Bone quality is partially recovered after the discontinuation of RANKL administration in rats by increased bone mass on existing trabeculae: an in vivo micro-CT study

2区 · 医学

Article

作者: Graeme M. Campbell ; Michael S. Ominsky ; Steven K. Boyd

Bone loss and recovery in a receptor activator for nuclear factor κ B ligand (RANKL)-administered rat model was assessed. Microarchitecture, mineralization and strength deteriorated faster than ovariectomy (OVX). Recovery was dependent on the loss of trabecular elements and connections. Early recovery suggests a natural mechanism in rats to overcome excess RANKL, and may have implications for long-term bone loss.PURPOSETo compare a model for experimental osteoporosis that induces bone loss by injecting RANKL into rats to an OVX rat model, and measure subsequent recovery of bone architecture, mineralization, and mechanics after stopping injections.METHODSMature, healthy, female Wistar rats were divided into high-dose RANKL, low-dose RANKL, OVX, and vehicle control groups. The right proximal tibiae were micro-computed tomography (micro-CT) scanned in vivo every 2 weeks from week 0 to week 12 and every 4 weeks from week 12 to week 20. Bone architectural, mineralization, and mechanical changes were determined. Serum calcium, RANKL, anti-RANKL, and osteoprotegerin were measured at weeks 0, 6, and 20.RESULTSHigh-dose RANKL administration resulted in severe deterioration of the trabecular architecture (39% of baseline BV/TV), and modest decreases in tissue mineralization, bone mass, and stiffness. Bone loss occurred more rapidly than in the OVX and low-dose RANKL group, and recovery occurred prior to stopping RANKL injections. Full recovery of trabecular thickness, tissue mineralization, and cortical bone mass, partial recovery of trabecular bone volume (55% of baseline), structural model index, bone mass (69% of baseline), and stiffness (90% of baseline) but no improvement in connectivity density or trabecular number was observed.CONCLUSIONRANKL administration resulted in rapid and dose-dependent bone loss. The recovery of trabecular bone volume and stiffness appeared to be dependent on the number of remaining trabecular elements and their interconnections. Uncontrolled recovery suggests that further investigation into the RANKL-injected rat as a model of bone loss is required.

Arthritis Research & Therapy2区 · 医学

RANKL increases the level of Mcl-1 in osteoclasts and reduces bisphosphonate-induced osteoclast apoptosis in vitro

2区 · 医学

ArticleOA

作者: Rogers, Helena L. ; Rogers, Michael J. ; Tosh, Denise ; Sutherland, Karen A.

AbstractIntroductionBisphosphonates are the most widely used class of drug for inhibiting osteoclast-mediated bone loss, but their effectiveness at preventing joint destruction in rheumatoid arthritis has generally been disappointing. We examined whether the ability of bisphosphonates to induce osteoclast apoptosis and inhibit bone resorption in vitro is influenced by the cytokine receptor activator of nuclear factor-kappa B ligand (RANKL), an important mediator of inflammation-induced bone loss.MethodsRabbit osteoclasts were treated with the bisphosphonates clodronate or alendronate for up to 48 hours in the absence or presence of RANKL. Changes in cell morphology and induction of apoptosis were examined by scanning electron microscopy, whilst resorptive activity was determined by measuring the area of resorption cavities. Changes in the level of anti-apoptotic proteins, including Mcl-1, Bcl-2, and Bcl-x>L, were determined in rabbit osteoclasts and in cytokine-starved mouse osteoclasts by Western blotting.ResultsRANKL significantly attenuated the ability of both clodronate and alendronate to induce osteoclast apoptosis and inhibit bone resorption. Treatment of rabbit osteoclasts with RANKL was associated with an increase in the anti-apoptotic protein Mcl-1 but not Bcl-2. A role for Mcl-1 in osteoclast survival was suggested using osteoclasts generated from mouse bone marrow macrophages in the presence of RANKL + macrophage colony-stimulating factor (M-CSF) since cytokine deprivation of mouse osteoclasts caused a rapid loss of Mcl-1 (but not Bcl-2 or Bcl-xL), which preceded the biochemical and morphological changes associated with apoptosis. Loss of Mcl-1 from mouse osteoclasts could be prevented by factors known to promote osteoclast survival (RANKL, M-CSF, tumour necrosis factor-alpha [TNF-α], or lipopolysaccharide [LPS]).ConclusionsRANKL protects osteoclasts from the apoptosis-inducing and anti-resorptive effects of bisphosphonates in vitro. The ability of RANKL (and other pro-inflammatory factors such as TNF-α and LPS) to increase the level of Mcl-1 in osteoclasts may explain the lack of effectiveness of some bisphosphonates in preventing inflammation-induced bone loss.

项与 RANKL (Psivant Therapeutics) 相关的新闻（医药）

2024-08-07

·Insight数据库

安进：第二季度收入增长 20% 至 84 亿美元，肿瘤药物收入超 20 亿美元

当地时间 8 月 6 日，安进发布了 Q2 财报。第二季度，该公司收入同比增长 20% 至 84 亿美元。若不包括收购 Horizon Therapeutics 带来的销售额，该公司产品销售额增长率为 5%，这主要得益于销量增长 10% 的推动。值得一提的是，安进有 12 种产品在二季度实现了至少两位数的销售增长，包括 Prolia（普罗力，地舒单抗）、Evenity（罗莫佐单抗）、Repatha（依洛尤单抗）、Tezspire（特泽鲁单抗）、Blincyto（贝林妥欧单抗）和 Tavneos（阿伐可泮）。截图来自：安进财报肿瘤业务销售额逾 20 亿美元 CD3×CD19 双抗贝林妥欧单抗第二季度销售额同比增长 28% 至 2.64 亿美元。 EGFR 抗体 Panitumumab (帕尼单抗) 第二季度销售额同比增长 9% 至 2.7 亿美元，这得益于更高的净销售价格和销量增长。蛋白酶体抑制剂 Carfilzomib (卡非佐米) 第二季度销售额同比增长 9% 至 3.77 亿美元，主要得益于美国以外地区的销量增长。 KRAS G12C抑制剂 Lumykras/Lumakras（索托拉西布）销售额在第二季度同比增长 10% 至 8500 万美元，主要得益于销量增长。 RANKL单抗 Xgeva（地舒单抗，安加维）第二季度销售额同比增长 6% 至 5.62 亿美元，主要得益于净销售价格上涨。血小板生成素(TPO)受体激动剂 Nplate（罗米普司亭）第二季度销售额同比增长 12% 至 3.46 亿美元。双特异性 T 细胞接合剂 (BiTE®) 疗法Imdelltra（塔拉妥单抗）第二季度销售额为 1200 万美元。Imdelltra 是首个也是唯一一个获得 FDA 批准的用于治疗广泛期小细胞肺癌 (ES-SCLC) 的双特异性 T 细胞接合剂疗法。 Mvasi（贝伐单抗生物类似药）第二季度销售额同比下降 20% 至 1.57 亿美元。截图来自：安进财报普药板块销售额超过 20 亿美元 PCSK9抑制剂 Repatha (依洛尤单抗) 销售额在第二季度同比增长 25% 至 5.32 亿美元，主要得益于 46% 的销量增长。骨质疏松新药 Evenity(罗莫佐单抗) 销售额在第二季度同比增长 39% 至 3.91 亿美元。 RANKL单抗 Prolia (地舒单抗，普罗力) 销售额在第二季度同比增长 13% 至 12 亿美元。截图来自：安进财报炎症领域产品销售额近 20 亿美元 TSLP单抗 Tezepelumab (特泽鲁单抗)销售额在第二季度同比增长 76% 至 2.34 亿美元，主要受销量增长推动。Tezepelumab 的独特差异化特性具有广泛的潜力，已经治疗了全球 250 万名患有严重、不受控制的哮喘患者。 PDE4 抑制剂 Apremilast(阿普米司特)销售额在第二季度同比下降 9% 至 5.44 亿美元，主要受净销售价格下降 7% 等因素影响。 TNF抑制剂 Etanercept(依那西普)销售额在第二季度同比下降 15% 至 9.09 亿美元，主要原因是净售价下降。截图来自：安进财报罕见病业务销售额超过 10 亿美元小分子 C5aR 拮抗剂 Tavneos (阿伐可泮) 在第二季度的销售额为 7100 万美元，同比增长 137%，主要得益于销量增长。Tavneos 是治疗严重活动性抗中性粒细胞胞浆自身抗体相关性血管炎 (ANCA 相关性血管炎) 的first-in-class 疗法。 IGF-1R 抗体 Tepezza(替妥木单抗)在第二季度实现了 4.79 亿美元的销售额。Tepezza 是首个也是唯一一个获得 FDA 批准的治疗甲状腺眼病 (TED) 的药物。 Krystexxa（培格洛酶）第二季度的销售额为 2.94 亿美元。Krystexxa 是首个也是唯一一个获得 FDA 批准的治疗慢性难治性痛风的药物。 CD19抗体 Uplizna (伊奈利珠单抗) 在第二季度的销售额为 9200 万美元。Uplizna 用于治疗患有视神经脊髓炎谱系障碍的成年患者。截图来自：安进财报成熟业务产品组合收入下降21% 成熟业务产品包括：红细胞生成刺激剂生物药 Epogen(epoetin alfa)、促红细胞生成素（EPO）Aranesp（达依泊汀α）、新一代拟钙剂Parsabiv（依特卡肽）和聚乙二醇（PEG）化重组人粒细胞刺激银子 Neulasta（培非格司亭），第二季度销售额为 5.91 亿美元，同比下降 21%。安进预计该部分业务产品的销量下降趋势将会继续发生。 2024年里程碑事件此外，安进还介绍了该公司各业务版块在 2024 年的重要的里程碑事件。其中，在肿瘤领域，双特异性抗体 Tarlatamab 于今年 5 月获 FDA 批准，治疗小细胞肺癌。CD3×CD19 双抗贝林妥欧单抗上半年获得 FDA 批准新适应症，用于治疗 CD19 阳性费城染色体阴性 B 细胞前体急性淋巴细胞白血病 (B-ALL) 成人和 1 个月及以上的儿童患者。截图来自：安进财报参考资料：AMGEN REPORTS SECOND QUARTER 2024 FINANCIAL RESULTS . https://investors.amgen.com/news-releases/news-release-details/amgen-reports-second-quarter-2024-financial-results 封面来源：企业 Logo 免责声明：本文仅作信息分享，不代表 Insight 立场和观点，也不作治疗方案推荐和介绍。如有需求，请咨询和联系正规医疗机构。编辑：馨药 PR 稿对接：微信 insightxb 投稿：微信 insightxb；邮箱 insight@dxy.cn 多样化功能、可溯源数据…… Insight 数据库网页版等你体验点击阅读原文，立刻解锁！

财报生物类似药免疫疗法并购

2024-07-27

·奇点网

R~A~N~K~L~

*仅供医学专业人士阅读参考提问：看到RANKL这五个字母，在座的各位会立刻想到什么？想到骨质疏松，这道题就足够拿满分了，不过奇点糕一直唠的是癌症相关的事情，这次提到RANKL也当然不会跑题，毕竟在这次要介绍的研究里，RANKL可是展现出了成为肺癌免疫治疗标志物的价值。罗马第一大学研究团队近日在Journal for ImmunoTherapy of Cancer期刊发表的论文显示，即使非小细胞肺癌（NSCLC）患者不存在骨转移等骨相关问题，RANKL水平也与PD-L1高表达患者接受免疫单药治疗的疗效显著相关，其中RANKL低水平+PD-L1高表达患者的中位无进展生存期（mPFS）长达22个月，无疑是极为适合免疫单药治疗的优势人群[1]。论文首页截图虽说RANKL最经典的影响对象是破骨细胞，也是它成为骨质疏松治疗靶点的主要原因，但真要追溯起源的话，RANKL最早可是在树突状细胞（DCs）中被识别出来的[2]，按今天的眼光来看，RANKL跟抗癌免疫应答无关才叫怪事。而在2018年也有基础研究显示，RANKL与其受体RANK结合传导的信号，是肺腺癌在小鼠身上发生发展的必要条件之一[3]。所以近年来，不少研究都把眼光放到了骨转移以外，想找到RANKL对癌症及免疫治疗的更深刻影响，比如开展此次研究的意大利团队就探索过RANKL预测肾癌患者预后的价值，这次的研究对象换成免疫治疗“主战场”NSCLC也不奇怪。研究共筛选了100例晚期NSCLC患者，拟定在一线和二线接受免疫单药治疗（PD-1/L1抑制剂）的患者各占一半，其中37例为RANKL高水平（Cut-off值为280.4 pg/mL），患者整体基线特征如下表所示，中位随访时间为54个月。患者整体基线特征分析结果表明，RANKL水平与PD-L1高表达（≥50%）患者接受免疫治疗后的24个月PFS率及生存率均显著相关（p=0.002/0.042），其中存活患者的RANKL水平较低（148 pg/mL vs. 335 pg/mL），与此前研究团队对肾癌患者开展的分析相符，但在PD-L1低表达患者中未观察到类似的相关性。RANKL水平与患者接受免疫治疗后的24个月PFS率及生存率均显著相关而将RANKL水平与PD-L1表达水平检测联合应用，还能识别出免疫单药治疗的优势人群：RANKL低水平+PD-L1高表达患者的mPFS长达22个月，中位总生存期（mOS）也有26个月，而其它患者的mPFS只有4-6个月，差异一目了然；分析对象仅限于RANKL低水平患者时，PD-L1高表达患者的mPFS和mOS也都显著较长。RANKL低水平+PD-L1高表达患者可能是免疫单药治疗优势人群事后分析表明，RANKL水平是本次研究中NSCLC患者预后（PFS和OS）的独立预测因子，不受患者年龄、性别、吸烟史和肿瘤组织学类型等因素的影响，且与患者预后呈负相关性；研究者们开展的生物信息学分析显示，RANKL水平较高的肿瘤往往生物学行为更具侵袭性，且有大量免疫抑制性细胞（如MDSCs）浸润，PD-1/L1通路是主要的免疫抑制机制。所以在PD-L1高表达肿瘤中，RANKL的大量存在就不利于免疫治疗起效，这也符合既往研究中RANKL直接影响T细胞和树突状细胞PD-L1表达水平的发现；而在PD-L1低表达患者中，PD-1/L1通路可能并不是束缚免疫系统的主要原因，RANKL水平才会显得缺乏预测效能，研究者们的这番推测合情合理，RANKL作为标志物的用法也就很明确了。参考文献：[1] Iuliani M, Simonetti S, Cristofani L, et al. Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)[J]. Journal for ImmunoTherapy of Cancer, 2024, 12(6): e009432.[2] Li B, Wang P, Jiao J, et al. Roles of the RANKL–RANK Axis in Immunity—Implications for Pathogenesis and Treatment of Bone Metastasis[J]. Frontiers in Immunology, 2022, 13: 824117.[3] Faget J, Contat C, Zangger N, et al. RANKL signaling sustains primary tumor growth in genetically engineered mouse models of lung adenocarcinoma[J]. Journal of Thoracic Oncology, 2018, 13(3): 387-398.本文作者丨谭硕

临床结果免疫疗法上市后研究

100 项与 RANKL (Psivant Therapeutics) 相关的药物交易

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