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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MDPI AG
2021-10-01
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:00:49Z |
| format | Article |
| id | doaj.art-89c9c71cfc674b7a85f12930560acd52 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:00:49Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-89c9c71cfc674b7a85f12930560acd522023-11-22T20:57:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211179110.3390/ijms222111791Combination of the Glutaminyl Cyclase Inhibitor PQ912 (Varoglutamstat) and the Murine Monoclonal Antibody PBD-C06 (m6) Shows Additive Effects on Brain Aβ Pathology in Transgenic MiceTorsten Hoffmann0Jens-Ulrich Rahfeld1Mathias Schenk2Falk Ponath3Koki Makioka4Birgit Hutter-Paier5Inge Lues6Cynthia A. Lemere7Stephan Schilling8Vivoryon Therapeutics N.V., Weinbergweg 22, 06120 Halle, GermanyFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, GermanyFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, GermanyDepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USADepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USAQPS Austria GmbH, Department of Neuropharmacology, Parkring 12, A-8074 Grambach, AustriaVivoryon Therapeutics N.V., Weinbergweg 22, 06120 Halle, GermanyDepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 60 Fenwood Rd., Boston, MA 02115, USAFraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle, GermanyCompelling 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.https://www.mdpi.com/1422-0067/22/21/11791glutaminyl cyclase inhibitoranti-pyroglutamyl β-amyloid antibodydrug combinationAlzheimer’s diseasehAPPsl×hQC miceimmunotherapy |
| spellingShingle | 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 International Journal of Molecular Sciences glutaminyl cyclase inhibitor anti-pyroglutamyl β-amyloid antibody drug combination Alzheimer’s disease hAPPsl×hQC mice immunotherapy |
| 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_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_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_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 |
| topic | glutaminyl cyclase inhibitor anti-pyroglutamyl β-amyloid antibody drug combination Alzheimer’s disease hAPPsl×hQC mice immunotherapy |
| url | https://www.mdpi.com/1422-0067/22/21/11791 |
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