the maintenance of a pretriggered (State-1) Env conformation and provide strategies for the preparation of lipid-nanodiscs containing native membrane Envs.

IMPORTANCE:

The human immunodeficiency virus (HIV-1) envelope glycoproteins (Envs) mediate virus entry into the host cell and are targeted by neutralizing antibodies elicited by natural infection or vaccines. Detailed studies of membrane proteins like Env rely on purification procedures that maintain their natural conformation. In this study, we show that an amphipathic copolymer A18 can directly extract HIV-1 Env from a membrane without the use of detergents. A18 promotes the formation of nanodiscs that contain Env and membrane lipids. Env in A18-lipid nanodiscs largely preserves features recognized by broadly neutralizing antibodies (bNAbs) and conceals features potentially recognized by poorly neutralizing antibodies (pNAbs). Our results underscore the importance of the membrane environment to the native conformation of HIV-1 Env. Purification methods that bypass the need for detergents could be useful for future studies of HIV-1 Env structure, interaction with receptors and antibodies, and immunogenicity.

2024-09-01·Advanced Science

Materials Containing Single‐, Di‐, Tri‐, and Multi‐Metal Atoms Bonded to C, N, S, P, B, and O Species as Advanced Catalysts for Energy, Sensor, and Biomedical Applications

Review

作者: Beloqui, Ana ; Kumar, Krishan ; Umer, Muhammad ; Safarkhani, Moein ; Bhaskaran, Gokul ; Tiwari, Jitendra N. ; Han, Young‐Kyu ; Huh, Yun Suk ; Vilian, A. T. Ezhil

Abstract:

Modifying the coordination or local environments of single‐, di‐, tri‐, and multi‐metal atom (SMA/DMA/TMA/MMA)‐based materials is one of the best strategies for increasing the catalytic activities, selectivity, and long‐term durability of these materials. Advanced sheet materials supported by metal atom‐based materials have become a critical topic in the fields of renewable energy conversion systems, storage devices, sensors, and biomedicine owing to the maximum atom utilization efficiency, precisely located metal centers, specific electron configurations, unique reactivity, and precise chemical tunability. Several sheet materials offer excellent support for metal atom‐based materials and are attractive for applications in energy, sensors, and medical research, such as in oxygen reduction, oxygen production, hydrogen generation, fuel production, selective chemical detection, and enzymatic reactions. The strong metal–metal and metal–carbon with metal–heteroatom (i.e., N, S, P, B, and O) bonds stabilize and optimize the electronic structures of the metal atoms due to strong interfacial interactions, yielding excellent catalytic activities. These materials provide excellent models for understanding the fundamental problems with multistep chemical reactions. This review summarizes the substrate structure‐activity relationship of metal atom‐based materials with different active sites based on experimental and theoretical data. Additionally, the new synthesis procedures, physicochemical characterizations, and energy and biomedical applications are discussed. Finally, the remaining challenges in developing efficient SMA/DMA/TMA/MMA‐based materials are presented.

项与 XR-303 相关的新闻（医药）

2024-10-03

·药明康德

2024年第四季度值得关注的9项临床试验

▎药明康德内容团队编辑行业媒体STAT今日发布了一篇文章，从诸多研发项目中挑选出了一些预计在今年第四季度公布结果的临床试验进行报道，这些试验预计将对生物医药行业产生显著影响。这些试验覆盖了广泛的研发领域，它们不仅代表了医药研发的最新成就，更有望为全球患者带来生命的转机。在本文中，药明康德内容团队将结合公开资料，与读者分享其中9项值得关注的临床试验。点击“阅读原文/Read More”即可阅读英文原文。图片来源：123RF 研发公司：安进（Amgen）疗法名称：Maridebart cafraglutide（MariTide，AMG 133）适应症：肥胖疗法类型：抗体多肽偶联药物临床试验：NCT05669599 试验阶段：2期临床试验 MariTide是一款潜在“first-in-class”的在研抗体多肽偶联药物，在靶向胃抑制肽受体（GIPR）的单克隆抗体的特定位点上偶联了两个胰高血糖素样肽1（GLP-1）类似物，在激活GLP-1受体的同时抑制GIPR。此前在Nature Metabolism上发表的1期临床试验结果显示，肥胖患者只需每月一针，接受高剂量MariTide治疗85天后，体重可降低14.5%（约26斤）。值得一提的是，这些患者在停药后150天，仍可维持体重降低11.2%。正在进行中的随机、安慰剂对照、双盲、剂量范围2期研究，旨在评估MariTide对超重或肥胖成年受试者（无论是否患有2型糖尿病）的疗效、安全性和耐受性，共招募592位患者，试验预计在今年10月初步完成。研发公司：诺和诺德（Novo Nordisk）疗法名称：CagriSema 适应症：肥胖疗法类型：多肽临床试验：REDEFINE 1（NCT05567796）、REDEFINE 2（NCT05394519）试验阶段：3期临床试验 CagriSema是一款一周一次皮下注射的司美格鲁肽（semaglutide，2.4 mg）与长效胰淀素类似物cagrilintide（2.4 mg）的固定剂量组合。在REDEFINE 1试验中，诺和诺德将检视CagriSema在约3400位没有糖尿病史的肥胖或超重患者中的减重效果；而在REDEFINE 2试验中，诺和诺德则将评估CagriSema在约1200位患有2型糖尿病（T2D）的肥胖或超重患者中的减重疗效。这两项随机3期试验预计分别在今年10月与12月初步完成。 CagriSema之前在一项为期20周的1期试验中展现积极的减重效果，CagriSema可导致患者于试验期间体重降幅达17.1%，而司美格鲁肽组患者在此数值上仅为9.8%。目前有五项CagriSema相关的临床3期试验正在进行当中。研发公司：艾伯维（AbbVie）疗法名称：Emraclidine（CVL-231）适应症：精神分裂症疗法类型：小分子临床试验：EMPOWER-1（NCT05227690）、EMPOWER-2（NCT05227703）试验阶段：2期临床试验 Cerevel Therapeutics开发的emraclidine是一款毒蕈碱M4选择性正变构调节剂（PAM），是一种潜在“best-in-class”的下一代抗精神病药物。在动物模型研究中，该分子显示出高度的脑渗透性以及与靶点特异性结合特性。艾伯维在去年12月以总额约87亿美元收购Cerevel Therapeutics囊获此款疗法。值得一提的是，emraclidine获选为猎药人网站（drughunter.com）2022年的年度小分子之一。之前公布emraclidine用于精神分裂症成人患者的早期临床数据结果显示，与安慰剂相比，emraclidine在阳性和阴性症状量表（PANSS）总分中显示出具有临床意义和统计学意义的改善，总体耐受性良好。动态血压监测试验结果显示，emraclidine长期给药不会引起精神分裂症患者血压升高。正在进行中的两项安慰剂对照2期试验共招募了约750名患者，旨在检视三种剂量的emraclidine是否能在六周内迅速缓解与精神分裂症相关的症状，包括兴奋和幻觉等“阳性”症状，以及情感退缩等“阴性”症状，试验的初步数据可能会在11月发布。研发公司：Scholar Rock 疗法名称：Apitegromab 适应症：脊髓性肌萎缩症（SMA）疗法类型：单克隆抗体临床试验：SAPPHIRE（NCT05156320）试验阶段：3期临床试验 Apitegromab是一款在研全人源单克隆抗体，通过与骨骼肌中的肌生长抑制素（myostatin）前体和潜伏形式结合，apitegromab可抑制肌生长抑制素的激活，为潜在治疗SMA的首个肌肉靶向疗法。SMA是一种罕见的进行性衰弱性运动神经元疾病，该病通常由运动神经元生存蛋白（SMN）的缺失或功能异常所致，患者肌肉的发育和生长受损，导致进行性无力和肌肉萎缩、运动功能降低、生活质量受损、甚至死亡。根据新闻稿，该疗法是在SMA领域中完成临床概念验证的首个肌肉靶向疗法。在TOPAZ临床2期试验中，在第四年时，超过90%无法行走的SMA患者在SMN靶向疗法（nusinersen或risdiplam）的基础上持续接受apitegromab治疗，研究人员并观察到患者获得持久的临床益处。相关3期试验SAPPHIRE的顶线结果预计在今年第四季度公布。研发公司：Biohaven Pharmaceuticals 疗法名称：Taldefgrobep alfa（BHV-2000）适应症：脊髓性肌萎缩症疗法类型：蛋白类药物临床试验：RESILIENT（NCT05337553）试验阶段：3期临床试验 Taldefgrobep alfa是一款肌肉生长抑制素拮抗剂和激活素1型受体抑制剂。该疗法属于一类名为adnectin的类抗体药物，旨在与肌肉生长抑制素特异性结合。Adnectin是基于人体血清中天然丰富的一种细胞外蛋白——人纤连蛋白（human fibronectin）的专有蛋白治疗类别。其内在特性与制造成功药物所需的特性一致，包括高效力、特异性、稳定性和良好的半衰期。 RESILIENT临床3期试验旨在评估taldefgrobep alfa与安慰剂相较，作为辅助疗法对已经接受稳定剂量nusinersen或risdiplam治疗或曾接受基因疗法Zolgensma（onasemnogene abeparvovec）SMA受试者的疗效和安全性。该试验结果预计在今年年底前公布。研发公司：Vertex Pharmaceuticals 疗法名称：Suzetrigine（VX-548）适应症：腰骶神经根病（LSR）疗法类型：小分子临床试验：NCT06176196 试验阶段：2期临床试验 Suzetrigine是一种口服选择性NaV1.8抑制剂，与其它NaV离子通道相比，它对NaV1.8具有高度选择性。NaV1.8是在外周神经系统的痛觉信号传导中起到关键性作用的电压门控钠通道。它是经过遗传学验证的疼痛治疗靶点。Vertex的策略是通过选择性抑制NaV1.8开发新的药物类型。该疗法用于治疗中度至重度急性疼痛的新药申请（NDA）已为美国FDA所接受并授予优先审评资格。除了用于治疗急性疼痛，suzetrigine也正在2期试验当中受检视用于治疗LSR。这是一种因腰椎区域神经根受损或损伤而引起的慢性疼痛。这项随机、双盲、安慰剂为对照的试验共招募了218名疼痛性腰骶神经根病（PLSR）患者，该试验结果预计在今年12月公布。研发公司：Alto Neuroscience 疗法名称：ALTO-100 适应症：抑郁症（MDD）疗法类型：小分子临床试验：NCT05712187 试验阶段：2b期临床试验 ALTO-100是由Alto Neuroscience利用其生物标志物平台所开发的一款口服药物，其靶点为脑源性神经营养因子（BDNF），可恢复患者的神经可塑性，使大脑能够灵活适应新信息。值得一提的是，Alto Neuroscience的精准精神病学平台通过分析脑电活动、行为表现、可穿戴设备数据、遗传学和其他因素来检测大脑生物标志物，以便为每个患者匹配合适的药物。之前公布的临床试验数据显示，ALTO-100治疗让带有生物标志物的MDD患者（n=59）在MADRS抑郁量表评分上出现15.5分的下降，此数值在不带有生物标志物的患者（n=64）身上仅为10.6分（p=0.001，d=0.6）。此外，有61%带有生物标志物的患者对该疗法产生临床应答（定义为抑郁症状减轻≥50%），而仅有33%无生物标志物的患者显示临床应答（p=0.004）。而正在进行中的2b期试验预计在这个月完成并公布结果。研发公司：Alector Therapeutics、艾伯维疗法名称：AL002 适应症：早期阿尔茨海默病（AD）疗法类型：单克隆抗体临床试验：INVOKE-2（NCT04592874）试验阶段：2期临床试验 AL002是Alector Therapeutics公司开发的在研人源化单克隆抗体，靶向骨髓细胞触发受体2（TREM2），它是散发性AD的一个重要遗传风险因素。TREM2是一种跨膜受体，在一部分先天性免疫细胞上表达，并在小胶质细胞上特异性地表达，这些细胞构成大脑的免疫系统。TREM2功能的降低可能会导致阿尔茨海默病和其他形式的痴呆症。AL002能够通过激活TREM2信号来改善细胞的存活和增殖，并增加小胶质细胞的活性，从而抵消这种功能的降低。这种活性的临床益处尚不清楚，也是AL002临床试验的重点。2017年10月，Alector Therapeutics与艾伯维达成协议，将共同开发AL002。 INVOKE-2是一项随机、双盲、安慰剂对照2期研究，旨在评估静脉注射AL002对早期阿尔茨海默病患者的疗效和安全性，共有381名患者入组。目前该研究已经完成，试验结果预计在今年第四季度公布。研发公司：Arcellx、吉利德科学（Gilead Sciences）疗法名称：Anitocabtagene autoleucel（anito-cel，CART-ddBCMA）适应症：复发或难治性多发性骨髓瘤（MM）疗法类型：细胞疗法临床试验：iMMagine-1（NCT05396885）试验阶段：2期临床试验 Anito-cel是一款BCMA靶向CAR-T细胞疗法，旨在治疗复发性或难治性MM患者。此前，该疗法已被美国FDA授予快速通道资格、孤儿药资格和再生医学先进疗法认定。之前公布的1期扩展研究结果显示，截至2023年10月15日，中位随访时间为26.5个月，共有38名患者可进行疗效和安全性分析评估。根据国际骨髓瘤工作组（IMWG）标准，所有受试者的总缓解率（ORR）达100%，并且带有预后不良因素的患者出现了深入而持久的缓解。中位PFS和OS尚未达到，Kaplan-Meier模型估计的PFS为28个月。而正在进行中的2期试验目前已招募110名复发性或难治性MM患者，初步结果预计在今年年底的美国血液学会（ASH）年会当中公布。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料： [1] The biotech scorecard for the fourth quarter: 14 stock-moving events to watch. Retrieved October 2, 2024 from https://www.statnews.com/2024/10/02/biotech-scorecard-fourth-quarter/ [2] Scholar Rock Reports Second Quarter 2024 Financial Results and Highlights Business Progress. Retrieved October 2, 2024 from https://investors.scholarrock.com/news-releases/news-release-details/scholar-rock-reports-second-quarter-2024-financial-results-and [3] Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease (REFOCUS-ALZ). Retrieved October 2, 2024 from https://clinicaltrials.gov/study/NCT05026177?intr=simufilam&limit=10&aggFilters=phase:3&rank=2 [4] Simufilam 100 mg for Mild-to-Moderate Alzheimer's Disease (RETHINK-ALZ). Retrieved October 2, 2024 from https://clinicaltrials.gov/study/NCT04994483?intr=simufilam&limit=10&aggFilters=phase:3&rank=3 [5] Study of Anitocabtagene-autoleucel in Relapsed or Refractory Multiple Myeloma (iMMagine-1) (iMMagine-1). Retrieved October 2, 2024 from https://clinicaltrials.gov/study/NCT05396885?intr=CART-ddBCMA&limit=10&rank=1 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
胰腺癌	临床2期	欧洲	Celtic Pharma Capital Ltd.	-
胰腺癌	临床2期	-	Cancer Research UK	-
胰腺癌	临床2期	-	Xenova Ltd.	-
结直肠癌	临床1期	马来西亚	Celtic Pharma Capital Ltd.	-
结直肠癌	临床1期	-	Cancer Research UK	-
结直肠癌	临床1期	-	Xenova Ltd.	-