A Phase 1b/2, Open-label, Randomized Study of MEDI-573 in Combination With Sorafenib Verses Sorafenib Alone in Adult Subjects With Unresectable or Metastatic Hepatocellular Carcinoma

A Phase 1b/2, open-label, randomized study to evaluate MEDI-573 in combination with standard of care in adult subjects with unresectable or metastatic hepatocellular carcinoma (HCC).

开始日期2012-01-17

申办/合作机构

MedImmune LLC

JPRN-jRCT2080221544 / Unknown status临床1期

A Phase 1, Open-label, Single-arm, Dose-escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI-573, a Fully Human Monoclonal Antibody Directed Against Insulin-like Growth Factors 1 and 2, in Japanese Subjects With Advanced Solid Tumours Refractory to Standard Therapy or for Which No Standard Therapy Exists

开始日期2011-08-12

申办/合作机构

AstraZeneca PLC

NCT01340040 / Completed临床1期

A Phase 1, Open-label, Single-arm, Dose-escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MEDI-573, a Fully Human Monoclonal Antibody Directed Against Insulin-like Growth Factors I and II, in Japanese Subjects With Advanced Solid Tumours Refractory to Standard Therapy or for Which No Standard Therapy Exists

The primary purpose of this study is to explore the safety and tolerability of MEDI-573 in Japanese subjects with advanced solid tumours refractory to standard therapy or for which no standard therapy exists.

开始日期2011-07-01

申办/合作机构

AstraZeneca PLC

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100 项与 Dusigitumab 相关的临床结果

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100 项与 Dusigitumab 相关的转化医学

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100 项与 Dusigitumab 相关的专利（医药）

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项与 Dusigitumab 相关的文献（医药）

2023-04-01·Lupus

Integrated analysis and clinical correlation analysis of hub genes, immune infiltration, and potential therapeutic agents related to lupus nephritis

Article

作者: Liang, Xiaofeng ; Lin, Weiyi ; Lin, Zien ; Peng, Zhishen ; Wei, Shanshan ; Lin, Xiaobing

Background:

Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE). This study aimed to explore biomarkers, mechanisms, and potential novel agents regarding LN through bioinformatic analysis.

Method:

Four expression profiles were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were acquired. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGGs) pathway enrichment analyses of DEGs were performed using the R software. The protein-protein interaction (PPI) network was developed using the STRING database. Additionally, five algorithms were used to screen out the hub genes. Expression of the hub genes were validated using Nephroseq v5. CIBERSORT was used to evaluate the infiltration of immune cells. Finally, The Drug-Gene Interaction Database was used to predict potential targeted drugs.

Result:

FOS and IGF1 were identified as hub genes, with excellent specificity and sensitivity diagnosis of LN. FOS was also related to renal injury. LN patients had lower activated and resting dendritic cells (DCs) and higher M1 macrophages and activated NK cells than healthy control (HC). FOS had a positive correlation with activated mast cells and a negative correlation with resting mast cells. IGF1 had a positive correlation with activated DCs and a negative correlation with monocytes. The targeted drugs were dusigitumab and xentuzumab target for IGF1.

Conclusion:

We analyzed the transcriptomic signature of LN along with the landscape of the immune cell. FOS and IGF1 are promising biomarkers for diagnosing and evaluating the progression of LN. The drug-gene interaction analyses provide a list of candidate drugs for the precise treatment of LN.

2017-02-09·Oncogene1区 · 医学

Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies

1区 · 医学

Article

作者: Chen, C ; Hollingsworth, R E ; Fazenbaker, C ; Huang, J ; Zhong, H ; Yao, X ; Yao, Y ; Ren, P ; Herbst, R ; Breen, S

Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.

2015-10-01·Clinical cancer research : an official journal of the American Association for Cancer Research1区 · 医学

Molecular Pathways: Clinical Applications and Future Direction of Insulin-like Growth Factor-1 Receptor Pathway Blockade

1区 · 医学

Review

作者: Iams, Wade T. ; Lovly, Christine M.

Abstract:

The IGF1R signaling pathway is a complex and tightly regulated network that is critical for cell proliferation, growth, and survival. IGF1R is a potential therapeutic target for patients with many different malignancies. This brief review summarizes the results of clinical trials targeting the IGF1R pathway in patients with breast cancer, sarcoma, and non–small cell lung cancer (NSCLC). Therapeutic agents discussed include both monoclonal antibodies to IGF1R (dalotuzumab, figitumumab, cixutumumab, ganitumab, R1507, AVE1642) and newer IGF1R pathway targeting strategies, including monoclonal antibodies to IGF1 and IGF2 (MEDI-573 and BI 836845) and a small-molecule tyrosine kinase inhibitor of IGF1R (linsitinib). The pullback of trials in patients with breast cancer and NSCLC based on several large negative trials is noted and contrasted with the sustained success of IGF1R inhibitor monotherapy in a subset of patients with sarcoma. Several different biomarkers have been examined in these trials with varying levels of success, including tumor expression of IGF1R and its pathway components, serum IGF ligand levels, alternate pathway activation, and specific molecular signatures of IGF1R pathway dependence. However, there remains a critical need to define predictive biomarkers in order to identify patients who may benefit from IGF1R-directed therapies. Ongoing research focuses on uncovering such biomarkers and elucidating mechanisms of resistance, as this therapeutic target is currently being analyzed from the bedside to bench. Clin Cancer Res; 21(19); 4270–7. ©2015 AACR.

项与 Dusigitumab 相关的新闻（医药）

2024-06-30

·生物制药小编

肥胖促癌：“3个紊乱”

至少13种肿瘤与肥胖相关（ N Engl J Med 375, 794–798）。 N Engl J Med 375, 794–798 第1乱：胰岛素和雌激素信号紊乱胰岛素受体有两个亚型，IR-A和IR-B，以不同的比例存在于不同的组织中，执行不同的功能。 IR-A在生命早期主要具有促进有丝分裂的作用，它在成年期的表达与胰岛素抵抗和不受调节的细胞增殖有关。IR-B在肝脏和其他成人组织中表达，并主要参与葡萄糖代谢。高水平的IR-A与肿瘤的发生有关，并在多种癌症中被发现，包括乳腺癌、子宫内膜癌、结肠癌和肝细胞癌。与IR-B相比，IR-A对IGF表现出更高的亲和力。IGF-1和IGF-2是在肝脏中响应生长激素而合成的小肽。虽然胰岛素主要以自由形式循环，但IGFs主要与IGF结合蛋白(IGFBPs)结合而循环，从而调节其水平和生物学功能。IGF-1和IGF-2通过与IGF-1受体(IGF-1R)结合，促进细胞生长和增殖，多项研究表明，IGF-1R在乳腺癌和子宫内膜癌中的表达增加。在肥胖的情况下，较高水平的IGF-2同时刺激IGF-1R和IR-A表达。 British Journal of Cancer (2021)125:495–509 肥胖患者，胰岛素和IGFR长期被激活，导致细胞中葡萄糖摄取增加、细胞增殖、血管生成，并最终产生恶性转化和恶性生长的潜力。内脏肥胖（非皮下脂肪肥胖）是比BMI更好的肿瘤风险预测因子。因为内脏肥胖会增加循环的游离脂肪酸，进而增加高胰岛素血症和胰岛素抵抗的发生，增加促炎细胞因子分泌，引起胰岛素受体和IGFR的过度激活，增加PI3K活化，促进肿瘤增殖。临床前模型中，PI3K抑制后，胰岛素的激增可以重新激活这一通路，并刺激进一步的肿瘤细胞增殖。药物靶点：IGF、IR-A、IGF1R、酪氨酸激酶。存在的问题：鉴于IR和IGF1R在人体组织中的普遍存在性，靶向这些受体，会产生off-tumor的相关的毒性。同时阻断IGF1R和IR可导致剂量限制性高血糖，仅抑制IGF1R可导致IR信号通路的代偿性激活。药物举例： IGFR Figitumumab Figitumumab是辉瑞研发的IGF1R单克隆抗体，与卡铂和紫杉醇联合治疗晚期非小细胞肺癌(NSCLC)。然而，由于严重不良事件的发生率增加，包括3/4级高血糖和与治疗相关的死亡，临床试验提前结束。 Linsitinib（OSI-906） Astellas Pharma研发的小分子抑制剂，靶向IGF1R and IR, 3期临床（ NCT00924989）治疗局部晚期或转移性肾上腺皮质癌，和对照组比较，无明显临床获益。没有新的临床研究开展。 IGF2 Dusigitumab/MEDI-573 Dusigitumab由MedImmune LLC研发，IgG2λ抗体，靶向IGF-2 和IGF-1，1期临床（NCT00816361，NCT01340040），最好的结果是疾病稳定（SD），未出现完全缓解（CR）或者部分缓解（PR）。没有新的临床研究开展。 Xentuzumab/BI836845 由Boehringer Ingelheim研发，IgG1抗体，结合IGF-2 和IGF-1，首次人体临床试验（NCT01403974; NCT01317420），显示耐受性良好，125例病人出现2例PR。16例EGFR突变的NSCLC患者（NCT02191891），Afatinib 联合Xentuzumab (BI 836845) Phase1b，没有出现PR，10例SD。NCT02123823，将xentuzumab 加入 everolimus/exemestane，治疗HER2阴性，雌激素受体阳性患者，没有改善PFS，但在没有内脏转移的患者中，观察到了PFS改善，随后开展2期临床XENERA™-1 (NCT03659136)。改变糖稳态重新利用治疗糖尿病的药物在癌症研究领域取得一些进展。二甲双胍在临床前模型中，二甲双胍可下调IGF信号通路，抑制子宫浆液性癌细胞的增殖。二甲双胍还能减弱乳腺癌、肺癌和胰腺癌细胞中IGF1的表达以及mTOR和Akt（胰岛素信号传导的下游效应因子）的激活。在乳腺癌的新辅助治疗中，二甲双胍与其他细胞毒性药物联合使用，改善了病理完全缓解率，但没有改善转移性患者的PFS。用二甲双胍抑制IGF1和PI3K信号通路可以降低子宫内膜肿瘤中的细胞增殖。在small window-of-opportunity（术前）试验中，二甲双胍降低了患者的肿瘤增殖(标记Ki-67)11.75%(P=0.008)，在另一项试验中降低了17.2%(P=0.002)，但这些发现在验证性3期试验中没有得到重复。第2乱：脂肪因子信号通路紊乱脂肪组织分泌的脂肪因子（激素和细胞因子）失调是过度肥胖的一个标志，可以促进肿瘤的生长。瘦素（leptin），脂肪细胞分泌的激素和肥胖的生物标志物，主要功能是下丘脑介导的食欲调节，它调节进食行为和能量消耗。肥胖个体的循环瘦素水平升高，并与癌症发展和进展的风险增加有关，如子宫内膜癌、乳腺癌、结肠癌和肾癌等。瘦素与瘦素受体结合，激活多个信号通路，包括JAK/STAT、MAPK和PI3K通路，最终促进细胞增殖。通过瘦素受体传递的信号也能激活乳腺癌干细胞，是其存活和维持所必需的。胰岛素和IGF1也可以增加乳腺上皮组织中瘦素及其受体的表达，这种表达的增加与乳腺癌预后较差有关。瘦素可以刺激血管生成，增加血管通透性，使恶性细胞进一步生长。因此，瘦素是肿瘤和肿瘤微环境(TME)之间相互作用的重要中介物。 British Journal of Cancer (2021) 125:495–509 另一种由脂肪细胞分泌的激素是脂联素(adiponectin)，它具有抗糖尿病和抗炎的特性。肥胖和代谢综合征血浆脂联素水平降低，脂联素受体(AdipoR1和AdipoR2)的表达也降低，导致脂联素敏感性进一步降低。低脂联素水平与胰岛素抵抗和肥胖相关恶性肿瘤的风险增加有关，包括乳腺癌和子宫内膜癌。脂联素激活AMPK通路，导致p53和p21的上调，从而调控细胞周期和凋亡。肥胖增加瘦素，降低脂联素水平，瘦素/脂联素比值被认为是乳腺癌生长的一个预测因子。其他脂肪因子的水平，如抵抗素（resistin）和内脂肪素（visfatin），在肥胖人体升高，是炎症的标志物，与各种癌症的发展和进展有关。抵抗素（resistin）被认为通过TLR4介导NF-κB和STAT3的激活来促进乳腺癌细胞的生长。药物靶点瘦素虽然瘦素和肿瘤发生发展的关系已经确定，但是目前尚无拮抗瘦素的药物进入临床。PEG-LPrA2是一种瘦素受体拮抗剂，已在三阴性乳腺癌的临床前模型中被研究，可以抑制瘦素信号通路并抑制乳腺癌的生长。脂联素 PPAR合成配体（罗格列酮和吡格列酮），是糖尿病治疗药物，通过调节葡萄糖代谢、减少高胰岛素血症和改变脂肪酸代谢。此外，PPARγ合成配体已被证明在临床前模型和人体研究，显示增加脂联素水平，可能有利于治疗肥胖驱动的癌症。 Statins 他汀类药物被广泛用于脂质水平管理，也可能具有抗癌特性。已经提出了几种抗癌机制的作用：通过抑制Ras和Rho激活，损害肿瘤细胞增殖；通过细胞周期阻滞抑制细胞增殖；诱导凋亡；剂量依赖性抑制血管生成；适当抗炎。但是临床结果并不一致。第3乱：雌激素信号紊乱 British Journal of Cancer (2021)125:495–509 绝经后，雌激素主要来自于雄激素转化（通过雌激素生物合成酶，芳香化酶）。肥胖引起癌症发生的一个重要因素就是增加脂肪组织中芳香化酶活性。芳香化酶抑制剂二甲双胍已被确定为一种潜在的乳腺特异性芳香化酶抑制剂。脂肪因子adiponectin和ghrelin也被证明以启动子特异性的方式抑制芳香化酶的表达，这可能有助于解释肥胖环境下低水平脂联素与乳腺癌生长之间的联系。特异性甾体和非甾体芳香化酶抑制剂已证明对预防和治疗ER+乳腺癌有效，ER+乳腺癌发展或复发的风险降低约50%。芳香化酶抑制剂也可能在ER+子宫内膜癌中有临床应用，但目前临床疗效有限。 Anastrozole是一种非甾体芳香化酶抑制剂，已被证明在新辅助治疗中可减少子宫内膜癌细胞的增殖，并对治疗复发性ER+子宫内膜癌具有一定的活性。 Trozole（非甾体芳香化酶抑制剂）联合everolimus（mTOR抑制剂），未被选择的子宫内膜癌人群中，总有效率为32%。 Exemestane一种不可逆的甾体芳香化酶抑制剂，目前正在被测试用于治疗子宫内膜增生和低级别子宫内膜癌(NCT03300557)。其他正在进行的试验，正在评估芳香化酶抑制剂与PI3K-mTOR通路抑制剂的各种组合(NCT02730923，NCT03008408)。饮食控制及体育锻炼饮食控制和体育锻炼，可以显著改善机体的炎症因子水平，恢复机体代谢稳态。国内和国际上，都有一些临床试验在评估其价值。主要参考文献 Lauby-Secretan B, Scoccianti C, Loomis D,Grosse Y, Bianchini F & Straif K (2016) Body fatness and cancer – viewpointof the IARC Working Group. N Engl J Med 375, 794–798 Johann de Bono et al, Two first-in-humanstudies of xentuzumab, a humanised insulin-like growth factor(IGF)-neutralising antibody,in patients with advance）dsolid tumours，British Journal of Cancer https://doi.org/10.1038/s41416-020-0774-1 Goodwin, P., Ennis, M., Cescon, D., Elser,C., Haq, R., Hamm, C. et al. Abstract P1- 16-03: phase II randomized clinicaltrial (RCT) of metformin (MET) vs placebo (PLAC) in combination withchemotherapy (CXT) in refractory locally advanced (LABC) or metastatic breastcancer (MBC). Cancer Res. 79, P1-16-03–P11-16-03 (2019) Maria M. Rubinstein, Kristy A. Brown andNeil . Iyengar. Targeting obesity-related dysfunction in hormonally drivencancers. British Journal of Cancer (2021) 125:495–50

临床结果临床2期

100 项与 Dusigitumab 相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D10352	Dusigitumab	-	DB12363

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
转移性乳腺癌	临床2期	美国	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	比利时	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	加拿大	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	法国	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	德国	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	匈牙利	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	以色列	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	波兰	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	西班牙	MedImmune LLC	2011-06-13
转移性乳腺癌	临床2期	巴哈马	MedImmune LLC	2011-06-13

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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


NCT01446159 (CTgov)	临床2期	转移性乳腺癌	188	Aromatase inhibitor+MEDI-573 (MEDI-573 30 mg/kg + AI)	淵醖齋遞夢襯顧網選繭(窪觸繭壓觸夢網鬱壓膚) = 獵衊製範簾蓋餘鬱糧廠齋構鹽醖選廠膚鏇廠繭 (餘膚構蓋齋範構鏇廠蓋, 齋觸壓艱鑰築壓廠構網 ~ 願淵艱鑰願襯觸製淵廠) 更多	-	2018-08-28
NCT01446159 (CTgov)	临床2期	转移性乳腺癌	188	Aromatase inhibitor+MEDI-573 (MEDI-573 45 mg/kg + AI)	淵醖齋遞夢襯顧網選繭(窪觸繭壓觸夢網鬱壓膚) = 簾簾鬱範築蓋蓋選鬱齋齋構鹽醖選廠膚鏇廠繭 (餘膚構蓋齋範構鏇廠蓋, 蓋壓獵製鏇簾糧範範簾 ~ 積鹹膚製觸窪遞壓鏇糧) 更多	-	2018-08-28
NCT01340040 (Pubmed \| Invest New Drugs) 人工标引	临床1期	晚期恶性实体瘤	10	MEDI-573	廠夢簾廠獵遞鑰蓋選遞(蓋鬱壓積鏇鑰簾憲構夢) = fatigue (n = 2 patients), pyrexia (n = 2), diarrhoea (n = 2) and electrocardiogram QT prolongation (n = 2) 顧廠構艱範鬱觸壓廠膚 (餘膚構壓膚選構艱鹽淵 )	积极	2015-02-01