Evidence map›Paper›PMID 30942916›Full record

ArticleProtein science : a publication of the Protein Society2019

Bismaleimide cross-linked anthrax toxin forms functional octamers with high specificity in tumor targeting.

Elyse S Fischer, Warren A Campbell, Shihui Liu, Rodolfo Ghirlando, Rasem J Fattah, Thomas H Bugge, Stephen H Leppla

Open access · bronzeAbstract read
In one paragraph

Article in Protein science : a publication of the Protein Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
0.1field-weighted citation impact, top 54% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 5 citations in OpenAlex.

  1. Review
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 3 institutions in 1 country.

Elyse S FischerLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Warren A CampbellLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Shihui LiuOral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, Maryland.
Rodolfo GhirlandoLaboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892.
Rasem J FattahLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
Thomas H BuggeOral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, Maryland.
Stephen H LepplaLaboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
National Institute of Allergy and Infectious Diseases · USNational Institute of Dental and Craniofacial Research · USNational Institute of Diabetes and Digestive and Kidney Diseases · US

Funding

Cell surface serine proteases in development, tissue repair, and malignancyZIADE000699 · NIDCR · NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH · PI BUGGE, THOMAS H · 2009 to 2025
$34.1M
Vaccines and Therapeutics for AnthraxZIAAI000929 · NIAID · NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES · PI LEPPLA, STEPHEN · 2009 to 2025
$15.9M
Biophysics of Macromolecular ComplexesZIADK033007 · NIDDK · NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES · PI BUCHANAN, SUSAN · 2009 to 2024
$4.9M
Intramural NIH HHS ZIA AI000929NIAID NIH HHS ZIA AI000929-15NIDCR NIH HHSNIDDK NIH HHS
6 · The paper itself

Abstract

In recent years, anthrax toxin has been reengineered to act as a highly specific antiangiogenic cancer therapeutic, shown to kill tumors in animal models. This has been achieved by modifying protective antigen (PA) so that its activation and toxicity require the presence of two proteases, matrix metalloproteinase (MMP) and urokinase plasminogen activator (uPA), which are upregulated in tumor microenvironments. These therapeutics consist of intercomplementing PA variants, which are individually nontoxic, but form functional toxins upon complementary oligomerization. Here, we have created a dual-protease requiring PA targeting system which utilizes bismaleimide cross-linked PA (CLPA) rather than the intercomplementing PA variants. Three different CLPA agents were tested and, as expected, found to exclusively form octamers. Two of the CLPA agents have in vitro toxicities equal to those of previous intercomplementing agents, while the third CLPA agent had compromised in vitro cleavage and was significantly less cytotoxic. We hypothesize this difference was due to steric hindrance caused by cross-linking two PA monomers in close proximity to the PA cleavage site. Overall, this work advances the development and use of the PA and LF tumor-targeting system as a practical cancer therapeutic, as it provides a way to reduce the drug components of the anthrax toxin drug delivery system from three to two, which may lower the cost and simplify testing in clinical trials. HIGHLIGHT: Previously, anthrax toxin has been reengineered to act as a highly specific antiangiogenic cancer therapeutic. Here, we present a version, which utilizes bismaleimide cross-linked protective antigen (PA) rather than intercomplementing PA variants. This advances the development of anthrax toxin as a practical cancer therapeutic as it reduces the components of the drug delivery system to two, which may lower the cost and simplify testing in clinical trials.

Indexed as

AnimalsAntigens, BacterialAntineoplastic AgentsBacterial ToxinsCell ProliferationCell SurvivalDrug Screening Assays, AntitumorFemaleHeLa CellsHT29 CellsHumansMiceMice, Inbred C57BLNeoplasms, ExperimentalRAW 264.7 Cellsanthrax toxinAntigens, BacterialAntineoplastic AgentsBacterial Toxinsanthrax toxinbismaleimide cross-linkercancer therapymatrix metalloproteaseoligomerizationprotective antigenurokinase plasminogen activator

Identifiers

PMID30942916
PMCPMC6511737
OpenAlexW2926260224

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.