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

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 cu...

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Autores principales:	Torsten Hoffmann, Jens-Ulrich Rahfeld, Mathias Schenk, Falk Ponath, Koki Makioka, Birgit Hutter-Paier, Inge Lues, Cynthia A. Lemere, Stephan Schilling
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	glutaminyl cyclase inhibitor anti-pyroglutamyl β-amyloid antibody drug combination Alzheimer’s disease hAPPsl×hQC mice immunotherapy Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/89c9c71cfc674b7a85f12930560acd52
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spelling	oai:doaj.org-article:89c9c71cfc674b7a85f12930560acd522021-11-11T17:14:26ZCombination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic Mice10.3390/ijms2221117911422-00671661-6596https://doaj.org/article/89c9c71cfc674b7a85f12930560acd522021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11791https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Compelling 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.Torsten HoffmannJens-Ulrich RahfeldMathias SchenkFalk PonathKoki MakiokaBirgit Hutter-PaierInge LuesCynthia A. LemereStephan SchillingMDPI AGarticleglutaminyl cyclase inhibitoranti-pyroglutamyl β-amyloid antibodydrug combinationAlzheimer’s diseasehAPPsl×hQC miceimmunotherapyBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11791, p 11791 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	glutaminyl cyclase inhibitor anti-pyroglutamyl β-amyloid antibody drug combination Alzheimer’s disease hAPPsl×hQC mice immunotherapy Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	glutaminyl cyclase inhibitor anti-pyroglutamyl β-amyloid antibody drug combination Alzheimer’s disease hAPPsl×hQC mice immunotherapy Biology (General) QH301-705.5 Chemistry QD1-999 Torsten Hoffmann Jens-Ulrich Rahfeld Mathias Schenk Falk Ponath Koki Makioka Birgit Hutter-Paier Inge Lues Cynthia A. Lemere Stephan Schilling 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
description	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.
format	article
author	Torsten Hoffmann Jens-Ulrich Rahfeld Mathias Schenk Falk Ponath Koki Makioka Birgit Hutter-Paier Inge Lues Cynthia A. Lemere Stephan Schilling
author_facet	Torsten Hoffmann Jens-Ulrich Rahfeld Mathias Schenk Falk Ponath Koki Makioka Birgit Hutter-Paier Inge Lues Cynthia A. Lemere Stephan Schilling
author_sort	Torsten Hoffmann
title	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
title_short	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
title_full	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
title_fullStr	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
title_full_unstemmed	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
title_sort	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
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/89c9c71cfc674b7a85f12930560acd52
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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

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