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

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.

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

“…The observation of moderate effect on cognition despite drastic amyloid brain reduction after anti-Aβ treatment suggests that more than 50% of the clinical progression is independent of Aβ deposition. Effects observed after the amyloid pathway together with positive results described in clinical trials targeting tau species and pro-inflammatory cytokines set the stage for alternative therapies and combined treatments [ 240 ]. Fifth, the delivery route of therapeutic agents has to be selected to ensure their efficient delivery to the right place and at the right time [ 241 ].…”

How Single Site Mutations Can Help Understanding Structure Formation of Amyloid β1−40

“…[135] The inhibition of the responsible enzyme glutamyl cyclase was found to reduce the pathological effects on some cognitive functions in mice models along with diminished A𝛽 x-40/42 plaque formation and gliosis rendering these modifications highly interesting. [96,136] From the biophysical point of view, the majority of studies agree on accelerating effects of this modification on the fibrillation kinetics but also increased fragmentation of the fibrils, [116,135,137] increased oligomer formation, [138][139][140] and enhanced (oligomer) cytotoxicity. [139][140][141] One of the potential mechanisms could be increased lipid peroxidation accompanied with a loss of plasma membrane integrity, [142] which fits to other theories about the cytotoxic mode of action of A𝛽.…”

“…[ 135 ] The inhibition of the responsible enzyme glutamyl cyclase was found to reduce the pathological effects on some cognitive functions in mice models along with diminished A β x–40/42 plaque formation and gliosis rendering these modifications highly interesting. [ 96,136 ]…”

Functions of glutaminyl cyclase and its isoform in diseases

“…Treatment with PQ912 in a mouse model of AD improves cognition and attenuates the pathology of AD [144,163]. PQ912 prevents the formation of pGlu3-Ab in different compartments of cells, and the combination of PQ912 and a pGlu3-Ab-specific antibody (m6) in transgenic mice exert additive effects on brain Ab pathology [164].…”