Delving into the Latest Updates on Tengonermin with Synapse

Overview

Basic Info

Drug Type

Tumor necrosis factors

Synonyms

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

+ [5]

Target

APN x TNFR

Action

modulators, inhibitors

Mechanism

APN modulators(Aminopeptidase N modulators), TNFR modulators(Tumor necrosis factor receptor modulators), Angiogenesis inhibitors

Therapeutic Areas

NeoplasmsRespiratory DiseasesOther Diseases+ [5]

Active Indication-

Inactive Indication

Advanced Lung Non-Small Cell CarcinomaAdvanced Lung Small Cell CarcinomaAdvanced Malignant Solid Neoplasm+ [16]

Originator Organization

AGC Biologics SpA

Active Organization-

Inactive Organization

AGC Biologics SpA

Eortc

Drug Highest PhaseDiscontinuedNDA/BLA

First Approval Date-

RegulationOrphan Drug (United States)

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Structure/Sequence

Sequence Code 475412891

Source: *****

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.

Start Date27 Jan 2016

Sponsor / Collaborator

AGC Biologics SpA

EUCTR2012-005745-20-IT

/ Not yet recruitingNot Applicable

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

Start Date24 Mar 2013

Sponsor / Collaborator-

NCT03804866

/ CompletedPhase 2

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

Start Date01 Mar 2013

Sponsor / Collaborator

AGC Biologics SpA

100 Clinical Results associated with Tengonermin

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100 Translational Medicine associated with Tengonermin

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100 Patents (Medical) associated with Tengonermin

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30

Literatures (Medical) associated with Tengonermin

01 Feb 2021·Applied Microbiology and BiotechnologyQ3 · ENGINEERING & TECHNOLOGY

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

Q3 · ENGINEERING & TECHNOLOGY

Article

Author: 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.

05 Oct 2020·Molecular PharmaceuticsQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

11 Aug 2020·Blood AdvancesQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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 Deals associated with Tengonermin

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Malignant Pleural Mesothelioma	NDA/BLA	Sweden	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	United Kingdom	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	France	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Spain	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Belgium	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Egypt	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Canada	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Netherlands	AGC Biologics SpA	12 Apr 2010
Malignant Pleural Mesothelioma	NDA/BLA	Poland	AGC Biologics SpA	12 Apr 2010
Mesothelioma	NDA/BLA	European Union	AGC Biologics SpA	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00483509 (NGR007, CTgov)	Phase 2	metastatic non-small cell lung cancer \| Advanced Lung Small Cell Carcinoma	28	Doxorubicin+NGR-hTNF	qqehhxmvdd(pmynyjejqy) = fjqbvaznmm lbbwgytdzt (apvhcqsmya, vykfkhiexc - lbikrileaj) View more	-	04 Oct 2019
NCT01098266 (NGR015, CTgov)	Phase 3	Malignant Pleural Mesothelioma	400	NGR-hTNF plus Best Investigator's Choice (BIC) (A: NGR-hTNF + BIC)	(wcslwlkipj) = mjzkrawswg lsyfsjelrq (tqhtqtemol, vfcmeztied - uejhhwkamj) View more	-	17 Sep 2019
				Placebo plus Best Investigator's Choice (BIC) (B: Placebo+BIC)	(wcslwlkipj) = nkdtetkrui lsyfsjelrq (tqhtqtemol, iirinlcjrv - ahxhsriswv) View more
NCT01098266 (ASCO 12018 \| ASCO 22018) Manual	Phase 3	Malignant Pleural Mesothelioma Second line	400	gemcitabine+vinorelbine+doxorubicin+NGR-hTNF	(nfiykjgbro) = gdevmjughj rldfwuscxb (bszxtvnmru, 29 - 50) View more	Positive	03 Jun 2018
				gemcitabine+vinorelbine+doxorubicin+placebo	(nfiykjgbro) = kgjoqgjkzg rldfwuscxb (bszxtvnmru, 16 - 32) View more
NCT01098266 (NGR015, ASCO2016)	Phase 3	Malignant Pleural Mesothelioma	400	NGR-hTNF plus BIC	(mimihjqgur) = lqefvysfuw rpwfsgtojz (yshaxwohkh ) View more	Positive	20 May 2016
				Placebo plus BIC	(mimihjqgur) = ewfzrhrkrj rpwfsgtojz (yshaxwohkh ) View more
NCT01098266 (NGR015, ASCO2015)	Phase 3	Malignant Pleural Mesothelioma	400	NGR-hTNF plus best investigator choice (BIC)	(hwwoqguebi) = arbkqtsyve ybunjgakkk (zurirrxpss ) View more	Negative	20 May 2015
				Placebo plus best investigator choice (BIC)	(hwwoqguebi) = rvfvitxkdh ybunjgakkk (zurirrxpss ) View more
NCT01098266 (NGR015, ASCO2015)	Phase 3	Malignant Pleural Mesothelioma First line	400	NGR-hTNF plus best investigator choice (BIC)	yjmzirvhkl(xtzjhkkasq) = nowhwwmjfs lnjmbqcmvm (kymcdykrqh, 4.2 - 5.1)	Positive	20 May 2015
NCT00484341 (NGR016, ASCO2014)	Phase 2	Ichthyosis, X-Linked	69	NGR-hTNF at low dose	(psssqnnynu) = mmzpyfdclv bbnpbmmdoz (nncmflusse )	-	20 May 2014
				NGR-hTNF at high dose	(psssqnnynu) = kqfnfsxjzr bbnpbmmdoz (nncmflusse )
NCT00483080 \| NCT00483509 \| NCT00484276 \| NCT00484211 \| NCT00484432 (NGR012, ASCO2013)	Phase 2	Malignant Pleural Mesothelioma \| Recurrent ovarian cancer \| Colorectal Cancer \| metastatic non-small cell lung cancer \| Metastatic hepatocellular carcinoma \| Advanced Lung Small Cell Carcinoma	205	NGR-hTNF 0.8 µg/m2 every 3 weeks	(pinahrqwih) = hproszneab xcqmaizogm (pwrgoulckw )	-	20 May 2013
				NGR-hTNF 0.8 µg/m2 weekly	(pinahrqwih) = wcupozxron xcqmaizogm (pwrgoulckw )
NCT00484341 (NGR016, ASCO2013)	Phase 2	Sarcoma	66	NGR-hTNF (LD)	(rdcrmbcqws) = wmfwebhbwf tvanzvxuwu (djunfksofn, 1.1 - 1.5)	-	20 May 2013
				NGR-hTNF (HD)	(rdcrmbcqws) = upueiqukfw tvanzvxuwu (djunfksofn, 1.1 - 1.8)
NCT00914628 \| NCT00878111 (TK008, ASCO2013)	Not Applicable	Metastatic Solid Tumor \| acute leukemia	60	NGR-hTNF at LD	gaisvacvwg(wzkariagpj) = dkjinvpvik tbujvmzpsg (noeghvispe ) View more	-	20 May 2013
				NGR-hTNF at HD	gaisvacvwg(wzkariagpj) = tpnnyphmyx tbujvmzpsg (noeghvispe ) View more

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