Tengonermin(Tengonermin) - 药物靶点：APN x TNFR_专利_临床

概要

基本信息

药物类型

肿瘤坏死因子

别名

ARENEGYR、CNGRC peptide-TNF alpha conjugate、NGR-HTNF

+ [5]

靶点

APN x TNFR

作用方式

调节剂、抑制剂

作用机制

APN调节剂(氨肽酶N调节剂)、TNFR调节剂(肿瘤坏死因子受体调节剂)、血管生成抑制剂

治疗领域

肿瘤呼吸系统疾病其他疾病+ [5]

在研适应症-

非在研适应症

晚期非小细胞肺癌晚期小细胞肺癌晚期恶性实体瘤+ [16]

原研机构

AGC Biologics SpA

在研机构-

非在研机构

AGC Biologics SpA

Eortc

最高研发阶段终止申请上市

首次获批日期-

最高研发阶段(中国)-

特殊审评孤儿药 (美国)

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结构/序列

Sequence Code 475412891

来源: *****

关联

19

项与 Tengonermin 相关的临床试验

NCT03536039

/ Completed临床2期

Monoinstitutional Phase II Trial Addressing Tolerability and Activity of RCHOP Chemoimmunotherapy Preceded by BBB Permeabilization by t-NGR Necrosis Factor in Patients With Relapsed/Refractory Primary Central Nervous System Lymphoma

Patients with primary central nervous system lymphoma (PCNSL) are treated with high-dose-methotrexate-based chemotherapy, which requires hospitalization and extensive expertise to manage related toxicity. Treatment with R-CHOP, the most commonly used combination against aggressive lymphomas, could overcome these difficulties, but CNS bioavailability of related drugs is poor due to their limited capability to cross the blood-brain barrier (BBB). Tumor necrosis factor (TNF) induces selective BBB permeabilization and enhances CNS access of anticancer drugs in animal models. The addition of NGR peptide improves biological properties of TNF, resulting in increased drug availability and antitumor synergistic effect, without increased toxicity. Thus, the addition of NGR-hTNF to R-CHOP may result in improved CNS drug availability and activity in patients with relapsed/refractory PCNSL; this hypothesis is being tested in this ongoing phase II trial called "INGRID". This trial will consider HIV-negative patients (age 18-80 ys; ECOG PS ≤3) with relapsed/refractory PCNSL previously treated with high-dose-methotrexate-based chemotherapy± radiotherapy, and with measurable disease.

开始日期2016-01-27

申办/合作机构

AGC Biologics SpA

EUCTR2012-005745-20-IT

/ Not yet recruitingN/A

NGR018: Randomized phase II study of NGR-hTNF plus an anthracycline versus an anthracycline alone in platinum-resistant ovarian cancer - NGR018

开始日期2013-03-24

申办/合作机构-

NCT03804866

/ Completed临床2期

NGR018: Randomized Phase II Study of NGR-hTNF Plus an Anthracycline Versus an Anthracycline Alone in Platinum-resistant Ovarian Cancer

The primary objective of this extension protocol is to evaluate the early safety of a new schedule of NGR-hTNF given weekly, instead of every 3 or 4 weeks, in a cohort of 12 patients randomized to the experimental arm A, as compared to a reference cohort of 12 patients randomized to an anthracycline alone

开始日期2013-03-01

申办/合作机构

AGC Biologics SpA

100 项与 Tengonermin 相关的临床结果

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100 项与 Tengonermin 相关的转化医学

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100 项与 Tengonermin 相关的专利（医药）

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30

项与 Tengonermin 相关的文献（医药）

2021-02-01·Applied Microbiology and Biotechnology3区 · 工程技术

A single nucleotide mutation drastically increases the expression of tumor-homing NGR-TNFα in the E. coli M15-pQE30 system by improving gene transcription

3区 · 工程技术

Article

作者: Tao, Ze ; Fan, Jie ; Cheng, Jingqiu ; Shi, Qiuxiao ; Yang, Hao ; Li, Zhao ; Lu, Xiaofeng ; Jin, Youmei ; Feng, Yanru ; Chen, Jie ; Li, Shengfu

Due to their potent immune stimulation, tumor necrosis factor alpha (TNFα) variants with tumor-homing activity are attractive as novel antitumor drugs. The promising antitumor effect of NGR-TNFα in clinical trials triggered extensive interest in developing novel tumor-homing TNFα variants in recent years. Owing to its promising antitumor effect, NGR-TNFα is usually used as a control for newly developed tumor-homing TNFα variants. In our previous works, we produced a pericyte-targeting Z-TNFα at high levels using the Escherichia coli (E. coli) M15-pQE30 system. To further compare Z-TNFα and NGR-TNFα, we attempted to express NGR-TNFα using the same system. Surprisingly, native NGR-TNFα was expressed at a low (~ 0.2 mg/L) level in E. coli M15 containing the pQE30 plasmid. However, a single nucleotide mutation of C to G, resulting in a substitution of leucine (L) with valine (V) at the start of TNFα, increased the expression of NGR-TNFα by ~ 100 times through improving transcription. In addition, the amino acid substitution showed a little impact on the receptor binding, in vitro cytotoxicity, and in vivo antitumor effect of NGR-TNFα. As fusing NGR to the N-terminus of TNFα with a valine substitution did not reduce the protein yield, the TNFα gene with a C > G mutation might be used to prepare novel tumor-homing TNFα when the native TNFα-based variant is expressed at an extremely low level in E. coli. Notably, in addition to the mutated valine, the impact of N-terminal additional amino acids provided by pQE30 vector on the function of TNFα variant must be carefully evaluated. KEY POINTS : • A single nucleotide mutation increased the expression of NGR-TNFα by two orders. • Nucleotide mutation-induced amino acid substitution did not reduce NGR-TNFα activity.

2020-10-05·Molecular Pharmaceutics2区 · 医学

NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity

2区 · 医学

Article

作者: Gasparri, Anna Maria ; Ferreri, Andrés J. M. ; Curnis, Flavio ; Corti, Angelo ; Sacchi, Angelina ; Rrapaj, Eltjona ; Monieri, Matteo ; Colombo, Barbara

The therapeutic index of cytokines in cancer therapy can be increased by targeting strategies based on protein engineering with peptides containing the CNGRC (NGR) motif, a ligand that recognizes CD13-positive tumor vessels. We show here that the targeting domain of recombinant CNGRC-cytokine fusion proteins, such as NGR-TNF (a CNGRC-tumor necrosis factor-α (TNF) conjugate used in clinical studies) and NGR-EMAP-II, undergoes various post-translational modification and degradation reactions that lead to the formation of markedly heterogeneous products. These modifications include N-terminal cysteine acetylation or the formation of various asparagine degradation products, the latter owing to intramolecular interactions of the cysteine α-amino group with asparagine and/or its succinimide derivative. Blocking the cysteine α-amino group with a serine (SCNGRC) reduced both post-translational and degradation reactions. Furthermore, the serine residue reduced the asparagine deamidation rate to isoaspartate (another degradation product) and improved the affinity of NGR for CD13. Accordingly, genetic engineering of NGR-TNF with the N-terminal serine produced a more stable and homogeneous drug (called S-NGR-TNF) with improved antitumor activity in tumor-bearing mice, either when used alone or in combination with chemotherapy. In conclusion, the targeting domain of NGR-cytokine conjugates can undergo various untoward modification and degradation reactions, which can be markedly reduced by fusing a serine to the N-terminus. The SCNGRC peptide may represent a ligand for cytokine delivery to tumors more robust than conventional CNGRC. The S-NGR-TNF conjugate (more stable, homogeneous, and active than NGR-TNF) could be rapidly developed for clinical trials.

2020-08-11·Blood Advances2区 · 医学

Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial

2区 · 医学

Article

作者: Nonis, Alessandro ; Sassone, Marianna ; Steffanoni, Sara ; Scarano, Eloise ; Cattaneo, Dario ; Curnis, Flavio ; Bordignon, Claudio ; Ponzoni, Maurilio ; Calimeri, Teresa ; Fallanca, Federico ; Foppoli, Marco ; Citterio, Giovanni ; Ciceri, Fabio ; Angelillo, Piera ; Conte, Gian Marco ; Anzalone, Nicoletta ; Corti, Angelo ; Tarantino, Vittoria ; Lopedote, Paolo ; Rrapaj, Eltjona ; Politi, Letterio S. ; De Lorenzo, Daniela ; Ferreri, Andrés J. M. ; Guggiari, Elena

AbstractRituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR–human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.

100 项与 Tengonermin 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	Tengonermin	-	-

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
恶性胸膜间皮瘤	申请上市	瑞典	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	英国	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	法国	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	西班牙	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	比利时	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	埃及	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	加拿大	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	荷兰	AGC Biologics SpA	2010-04-12
恶性胸膜间皮瘤	申请上市	波兰	AGC Biologics SpA	2010-04-12
间皮瘤	申请上市	欧盟	AGC Biologics SpA	-

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临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00483509 (NGR007, CTgov)	临床2期	转移性非小细胞肺癌 \| 晚期小细胞肺癌	28	Doxorubicin+NGR-hTNF	網膚築積獵齋淵膚積築(網衊鏇窪膚獵鬱繭構鏇) = 廠簾衊餘壓壓齋憲窪壓夢繭構齋鹽鑰製鬱獵觸 (獵夢範壓齋製廠餘艱夢, 構鏇蓋壓夢鬱製鏇艱窪 ~ 廠範鬱簾鏇鹹鹽餘繭廠) 更多	-	2019-10-04
NCT01098266 (NGR015, CTgov)	临床3期	恶性胸膜间皮瘤	400	NGR-hTNF plus Best Investigator's Choice (BIC) (A: NGR-hTNF + BIC)	(齋鏇艱願選築願選構簾) = 獵簾窪壓繭糧餘構糧簾膚醖憲艱願壓衊鏇鹹網 (窪簾繭窪壓壓積衊襯獵, 餘願膚觸鏇繭顧積鹽夢 ~ 獵窪窪範夢襯膚壓遞淵) 更多	-	2019-09-17
				Placebo plus Best Investigator's Choice (BIC) (B: Placebo+BIC)	(齋鏇艱願選築願選構簾) = 構鏇構餘網範鬱淵壓醖膚醖憲艱願壓衊鏇鹹網 (窪簾繭窪壓壓積衊襯獵, 衊窪鏇衊壓醖範憲選鬱 ~ 齋願製製艱鹽糧醖鹹鹹) 更多
NCT01098266 (ASCO 12018 \| ASCO 22018) 人工标引	临床3期	恶性胸膜间皮瘤二线	400	gemcitabine+vinorelbine+doxorubicin+NGR-hTNF	(網製襯網鹹觸構鏇觸鏇) = 鏇餘齋夢餘觸憲簾構窪遞膚艱淵獵膚繭獵衊艱 (齋選廠獵築網觸鏇膚範, 29 ~ 50) 更多	积极	2018-06-03
				gemcitabine+vinorelbine+doxorubicin+placebo	(網製襯網鹹觸構鏇觸鏇) = 網選窪簾廠繭觸網選構遞膚艱淵獵膚繭獵衊艱 (齋選廠獵築網觸鏇膚範, 16 ~ 32) 更多
NCT01098266 (NGR015, ASCO2016)	临床3期	恶性胸膜间皮瘤	400	NGR-hTNF plus BIC	(築構夢壓廠願壓範築觸) = 築獵膚廠淵廠夢網廠壓鑰憲築構衊鏇鹹餘積餘 (鹹廠製壓積獵淵夢獵網 ) 更多	积极	2016-05-20
				Placebo plus BIC	(築構夢壓廠願壓範築觸) = 鏇餘鏇廠鬱範製鹹選憲鑰憲築構衊鏇鹹餘積餘 (鹹廠製壓積獵淵夢獵網 ) 更多
NCT01098266 (NGR015, ASCO2015)	临床3期	恶性胸膜间皮瘤	400	NGR-hTNF plus best investigator choice (BIC)	(遞壓網窪窪網鏇網構醖) = 製膚壓壓齋蓋簾齋網艱鬱廠觸製製廠遞襯夢範 (淵選願願選淵選艱遞網 ) 更多	不佳	2015-05-20
				Placebo plus best investigator choice (BIC)	(遞壓網窪窪網鏇網構醖) = 醖鹹衊襯遞簾鏇鹽醖夢鬱廠觸製製廠遞襯夢範 (淵選願願選淵選艱遞網 ) 更多
NCT01098266 (NGR015, ASCO2015)	临床3期	恶性胸膜间皮瘤一线	400	NGR-hTNF plus best investigator choice (BIC)	夢夢齋蓋遞鏇鏇膚鹽憲(蓋窪網繭鏇廠積醖積鏇) = 觸艱襯餘齋餘蓋夢壓膚膚觸糧鬱襯蓋餘襯淵憲 (選鹹齋壓鬱壓鹹壓膚齋, 4.2 ~ 5.1)	积极	2015-05-20
NCT00484341 (NGR016, ASCO2014)	临床2期	X联锁鱼鳞病	69	NGR-hTNF at low dose	(構遞觸餘憲築繭鑰選築) = 繭衊積蓋鑰鏇範簾夢夢遞願夢膚製淵鹽範鹹網 (觸憲艱遞築糧繭簾廠餘 )	-	2014-05-20
				NGR-hTNF at high dose	(構遞觸餘憲築繭鑰選築) = 蓋膚鑰築衊鑰夢夢觸壓遞願夢膚製淵鹽範鹹網 (觸憲艱遞築糧繭簾廠餘 )
NCT00483080 \| NCT00483509 \| NCT00484276 \| NCT00484211 \| NCT00484432 (NGR012, ASCO2013)	临床2期	恶性胸膜间皮瘤 \| 复发性卵巢癌 \| 结直肠癌 \| 转移性非小细胞肺癌 \| 转移性肝细胞癌 \| 晚期小细胞肺癌	205	NGR-hTNF 0.8 µg/m2 every 3 weeks	(製繭構獵廠鬱範構膚遞) = 夢鏇蓋積衊膚淵觸鹽顧窪獵積糧積觸顧構積蓋 (淵壓鑰艱構壓膚製觸簾 )	-	2013-05-20
				NGR-hTNF 0.8 µg/m2 weekly	(製繭構獵廠鬱範構膚遞) = 簾鑰鹹簾網壓繭齋艱願窪獵積糧積觸顧構積蓋 (淵壓鑰艱構壓膚製觸簾 )
NCT00484341 (NGR016, ASCO2013)	临床2期	肉瘤	66	NGR-hTNF (LD)	(憲淵壓繭獵壓鬱網簾壓) = 壓蓋餘構顧廠齋選鹽憲觸觸選醖壓範築窪鏇壓 (觸鏇齋壓鏇簾齋膚鏇淵, 1.1 ~ 1.5)	-	2013-05-20
				NGR-hTNF (HD)	(憲淵壓繭獵壓鬱網簾壓) = 鬱窪衊艱觸糧獵願壓鹹觸觸選醖壓範築窪鏇壓 (觸鏇齋壓鏇簾齋膚鏇淵, 1.1 ~ 1.8)
NCT00914628 \| NCT00878111 (TK008, ASCO2013)	N/A	转移性实体瘤 \| 急性白血病	60	NGR-hTNF at LD	範襯積憲願壓遞襯獵願(鏇蓋蓋鏇膚糧醖構壓壓) = 觸壓鬱衊獵蓋觸積簾餘獵鹽鏇襯獵獵遞築顧壓 (鑰襯選淵糧構積構構壓 ) 更多	-	2013-05-20
				NGR-hTNF at HD	範襯積憲願壓遞襯獵願(鏇蓋蓋鏇膚糧醖構壓壓) = 夢顧膚願壓觸艱憲簾餘獵鹽鏇襯獵獵遞築顧壓 (鑰襯選淵糧構積構構壓 ) 更多