Evidence map›Paper›PMID 34769222›Full record

ArticleInternational journal of molecular sciences2021

Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice.

Torsten Hoffmann, Jens-Ulrich Rahfeld, Mathias Schenk, Falk Ponath, Koki Makioka, Birgit Hutter-Paier, Inge Lues, Cynthia A Lemere, Stephan Schilling

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in International journal of molecular sciences, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
–field-weighted citation impact
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

9 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
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  6. Article
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  8. Review
  9. Small-molecule drugs development for Alzheimer's disease.Frontiers in aging neuroscience · 2022
    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

9 authors.

Torsten HoffmannVivoryon Therapeutics N.V., Weinbergweg 22, 06120 Halle, Germany.
Jens-Ulrich RahfeldFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, Germany.ORCID 0000-0002-8979-581X
Mathias SchenkFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, Germany.ORCID 0000-0001-6010-2672
Falk PonathDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA.
Koki MakiokaDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA.
Birgit Hutter-PaierQPS Austria GmbH, Department of Neuropharmacology, Parkring 12, A-8074 Grambach, Austria.
Inge LuesVivoryon Therapeutics N.V., Weinbergweg 22, 06120 Halle, Germany.
Cynthia A LemereDepartment of Neurology, Brigham and Women's Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA.
Stephan SchillingFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, Germany.

Funding

AD Immunotherapy with a Novel CDC-Mutant Anti-Pyroglutamate-3 Abeta Antibody to Avoid Vascular Side EffectsRF1AG058657 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI LEMERE, CYNTHIA A · 2018 to 2018
$2.2M
Pyroglutamate Amyloid-beta as an Immunotherapeutic Target for Alzheimer's DiseaseR01AG040092 · NIA · BRIGHAM AND WOMEN'S HOSPITAL · PI LEMERE, CYNTHIA A · 2012 to 2015
$1.5M
NIA NIH HHS R01 AG040092NIA NIH HHS RF1 AG058657
6 · The paper itself

Abstract

Compelling evidence suggests that pyroglutamate-modified Aβ (pGlu3-Aβ; AβN3pG) peptides play a pivotal role in the development and progression of Alzheimer's disease (AD). Approaches targeting pGlu3-Aβ by glutaminyl cyclase (QC) inhibition (Varoglutamstat) or monoclonal antibodies (Donanemab) are currently in clinical development. Here, we aimed at an assessment of combination therapy of Varoglutamstat (PQ912) and a pGlu3-Aβ-specific antibody (m6) in transgenic mice. Whereas the single treatments at subtherapeutic doses show moderate (16-41%) but statistically insignificant reduction of Aβ42 and pGlu-Aβ42 in mice brain, the combination of both treatments resulted in significant reductions of Aβ by 45-65%. Evaluation of these data using the Bliss independence model revealed a combination index of ≈1, which is indicative for an additive effect of the compounds. The data are interpreted in terms of different pathways, in which the two drugs act. While PQ912 prevents the formation of pGlu3-Aβ in different compartments, the antibody is able to clear existing pGlu3-Aβ deposits. The results suggest that combination of the small molecule Varoglutamstat and a pE3Aβ-directed monoclonal antibody may allow a reduction of the individual compound doses while maintaining the therapeutic effect.

Indexed as

Alzheimer DiseaseAminoacyltransferasesAmyloid beta-PeptidesAnimalsAntibodies, Monoclonal, Murine-DerivedBenzimidazolesHumansImidazolinesMiceMice, TransgenicPeptide Fragments1-(1H-benzo(d)imidazol-5-yl)-5-(4-propoxyphenyl)imidazolidin-2-oneAminoacyltransferasesAmyloid beta-Peptidesamyloid beta-protein (1-42)Antibodies, Monoclonal, Murine-DerivedBenzimidazolesglutaminyl-peptide cyclotransferaseImidazolinesPeptide FragmentsAlzheimer’s diseaseanti-pyroglutamyl β-amyloid antibodydrug combinationglutaminyl cyclase inhibitorhAPPsl×hQC miceimmunotherapy

Identifiers

PMID34769222
PMCPMC8584206

What OpenQuestion holds

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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.