Emibetuzumab(Emibetuzumab) - 药物靶点：c-Met_在研适应症：转移性非小细胞肺癌_专利_临床

概要

基本信息

药物类型

单克隆抗体

别名

Anti-c-MET-monoclonal-antibody-Eli-Lilly、c-MET monoclonal antibody - Eli Lilly、c-MET-mAb-Eli-Lilly

+ [4]

靶点

c-Met

作用方式

抑制剂

作用机制

c-Met抑制剂(肝细胞生长因子受体抑制剂)

治疗领域

肿瘤呼吸系统疾病

在研适应症

转移性非小细胞肺癌

非在研适应症

晚期癌症c-Met阳性非小细胞肺癌c-Met阳性胃癌+ [5]

原研机构

Eli Lilly & Co.

在研机构

Eli Lilly & Co.

非在研机构-

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

Sequence Code 189125L

来源: *****

Sequence Code 9060734H

来源: *****

关联

9

项与 Emibetuzumab 相关的临床试验

NCT02082210

/ Completed临床1/2期

A Phase 1b/2 Study of Ramucirumab in Combination With LY2875358 in Patients With Advanced Cancer

The purpose of this study is to find a recommended schedule and dose range for Emibetuzumab when given with ramucirumab that may be safely given to participants with cancer. In Part A of this study, escalating doses of Emibetuzumab will be given in combination with a fixed dose of ramucirumab to evaluate the safety of the combination. After a recommended schedule and dose range of Emibetuzumab and ramucirumab has been established, Part B of the study will confirm safety and to see how well certain tumors respond to the combination of study drugs. The average amount of time on study is expected to be about 6 months.

开始日期2014-03-07

申办/合作机构

Eli Lilly & Co.

NCT01897480

/ Active, not recruiting临床2期

A Randomized, Controlled Phase 2 Study Evaluating LY2875358 Plus Erlotinib Versus Erlotinib as First-Line Treatment in Metastatic Non-Small Cell Lung Cancer Patients With Activating EGFR Mutations Who Have Disease Control After an 8-Week Lead-In Treatment With Erlotinib

The primary purpose of this study is to compare the efficacy of the study drug LY2875358, given together with erlotinib, against erlotinib, alone. Participants will have Non-Small Cell Lung Cancer (NSCLC) that has advanced to Stage IV. Participants should not have been treated with drugs for Stage IV NSCLC, previously. All participants will get erlotinib alone, for approximately 8 weeks. Participants with radiographic disease control at the end of the erlotinib lead-in study period will be randomly assigned to receive LY2875358 plus erlotinib or erlotinib alone. Participants, who were chosen to receive erlotinib, alone, may cross over to the combination treatment at the time of progression.

开始日期2013-08-28

申办/合作机构

Eli Lilly & Co.

NCT01874938

/ Completed临床2期

A Non-Randomized, Open-Label, Single-Arm, Phase 2 Study of LY2875358 in Patients With MET Diagnostic Positive, Advanced Gastric Cancer

The main purpose of this study is to evaluate the effectiveness of LY2875358 in participants with MET diagnostic positive (+), advanced gastric or gastroesophageal junction (GEJ) cancer.

开始日期2013-08-01

申办/合作机构

Eli Lilly & Co.

100 项与 Emibetuzumab 相关的临床结果

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100 项与 Emibetuzumab 相关的转化医学

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100 项与 Emibetuzumab 相关的专利（医药）

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20

项与 Emibetuzumab 相关的文献（医药）

2023-12-01·JOURNAL OF MOLECULAR MODELING

Evaluating the chaos game representation of proteins for applications in machine learning models: prediction of antibody affinity and specificity as a case study

Article

作者: Arsiccio, Andrea ; Menzen, Tim ; Stratta, Lorenzo

CONTEXT:

Machine learning techniques are becoming increasingly important in the selection and optimization of therapeutic molecules, as well as for the selection of formulation components and the prediction of long-term stability. Compared to first-principle models, machine learning techniques are easier to implement, and can identify correlations that would be hard to describe at a mechanistic level, but strongly rely on high-quality input training data. Here, we evaluate the potential of the "chaos game" representation to provide input data for machine learning models. The chaos game is an algorithm originally developed for the production of fractal structures, and later on applied also to the representation of biological sequences, such as genes and proteins. Our results show that the combination of the chaos game representation with convolutional neural networks results in comparable accuracy to other machine learning approaches, thus indicating that chaos game representations could be a valid alternative to existing featurization strategies for machine learning models of biological sequences.

METHODS:

We implement the chaos game in Python 3.8.10, and use it to produce fractal as well as novel expanding representations of protein sequences. We then feed the resulting images to a convolutional neural network, built in Python 3.8.10, using TensorFlow 2.9.1, Keras 2.9.0, and the scikit-learn 1.1.1 packages. We select as case study a recently published dataset for the antibody emibetuzumab, with the objective of co-optimizing antibodies variants with both high affinity and low non-specific binding.

2023-09-02·Bioinformatics (Oxford, England)

Position-Specific Enrichment Ratio Matrix scores predict antibody variant properties from deep sequencing data

Article

作者: Makowski, Emily K ; Tessier, Peter M ; Case, Marshall A ; Smith, Matthew D

Abstract:

Motivation:

Deep sequencing of antibody and related protein libraries after phage or yeast-surface display sorting is widely used to identify variants with increased affinity, specificity, and/or improvements in key biophysical properties. Conventional approaches for identifying optimal variants typically use the frequencies of observation in enriched libraries or the corresponding enrichment ratios. However, these approaches disregard the vast majority of deep sequencing data and often fail to identify the best variants in the libraries.

Results:

Here, we present a method, Position-Specific Enrichment Ratio Matrix (PSERM) scoring, that uses entire deep sequencing datasets from pre- and post-selections to score each observed protein variant. The PSERM scores are the sum of the site-specific enrichment ratios observed at each mutated position. We find that PSERM scores are much more reproducible and correlate more strongly with experimentally measured properties than frequencies or enrichment ratios, including for multiple antibody properties (affinity and non-specific binding) for a clinical-stage antibody (emibetuzumab). We expect that this method will be broadly applicable to diverse protein engineering campaigns.

Availability and implementation:

All deep sequencing datasets and code to perform the analyses presented within are available via https://github.com/Tessier-Lab-UMich/PSERM_paper.

2022-06-01·Clinical lung cancer

A Randomized, Open-Label Phase II Study Evaluating Emibetuzumab Plus Erlotinib and Emibetuzumab Monotherapy in MET Immunohistochemistry Positive NSCLC Patients with Acquired Resistance to Erlotinib

Article

作者: Mileham, Kathryn ; Demedts, Ingel ; Wacheck, Volker ; Smit, Egbert ; Park, Keunchil ; Wijayawardana, Sameera R ; Grosch, Heidrun ; Juan-Vidal, Oscar ; Moran, Teresa ; Goldman, Jonathan W ; Wallin, Johan ; Wang, Xuejing Aimee ; Bepler, Gerold ; Camidge, D Ross ; Molina, Julian

INTRODUCTION:

The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib.

PATIENT AND METHODS:

Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (≥ 10% of cells expressing MET at ≥ 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in ≥ 60% of cells ≥ 2+ (MET ≥ 60%).

RESULTS:

One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET ≥ 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101).

CONCLUSION:

Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit.

1

项与 Emibetuzumab 相关的新闻（医药）

2025-03-12

·Antibody Research

新锐ADC公司：安领科EGFR/cMET双抗ADC获批临床

中国国家药监局药品审评中心（CDE）官网最新公示，安领科生物申报的1类新药注射用ALK202获批临床，拟用于既往标准治疗失败或无标准治疗（包括无法接受标准治疗）的成人局部晚期或转移性实体瘤。根据官网公开信息，ALK202为安领科旗下第二款临床获批的ADC，为EGFR/cMET双抗ADC。根据clinicaltrials官网，ALK202的一期临床研究旨在晚期实体瘤患者中评估ALK202的安全性、耐受性、药代动力学（PK）和抗肿瘤活性。该研究为国际多中心临床研究，拟在全球范围内入组234名受试者。 2024年9月27日，艾伯维宣布向美国食品药品监督管理局 (FDA) 提交生物制品许可申请 (BLA)，以加速批准 telisotuzumab vedotin (Teliso-V) 用于治疗先前接受过治疗的局部晚期或转移性表皮生长因子受体 (EGFR) 野生型、非鳞状非小细胞肺癌 (NSCLC) 且 cMet蛋白过表达的成年患者。该款药物属于艾伯维cMET MMAE ADC，第二代cMET topoi ADC也已迅速推进至后期临床。 BLA 申请基于2 期 LUMINOSITY 试验研究。结果显示，总人群、c-Met高表达和c-Met中等表达患者经独立中央审查（ICR）评估的总体缓解率分别为28.6%、34.6%和22.9%，中位缓解持续时间（DOR）分别为8.3个月、9.0个月和7.2个月，中位总生存期（OS）分别为14.5个月、14.6个月和14.2个月，中位无进展生存期（PFS）分别为5.7个月、5.5个月和6.0个月。 Teliso-V的安全性与之前的研究结果一致，没有发现新的安全性问题。最常见的任何级别治疗相关不良事件（TRAE）是外周感觉神经病变（30%）、外周性水肿（16%）和疲劳（14%），最常见的≥3级AE是外周感觉神经病变（7%）。三期临床也在开展之中，Teliso-V对比多西他赛二线治疗c-Met蛋白过表达、EGFR野生型晚期/转移性非鳞状NSCLC成人患者的疗效和安全性。新一代TOPOi cMET ADC，ABV-400也已推进至三期临床。迄今为止，针对cMET靶点，只有cMETxEGFR双特异性抗体Amivantamab(RYBREVANT) 获得了 FDA 的批准。先前一些被广泛研究的抗cMET抗体包括 Onartuzumab (MetMab)、Emibetuzumab (LY2875358)、Telituzumab (ABT-700)、Sym015、SAIT301 和 HLX55，都没有太好的临床进展。源于cMET单克隆抗体倾向于诱导激动活性，从而导致肿瘤细胞增殖而不是凋亡。后续迭代抗体通过构建单臂抗体来避免这种情况，从而防止受体二聚化的发生，或者通过发现和进一步铰链区设计不表现出功能性激动剂活性的单克隆抗体，如Telituzumab (ABT-700)。 Telituzumab (ABT-700)来源于Pierre Fabre开发的一款cMet拮抗型（Antagonist）抗体h224G11，在人源化后，发现有激活作用，后又根据母本鼠抗的铰链区和人IgG2铰链区进行工程化设计，多了一对二硫键。ABT-700 结合细胞 c-Met，并破坏其由 HGF 或细胞表面高密度 c-Met 诱导的二聚化和活化，不依赖于配体。大多数二价cMET单抗都有激活作用。这也是后来多数cMET抗体开发为单价的原因。该抗体国内到2029年专利过期，以目前的时间来看，可以使用。 cMET作为肺癌的重要布局靶点，大约 85% 的肺癌被归类为 NSCLC ，尽管治疗取得了一定进步，然而肺癌仍然是全世界男性和女性癌症相关死亡的主要原因。在大约25%的晚期 EGFR 野生型 NSCLC 患者中发现了 c-Met 蛋白过度表达，并且与这些患者的不良预后相关。从基因层面，EGFR，cMET具有很好的相关性，但同时也存在表达差异。也就是说多数情况下，EGFRxcMET ADC并不会差于单抗cMET ADC。当然在EGFR极度不表达的情况下，只有cMET表达，cMET单抗ADC可能会优于EGFRxcMET ADC，反之亦然。从蛋白层面来看，多数情况下EGFR表达优于cMET，双抗ADC可能会更偏向于EGFR驱动药效。不可避免的会迎来这EGFR ADC，EGFRxcMET ADC（二价），cMET ADC的差异性。EGFR ADC在多种肿瘤中可能因EGFR表达优势会占据疗效优势，而EGFRxcMET ADC在于具有广谱性和在某些肿瘤的上两者的协同作用。也就是说需要寻找适合的适应症来发挥这几款药物的真正优势。开发的早，这种寻找优势的对比要求就弱很多，但开发的越晚要求越高。 EGFR，cMET作为优异的靶点，都是ADC领域布局的热门。需要提醒的是，抗体并不能等同于ADC，并不是双抗ADC成功就没有必要开发双抗，也不是双抗成功了也无需开发双抗ADC，这两者的类型和作用机制完全不同。同时开发，也许更能充分的进行细分适应症的布局。因此安领科也开发了EGFR/cMET的双特异抗体。关于EGFR/cMET的双特异抗体，2023年10月26日，强生的埃万妥单抗注射液（Rybrevant/Amivantamab）在国内申报上市申请获得受理。埃万妥单抗是强生旗下的一款EGFR/cMET的双特异抗体。该抗体已经在2021年5月21日获得FDA批准上市，用于治疗铂类化疗后进展、携带EGFR外显子20插入突变的转移性非小细胞肺癌（NSCLC）的患者。在MARIPOSA研究中，针对EGFR外显子19缺失（ex19del）或替代突变局部晚期或转移性NSCLC患者，埃万妥单抗联合lazertinib对比奥希替尼和lazertinib单药一线治疗的疗效。在无进展生存期方面和总生存期方面，埃万妥单抗都表现出具有统计学和临床意义的改善。体现这一双抗的开发价值。 2025年1月7日，强生宣布了3期MARIPOSA研究的癌症治疗金标准终点总生存期 (OS) 的积极顶线结果，该研究评估了 RYBREVANT ® (amivantamab-vmjw) 加 LAZCLUZE™ (lazertinib) 作为表皮生长因子受体 (EGFR) 外显子 19 缺失 (ex19del) 或 L858R 替代突变的局部晚期或转移性非小细胞肺癌 (NSCLC) 患者的一线治疗。无化疗联合方案达到了最终预先指定的 OS 次要终点，并且与目前的标准治疗药物奥希替尼相比，OS 具有临床意义和统计学意义的改善。预计中位 OS 改善将超过一年。但EGFR/cMET双特异抗体，跟EGFR/cMET ADC机制并不相同。EGFR/cMET ADC为靶向化疗，而EGFR/cMET双特异抗体是通过阻断靶点本身的机制，同时引起NK等免疫细胞对肿瘤细胞的杀伤。ADC和抗体，是有明显区别的，在很大程度上并不等同。但同样都具有很大的开发价值。奥希替尼联合化疗一线治疗EGFR突变晚期NSCLC的III期随机临床试验——FLAURA2研究公布临床试验结果，PFS结果显示，无论是经研究者评估还是经BICR评估，奥希替尼联合化疗组的PFS均较奥希替尼单药组延长约9个月。其中，两组经BICR评估的中位PFS分别为29.4个月 vs 19.9个月（HR=0.62；P=0.0002），经研究者评估的中位PFS分别为25.5个月 vs 16.7个月（HR=0.62；P<0.0001），使得疾病进展或死亡风险均降低了38%。安全性结果显示，并未发现新的安全信号，奥希替尼联合化疗整体安全可控。这为后续奥希替尼联合EGFR/cMET ADC提供了一定的理论基础。但双抗在一定程度上具有更高的安全性。而对于后线，奥希替尼（或其他TKI抑制剂）联合EGFR/cMET ADC可能依然有效。也就是说，双抗和双抗ADC联合奥希替尼等TKI抑制剂，根据其机制的不同可以形成序惯治疗。未来第四代EGFR TKI抑制剂，联合EGFR/cMET ADC或EGFR/cMET双抗，也会成为重要趋势。内容来源于网络，如有侵权，请联系删除。

抗体药物偶联物申请上市临床结果

100 项与 Emibetuzumab 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Emibetuzumab	-	DB11849

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
晚期癌症	临床2期	美国	Eli Lilly & Co.	2014-03-07
胃食管交界处腺癌	临床2期	美国	Eli Lilly & Co.	2014-03-07
肝细胞癌	临床2期	美国	Eli Lilly & Co.	2014-03-07
肾细胞癌	临床2期	美国	Eli Lilly & Co.	2014-03-07
胃腺癌	临床2期	美国	Eli Lilly & Co.	2014-03-07
转移性非小细胞肺癌	临床2期	美国	Eli Lilly & Co.	2013-08-28
转移性非小细胞肺癌	临床2期	丹麦	Eli Lilly & Co.	2013-08-28
转移性非小细胞肺癌	临床2期	法国	Eli Lilly & Co.	2013-08-28
转移性非小细胞肺癌	临床2期	德国	Eli Lilly & Co.	2013-08-28
转移性非小细胞肺癌	临床2期	意大利	Eli Lilly & Co.	2013-08-28

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临床结果

适应症

分期

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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


NCT01897480 (Pubmed \| J Thorac Oncol) 人工标引	临床2期	EGFR阳性非小细胞肺癌一线 MET Overexpression \| EGFR Positive	-	erlotinib+emibetuzumab	壓繭餘遞積蓋鏇壓蓋遞(選積鑰鏇糧鹹襯窪觸獵) = 膚觸顧鏇鹹鏇淵廠範構餘築鹽遞壓壓壓繭積齋 (廠鬱願選膚製艱壓醖餘 ) 更多	积极	2020-01-01
				erlotinib	壓繭餘遞積蓋鏇壓蓋遞(選積鑰鏇糧鹹襯窪觸獵) = 願觸夢廠淵構構鹽鑰醖餘築鹽遞壓壓壓繭積齋 (廠鬱願選膚製艱壓醖餘 ) 更多
NCT02082210 (Pubmed \| Clin Cancer Res) 人工标引	临床1/2期	晚期癌症 MET Positive	97	Ramucirumab+Emibetuzumab	鹽窪築鹹鑰膚積衊醖製(襯夢築願積遞願糧鑰選) = Common adverse events were primarily mild or moderate and included fatigue (36.1%), peripheral edema (28.9%), and nausea (14.4%). 願構夢膚夢構憲製餘範 (遞衊壓簾衊憲鏇餘膚壓 ) 更多	积极	2019-09-01
				Ramucirumab+Emibetuzumab (pts with HCC)
NCT01874938 (Pubmed) 人工标引	临床2期	c-Met阳性胃癌 MET Positive	15	emibetuzumab	鹽網夢構網廠鬱鏇醖鬱(醖鹹淵餘壓網簾廠鏇製) = 艱網鹹鏇網獵廠選製鹹衊淵觸衊齋獵構觸鬱夢 (願願蓋範餘衊範齋廠鑰, 33 ~ 59) 更多	不佳	2017-12-01
NCT02082210 (AACR2017)	临床1/2期	晚期恶性实体瘤	97	Ramucirumab 8 mg/kg + Emibetuzumab 750 mg	鹹簾鏇齋願遞夢願齋鹽(鏇築製鹽鹽膚醖壓鑰觸) = Common possibly related AEs of all grades included dyspnea (16%) 餘獵壓齋築衊淵蓋網積 (鹹選鑰醖襯鑰廠膚艱醖 ) 更多	-	2017-07-01
				Ramucirumab 8 mg/kg + Emibetuzumab 2000 mg
NCT01287546 (Pubmed \| Clin Cancer Res) 人工标引	临床1期	晚期癌症	37	Emibetuzumab (solid tumors)	鹽顧願膚襯餘憲簾醖顧(鏇夢襯顧鏇憲鏇鏇夢夢) = Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. 範襯製鑰選糧夢遞製網 (鏇網膚淵獵壓蓋選網範 ) 更多	积极	2017-04-15
				erlotinib+Emibetuzumab (NSCLC)
NCT01900652 (ASCO2016) 人工标引	临床2期	c-Met阳性非小细胞肺癌 MET Positive	111	erlotinib+emibetuzumab	醖憲鹽淵壓艱襯觸獵願(廠蓋選積構簾夢鹽廠鹽) = 鹽選襯夢鬱淵窪鹹製廠顧衊膚鬱積選鬱鹽膚糧 (淵夢觸廠襯齋夢淵積餘 ) 更多	积极	2016-06-04
				emibetuzumab	醖憲鹽淵壓艱襯觸獵願(廠蓋選積構簾夢鹽廠鹽) = 窪壓遞鏇網廠觸鹹鑰鬱顧衊膚鬱積選鬱鹽膚糧 (淵夢觸廠襯齋夢淵積餘 ) 更多