Pharmacokinetics and Safety of Roledumab, a Fully Human Recombinant Monoclonal Anti-RhD Antibody, in RhD-negative Pregnant Woman Carrying an RhD-positive Foetus: a Phase IIb, Multicenter, Open-label Study

The aim of this study is to assess the pharmacokinetic profile of Roledumab 300μg IM / IV in RhD-negative pregnant women carrying an RhD-positive foetus.
To assess the safety of Roledumab in RhD-negative pregnant women and in RhD-positive fetus and newborns.
In addition the efficacy of Roledumab 300μg IM and IV to prevent RhD alloimmunisation in RhD-negative pregnant women carrying an RhD-positive fetus and the immunogenicity of Roledumab will be assessed.

开始日期2014-04-01

申办/合作机构

Laboratoire Français du Fractionnement et des Biotechnologies

EUCTR2009-011017-24-DE / Not yet recruitingN/A

A Phase II, open-label, randomised, dose-finding study to compare the efficacy (in terms of clearance of RhD-positive RBCs) and safety of LFB-R593, a monoclonal anti-RhD antibody, vs Rhophylac®, a polyclonal anti-RhD immunoglobulin in healthy RhD negative volunteers

开始日期2009-08-03

申办/合作机构

LFB Biotechnologies SASU

NCT00952575 / Completed临床2期

A Phase II, Open-label, Randomised, Dose-finding Study to Compare the Efficacy (in Terms of Clearance of RhD-positive RBCs) and Safety of LFB-R593, a Monoclonal Anti-RhD Antibody vs a Polyclonal Anti-RhD Immunoglobulin in Healthy RhD Negative Volunteers

This phase II study is designed to demonstrate the ability of LFB-R593 to effectively eliminate exogenously-administered RhD-positive red blood cells from the circulation of an RhD-negative individual, thereby preventing RhD-alloimmunisation.

开始日期2009-08-01

申办/合作机构

Laboratoire Français du Fractionnement et des Biotechnologies

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100 项与 Roledumab 相关的临床结果

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100 项与 Roledumab 相关的转化医学

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100 项与 Roledumab 相关的专利（医药）

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项与 Roledumab 相关的文献（医药）

2023-12-15·Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery

[Research on Runx2 gene induced differentiation of human amniotic mesenchymal stem cells into ligament fibroblasts in vitro and promotion of tendon-bone healing in rabbits].

Article

作者: Xie, Tao ; Zhong, Hehe ; Xiang, Kuan ; Jin, Ying ; Chen, Fang ; Wu, Shuhong ; Liu, Xiuqi

Objective:

To investigate whether the Runx2 gene can induce the differentiation of human amniotic mesenchymal stem cells (hAMSCs) to ligament fibroblasts in vitro and promote the tendon-bone healing in rabbits.

Methods:

hAMSCs were isolated from the placentas voluntarily donated from healthy parturients and passaged, and then identified by flow cytometric identification. Adenoviral vectors carrying Runx2 gene (Ad-Runx2) and empty vector adenovirus (Ad-NC) were constructed and viral titer assay; then, the 3rd generation hAMSCs were transfected with Ad-Runx2 (Ad-Runx2 group) or Ad-NC (Ad-NC group). The real-time fluorescence quantitative PCR and Western blot were used to detect Runx2 gene and protein expression to verify the effectiveness of Ad-Runx2 transfection of hAMSCs; and at 3 and 7 days after transfection, real-time fluorescence quantitative PCR was further used to detect the expressions of ligament fibroblast-related genes [vascular endothelial growth factor (VEGF), collagen type Ⅰ, Fibronectin, and Tenascin-C]. The hAMSCs were used as a blank control group. The hAMSCs, hAMSCs transfected with Ad-NC, and hAMSCs were mixed with Matrigel according to the ratio of 1 : 1 and 1 : 2 to construct the cell-scaffold compound. Cell proliferation was detected by cell counting kit 8 (CCK-8) assay, and the corresponding cell-scaffold compound with better proliferation were taken for subsequent animal experiments. Twelve New Zealand white rabbits were randomly divided into 4 groups of sham operation group (Sham group), anterior cruciate ligament reconstruction group (ACLR group), anterior cruciate ligament reconstruction+hAMSCs transfected with Ad-NC-scaffold compound group (Ad-NC group), and anterior cruciate ligament reconstruction+hAMSCs transfected with Ad-Runx2-scaffold compound group (Ad-Runx2 group), with 3 rabbits in each group. After preparing the ACL reconstruction model, the Ad-NC group and the Ad-Runx2 group injected the optimal hAMSCs-Matrigel compunds into the bone channel correspondingly. The samples were taken for gross, histological (HE staining and sirius red staining), and immunofluorescence staining observation at 1 month after operation to evaluate the inflammatory cell infiltration as well as collagen and Tenascin-C content in the ligament tissues.

Results:

Flow cytometric identification of the isolated cells conformed to the phenotypic characteristics of MSCs. The Runx2 gene was successfully transfected into hAMSCs. Compared with the Ad-NC group, the relative expressions of VEGF and collagen type Ⅰ genes in the Ad-Runx2 group significantly increased at 3 and 7 days after transfection ( P<0.05), Fibronectin significantly increased at 3 days ( P<0.05), and Tenascin-C significantly increased at 3 days and decreased at 7 days ( P<0.05). CCK-8 detection showed that there was no significant difference ( P>0.05) in the cell proliferation between groups and between different time points after mixed culture of two ratios. So the cell-scaffold compound constructed in the ratio of 1∶1 was selected for subsequent experiments. Animal experiments showed that at 1 month after operation, the continuity of the grafted tendon was complete in all groups; HE staining showed that the tissue repair in the Ad-Runx2 group was better and there were fewer inflammatory cells when compared with the ACLR group and the Ad-NC group; sirius red staining and immunofluorescence staining showed that the Ad-Runx2 group had more collagen typeⅠ and Ⅲ fibers, tending to form a normal ACL structure. However, the fluorescence intensity of Tenascin-C protein was weakening when compared to the ACLR and Ad-NC groups.

Conclusion:

Runx2 gene transfection of hAMSCs induces directed differentiation to ligament fibroblasts and promotes tendon-bone healing in reconstructed anterior cruciate ligament in rabbits.

2023-09-21·Blood

Antibody-mediated antigen loss switches augmented immunity to antibody-mediated immunosuppression

Article

作者: Chonat, Satheesh ; Chai, Li ; Zerra, Patricia E. ; Maier, Cheryl L. ; Luckey, C. John ; Hudson, Krystalyn E. ; Josephson, Cassandra D. ; Ayona, Diyoly ; Fasano, Ross M. ; Arthur, Connie M. ; Hendrickson, Jeanne E. ; Morais, Dominique ; Roback, John D. ; Stowell, Sean R. ; Patel, Kashyap R. ; Allen, Jerry William L. ; Wu, Shang-Chuen ; Manis, John P. ; Jajosky, Ryan P. ; Eisenbarth, Stephanie C.

Abstract:

Antibodies against fetal red blood cell (RBC) antigens can cause hemolytic disease of the fetus and newborn (HDFN). Reductions in HDFN due to anti-RhD antibodies have been achieved through use of Rh immune globulin (RhIg), a polyclonal antibody preparation that causes antibody-mediated immunosuppression (AMIS), thereby preventing maternal immune responses against fetal RBCs. Despite the success of RhIg, it is only effective against 1 alloantigen. The lack of similar interventions that mitigate immune responses toward other RBC alloantigens reflects an incomplete understanding of AMIS mechanisms. AMIS has been previously attributed to rapid antibody-mediated RBC removal, resulting in B-cell ignorance of the RBC alloantigen. However, our data demonstrate that antibody-mediated RBC removal can enhance de novo alloimmunization. In contrast, inclusion of antibodies that possess the ability to rapidly remove the target antigen in the absence of detectable RBC clearance can convert an augmented antibody response to AMIS. These results suggest that the ability of antibodies to remove target antigens from the RBC surface can trigger AMIS in situations in which enhanced immunity may otherwise occur. In doing so, these results hold promise in identifying key antibody characteristics that can drive AMIS, thereby facilitating the design of AMIS approaches toward other RBC antigens to eliminate all forms of HDFN.

2023-08-29·Journal of Alzheimer's disease : JAD

Neuropathologic Changes of Alzheimer’s Disease and Related Dementias: Relevance to Future Prevention

Article

作者: Kawas, Claudia H. ; Flanagan, Margaret E. ; Corrada, Maria M. ; Edland, Steve E. ; White, Lon R. ; Cholerton, Brenna A. ; Montine, Thomas J.

Background: Decedents with late-life dementia are often found at autopsy to have vascular pathology, cortical Lewy bodies, hippocampal sclerosis, and/or TDP-43 encephalopathy alone or with concurrent Alzheimer’s disease (AD) lesions. Nonetheless, it is commonly believed that AD neuropathologic changes (NC) are the dominant or exclusive drivers of late-life dementia. Objective: Assess associations of end-of-life cognitive impairment with any one or any combination of five distinct NC. Assess impairment prevalence among subjects having natural resistance to each type of NC. Methods: Brains from 1,040 autopsied participants of the Honolulu-Asia Study, the Nun Study, and the 90 + Study were examined for NC of AD, Lewy body dementia, microvascular brain injury, hippocampal sclerosis, and limbic predominate TDP-43 encephalopathy. Associations with impairment were assessed for each NC and for NC polymorbidity (variable combinations of 2-5 concurrent NC). Results: Among 387 autopsied decedents with severe cognitive impairment, 20.4% had only AD lesions (ADNC), 25.3% had ADNC plus 1 other NC, 11.1% had ADNC plus 2 or more other NC, 28.7% had no ADNC but 1-4 other NC, and 14.5% had no/negligible NC. Combinations of any two, three, or four NC were highly frequent among the impaired. Natural resistance to ADNC or any other single NC had a modest impact on overall cohort impairment levels. Conclusion: Polymorbidity involving 1-5 types of concurrent NC is a dominant neuropathologic feature of AD and related dementias. This represents a daunting challenge to future prevention and could explain failures of prior preventive intervention trials and of efforts to identify risk factors.

项与 Roledumab 相关的新闻（医药）

2024-05-07

·奇点网

《自然·医学》：重新定义APOE4与阿尔茨海默病的关系！科学家证实APOE4是AD致病基因，纯合型AD或成最常见单基因遗传病之一

*仅供医学专业人士阅读参考阿尔茨海默病（AD）难以攻破，其复杂的病理和难解的病因要担一份责任。AD的发病涉及颇多遗传变异，第一档要数APP、PSEN1和PSEN2三个基因，这三者的突变会导致早发性常染色体显性遗传性阿尔茨海默病（ADAD）；其次是唐氏综合征带来的APP基因多拷贝，由此发展为唐氏综合征相关的阿尔茨海默病（DSAD）。在这两种遗传性AD之外，散发性/迟发性AD占了病例中的更多数，与之相关的风险基因也有数十个之多，其中风险最高的莫过于APOE4基因。今日，来自西班牙的科学团队在《自然·医学》发文，研究者们提出，APOE4不应当仅被视为AD的风险基因，而是应当被认定为AD的致病基因。APOE4纯合完全满足遗传性AD的三大主要特征，即近乎完全的疾病外显率、症状发作年龄的可预测性、病理/生物标志物/临床表现的可预测变化。考虑到APOE4纯合在全球人口中高达2%的流行率，APOE4遗传性AD或将一跃成为最常见的单基因遗传病之一。而将APOE4视为AD的致病基因，这无论是对AD的诊断治疗，还是临床药物的研发与试验设计，都会产生巨大的影响。论文题图其实，APOE4早就表现出了与其他风险基因不同的“风采”。APOE4纯合者患AD痴呆风险，在85岁时可高达60%，远高于杂合携带者或非携带者。这一数值也与其他全基因组关联研究发现的低风险基因并不匹配，已经达到了孟德尔遗传病（即单基因遗传病）的量级。研究者调取了来自美国国家阿尔茨海默病协调中心（NACC）的3297名捐献者的脑病理数据，以及其他5个已发表的大型多中心AD生物标志物队列研究的10039人数据，对其中APOE4相关内容进行了分析。生物标志物分析结果显示，几乎所有的APOE4纯合者都表现出了高或中的阿尔茨海默病神经病理学变化评分（ADNC），而APOE3纯合者中仅有50%符合这一情况。此外，无论死亡时年龄如何，APOE4纯合者的神经病理学结果都是一致的。针对脑脊液Aβ42、脑脊液pTau181的进一步分析显示，从55岁开始，APOE4纯合者体内的生物标志物水平始终高于APOE3纯合者；到65岁时，几乎所有APOE4纯合者都表现出异常的脑脊液Aβ42水平、PET呈淀粉样蛋白阳性；80岁时，生物标志物外显率达到88%。APOE4纯合在AD中的外显率对疾病进展阶段的分析显示，APOE4纯合者约在65.6岁时开始出现AD症状，71.8岁时出现轻度认知障碍（MCI），73.6岁进展为痴呆，77.2岁死亡，比APOE3纯合者早约7-10年。Kaplan-Meier生存分析显示，APOE4对发病年龄和死亡年龄具有显著的剂量效应。APOE4有显著的剂量效应分析生物标志物变化自然史也可以发现，APOE4纯合者与ADAD和DSAD存在时间的相似性。APOE4纯合（左），DSAD（中），ADAD（右）此外，APOE3/4杂合无论生物外显率、认知改变年龄、临床表现还是生物标志物变化，表型始终介于APOE3纯合和APOE4纯合之间，强调了APOE4的剂量效应。综上，APOE4已经完全满足了遗传性阿尔茨海默病的三大主要特征——近乎完全的疾病外显率、症状发作年龄的可预测性、病理/生物标志物/临床表现的可预测变化。与此形成呼应的是，前段时间发表在《神经元》杂志上的一项研究也发现，APOE4通过异常功能的获得驱动AD，并支持了将APOE4的沉默或敲除作为一种可行的治疗方案。将APOE4重新定义为AD的致病基因，将对AD的研究产生巨大的影响。APOE4在AD发展中究竟扮演什么样的角色会成为今后研究的重点，直接靶向APOE4的新药也将被纳入视野，基因疗法和细胞替代疗法潜力大增，临床试验设计也需要格外考虑APOE基因型分组。参考资料：[1]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41591-024-02931-w[2]https://www-nature-com.libproxy1.nus.edu.sg/articles/s41591-024-02923-w本文作者丨代丝雨

临床结果

2023-01-07

·生物谷

如何避免阿尔茨海默症错过早期诊疗？这个新技术或许能帮上大忙！

阿尔茨海默症的早期阶段诊断并不容易。在目前的医学指南中，有三种不同的标志物可作为检测对象来帮助诊断阿尔茨海默症：淀粉样蛋白、Tau蛋白的异常积累，以及神经变性（大脑特定区域神经元细胞的缓慢和渐进性丧失）（妙佑医疗国际）。这些标志物的检测可以结合脑成像和脑脊液分析来完成。然而，腰椎穿刺的过程会很痛苦，术后患者可能会发生头痛或背痛等不良反应。脑部成像的检查方法往往费用昂贵，可能需要预约排队并等待很长时间。相比而言，血液检测更经济、更安全、更方便，假如这种方法真的可以实际应用于临床，将会为患者的尽早诊断和提前治疗带来重要的意义。近日，来自瑞典、英国、美国等国家的科学家联合发布了题目为Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration的研究论文。为了应对基于血液的神经变性标志物神经丝光（neurofilament light）并非特异于阿尔茨海默症、总tau与脑脊液总tau缺乏相关性等挑战，研究人员生成了一种选择性结合脑源性tau（BD-tau）并避免外周表达的“大tau”亚型的抗tau抗体。并应用这种抗体开发了一种超灵敏的基于血液的BD-tau测定方法，且在五个独立的人群队列（n=609）中进行了验证，此方法将有助于评估阿尔茨海默症依赖性神经退行性过程，以及用于临床和研究目的。研究人员专门设计了一种TauJ.5H3 抗体，可选择性结合来源于中枢神经系统的tau亚型上的连续外显子4-5序列（如下图A所示）。该抗体如预期那样确实可以浓度依赖的方式特异性与代表外显子4-5的重组蛋白构建体结合。然而，TauJ.5H3抗体无法识别包含外显子4a插入片段的重组蛋白构建体（图C、D、E所示）。这些结果表明TauJ.5H3抗体可以特异性识别来源于中枢神经系统的tau亚型，但不包括主要在外周组织中表达的外显子4a区域的tau亚型。图注：对来源于中枢神经系统（CNS）的tau异构体具有特异性的TauJ.5H3绵羊单克隆抗体的设计和表征。（来源：Gonzalez-Ortiz, F., et al. 2022）BD-tau测定在血浆和血清中显示出良好的分析性能。研究人员通过将TauJ.5H3抗体与N末端tau靶向抗体配对，开发了一种新的免疫测定法来测量血液中的BD-tau。在三个不同稀释倍数下，内源性血液样本中生物标志物的浓度呈线性下降（下图A所示）。五个独立的分析批次中显示稳定性为92-95%（下图B所示）。这个检测方法的量化下限估计为0.03pg/mL。图注：测量血液中BD-tau新方法的技术验证。（来源：Gonzalez-Ortiz, F., et al. 2022）为了研究BD-tau是否会受外周tau污染的影响，研究人员应用成对的血清和脑脊液样本进行了配对分析，与对照组相比，阿尔茨海默症患者的BD-tau水平升高（P ≤ 0.0001；下图A所示），然而，阿尔茨海默症患者的t-tau蛋白在脑脊液中比对照组高(P = 0.0076)，但在配对血清样本中却没有（P = 0.2176）。这些结果表明，血清BD-tau的诊断准确性为100%，而血清t-tau的诊断准确性为67.0%[5%置信区间(CI) = 42.3–91.7%]。图注：成对血清和脑脊液样本中BD-tau的浓度和相关性。（来源：Gonzalez-Ortiz, F., et al. 2022）在神经病理学队列中，与非阿尔茨海默症相比，血浆BD-tau在阿尔茨海默症中有增加（Mann-Whitney U = 83.5，P < 0.0001），诊断准确率为86.4%（95% CI = 75.6–97.1%；如下图所示)。在二级分析中，研究人员将阿尔茨海默症人群分为高ADNC（阿尔茨海默症神经病理学改变）和高ADNC+其他（阿尔茨海默症伴有路易体痴呆和海马硬化等病理）两个亚组，将非阿尔茨海默症人群分为低度或其他病理亚组。结果发现高ADNC和高ADNC+其他亚组之间的血浆BD-tau没有差异（P > 0.999），低病理亚组和其他病理亚组之间也没有差异（P > 0.999）。然而，血浆BD-tau在其他病理亚组与高ADNC和高ADNC+其他亚组间有差异（P ≤ 0.0036）。表明血浆BD-tau可将阿尔茨海默症与其他神经退行性疾病区分开来。图注：血浆BD-tau可以准确地区分经过尸检证实的阿尔茨海默症与其他神经退行性疾病。（来源：Gonzalez-Ortiz, F., et al. 2022）综上所述，这项研究证明了血浆BD-tau是阿尔茨海默症型神经变性的生物标志物，它可以区分阿尔茨海默症与其他神经退行性疾病，并与神经病理学队列中疾病的临床严重程度相关。这种方法具有检测阿尔茨海默症神经变性的高诊断准确性。参考来源：1. 诊断阿尔茨海默症：如何诊断阿尔茨海默症（妙佑医疗国际）2. Gonzalez-Ortiz, Fernando, et al. "Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration." Brain (2022).撰文 | 拉缇莎编辑 | cici精彩推荐：1、新冠免疫“重男轻女”？Nature：新冠病毒改变免疫系统，男性更易引发过度免疫反应！2、再立新功！最佳健康饮食榜五连冠「地中海饮食」，最新研究：坚持地中海饮食或可提高生育能力！3、类器官新进展！人鼠混合大脑类器官首次对视觉刺激做出反应！NAT COMMUN：脑类器官移植的多模态监测4、喝水喝的好，还能抗衰老？《柳叶刀》子刊25年随访研究发现：喝水充足慢病风险更低，寿命更长！5、重磅头对头研究！NEJM：国产新冠口服药疗效不劣于Paxlovid且安全性更佳

免疫疗法临床结果临床研究

100 项与 Roledumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
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适应症	最高研发状态	国家/地区	公司	日期
胎儿成红细胞增多症	临床3期	法国	LFB Biotechnologies SASU	2014-03-12
溶血性贫血	临床2期	法国	Laboratoire Français du Fractionnement et des Biotechnologies	2014-04-01
Rh-Null 疾病，调节子型	临床2期	法国	Laboratoire Français du Fractionnement et des Biotechnologies	2014-04-01
风湿性心脏病	临床2期	法国	Laboratoire Français du Fractionnement et des Biotechnologies	2014-04-01

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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


NCT02287896 (CTgov)	临床2期	风湿性心脏病 \| Rh-Null 疾病，调节子型	62	Roledumab (Population PK (PKS1))	壓齋繭淵遞製廠顧鏇顧(壓製衊餘齋選淵蓋獵壓) = 鑰觸憲範鹹鬱願襯鹽繭蓋醖鏇鑰積顧鹽構積範 (襯衊膚艱製選壓獵願鬱, 鏇糧築簾遞膚遞簾壓鹽 ~ 製齋鹹夢窪鹹膚廠觸顧) 更多	-	2019-08-16
				Roledumab (IM Arm Roledumab)	鹹範鹹襯鹽繭鏇鑰鏇鬱(憲顧蓋鏇鹽蓋積衊簾願) = 窪網鏇淵艱繭廠艱願築鹹糧壓觸鹹遞簾願鑰製 (築齋壓齋蓋網積鹹襯築, 壓簾鑰積艱構願淵蓋鑰 ~ 襯願選鹽鹽鬱憲廠鏇鹽) 更多