Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling

Valentinis, Barbara; Porcellini, Simona; Asperti, Claudia; Cota, Manuela; Zhou, Dan; Matteo, P. Di; Garau, Gianpiero; Zucchelli, Chiara; Avanzi, Nilla; Rizzardi, Gian Paolo; Degano, Massimo; Musco, Giovanna; Traversari, Catia

doi:10.3390/ijms20184511

Cited by 15 publications

(17 citation statements)

References 71 publications

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“…7−22 The prototypic example of the latter class of compounds is a recombinant protein consisting of CNGRC-G fused to tumor necrosis factor-α (TNF), an inflammatory cytokine endowed of potent antitumor activity. 20,23,24 Studies in various murine models of solid tumors have shown that picogram doses of this drug (called NGR-TNF), but not of unmodified TNF, can target the tumor vasculature, reduce drug penetration barriers, and exert synergistic antitumor effects with various chemotherapeutic drugs. 20,25,26 Low-dose NGR-TNF can also up-regulate leukocyte adhesion molecules on tumor vessels, promote lymphocyte extravasation in tumors, exert synergistic effects with active and adoptive immunotherapy, and enhance the therapeutic efficacy of immune checkpoint blockers in combination with adoptive cell therapy.…”

Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: ■ Introductionmentioning

confidence: 99%

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

et al. 2020

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“…NGR-hTNF modifies the tumor microenvironment through the NGR motif. Through the improved permeabilization of newly formed tumor vasculature, NGR-hTNF increases the penetration of intratumoral CTX and leukocyte trafficking [ 22 , 36 ]. NGR-hTNF induces apoptosis in both tumor and endothelial cells in vivo, reducing tumor growth [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis

Tsai

Chen

Lee

et al. 2021

Cancers

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Patients with malignant pleural mesothelioma (MPM) have very poor prognoses, and pemetrexed plus platinum is the standard first-line therapy. However, the second-line therapy for relapsed MPM remains controversial. A comprehensive search was performed to identify randomized controlled trials (RCTs) evaluating various second-line regimens in patients with relapsed MPM. Indirect comparisons of overall survival (OS) and progression-free survival (PFS) were performed using network meta-analysis. Surface under the cumulative ranking curve (SUCRA) values were used to rank the included treatments according to each outcome. Nivolumab alone or nivolumab plus ipilimumab provided significantly longer OS than placebo (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55–0.94 for nivolumab alone; HR: 0.54, 95% CI: 0.31–0.92 for nivolumab plus ipilimumab). The best SUCRA ranking for OS was identified for nivolumab plus ipilimumab (SUCRA: 90.8%). Tremelimumab, vorinostat, nivolumab alone, chemotherapy (CTX), asparagine–glycine–arginine–human tumor necrosis factor plus CTX, and nivolumab plus ipilimumab all produced noticeable PFS benefits compared with placebo. Nivolumab plus ipilimumab had the best PFS ranking (SUCRA: 92.3%). Second-line treatment with nivolumab plus ipilimumab provided the OS and PFS outcomes for patients with relapsed MPM.

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“…Currently, two fusion proteins are in clinical trials as peptide-drug conjugates: NGR-human tumor necrosis factor (hTNF) and truncated tissue factor (tTF)-NGR [44]. A Phase III study on malignant pleural mesothelioma and multiple Phase II studies have been completed.…”

Section: Receptors Targeted By Peptide-drug Conjugatesmentioning

confidence: 99%

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

Zhu

Tang

2021

Trends in Pharmacological Sciences

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Drug delivery systems are generally believed to comprise drugs and excipients. A peptide-drug conjugate is a single molecule that can simultaneously play multiple roles in a drug delivery system, such as in vivo drug distribution, targeted release, and bioactivity functions. This molecule can be regarded as an integrated drug delivery system, so it is called a molecular drug delivery system. In the context of cancer therapy, a peptide-drug conjugate comprises a tumor-targeting peptide, a payload, and a linker. Tumor-targeting peptides specifically identify membrane receptors on tumor cells, improve drug-targeted therapeutic effects, and reduce toxic and side effects. Payloads with bioactive functions connect to tumor-targeting peptides through linkers. In this review, we explored ongoing clinical work on peptide-drug conjugates targeting various receptors. We discuss the binding mechanisms of tumor-targeting peptides and related receptors, as well as the limiting factors for peptide-drug conjugate-based molecular drug delivery systems. Towards enhanced targeting on tumorsDespite the rapid development of anticancer drugs in the past few decades, cancer is one of the leading causes of death in the world [1]. Due to the lack of an effective means to distinguish tumor cells from normal cells [2], the accumulation efficiency of anticancer drugs in tumor cells is low and the toxic side effects on normal tissues are high. In the treatment process, drug resistance problems are caused by tumor heterogeneity [3], drug inactivation, transport, and metabolism, changes in drug targets, and tumor microenvironment dysfunction [4]. Although advanced drug delivery methods can partially solve problems of targeting, toxicity, and drug resistance [5], difficult industrialization, complicated process control, and huge costs remain insurmountable obstacles.Peptide-drug conjugates are emerging molecular drug delivery system (see Glossary) that achieve precise drug delivery and tumor-targeted release at the molecular level [6]. Current drug delivery systems, such as nano-drug delivery systems, use various complex excipients to assemble nanoscale particles that encapsulate drugs to be passively or actively delivered to target organs. The anticancer efficacy of nano-drug delivery systems is improved by an enhanced permeability retention effect to increase drug accumulation in tumors and the toxicity of nanodrug delivery systems is reduced by the long systemic circulation to decrease drug accumulation in normal organs [7]. However, a reappraisal of nano-drug delivery system design is suggested to improve their clinical efficacy and safety in cancer patients [8].By contrast, molecular drug delivery systems use a single peptide-drug conjugate molecule to achieve in vivo drug delivery, targeted drug release, and bioactivity, which can maximize the targeting effect and reduce drug resistance. Peptide-drug conjugates, which were first reported in 1972 by Freer et al.[9] (Box 1), are similar to the tethering of ligand-targeted drugs [10],

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Mechanism of Action of the Tumor Vessel Targeting Agent NGR-hTNF: Role of Both NGR Peptide and hTNF in Cell Binding and Signaling

Cited by 15 publications

References 71 publications

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

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

Salvage Therapy for Relapsed Malignant Pleural Mesothelioma: A Systematic Review and Network Meta-Analysis

Peptide–drug conjugate-based novel molecular drug delivery system in cancer

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