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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

1
Vivoryon Therapeutics N.V., Weinbergweg 22, 06120 Halle, Germany
2
Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, Germany
3
Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USA
4
QPS Austria GmbH, Department of Neuropharmacology, Parkring 12, A-8074 Grambach, Austria
5
Anhalt University of Applied Sciences, Bernburger Straße 55, 06366 Köthen, Germany
*
Authors to whom correspondence should be addressed.
Academic Editors: Botond Penke and Maria Laura Giuffrida
Int. J. Mol. Sci. 2021, 22(21), 11791; https://doi.org/10.3390/ijms222111791
Received: 6 September 2021 / Revised: 7 October 2021 / Accepted: 27 October 2021 / Published: 30 October 2021
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. View Full-Text
Keywords: glutaminyl cyclase inhibitor; anti-pyroglutamyl β-amyloid antibody; drug combination; Alzheimer’s disease; hAPPsl×hQC mice; immunotherapy glutaminyl cyclase inhibitor; anti-pyroglutamyl β-amyloid antibody; drug combination; Alzheimer’s disease; hAPPsl×hQC mice; immunotherapy
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MDPI and ACS Style

Hoffmann, T.; Rahfeld, J.-U.; Schenk, M.; Ponath, F.; Makioka, K.; Hutter-Paier, B.; Lues, I.; Lemere, C.A.; Schilling, S. 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. Int. J. Mol. Sci. 2021, 22, 11791. https://doi.org/10.3390/ijms222111791

AMA Style

Hoffmann T, Rahfeld J-U, Schenk M, Ponath F, Makioka K, Hutter-Paier B, Lues I, Lemere CA, Schilling S. 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. International Journal of Molecular Sciences. 2021; 22(21):11791. https://doi.org/10.3390/ijms222111791

Chicago/Turabian Style

Hoffmann, Torsten, Jens-Ulrich Rahfeld, Mathias Schenk, Falk Ponath, Koki Makioka, Birgit Hutter-Paier, Inge Lues, Cynthia A. Lemere, and Stephan Schilling. 2021. "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" International Journal of Molecular Sciences 22, no. 21: 11791. https://doi.org/10.3390/ijms222111791

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