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

doi:10.3390/ijms222111791

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.

Highlights

Dementia currently affects about 50 million people worldwide, representing the 5th leading cause of death [1]
The recent promising results from clinical studies with e.g., Lecanemab (BAN2401), which targets large soluble Aβ protofibrils, or Donanemab, which is directed to pGlu3-Aβ, and the accelerated approval of Aducanumab provide prominent support for the amyloid hypothesis and give rise to the assumption that targeting Aβ is a valid approach to developing treatments for Alzheimer’s disease [2,3,4,5]
Numerous studies have shown that formation of certain N-truncated Aβ is followed by glutaminyl cyclase (QC)

Summary

Introduction

Dementia currently affects about 50 million people worldwide, representing the 5th leading cause of death [1]. The recent promising results from clinical studies with e.g., Lecanemab (BAN2401), which targets large soluble Aβ protofibrils, or Donanemab, which is directed to pGlu3-Aβ, and the accelerated approval of Aducanumab (a human monoclonal antibody preferentially binds Aβ oligomers and fibrils) provide prominent support for the amyloid hypothesis and give rise to the assumption that targeting Aβ is a valid approach to developing treatments for Alzheimer’s disease [2,3,4,5] Among these antibody molecules, Donanemab recently showed significant removal of amyloid load and cognitive stabilization in a Phase 2 clinical trial [6,7]. Numerous studies have shown that formation of certain N-truncated Aβ is followed by glutaminyl cyclase (QC)

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